Embryonic Cerebrospinal Fluid Increases Neurogenic Activity in the Brain Ventricular-Subventricular Zone of Adult Mice

PubMed Central

Alonso, Maria I.; Lamus, Francisco; Carnicero, Estela; Moro, Jose A.; de la Mano, Anibal; Fernández, Jose M. F.; Desmond, Mary E.; Gato, Angel

2017-01-01

Neurogenesis is a very intensive process during early embryonic brain development, becoming dramatically restricted in the adult brain in terms of extension and intensity. We have previously demonstrated the key role of embryonic cerebrospinal fluid (CSF) in developing brain neurogenic activity. We also showed that cultured adult brain neural stem cells (NSCs) remain competent when responding to the neurogenic influence of embryonic CSF. However, adult CSF loses its neurogenic inductive properties. Here, by means of an organotypic culture of adult mouse brain sections, we show that local administration of embryonic CSF in the subventricular zone (SVZ) niche is able to trigger a neurogenic program in NSCs. This leads to a significant increase in the number of non-differentiated NSCs, and also in the number of new neurons which show normal migration, differentiation and maturation. These new data reveal that embryonic CSF activates adult brain NSCs, supporting the previous idea that it contains key instructive components which could be useful in adult brain neuroregenerative strategies. PMID:29311854

Direct observation of cerebrospinal fluid bulk flow in the brain

NASA Astrophysics Data System (ADS)

Mestre, Humberto; Tithof, Jeffrey; Thomas, John; Kelley, Douglas; Nedergaard, Maiken

2017-11-01

Cerebrospinal fluid (CSF) serves a vital role in normal brain function. Its adequate flow and exchange with interstitial fluid through perivascular spaces (PVS) has been shown to be important in the clearance of toxic metabolites like amyloid- β, and its disturbance can cause severe neurological diseases. It has long been suspected that bulk flow may transport CSF, but limitations in imaging techniques have prevented direct observation of such flows in the PVS. In this talk, we describe a novel approach using high speed two photon laser scanning microscopy which has allowed for the first ever direct observation of CSF flow in the PVS of a mouse brain. By performing particle tracking velocimetry, we quantify the CSF bulk flow speeds and PVS geometry. This technique enables future studies of CSF flow disturbances on a new scale and will pave the way for evaluating the role of these fluxes in neurodegenerative disease. R01NS100366 (to M.N.).

A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules

PubMed Central

Aspelund, Aleksanteri; Antila, Salli; Proulx, Steven T.; Karlsen, Tine Veronica; Karaman, Sinem; Detmar, Michael; Wiig, Helge

2015-01-01

The central nervous system (CNS) is considered an organ devoid of lymphatic vasculature. Yet, part of the cerebrospinal fluid (CSF) drains into the cervical lymph nodes (LNs). The mechanism of CSF entry into the LNs has been unclear. Here we report the surprising finding of a lymphatic vessel network in the dura mater of the mouse brain. We show that dural lymphatic vessels absorb CSF from the adjacent subarachnoid space and brain interstitial fluid (ISF) via the glymphatic system. Dural lymphatic vessels transport fluid into deep cervical LNs (dcLNs) via foramina at the base of the skull. In a transgenic mouse model expressing a VEGF-C/D trap and displaying complete aplasia of the dural lymphatic vessels, macromolecule clearance from the brain was attenuated and transport from the subarachnoid space into dcLNs was abrogated. Surprisingly, brain ISF pressure and water content were unaffected. Overall, these findings indicate that the mechanism of CSF flow into the dcLNs is directly via an adjacent dural lymphatic network, which may be important for the clearance of macromolecules from the brain. Importantly, these results call for a reexamination of the role of the lymphatic system in CNS physiology and disease. PMID:26077718

A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules.

PubMed

Aspelund, Aleksanteri; Antila, Salli; Proulx, Steven T; Karlsen, Tine Veronica; Karaman, Sinem; Detmar, Michael; Wiig, Helge; Alitalo, Kari

2015-06-29

The central nervous system (CNS) is considered an organ devoid of lymphatic vasculature. Yet, part of the cerebrospinal fluid (CSF) drains into the cervical lymph nodes (LNs). The mechanism of CSF entry into the LNs has been unclear. Here we report the surprising finding of a lymphatic vessel network in the dura mater of the mouse brain. We show that dural lymphatic vessels absorb CSF from the adjacent subarachnoid space and brain interstitial fluid (ISF) via the glymphatic system. Dural lymphatic vessels transport fluid into deep cervical LNs (dcLNs) via foramina at the base of the skull. In a transgenic mouse model expressing a VEGF-C/D trap and displaying complete aplasia of the dural lymphatic vessels, macromolecule clearance from the brain was attenuated and transport from the subarachnoid space into dcLNs was abrogated. Surprisingly, brain ISF pressure and water content were unaffected. Overall, these findings indicate that the mechanism of CSF flow into the dcLNs is directly via an adjacent dural lymphatic network, which may be important for the clearance of macromolecules from the brain. Importantly, these results call for a reexamination of the role of the lymphatic system in CNS physiology and disease. © 2015 Aspelund et al.

Cerebrospinal fluid levels of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in subacute sclerosing panencephalitis.

PubMed

Ichiyama, Takashi; Matsushige, Takeshi; Siba, Peter; Suarkia, Dagwin; Takasu, Toshiaki; Miki, Kenji; Furukawa, Susumu

2008-05-01

To investigate the brain inflammation and damage in subacute sclerosing panencephalitis (SSPE), the cerebrospinal fluid (CSF) concentrations of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were determined in SSPE patients. CSF MMP-9 and TIMP-1 levels were measured in 23 patients with SSPE in Papua New Guinea by ELISA. CSF MMP-9 levels and MMP-9/TIMP-1 ratios of SSPE patients were significantly higher than controls (p<0.001 and p=0.005, respectively). There were no significant differences in CSF TIMP-1 levels between SSPE patients and controls. Previous studies suggested that CSF MMP-9 levels reflect inflammatory damage to the brain. Our findings suggest that the MMP-9 level in CSF is an indicator of inflammatory damage to the brain in SSPE.

Cerebrospinal fluid bulk flow is driven by the cardiac cycle

NASA Astrophysics Data System (ADS)

Tithof, Jeffrey; Mestre, Humberto; Thomas, John; Nedergaard, Maiken; Kelley, Douglas

2017-11-01

Recent discoveries have uncovered a cerebrospinal fluid (CSF) transport system in the perivascular spaces (PVS) of the mammalian brain which clears excess extracellular fluid and protein waste products. The oscillatory pattern of CSF flow has long been attributed to arterial pulsations due to cardiac contractility but limitations in imaging techniques have impeded quantitative measurement of flow rates within the PVS. In this talk, we describe quantitative measurements from the first ever direct imaging of CSF flow in the PVS of a mouse brain. We perform particle tracking velocimetry to obtain time-resolved velocity measurements. To identify the cardiac and/or respiratory dependence of the flow, while imaging, we simultaneously record the mouse's electrocardiogram and respiration. Our measurements conclusively indicate that CSF pulsatility in the arterial PVS is directly driven by the cardiac cycle and not by the respiratory cycle or cerebral vasomotion. These results offer a substantial step forward in understanding bulk flow of CSF in the mammalian brain and may have important implications related to neurodegenerative diseases.

Brain-wide pathway for waste clearance captured by contrast-enhanced MRI.

PubMed

Iliff, Jeffrey J; Lee, Hedok; Yu, Mei; Feng, Tian; Logan, Jean; Nedergaard, Maiken; Benveniste, Helene

2013-03-01

The glymphatic system is a recently defined brain-wide paravascular pathway for cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange that facilitates efficient clearance of solutes and waste from the brain. CSF enters the brain along para-arterial channels to exchange with ISF, which is in turn cleared from the brain along para-venous pathways. Because soluble amyloid β clearance depends on glymphatic pathway function, we proposed that failure of this clearance system contributes to amyloid plaque deposition and Alzheimer's disease progression. Here we provide proof of concept that glymphatic pathway function can be measured using a clinically relevant imaging technique. Dynamic contrast-enhanced MRI was used to visualize CSF-ISF exchange across the rat brain following intrathecal paramagnetic contrast agent administration. Key features of glymphatic pathway function were confirmed, including visualization of para-arterial CSF influx and molecular size-dependent CSF-ISF exchange. Whole-brain imaging allowed the identification of two key influx nodes at the pituitary and pineal gland recesses, while dynamic MRI permitted the definition of simple kinetic parameters to characterize glymphatic CSF-ISF exchange and solute clearance from the brain. We propose that this MRI approach may provide the basis for a wholly new strategy to evaluate Alzheimer's disease susceptibility and progression in the live human brain.

Brain-wide pathway for waste clearance captured by contrast-enhanced MRI

PubMed Central

Iliff, Jeffrey J.; Lee, Hedok; Yu, Mei; Feng, Tian; Logan, Jean; Nedergaard, Maiken; Benveniste, Helene

2013-01-01

The glymphatic system is a recently defined brain-wide paravascular pathway for cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange that facilitates efficient clearance of solutes and waste from the brain. CSF enters the brain along para-arterial channels to exchange with ISF, which is in turn cleared from the brain along para-venous pathways. Because soluble amyloid β clearance depends on glymphatic pathway function, we proposed that failure of this clearance system contributes to amyloid plaque deposition and Alzheimer’s disease progression. Here we provide proof of concept that glymphatic pathway function can be measured using a clinically relevant imaging technique. Dynamic contrast-enhanced MRI was used to visualize CSF-ISF exchange across the rat brain following intrathecal paramagnetic contrast agent administration. Key features of glymphatic pathway function were confirmed, including visualization of para-arterial CSF influx and molecular size-dependent CSF-ISF exchange. Whole-brain imaging allowed the identification of two key influx nodes at the pituitary and pineal gland recesses, while dynamic MRI permitted the definition of simple kinetic parameters to characterize glymphatic CSF-ISF exchange and solute clearance from the brain. We propose that this MRI approach may provide the basis for a wholly new strategy to evaluate Alzheimer’s disease susceptibility and progression in the live human brain. PMID:23434588

Early awareness of cerebrospinal fluid hypovolemia after craniotomy for microsurgical aneurysmal clipping.

PubMed

Kawahara, Ichiro; Tsutsumi, Keisuke; Matsunaga, Yuki; Takahata, Hideaki; Ono, Tomonori; Toda, Keisuke; Baba, Hiroshi

2013-08-01

Mild cerebrospinal fluid (CSF) hypovolemia is a well-known clinical entity, but critical CSF hypovolemia that can cause transtentorial herniation is an unusual and rare clinical entity that occurs after craniotomy. We investigated CSF hypovolemia after microsurgical aneurysmal clipping for subarachnoid hemorrhage (SAH). This study included 144 consecutive patients with SAH. Lumbar drainage (LD) was inserted after general anesthesia or postoperatively as a standard perioperative protocol. CSF hypovolemia diagnosis was based on three criteria. Eleven patients (7.6%) were diagnosed with CSF hypovolemia according to diagnostic criteria in a postoperative range of 0-8 days. In all patients, signs or symptoms of CSF hypovolemia improved within 24 hours by clamping LD and using the Trendelenburg position. As a cause of acute clinical deterioration after aneurysmal clipping, CSF hypovolemia is likely under-recognized, and may actually be misdiagnosed as vasospasm or brain swelling. We should always take the etiology of CSF hypovolemia into consideration, and especially pay attention in patients with pneumocephalus and subdural fluid collection alongside brain sag on computed tomography. These patients are at higher risk developing of pressure gradients between their cranial and spinal compartments, and therefore, brain sagging after LD, than after ventricular drainage. We should be vigilant to strictly manage LD so as not to produce high pressure gradients.

Lumbar puncture (image)

MedlinePlus

... is a clear fluid that circulates in the space surrounding the spinal cord and brain. CSF protects the brain and spinal cord from injury by acting like a liquid cushion. CSF is usually obtained through a lumbar ...

Metronidazole and hydroxymetronidazole central nervous system distribution: 2. cerebrospinal fluid concentration measurements in patients with external ventricular drain.

PubMed

Frasca, Denis; Dahyot-Fizelier, Claire; Adier, Christophe; Mimoz, Olivier; Debaene, Bertrand; Couet, William; Marchand, Sandrine

2014-01-01

This study explored metronidazole and hydroxymetronidazole distribution in the cerebrospinal fluid (CSF) of brain-injured patients. Four brain-injured patients with external ventricular drain received 500 mg of metronidazole over 0.5 h every 8 h. CSF and blood samples were collected at steady state over 8 h, and the metronidazole and hydroxymetronidazole concentrations were assayed by high-pressure liquid chromatograph. A noncompartmental analysis was performed. Metronidazole is distributed extensively within CSF, with a mean CSF to unbound plasma AUC0-τ ratio of 86% ± 16%. However, the concentration profiles in CSF were mostly flat compared to the plasma profiles. Hydroxymetronidazole concentrations were much lower than those of metronidazole both in plasma and in CSF, with a corresponding CSF/unbound plasma AUC0-τ ratio of 79% ± 16%. We describe here for the first time in detail the pharmacokinetics of metronidazole and hydroxymetronidazole in CSF.

More Than the Brain's Drain: Does Cerebrospinal Fluid Help the Brain Convey Messages?

ERIC Educational Resources Information Center

Travis, John

1999-01-01

Examines the role of cerebrospinal fluid (CSF), a clear, colorless liquid that constantly bathes the brain and spinal cord. Scientists argue that cerebrospinal fluid carries important signals for sleep, appetite, and sex. Evaluates past and current research documenting the purpose of cerebrospinal fluid in the brain. (CCM)

Potential Pathways for CNS Drug Delivery Across the Blood-Cerebrospinal Fluid Barrier

PubMed Central

Strazielle, Nathalie; Ghersi-Egea, Jean-François

2016-01-01

The blood-brain interfaces restrict the cerebral bioavailability of pharmacological compounds. Various drug delivery strategies have been developed to improve drug penetration into the brain. Most strategies target the microvascular endothelium forming the blood-brain barrier proper. Targeting the blood-cerebrospinal fluid (CSF) barrier formed by the epithelium of the choroid plexuses in addition to the blood-brain barrier may offer added-value for the treatment of central nervous system diseases. For instance, targeting the CSF spaces, adjacent tissue, or the choroid plexuses themselves is of interest for the treatment of neuroinflammatory and infectious diseases, cerebral amyloid angiopathy, selected brain tumors, hydrocephalus or neurohumoral dysregulation. Selected CSF-borne materials seem to reach deep cerebral structures by mechanisms that need to be understood in the context of chronic CSF delivery. Drug delivery through both barriers can reduce CSF sink action towards parenchymal drugs. Finally, targeting the choroid plexus-CSF system can be especially relevant in the context of neonatal and pediatric diseases of the central nervous system. Transcytosis appears the most promising mechanism to target in order to improve drug delivery through brain barriers. The choroid plexus epithelium displays strong vesicular trafficking and secretory activities that deserve to be explored in the context of cerebral drug delivery. Folate transport and exosome release into the CSF, plasma protein transport, and various receptor-mediated endocytosis pathways may prove useful mechanisms to exploit for efficient drug delivery into the CSF. This calls for a clear evaluation of transcytosis mechanisms at the blood-CSF barrier, and a thorough evaluation of CSF drug delivery rates. PMID:27464721

Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brain.

PubMed

Iliff, Jeffrey J; Wang, Minghuan; Zeppenfeld, Douglas M; Venkataraman, Arun; Plog, Benjamin A; Liao, Yonghong; Deane, Rashid; Nedergaard, Maiken

2013-11-13

CSF from the subarachnoid space moves rapidly into the brain along paravascular routes surrounding penetrating cerebral arteries, exchanging with brain interstitial fluid (ISF) and facilitating the clearance of interstitial solutes, such as amyloid β, in a pathway that we have termed the "glymphatic" system. Prior reports have suggested that paravascular bulk flow of CSF or ISF may be driven by arterial pulsation. However, cerebral arterial pulsation could not be directly assessed. In the present study, we use in vivo two-photon microscopy in mice to visualize vascular wall pulsatility in penetrating intracortical arteries. We observed that unilateral ligation of the internal carotid artery significantly reduced arterial pulsatility by ~50%, while systemic administration of the adrenergic agonist dobutamine increased pulsatility of penetrating arteries by ~60%. When paravascular CSF-ISF exchange was evaluated in real time using in vivo two-photon and ex vivo fluorescence imaging, we observed that internal carotid artery ligation slowed the rate of paravascular CSF-ISF exchange, while dobutamine increased the rate of paravascular CSF-ISF exchange. These findings demonstrate that cerebral arterial pulsatility is a key driver of paravascular CSF influx into and through the brain parenchyma, and suggest that changes in arterial pulsatility may contribute to accumulation and deposition of toxic solutes, including amyloid β, in the aging brain.

Volumetric analysis of cerebrospinal fluid and brain parenchyma in a patient with hydranencephaly and macrocephaly--case report.

PubMed

Radoš, Milan; Klarica, Marijan; Mučić-Pucić, Branka; Nikić, Ines; Raguž, Marina; Galkowski, Valentina; Mandić, Dora; Orešković, Darko

2014-08-28

The aim of this study was to perform for the first time the intracranial volumetric analysis of cerebrospinal fluid (CSF) and brain parenchyma in the supratentorial and infratentorial space in a 30-year-old female patient with hydranencephaly and macrocephaly. A head scan performed using a 3T magnetic resonance was followed by manual segmentation of the brain parenchyma and CSF on T2 coronal brain sections. The volume of CSF and brain parenchyma was measured separately for the supratentorial and infratentorial space. The total volume of the intracranial space was 3645.5 cm3. In the supratentorial space, the volume of CSF was 3375.2 cm3 and the volume of brain parenchyma was 80.3 cm3. In the infratentorial space, the volume of CSF was 101.3 cm3 and the volume of the brain parenchyma was 88.7 cm3. In the supratentorial space, there was severe malacia of almost all brain parenchyma with no visible remnants of the choroid plexuses. Infratentorial structures of the brainstem and cerebellum were hypoplastic but completely developed. Since our patient had no choroid plexuses in the supratentorial space and no obstruction between dural sinuses and CSF, development of hydrocephalus and macrocephaly cannot be explained by the classic hypothesis of CSF physiology with secretion, unidirectional circulation, and absorption as its basic postulates. However, the origin and turnover of the enormous amount of intracranial CSF volume, at least 10-fold larger than normal, and the mechanisms of macroencephaly development could be elucidated by the new hypothesis of CSF physiology recently published by our research team.

Numerical Cerebrospinal System Modeling in Fluid-Structure Interaction.

PubMed

Garnotel, Simon; Salmon, Stéphanie; Balédent, Olivier

2018-01-01

Cerebrospinal fluid (CSF) stroke volume in the aqueduct is widely used to evaluate CSF dynamics disorders. In a healthy population, aqueduct stroke volume represents around 10% of the spinal stroke volume while intracranial subarachnoid space stroke volume represents 90%. The amplitude of the CSF oscillations through the different compartments of the cerebrospinal system is a function of the geometry and the compliances of each compartment, but we suspect that it could also be impacted be the cardiac cycle frequency. To study this CSF distribution, we have developed a numerical model of the cerebrospinal system taking into account cerebral ventricles, intracranial subarachnoid spaces, spinal canal and brain tissue in fluid-structure interactions. A numerical fluid-structure interaction model is implemented using a finite-element method library to model the cerebrospinal system and its interaction with the brain based on fluid mechanics equations and linear elasticity equations coupled in a monolithic formulation. The model geometry, simplified in a first approach, is designed in accordance with realistic volume ratios of the different compartments: a thin tube is used to mimic the high flow resistance of the aqueduct. CSF velocity and pressure and brain displacements are obtained as simulation results, and CSF flow and stroke volume are calculated from these results. Simulation results show a significant variability of aqueduct stroke volume and intracranial subarachnoid space stroke volume in the physiological range of cardiac frequencies. Fluid-structure interactions are numerous in the cerebrospinal system and difficult to understand in the rigid skull. The presented model highlights significant variations of stroke volumes under cardiac frequency variations only.

Cerebrospinal fluid dehydroepiandrosterone levels are correlated with brain dehydroepiandrosterone levels, elevated in Alzheimer's disease, and related to neuropathological disease stage.

PubMed

Naylor, Jennifer C; Hulette, Christine M; Steffens, David C; Shampine, Lawrence J; Ervin, John F; Payne, Victoria M; Massing, Mark W; Kilts, Jason D; Strauss, Jennifer L; Calhoun, Patrick S; Calnaido, Rohana P; Blazer, Daniel G; Lieberman, Jeffrey A; Madison, Roger D; Marx, Christine E

2008-08-01

It is currently unknown whether cerebrospinal fluid (CSF) neurosteroid levels are related to brain neurosteroid levels in humans. CSF and brain dehydroepiandrosterone (DHEA) levels are elevated in patients with Alzheimer's disease (AD), but it is unclear whether CSF DHEA levels are correlated with brain DHEA levels within the same subject cohort. We therefore determined DHEA and pregnenolone levels in AD patients (n = 25) and cognitively intact control subjects (n = 16) in both CSF and temporal cortex. DHEA and pregnenolone levels were determined by gas chromatography/mass spectrometry preceded by HPLC. Frozen CSF and temporal cortex specimens were provided by the Alzheimer's Disease Research Center at Duke University Medical Center. Data were analyzed by Mann-Whitney U test statistic and Spearman correlational analyses. CSF DHEA levels are positively correlated with temporal cortex DHEA levels (r = 0.59, P < 0.0001) and neuropathological disease stage (Braak and Braak) (r = 0.42, P = 0.007). CSF pregnenolone levels are also positively correlated with temporal cortex pregnenolone levels (r = 0.57, P < 0.0001) and tend to be correlated with neuropathological disease stage (Braak) (r = 0.30, P = 0.06). CSF DHEA levels are elevated (P = 0.032), and pregnenolone levels tend to be elevated (P = 0.10) in patients with AD, compared with cognitively intact control subjects. These findings indicate that CSF DHEA and pregnenolone levels are correlated with temporal cortex brain levels of these neurosteroids and that CSF DHEA is elevated in AD and related to neuropathological disease stage. Neurosteroids may thus be relevant to the pathophysiology of AD.

Understanding How the Subcommissural Organ and Other Periventricular Secretory Structures Contribute via the Cerebrospinal Fluid to Neurogenesis

PubMed Central

Guerra, Maria M.; González, César; Caprile, Teresa; Jara, Maryoris; Vío, Karin; Muñoz, Rosa I.; Rodríguez, Sara; Rodríguez, Esteban M.

2015-01-01

The dynamic and molecular composition of the cerebrospinal fluid (CSF) and, consequently, the CSF physiology is much more complex and fascinating than the simplistic view held for decades. Signal molecules either transported from blood to CSF or secreted into the CSF by circumventricular organs and CSF-contacting neurons, use the CSF to reach their targets in the brain, including the pre- and postnatal neurogenic niche. The subcommissural organ (SCO), a highly conserved brain gland present throughout the vertebrate phylum, is one of the sources for signals, as well as the choroid plexus, tanycytes and CSF-contacting neurons. The SCO secretes into the fetal and adult CSF SCO-spondin, transthyretin, and basic fibroblast growth factor. These proteins participate in certain aspects of neurogenesis, such as cell cycle of neural stem cells, neuronal differentiation, and axon pathfinding. Through the CSF, the SCO-secretory proteins may reach virtually any target in the embryonic and adult central nervous system. Since the SCO continues to secrete throughout life span, it seems likely that the neurogenetic property of the SCO compounds would be targeted to the niches where neurogenesis continues in adulthood. This review is aimed to bring into discussion early and new evidence concerning the role(s) of the SCO, and the probable mechanisms by which SCO compounds can readily reach the neurogenic niche of the subventricular zone flowing with the CSF to participate in the regulation of the neurogenic niche. As we unfold the multiples trans-fluid talks between discrete brain domains we will have more tools to influence such talks. PMID:26778959

Sphingolipid Metabolism Correlates with Cerebrospinal Fluid Beta Amyloid Levels in Alzheimer’s Disease

PubMed Central

Fonteh, Alfred N.; Ormseth, Cora; Chiang, Jiarong; Cipolla, Matthew; Arakaki, Xianghong; Harrington, Michael G.

2015-01-01

Sphingolipids are important in many brain functions but their role in Alzheimer’s disease (AD) is not completely defined. A major limit is availability of fresh brain tissue with defined AD pathology. The discovery that cerebrospinal fluid (CSF) contains abundant nanoparticles that include synaptic vesicles and large dense core vesicles offer an accessible sample to study these organelles, while the supernatant fluid allows study of brain interstitial metabolism. Our objective was to characterize sphingolipids in nanoparticles representative of membrane vesicle metabolism, and in supernatant fluid representative of interstitial metabolism from study participants with varying levels of cognitive dysfunction. We recently described the recruitment, diagnosis, and CSF collection from cognitively normal or impaired study participants. Using liquid chromatography tandem mass spectrometry, we report that cognitively normal participants had measureable levels of sphingomyelin, ceramide, and dihydroceramide species, but that their distribution differed between nanoparticles and supernatant fluid, and further differed in those with cognitive impairment. In CSF from AD compared with cognitively normal participants: a) total sphingomyelin levels were lower in nanoparticles and supernatant fluid; b) levels of ceramide species were lower in nanoparticles and higher in supernatant fluid; c) three sphingomyelin species were reduced in the nanoparticle fraction. Moreover, three sphingomyelin species in the nanoparticle fraction were lower in mild cognitive impairment compared with cognitively normal participants. The activity of acid, but not neutral sphingomyelinase was significantly reduced in the CSF from AD participants. The reduction in acid sphingomylinase in CSF from AD participants was independent of depression and psychotropic medications. Acid sphingomyelinase activity positively correlated with amyloid β42 concentration in CSF from cognitively normal but not impaired participants. In dementia, altered sphingolipid metabolism, decreased acid sphingomyelinase activity and its lost association with CSF amyloid β42 concentration, underscores the potential of sphingolipids as disease biomarkers, and acid sphingomyelinase as a target for AD diagnosis and/or treatment. PMID:25938590

Metronidazole and Hydroxymetronidazole Central Nervous System Distribution: 2. Cerebrospinal Fluid Concentration Measurements in Patients with External Ventricular Drain

PubMed Central

Frasca, Denis; Dahyot-Fizelier, Claire; Adier, Christophe; Mimoz, Olivier; Debaene, Bertrand; Couet, William

2014-01-01

This study explored metronidazole and hydroxymetronidazole distribution in the cerebrospinal fluid (CSF) of brain-injured patients. Four brain-injured patients with external ventricular drain received 500 mg of metronidazole over 0.5 h every 8 h. CSF and blood samples were collected at steady state over 8 h, and the metronidazole and hydroxymetronidazole concentrations were assayed by high-pressure liquid chromatograph. A noncompartmental analysis was performed. Metronidazole is distributed extensively within CSF, with a mean CSF to unbound plasma AUC0–τ ratio of 86% ± 16%. However, the concentration profiles in CSF were mostly flat compared to the plasma profiles. Hydroxymetronidazole concentrations were much lower than those of metronidazole both in plasma and in CSF, with a corresponding CSF/unbound plasma AUC0–τ ratio of 79% ± 16%. We describe here for the first time in detail the pharmacokinetics of metronidazole and hydroxymetronidazole in CSF. PMID:24277050

Exploring the Virchow–Robin spaces function: A unified theory of brain diseases

PubMed Central

Cherian, Iype; Beltran, Margarita; Kasper, Ekkehard M.; Bhattarai, Binod; Munokami, Sunil; Grasso, Giovanni

2016-01-01

Background: Cerebrospinal fluid (CSF) transport across the central nervous system (CNS) is no longer believed to be on the conventional lines. The Virchow–Robin space (VRS) that facilitates CSF transport from the basal cisterns into the brain interstitial fluid (ISF) has gained interest in a whole new array of studies. Moreover, new line of evidence suggests that VRS may be involved in different pathological mechanisms of brain diseases. Methods: Here, we review emerging studies proving the feasible role of VRS in sleep, Alzheimer's disease, chronic traumatic encephalopathy, and traumatic brain injury (TBI). Results: In this study, we have outlined the possible role of VRS in different pathological conditions. Conclusion: The new insights into the physiology of the CSF circulation may have important clinical relevance for understanding the mechanisms underlying brain pathologies and their cure. PMID:27857861

Volume transmission-mediated encephalopathies: a possible new concept?

PubMed

Hartung, Hans-Peter; Dihné, Marcel

2012-03-01

There is strong evidence that the composition of cerebrospinal fluid (CSF) influences brain development, neurogenesis, and behavior. The bidirectional exchange of CSF and interstitial fluid (ISF) across the ependymal and pia-glial membranes is required for these phenomena to occur. Because ISF surrounds the parenchymal compartment, neuroactive substances in the CSF and ISF can influence neuronal activity. Functionally important neuroactive substances are distributed to distant sites of the central nervous system by the convection and diffusion of CSF and ISF, a process known as volume transmission. It has recently been shown that pathologically altered CSF from patients with acute traumatic brain injury suppresses in vitro neuronal network activity (ivNNA) recorded by multielectrode arrays measuring synchronously bursting neural populations. Functionally relevant substances in pathologically altered CSF have been biochemically identified, and ivNNA has been partially recovered by pharmacologic intervention. It remains unclear whether the in vivo parenchymal compartment remains unaffected by pathologically altered CSF that significantly impairs ivNNA. We hypothesize that pathologic CSF alterations are not just passive indicators of brain diseases but that they actively and directly evoke functional disturbances in global brain activity through the distribution of neuroactive substances, for instance, secondary to focal neurologic disease. For this mechanism, we propose the new term volume transmission-mediated encephalopathies (VTE). Recording ivNNA in the presence of pure human CSF could help to identify and monitor functionally relevant CSF alterations that directly result in VTEs, and the collected data might point to therapeutic ways to antagonize these alterations.

Cerebrospinal fluid biochemical studies in patients with Parkinson's disease: toward a potential search for biomarkers for this disease

PubMed Central

Jiménez-Jiménez, Félix J.; Alonso-Navarro, Hortensia; García-Martín, Elena; Agúndez, José A. G.

2014-01-01

The blood-brain barrier supplies brain tissues with nutrients and filters certain compounds from the brain back to the bloodstream. In several neurodegenerative diseases, including Parkinson's disease (PD), there are disruptions of the blood-brain barrier. Cerebrospinal fluid (CSF) has been widely investigated in PD and in other parkinsonian syndromes with the aim of establishing useful biomarkers for an accurate differential diagnosis among these syndromes. This review article summarizes the studies reported on CSF levels of many potential biomarkers of PD. The most consistent findings are: (a) the possible role of CSF urate on the progression of the disease; (b) the possible relations of CSF total tau and phosphotau protein with the progression of PD and with the preservation of cognitive function in PD patients; (c) the possible value of CSF beta-amyloid 1-42 as a useful marker of further cognitive decline in PD patients, and (d) the potential usefulness of CSF neurofilament (NFL) protein levels in the differential diagnosis between PD and other parkinsonian syndromes. Future multicentric, longitudinal, prospective studies with long-term follow-up and neuropathological confirmation would be useful in establishing appropriate biomarkers for PD. PMID:25426023

Prototype of an opto-capacitive probe for non-invasive sensing cerebrospinal fluid circulation

NASA Astrophysics Data System (ADS)

Myllylä, Teemu; Vihriälä, Erkki; Pedone, Matteo; Korhonen, Vesa; Surazynski, Lukasz; Wróbel, Maciej; Zienkiewicz, Aleksandra; Hakala, Jaakko; Sorvoja, Hannu; Lauri, Janne; Fabritius, Tapio; Jedrzejewska-Szczerska, Małgorzata; Kiviniemi, Vesa; Meglinski, Igor

2017-03-01

In brain studies, the function of the cerebrospinal fluid (CSF) awakes growing interest, particularly related to studies of the glymphatic system in the brain, which is connected with the complex system of lymphatic vessels responsible for cleaning the tissues. The CSF is a clear, colourless liquid including water (H2O) approximately with a concentration of 99 %. In addition, it contains electrolytes, amino acids, glucose, and other small molecules found in plasma. The CSF acts as a cushion behind the skull, providing basic mechanical as well as immunological protection to the brain. Disturbances of the CSF circulation have been linked to several brain related medical disorders, such as dementia. Our goal is to develop an in vivo method for the non-invasive measurement of cerebral blood flow and CSF circulation by exploiting optical and capacitive sensing techniques simultaneously. We introduce a prototype of a wearable probe that is aimed to be used for long-term brain monitoring purposes, especially focusing on studies of the glymphatic system. In this method, changes in cerebral blood flow, particularly oxy- and deoxyhaemoglobin, are measured simultaneously and analysed with the response gathered by the capacitive sensor in order to distinct the dynamics of the CSF circulation behind the skull. Presented prototype probe is tested by measuring liquid flows inside phantoms mimicking the CSF circulation.

Cerebrospinal and Interstitial Fluid Transport via the Glymphatic Pathway Modeled by Optimal Mass Transport

PubMed Central

Ratner, Vadim; Gao, Yi; Lee, Hedok; Elkin, Rena; Nedergaard, Maiken; Benveniste, Helene; Tannenbaum, Allen

2017-01-01

The glymphatic pathway is a system which facilitates continuous cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange and plays a key role in removing waste products from the rodent brain. Dysfunction of the glymphatic pathway may be implicated in the pathophysiology of Alzheimer's disease. Intriguingly, the glymphatic system is most active during deep wave sleep general anesthesia. By using paramagnetic tracers administered into CSF of rodents, we previously showed the utility of MRI in characterizing a macroscopic whole brain view of glymphatic transport but we have yet to define and visualize the specific flow patterns. Here we have applied an alternative mathematical analysis approach to a dynamic time series of MRI images acquired every 4 min over ∼3 hrs in anesthetized rats, following administration of a small molecular weight paramagnetic tracer into the CSF reservoir of the cisterna magna. We use Optimal Mass Transport (OMT) to model the glymphatic flow vector field, and then analyze the flow to find the network of CSF-ISF flow channels. We use 3D visualization computational tools to visualize the OMT defined network of CSF-ISF flow channels in relation to anatomical and vascular key landmarks from the live rodent brain. The resulting OMT model of the glymphatic transport network agrees largely with the current understanding of the glymphatic transport patterns defined by dynamic contrast-enhanced MRI revealing key CSF transport pathways along the ventral surface of the brain with a trajectory towards the pineal gland, cerebellum, hypothalamus and olfactory bulb. In addition, the OMT analysis also revealed some interesting previously unnoticed behaviors regarding CSF transport involving parenchymal streamlines moving from ventral reservoirs towards the surface of the brain, olfactory bulb and large central veins. PMID:28323163

Cerebrospinal and interstitial fluid transport via the glymphatic pathway modeled by optimal mass transport.

PubMed

Ratner, Vadim; Gao, Yi; Lee, Hedok; Elkin, Rena; Nedergaard, Maiken; Benveniste, Helene; Tannenbaum, Allen

2017-05-15

The glymphatic pathway is a system which facilitates continuous cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange and plays a key role in removing waste products from the rodent brain. Dysfunction of the glymphatic pathway may be implicated in the pathophysiology of Alzheimer's disease. Intriguingly, the glymphatic system is most active during deep wave sleep general anesthesia. By using paramagnetic tracers administered into CSF of rodents, we previously showed the utility of MRI in characterizing a macroscopic whole brain view of glymphatic transport but we have yet to define and visualize the specific flow patterns. Here we have applied an alternative mathematical analysis approach to a dynamic time series of MRI images acquired every 4min over ∼3h in anesthetized rats, following administration of a small molecular weight paramagnetic tracer into the CSF reservoir of the cisterna magna. We use Optimal Mass Transport (OMT) to model the glymphatic flow vector field, and then analyze the flow to find the network of CSF-ISF flow channels. We use 3D visualization computational tools to visualize the OMT defined network of CSF-ISF flow channels in relation to anatomical and vascular key landmarks from the live rodent brain. The resulting OMT model of the glymphatic transport network agrees largely with the current understanding of the glymphatic transport patterns defined by dynamic contrast-enhanced MRI revealing key CSF transport pathways along the ventral surface of the brain with a trajectory towards the pineal gland, cerebellum, hypothalamus and olfactory bulb. In addition, the OMT analysis also revealed some interesting previously unnoticed behaviors regarding CSF transport involving parenchymal streamlines moving from ventral reservoirs towards the surface of the brain, olfactory bulb and large central veins. Copyright © 2017. Published by Elsevier Inc.

Knowledge-base for interpretation of cerebrospinal fluid data patterns. Essentials in neurology and psychiatry.

PubMed

Reiber, Hansotto

2016-06-01

The physiological and biophysical knowledge base for interpretations of cerebrospinal fluid (CSF) data and reference ranges are essential for the clinical pathologist and neurochemist. With the popular description of the CSF flow dependent barrier function, the dynamics and concentration gradients of blood-derived, brain-derived and leptomeningeal proteins in CSF or the specificity-independent functions of B-lymphocytes in brain also the neurologist, psychiatrist, neurosurgeon as well as the neuropharmacologist may find essentials for diagnosis, research or development of therapies. This review may help to replace the outdated ideas like "leakage" models of the barriers, linear immunoglobulin Index Interpretations or CSF electrophoresis. Calculations, Interpretations and analytical pitfalls are described for albumin quotients, quantitation of immunoglobulin synthesis in Reibergrams, oligoclonal IgG, IgM analysis, the polyspecific ( MRZ- ) antibody reaction, the statistical treatment of CSF data and general quality assessment in the CSF laboratory. The diagnostic relevance is documented in an accompaning review.

Comparison between cerebrospinal fluid and serum lactate concentrations in neurologic dogs with and without structural intracranial disease.

PubMed

Benedicenti, Leontine; Gianotti, Giacomo; Galban, Evelyn M

2018-04-01

The objectives of this study were to investigate the relationship between cerebrospinal fluid lactate and serum concentrations in dogs with clinical signs of central nervous system disease and to establish if cerebrospinal fluid lactate (CSF) concentrations are higher in dogs with structural intracranial disease (Group Pos-MRI) compared to dogs that have clinical signs of intracranial disease but no structural brain disease (Group Neg-MRI) based on magnetic resonance imaging (MRI) findings. Using a prospective study canine blood and cerebrospinal fluid were collected in 24 dogs with neurological signs after undergoing brain MRI. Dogs were divided in 2 groups. No significant difference between serum lactate (1.57 ± 0.9 mmol/L) and CSF lactate concentration (1.34 ± 0.3 mmol/L) was detected. There was a direct correlation between CSF and serum lactate concentration ( R = 0.731; P = 0.01). No significant difference was found in CSF lactate concentration between the 2 groups of dogs ( P = 0.13).

Soluble Megalin is Reduced in Cerebrospinal Fluid Samples of Alzheimer's Disease Patients.

PubMed

Spuch, Carlos; Antequera, Desireé; Pascual, Consuelo; Abilleira, Soledad; Blanco, María; Moreno-Carretero, María José; Romero-López, Jesús; Ishida, Tetsuya; Molina, Jose Antonio; Villarejo, Alberto; Bermejo-Pareja, Felix; Carro, Eva

2015-01-01

Megalin or low-density lipoprotein receptor-related protein-2 is a member of the low-density lipoprotein receptor family, which has been linked to Alzheimer's disease (AD) by clearing brain amyloid β-peptide (Aβ) across the blood-cerebrospinal fluid barrier at the choroid plexus. Here, we found a soluble form of megalin secreted from choroid plexus epithelial cells. Soluble megalin levels were also localized in the human cerebrospinal fluid (CSF), being reduced in AD patients. We have also shown that soluble megalin binding to Aβ is decreased in the CSF of AD patients, suggesting that decreased sequestration of Aβ in the CSF could be associated with defective clearance of Aβ and an increase of brain Aβ levels. Thus, therapies, which increase megalin expression, at the choroid plexus and/or enhance circulating soluble megalin hold potential to control brain Aβ-related pathologies in AD.

Soluble Megalin is Reduced in Cerebrospinal Fluid Samples of Alzheimer’s Disease Patients

PubMed Central

Spuch, Carlos; Antequera, Desireé; Pascual, Consuelo; Abilleira, Soledad; Blanco, María; Moreno-Carretero, María José; Romero-López, Jesús; Ishida, Tetsuya; Molina, Jose Antonio; Villarejo, Alberto; Bermejo-Pareja, Felix; Carro, Eva

2015-01-01

Megalin or low-density lipoprotein receptor-related protein-2 is a member of the low-density lipoprotein receptor family, which has been linked to Alzheimer’s disease (AD) by clearing brain amyloid β-peptide (Aβ) across the blood–cerebrospinal fluid barrier at the choroid plexus. Here, we found a soluble form of megalin secreted from choroid plexus epithelial cells. Soluble megalin levels were also localized in the human cerebrospinal fluid (CSF), being reduced in AD patients. We have also shown that soluble megalin binding to Aβ is decreased in the CSF of AD patients, suggesting that decreased sequestration of Aβ in the CSF could be associated with defective clearance of Aβ and an increase of brain Aβ levels. Thus, therapies, which increase megalin expression, at the choroid plexus and/or enhance circulating soluble megalin hold potential to control brain Aβ-related pathologies in AD. PMID:25926771

Pathophysiology of increased cerebrospinal fluid pressure associated to brain arteriovenous malformations: The hydraulic hypothesis.

PubMed

Rossitti, Sandro

2013-01-01

Brain arteriovenous malformations (AVMs) produce circulatory and functional disturbances in adjacent as well as in remote areas of the brain, but their physiological effect on the cerebrospinal fluid (CSF) pressure is not well known. The hypothesis of an intrinsic disease mechanism leading to increased CSF pressure in all patients with brain AVM is outlined, based on a theory of hemodynamic control of intracranial pressure that asserts that CSF pressure is a fraction of the systemic arterial pressure as predicted by a two-resistor series circuit hydraulic model. The resistors are the arteriolar resistance (that is regulated by vasomotor tonus), and the venous resistance (which is mechanically passive as a Starling resistor). This theory is discussed and compared with the knowledge accumulated by now on intravasal pressures and CSF pressure measured in patients with brain AVM. The theory provides a basis for understanding the occurrence of pseudotumor cerebri syndrome in patients with nonhemorrhagic brain AVMs, for the occurrence of local mass effect and brain edema bordering unruptured AVMs, and for the development of hydrocephalus in patients with unruptured AVMs. The theory also contributes to a better appreciation of the pathophysiology of dural arteriovenous fistulas, of vein of Galen aneurismal malformation, and of autoregulation-related disorders in AVM patients. The hydraulic hypothesis provides a comprehensive frame to understand brain AVM hemodynamics and its effect on the CSF dynamics.

Pathophysiology of increased cerebrospinal fluid pressure associated to brain arteriovenous malformations: The hydraulic hypothesis

PubMed Central

Rossitti, Sandro

2013-01-01

Background: Brain arteriovenous malformations (AVMs) produce circulatory and functional disturbances in adjacent as well as in remote areas of the brain, but their physiological effect on the cerebrospinal fluid (CSF) pressure is not well known. Methods: The hypothesis of an intrinsic disease mechanism leading to increased CSF pressure in all patients with brain AVM is outlined, based on a theory of hemodynamic control of intracranial pressure that asserts that CSF pressure is a fraction of the systemic arterial pressure as predicted by a two-resistor series circuit hydraulic model. The resistors are the arteriolar resistance (that is regulated by vasomotor tonus), and the venous resistance (which is mechanically passive as a Starling resistor). This theory is discussed and compared with the knowledge accumulated by now on intravasal pressures and CSF pressure measured in patients with brain AVM. Results: The theory provides a basis for understanding the occurrence of pseudotumor cerebri syndrome in patients with nonhemorrhagic brain AVMs, for the occurrence of local mass effect and brain edema bordering unruptured AVMs, and for the development of hydrocephalus in patients with unruptured AVMs. The theory also contributes to a better appreciation of the pathophysiology of dural arteriovenous fistulas, of vein of Galen aneurismal malformation, and of autoregulation-related disorders in AVM patients. Conclusions: The hydraulic hypothesis provides a comprehensive frame to understand brain AVM hemodynamics and its effect on the CSF dynamics. PMID:23607064

Automatic, accurate, and reproducible segmentation of the brain and cerebro-spinal fluid in T1-weighted volume MRI scans and its application to serial cerebral and intracranial volumetry

NASA Astrophysics Data System (ADS)

Lemieux, Louis

2001-07-01

A new fully automatic algorithm for the segmentation of the brain and cerebro-spinal fluid (CSF) from T1-weighted volume MRI scans of the head was specifically developed in the context of serial intra-cranial volumetry. The method is an extension of a previously published brain extraction algorithm. The brain mask is used as a basis for CSF segmentation based on morphological operations, automatic histogram analysis and thresholding. Brain segmentation is then obtained by iterative tracking of the brain-CSF interface. Grey matter (GM), white matter (WM) and CSF volumes are calculated based on a model of intensity probability distribution that includes partial volume effects. Accuracy was assessed using a digital phantom scan. Reproducibility was assessed by segmenting pairs of scans from 20 normal subjects scanned 8 months apart and 11 patients with epilepsy scanned 3.5 years apart. Segmentation accuracy as measured by overlap was 98% for the brain and 96% for the intra-cranial tissues. The volume errors were: total brain (TBV): -1.0%, intra-cranial (ICV):0.1%, CSF: +4.8%. For repeated scans, matching resulted in improved reproducibility. In the controls, the coefficient of reliability (CR) was 1.5% for the TVB and 1.0% for the ICV. In the patients, the Cr for the ICV was 1.2%.

Association of cerebrospinal fluid Aβ42 with A2M gene in cognitively normal subjects

PubMed Central

Millard, Steven P.; Lutz, Franziska; Li, Ge; Galasko, Douglas R.; Farlow, Martin R.; Quinn, Joseph F.; Kaye, Jeffrey A.; Leverenz, James B.; Tsuang, Debby; Yu, Chang-En; Peskind, Elaine R.; Bekris, Lynn M.

2013-01-01

Low cerebrospinal fluid (CSF) Aβ42 levels correlate with increased brain Aβ deposition in Alzheimer’s disease (AD), which suggests a disruption in the degradation and clearance of Aβ from the brain. In addition, APOE ε4 carriers have lower CSF Aβ42 levels than non-carriers. The hypothesis of this investigation was that CSF Aβ42 levels correlate with regulatory region variation in genes that are biologically associated with degradation or clearance of Aβ from the brain. CSF Aβ42 levels were tested for associations with Aβ degradation and clearance genes and APOE ε4. Twenty-four SNPs located within the 5′ and 3′ regions of 12 genes were analyzed. The study sample consisted of 99 AD patients and 168 cognitively normal control subjects. CSF Aβ42 levels were associated with APOE ε4 status in controls but not in AD patients; A2M regulatory region SNPs were also associated with CSF Aβ42 levels in controls, but not in AD patients, even after adjusting for APOE ε4. These results suggest that genetic variation within the A2M gene influences CSF Aβ42 levels. PMID:24011543

Neonatal hypoxia-ischemia in rat increases doublecortin concentration in the cerebrospinal fluid.

PubMed

Brégère, Catherine; Fisch, Urs; Sailer, Martin H; Lieb, Wolfgang S; Chicha, Laurie; Goepfert, Fabienne; Kremer, Thomas; Guzman, Raphael

2017-07-01

Doublecortin (DCX) is a microtubule-associated protein widely used as an indicator of neurogenesis in immunohistochemical analyses of the postmortem adult brain. A recent study reported that DCX can be quantified in the cerebrospinal fluid (CSF) from healthy rats between postnatal day 0 (P0) and P30. However, it is currently unclear whether the concentration of DCX in the CSF (CSF-DCX) may represent a measure of endogenous neurogenesis. To address this question, this study examined the impact of a neonatal hypoxic-ischemic (HI) brain injury, known to induce neurogenesis, on CSF-DCX. HI was elicited at P7 in Sprague-Dawley rat neonates, and CSF was collected serially from the cisterna magna at P5 and P10, or at P10 and P15. A sandwich immunoassay was used to measure CSF-DCX. Brains from P10 neonates were analyzed immunohistochemically for neurogenesis and cell death markers. Mean CSF-DCX was significantly higher in HI- than in sham-exposed animals, at both P10 and P15. In the HI group at P10, CSF-DCX and stroke severity correlated positively. DCX immunoreactivity was increased in the ipsilateral neurogenic niches from the P10 HI brains in comparison with that of shams. The number of proliferative DCX-positive cells was higher in the ipsilateral hippocampal subgranular zone (SGZ) than in the HI contralateral or sham SGZ. Thus, neonatal HI brain injury disrupts the developmental time-course of DCX levels in the CSF. Our data suggest that the increased concentration of DCX in the CSF after neonatal HI is the result of both cellular injury and increased neurogenesis. © 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Increased transfer of 45Ca into brain and cerebrospinal fluid from plasma during chronic hypocalcemia in rats.

PubMed

Murphy, V A; Rapoport, S I

1988-06-28

Recent studies have shown regulation of central nervous system [Ca] after chronic hypo- and hypercalcemia. To investigate the mechanism of this regulation, 3-week-old rats were fed diets for 8 weeks that contained low or normal levels of Ca. Plasma [Ca] was 40% less in rats fed the low Ca diet than in animals fed normal diet. Unidirectional transfer coefficients for Ca (KCa) and Cl (KCl) into cerebrospinal fluid (CSF) and brain were determined from the 10 min uptake of intravenously injected 45Ca and 36Cl in awake animals. KCa for CSF was 68% greater in low-Ca rats than in normal rats. Likewise, the values of KCa for brain regions with areas adjacent to the ventricles like the hippocampus and pons-medulla were 50% higher than in normal animals. On the other hand, KCas for parietal cortex, a brain region distant from the choroid plexus and not expected to be influenced by Ca entry into CSF, were similar between the groups. Comparison of the regional ratios of KCa/KCl revealed that a selective increase of Ca transport occurred into CSF and all brain regions except the parietal cortex in Ca-deficient rats. The results suggest that Ca homeostasis of CSF and brain [Ca] during chronic hypocalcemia is due to increased transfer of Ca from blood to brain, and that the regulation occurs via the CSF, possibly at the choroid plexus, but not via the cerebral capillaries.

Suppression of glymphatic fluid transport in a mouse model of Alzheimer's disease.

PubMed

Peng, Weiguo; Achariyar, Thiyagarajan M; Li, Baoman; Liao, Yonghong; Mestre, Humberto; Hitomi, Emi; Regan, Sean; Kasper, Tristan; Peng, Sisi; Ding, Fengfei; Benveniste, Helene; Nedergaard, Maiken; Deane, Rashid

2016-09-01

Glymphatic transport, defined as cerebrospinal fluid (CSF) peri-arterial inflow into brain, and interstitial fluid (ISF) clearance, is reduced in the aging brain. However, it is unclear whether glymphatic transport affects the distribution of soluble Aβ in Alzheimer's disease (AD). In wild type mice, we show that Aβ40 (fluorescently labeled Aβ40 or unlabeled Aβ40), was distributed from CSF to brain, via the peri-arterial space, and associated with neurons. In contrast, Aβ42 was mostly restricted to the peri-arterial space due mainly to its greater propensity to oligomerize when compared to Aβ40. Interestingly, pretreatment with Aβ40 in the CSF, but not Aβ42, reduced CSF transport into brain. In APP/PS1 mice, a model of AD, with and without extensive amyloid-β deposits, glymphatic transport was reduced, due to the accumulation of toxic Aβ species, such as soluble oligomers. CSF-derived Aβ40 co-localizes with existing endogenous vascular and parenchymal amyloid-β plaques, and thus, may contribute to the progression of both cerebral amyloid angiopathy and parenchymal Aβ accumulation. Importantly, glymphatic failure preceded significant amyloid-β deposits, and thus, may be an early biomarker of AD. By extension, restoring glymphatic inflow and ISF clearance are potential therapeutic targets to slow the onset and progression of AD. Copyright © 2016 Elsevier Inc. All rights reserved.

Cerebrospinal fluid enhancement on fluid attenuated inversion recovery images after carotid artery stenting with neuroprotective balloon occlusions: hemodynamic instability and blood-brain barrier disruption.

PubMed

Ogami, Ryo; Nakahara, Toshinori; Hamasaki, Osamu; Araki, Hayato; Kurisu, Kaoru

2011-10-01

A rare complication of carotid artery stenting (CAS), prolonged reversible neurological symptoms with delayed cerebrospinal fluid (CSF) space enhancement on fluid attenuated inversion recovery (FLAIR) images, is associated with blood-brain barrier (BBB) disruption. We prospectively identified patients who showed CSF space enhancement on FLAIR images. Nineteen patients-5 acute-phase and 14 scheduled-underwent 21 CAS procedures. Balloon catheters were navigated across stenoses, angioplasty was performed using a neuroprotective balloon, and stents were placed with after dilation under distal balloon protection. CSF space hyperintensity or obscuration on FLAIR after versus before CAS indicated CSF space enhancement. Correlations with clinical factors were examined. CSF space was enhanced on FLAIR in 12 (57.1%) cases. Postprocedural CSF space enhancement was significantly related to age, stenosis rate, acute-stage procedure, and total occlusion time. All acute-stage CAS patients showed delayed enhancement. Only age was associated with delayed CSF space enhancement in scheduled CAS patients. Ischemic intolerance for severe carotid artery stenosis and temporary neuroprotective balloon occlusion, causing reperfusion injury, seem to be the main factors that underlie BBB disruption with delayed CSF space enhancement shortly after CAS, rather than sudden poststenting hemodynamic change. Our results suggest that factors related to hemodynamic instability or ischemic intolerance seem to be associated with post-CAS BBB vulnerability. Patients at risk for hemodynamic instability or with ischemic intolerance, which decrease BBB integrity, require careful management to prevent intracranial hemorrhagic and other post-CAS complications.

Upregulation of Aβ42 in the Brain and Bodily Fluids of Rhesus Monkeys with Aging.

PubMed

Zhao, Qiao; Lu, Jing; Yao, Zitong; Wang, Shubo; Zhu, Liming; Wang, Ju; Chen, Baian

2017-01-01

The cerebral accumulation of amyloid beta (Aβ) is one of the key pathological hallmarks of Alzheimer's disease (AD). Aβ is also found in bodily fluids such as the cerebrospinal fluid (CSF) and plasma. However, the significance of Aβ accumulation in the brain and different bodily pools, as well as its correlation with aging and cerebral amyloid pathology, is not completely understood. To better understand this question, we selected the rhesus monkey, which is phylogenetically and physiologically highly similar to the human, as a model to study. We quantified the levels of the two main Aβ isoforms (Aβ42 and Aβ40) in different sections of the brain (frontal cortex, temporal cortex, and hippocampus) and bodily fluids (CSF and plasma) of rhesus monkeys at different developmental phases (young, 5-9 years of age; mature, 10-19 years of age; and old, 21-24 years of age). We found that the levels of neuronal and insoluble Aβ42 increased significantly in the brain with aging, suggesting that this specific isoform might be directly involved in aging and AD-like pathophysiology. There was no significant change in the Aβ40 level in the brain with aging. In addition, the Aβ42 level, but not the Aβ40 level, in both the CSF and plasma increased with aging. We also identified a positive correlation between Aβ42 in the CSF and plasma and Aβ42 in the brain. Taken collectively, our results indicate that there is an association between Aβ accumulation and age. These results support the increased incidence of AD with aging.

Distribution Assessments of Coumarins from Angelicae Pubescentis Radix in Rat Cerebrospinal Fluid and Brain by Liquid Chromatography Tandem Mass Spectrometry Analysis.

PubMed

Yang, Yan-Fang; Zhang, Lei; Yang, Xiu-Wei

2018-01-20

Angelicae Pubescentis Radix (APR) is a widely-used traditional Chinese medicine. Pharmacological studies have begun to probe its biological activities on neurological disorders recently. To assess the brain penetration and distribution of APR, a validated ultra-performance liquid chromatography tandem mass spectrometry method was applied to the simultaneous determinations of the main coumarins from APR in the rat cerebrospinal fluid (CSF) and brain after oral administration of APR extract, including psoralen, xanthotoxin, bergapten, isoimperatorin, columbianetin, columbianetin acetate, columbianadin, oxypeucedanin hydrate, angelol B, osthole, meranzin hydrate and nodakenetin. Most of the tested coumarins entered the rat CSF and brain quickly, and double-peak phenomena in concentration-time curves were similar to those of their plasma pharmacokinetics. Columbianetin had the highest concentration in the CSF and brain, while psoralen and columbianetin acetate had the largest percent of CSF/plasma and brain/plasma, indicating that these three coumarins may be worthy of further research on the possible nervous effects. Correlations between the in vivo brain distributions and plasma pharmacokinetics of these coumarins were well verified. These results provided valuable information for the overall in vivo brain distribution characteristics of APR and also for its further studies on the active substances for the central nervous system.

Fructose levels are markedly elevated in cerebrospinal fluid compared to plasma in pregnant women.

PubMed

Hwang, Janice J; Johnson, Andrea; Cline, Gary; Belfort-DeAguiar, Renata; Snegovskikh, Denis; Khokhar, Babar; Han, Christina S; Sherwin, Robert S

2015-01-01

Fructose, unlike glucose, promotes feeding behavior in rodents and its ingestion exerts differential effects in the human brain. However, plasma fructose is typically 1/1000 th of glucose levels and it is unclear to what extent fructose crosses the blood-brain barrier. We investigated whether local endogenous central nervous system (CNS) fructose production from glucose via the polyol pathway (glucose → sorbitol → fructose) contributes to brain exposure to fructose. In this observational study, fasting glucose, sorbitol and fructose concentrations were measured using gas-chromatography-liquid mass spectroscopy in cerebrospinal fluid (CSF), maternal plasma, and venous cord blood collected from 25 pregnant women (6 lean, 10 overweight/obese, and 9 T2DM/gestational DM) undergoing spinal anesthesia and elective cesarean section. As expected, CSF glucose was ~ 60% of plasma glucose levels. In contrast, fructose was nearly 20-fold higher in CSF than in plasma (p < 0.001), and CSF sorbitol was ~ 9-times higher than plasma levels (p < 0.001). Moreover, CSF fructose correlated positively with CSF glucose (ρ 0.45, p = 0.02) and sorbitol levels (ρ 0.75, p < 0.001). Cord blood sorbitol was also ~ 7-fold higher than maternal plasma sorbitol levels (p = 0.001). There were no differences in plasma, CSF, and cord blood glucose, fructose, or sorbitol levels between groups. These data raise the possibility that fructose may be produced endogenously in the human brain and that the effects of fructose in the human brain and placenta may extend beyond its dietary consumption.

Fructose Levels Are Markedly Elevated in Cerebrospinal Fluid Compared to Plasma in Pregnant Women

PubMed Central

Hwang, Janice J.; Johnson, Andrea; Cline, Gary; Belfort-DeAguiar, Renata; Snegovskikh, Denis; Khokhar, Babar; Han, Christina S.; Sherwin, Robert S.

2015-01-01

Background Fructose, unlike glucose, promotes feeding behavior in rodents and its ingestion exerts differential effects in the human brain. However, plasma fructose is typically 1/1000th of glucose levels and it is unclear to what extent fructose crosses the blood-brain barrier. We investigated whether local endogenous central nervous system (CNS) fructose production from glucose via the polyol pathway (glucose→sorbitol→fructose) contributes to brain exposure to fructose. Methods In this observational study, fasting glucose, sorbitol and fructose concentrations were measured using gas-chromatography-liquid mass spectroscopy in cerebrospinal fluid (CSF), maternal plasma, and venous cord blood collected from 25 pregnant women (6 lean, 10 overweight/obese, and 9 T2DM/gestational DM) undergoing spinal anesthesia and elective cesarean section. Results As expected, CSF glucose was ~60% of plasma glucose levels. In contrast, fructose was nearly 20-fold higher in CSF than in plasma (p < 0.001), and CSF sorbitol was ~9-times higher than plasma levels (p < 0.001). Moreover, CSF fructose correlated positively with CSF glucose (ρ 0.45, p = 0.02) and sorbitol levels (ρ 0.75, p < 0.001). Cord blood sorbitol was also ~7-fold higher than maternal plasma sorbitol levels (p = 0.001). There were no differences in plasma, CSF, and cord blood glucose, fructose, or sorbitol levels between groups. Conclusions These data raise the possibility that fructose may be produced endogenously in the human brain and that the effects of fructose in the human brain and placenta may extend beyond its dietary consumption. PMID:26035307

Cerebrospinal Fluid Enhancement on Fluid Attenuated Inversion Recovery Images After Carotid Artery Stenting with Neuroprotective Balloon Occlusions: Hemodynamic Instability and Blood-Brain Barrier Disruption

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ogami, Ryo, E-mail: ogami.r@mazda.co.jp; Nakahara, Toshinori; Hamasaki, Osamu

2011-10-15

Purpose: A rare complication of carotid artery stenting (CAS), prolonged reversible neurological symptoms with delayed cerebrospinal fluid (CSF) space enhancement on fluid attenuated inversion recovery (FLAIR) images, is associated with blood-brain barrier (BBB) disruption. We prospectively identified patients who showed CSF space enhancement on FLAIR images. Methods: Nineteen patients-5 acute-phase and 14 scheduled-underwent 21 CAS procedures. Balloon catheters were navigated across stenoses, angioplasty was performed using a neuroprotective balloon, and stents were placed with after dilation under distal balloon protection. CSF space hyperintensity or obscuration on FLAIR after versus before CAS indicated CSF space enhancement. Correlations with clinical factors weremore » examined. Results: CSF space was enhanced on FLAIR in 12 (57.1%) cases. Postprocedural CSF space enhancement was significantly related to age, stenosis rate, acute-stage procedure, and total occlusion time. All acute-stage CAS patients showed delayed enhancement. Only age was associated with delayed CSF space enhancement in scheduled CAS patients. Conclusions: Ischemic intolerance for severe carotid artery stenosis and temporary neuroprotective balloon occlusion, causing reperfusion injury, seem to be the main factors that underlie BBB disruption with delayed CSF space enhancement shortly after CAS, rather than sudden poststenting hemodynamic change. Our results suggest that factors related to hemodynamic instability or ischemic intolerance seem to be associated with post-CAS BBB vulnerability. Patients at risk for hemodynamic instability or with ischemic intolerance, which decrease BBB integrity, require careful management to prevent intracranial hemorrhagic and other post-CAS complications.« less

Pharmacokinetic modelling of interleukin-1 receptor antagonist in plasma and cerebrospinal fluid of patients following subarachnoid haemorrhage.

PubMed

Gueorguieva, Ivelina; Clark, Simon R; McMahon, Catherine J; Scarth, Sylvia; Rothwell, Nancy J; Tyrrell, Pippa J; Tyrell, Pippa J; Hopkins, Stephen J; Rowland, Malcolm

2008-03-01

What is already known about this subject? The naturally occurring interlukin-1 receptor antagonist (IL-1RA) markedly protects rodents against ischaemic, excitotoxic and traumatic brain injury, suggesting it may be of therapeutic value. When administered intravenously to patients soon after stroke, IL-1RA is safe and reduces the peripheral inflammatory response. However, IL-1RA is a large protein (17 kDa), which may limit brain penetration, thereby limiting its potential utility in brain injury. What this study adds. The purpose of these experiments was to determine the pharmacokinetics of IL-1RA in cerebrospinal fluid (CSF) of patients, to allow modelling that would aid development of therapeutic regimens. Peripherally administered IL-1RA crosses slowly into and out of the CSF of patients with subarachnoid haemorrhage and, at steady state, CSF IL-1RA concentration (range 115-886 ng ml(-1)) was similar to that found to be neuroprotective in rats (range 91-232 ng ml(-1)), although there was considerable variability among patients. However, there is a large concentration gradient of IL-1RA between plasma and CSF. These CSF:plasma data are consistent with very low permeation of IL-1RA into the CSF and elimination kinetics from it controlled by the volumetric turnover of CSF. The naturally occurring interlukin-1 receptor antagonist (IL-1RA) markedly protects rodents against ischaemic, excitotoxic and traumatic brain injury, suggesting it may be of therapeutic value. The aim was to determine the pharmacokinetics of IL-1RA in cerebrospinal fluid (CSF) of patients, to allow modelling that would aid development of therapeutic regimens. When administered intravenously to patients soon after stroke, IL-1RA is safe and reduces the peripheral inflammatory response. However, IL-1RA is a large protein (17 kDa), which may limit brain penetration, thereby limiting its potential utility in brain injury. In seven patients with subarchnoid haemorrhage (SAH), IL-1RA was administered by intravenous bolus, then infusion for 24 h, and both blood and CSF, via external ventricular drains, were sampled during and after stopping the infusion. Plasma steady-state concentrations were rapidly attained and maintained throughout the infusion, whereas CSF concentrations rose slowly towards a plateau during the 24-h infusion, reaching at best only 4% of that in plasma. Plasma kinetic parameters were within the literature range. Modelling of the combined data yielded rate constants entering and leaving the CSF of 0.0019 h(-1)[relative standard error (RSE) = 19%] and 0.1 h(-1) (RSE = 19%), respectively. Peripherally administered IL-1RA crosses slowly into and out of the CSF of patients with SAH. However, there is a large concentration gradient of IL-1RA between plasma and CSF. These CSF:plasma data are consistent with very low permeation of IL-1RA into the CSF and elimination kinetics from it controlled by the volumetric turnover of CSF.

Prediction of Clinical Outcomes by Chemokine and Cytokine Profiling In CSF from Radiation Treated Breast Cancer Primary with Brain Metastases

NASA Astrophysics Data System (ADS)

Lok, Edwin

Whole brain radiation is the standard treatment for patients with brain metastasis but unfortunately tumors can recover from radiation-induced damage with the help of the immune system. The hypothesis that differences in immunokines in the cerebrospinal fluid (CSF) pre- and post-irradiation could reveal tumor biology and correlate with outcome of patients with metastatic breast cancer to the brain is tested. Collected CSF samples were analyzed using Luminex's multiplexing assays to survey global immunokine levels while Enzyme-Linked Immunosorbent Assays were used to quantify each individual immunokines. Cluster analysis was performed to segregate patients based on their common immunokine profile and each cluster was correlated with survival and other clinical parameters. Breast cancer brain metastasis was found to have altered immunokine profiles in the CSF, and that Interleukin-1α expression was elevated after irradiation. Therefore, immunokine profiling in the CSF could enable cancer physicians to monitor the status of brain metastases.

Intranasal Delivery of Granulocyte Colony-Stimulating Factor Enhances Its Neuroprotective Effects Against Ischemic Brain Injury in Rats.

PubMed

Sun, Bao-Liang; He, Mei-Qing; Han, Xiang-Yu; Sun, Jing-Yi; Yang, Ming-Feng; Yuan, Hui; Fan, Cun-Dong; Zhang, Shuai; Mao, Lei-Lei; Li, Da-Wei; Zhang, Zong-Yong; Zheng, Cheng-Bi; Yang, Xiao-Yi; Li, Yang V; Stetler, R Anne; Chen, Jun; Zhang, Feng

2016-01-01

Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth factor with strong neuroprotective properties. However, it has limited capacity to cross the blood-brain barrier and thus potentially limiting its protective capacity. Recent studies demonstrated that intranasal drug administration is a promising way in delivering neuroprotective agents to the central nervous system. The current study therefore aimed at determining whether intranasal administration of G-CSF increases its delivery to the brain and its neuroprotective effect against ischemic brain injury. Transient focal cerebral ischemia in rat was induced with middle cerebral artery occlusion. Our resulted showed that intranasal administration is 8-12 times more effective than subcutaneous injection in delivering G-CSF to cerebrospinal fluid and brain parenchyma. Intranasal delivery enhanced the protective effects of G-CSF against ischemic injury in rats, indicated by decreased infarct volume and increased recovery of neurological function. The neuroprotective mechanisms of G-CSF involved enhanced upregulation of HO-1 and reduced calcium overload following ischemia. Intranasal G-CSF application also promoted angiogenesis and neurogenesis following brain ischemia. Taken together, G-CSF is a legitimate neuroprotective agent and intranasal administration of G-CSF is more effective in delivery and neuroprotection and could be a practical approach in clinic.

Elevated immunoglobulin levels in the cerebrospinal fluid from lupus-prone mice

PubMed Central

Sidor, Michelle M.; Sakic, Boris; Malinowski, Paul M.; Ballok, David A.; Oleschuk, Curtis J.; Macri, Joseph

2006-01-01

The systemic autoimmune disease lupus erythematosus (SLE) is frequently accompanied by neuropsychiatric manifestations and brain lesions of unknown etiology. The MRL-lpr mice show behavioral dysfunction concurrent with progression of a lupus-like disease, thus providing a valuable model in understanding the pathogenesis of autoimmunity-induced CNS damage. Profound neurodegeneration in the limbic system of MRL-lpr mice is associated with cytotoxicity of their cerebrospinal fluid (CSF) to mature and immature neurons. We have recently shown that IgG-rich CSF fraction largely accounts for this effect. The present study examines IgG levels in serum and CSF, as well as the permeability of the blood–brain barrier in mice that differ in immune status, age, and brain morphology. In comparison to young MRL-lpr mice and age-matched congenic controls, a significant elevation of IgG and albumin levels were detected in the CSF of aged autoimmune MRL-lpr mice. Two-dimensional gel electrophoresis and MALDI-TOF MS confirmed elevation in IgG heavy and Ig light chain isoforms in the CSF. Increased permeability of the blood–brain barrier correlated with neurodegeneration (as revealed by Fluoro Jade B staining) in periventricular areas. Although the source and specificity of neuropathogenic antibodies remain to be determined, these results support the hypothesis that a breached blood–brain barrier and IgG molecules are involved in the etiology of CNS damage during SLE-like disease. PMID:15972238

Increased cerebrospinal fluid albumin and immunoglobulin A fractions forecast cortical atrophy and longitudinal functional deterioration in relapsing-remitting multiple sclerosis.

PubMed

Kroth, Julia; Ciolac, Dumitru; Fleischer, Vinzenz; Koirala, Nabin; Krämer, Julia; Muthuraman, Muthuraman; Luessi, Felix; Bittner, Stefan; Gonzalez-Escamilla, Gabriel; Zipp, Frauke; Meuth, Sven G; Groppa, Sergiu

2017-12-01

Currently, no unequivocal predictors of disease evolution exist in patients with multiple sclerosis (MS). Cortical atrophy measurements are, however, closely associated with cumulative disability. Here, we aim to forecast longitudinal magnetic resonance imaging (MRI)-driven cortical atrophy and clinical disability from cerebrospinal fluid (CSF) markers. We analyzed CSF fractions of albumin and immunoglobulins (Ig) A, G, and M and their CSF to serum quotients. Widespread atrophy was highly associated with increased baseline CSF concentrations and quotients of albumin and IgA. Patients with increased CSF IgA and CSF IgM showed higher functional disability at follow-up. CSF markers of blood-brain barrier integrity and specific immune response forecast emerging gray matter pathology and disease progression in MS.

Quantification and regulation of the adipokines resistin and progranulin in human cerebrospinal fluid.

PubMed

Berghoff, Martin; Hochberg, Alexandra; Schmid, Andreas; Schlegel, Jutta; Karrasch, Thomas; Kaps, Manfred; Schäffler, Andreas

2016-01-01

Adipokines bearing the potential to cross the blood-brain barrier (BBB) are promising candidates for the endocrine regulation of central nervous processes and of a postulated fat-brain axis. Resistin and progranulin concentrations in paired serum and cerebrospinal fluid (CSF) samples of patients undergoing neurological evaluation and spinal puncture were investigated. Samples of n = 270 consecutive patients with various neurological diseases were collected without prior selection. Adipokine serum and CSF concentrations were measured by enzyme-linked immunosorbent assay and serum and CSF routine parameters by standard procedures. Anthropometric data, medication and patient history were available. Serum levels of resistin and progranulin were positively correlated among each other, with respective CSF levels, low-density lipoprotein cholesterol levels and markers of systemic inflammation. CSF resistin concentrations were generally low. Progranulin CSF concentrations and CSF/serum progranulin ratio were significantly higher in patients with infectious diseases, with disturbed BBB function and with elevated CSF cell count and presence of oligoclonal bands. Both adipokines are able to cross the BBB depending on a differing patency that increases with increasing grade of barrier dysfunction. Whereas resistin represents a systemic marker of inflammation, CSF progranulin levels strongly depend on the underlying disease and dysfunction of blood-CSF barrier. Resistin and progranulin represent novel and putative regulators of the fat-brain axis by their ability to cross the BBB under physiological and pathophysiological conditions. The presented data provide insight into the characteristics of BBB function regarding progranulin and resistin and the basis for future establishment of normal values for CSF concentrations and CSF/serum ratios. © 2015 Stichting European Society for Clinical Investigation Journal Foundation.

Quantitative estimation of a ratio of intracranial cerebrospinal fluid volume to brain volume based on segmentation of CT images in patients with extra-axial hematoma.

PubMed

Nguyen, Ha Son; Patel, Mohit; Li, Luyuan; Kurpad, Shekar; Mueller, Wade

2017-02-01

Background Diminishing volume of intracranial cerebrospinal fluid (CSF) in patients with space-occupying masses have been attributed to unfavorable outcome associated with reduction of cerebral perfusion pressure and subsequent brain ischemia. Objective The objective of this article is to employ a ratio of CSF volume to brain volume for longitudinal assessment of space-volume relationships in patients with extra-axial hematoma and to determine variability of the ratio among patients with different types and stages of hematoma. Patients and methods In our retrospective study, we reviewed 113 patients with surgical extra-axial hematomas. We included 28 patients (age 61.7 +/- 17.7 years; 19 males, nine females) with an acute epidural hematoma (EDH) ( n = 5) and subacute/chronic subdural hematoma (SDH) ( n = 23). We excluded 85 patients, in order, due to acute SDH ( n = 76), concurrent intraparenchymal pathology ( n = 6), and bilateral pathology ( n = 3). Noncontrast CT images of the head were obtained using a CT scanner (2004 GE LightSpeed VCT CT system, tube voltage 140 kVp, tube current 310 mA, 5 mm section thickness) preoperatively, postoperatively (3.8 ± 5.8 hours from surgery), and at follow-up clinic visit (48.2 ± 27.7 days after surgery). Each CT scan was loaded into an OsiriX (Pixmeo, Switzerland) workstation to segment pixels based on radiodensity properties measured in Hounsfield units (HU). Based on HU values from -30 to 100, brain, CSF spaces, vascular structures, hematoma, and/or postsurgical fluid were segregated from bony structures, and subsequently hematoma and/or postsurgical fluid were manually selected and removed from the images. The remaining images represented overall brain volume-containing only CSF spaces, vascular structures, and brain parenchyma. Thereafter, the ratio between the total number of voxels representing CSF volume (based on values between 0 and 15 HU) to the total number of voxels representing overall brain volume was calculated. Results CSF/brain volume ratio varied significantly during the course of the disease, being the lowest preoperatively, 0.051 ± 0.032; higher after surgical evacuation of hematoma, 0.067 ± 0.040; and highest at follow-up visit, 0.083 ± 0.040 ( p < 0.01). Using a repeated regression analysis, we found a significant association ( p < 0.01) of the ratio with age (odds ratio, 1.019; 95% CI, 1.009-1.029) and type of hematoma (odds ratio, 0.405; 95% CI, 0.303-0.540). Conclusion CSF/brain volume ratio calculated from CT images has potential to reflect dynamics of intracranial volume changes in patients with space-occupying mass.

Clearing Extracellular Alpha-Synuclein from Cerebrospinal Fluid: A New Therapeutic Strategy in Parkinson’s Disease

PubMed Central

Padilla-Zambrano, Huber S.; Tomás-Zapico, Cristina; García, Benjamin Fernández

2018-01-01

This concept article aims to show the rationale of targeting extracellular α-Synuclein (α-Syn) from cerebrospinal fluid (CSF) as a new strategy to remove this protein from the brain in Parkinson’s disease (PD). Misfolding and intracellular aggregation of α-synuclein into Lewy bodies are thought to be crucial in the pathogenesis of PD. Recent research has shown that small amounts of monomeric and oligomeric α-synuclein are released from neuronal cells by exocytosis and that this extracellular alpha-synuclein contributes to neurodegeneration, progressive spreading of alpha-synuclein pathology, and neuroinflammation. In PD, extracellular oligomeric-α-synuclein moves in constant equilibrium between the interstitial fluid (ISF) and the CSF. Thus, we expect that continuous depletion of oligomeric-α-synuclein in the CSF will produce a steady clearance of the protein in the ISF, preventing transmission and deposition in the brain. PMID:29570693

Clearing Extracellular Alpha-Synuclein from Cerebrospinal Fluid: A New Therapeutic Strategy in Parkinson's Disease.

PubMed

Menéndez-González, Manuel; Padilla-Zambrano, Huber S; Tomás-Zapico, Cristina; García, Benjamin Fernández

2018-03-23

This concept article aims to show the rationale of targeting extracellular α-Synuclein (α-Syn) from cerebrospinal fluid (CSF) as a new strategy to remove this protein from the brain in Parkinson's disease (PD). Misfolding and intracellular aggregation of α-synuclein into Lewy bodies are thought to be crucial in the pathogenesis of PD. Recent research has shown that small amounts of monomeric and oligomeric α-synuclein are released from neuronal cells by exocytosis and that this extracellular alpha-synuclein contributes to neurodegeneration, progressive spreading of alpha-synuclein pathology, and neuroinflammation. In PD, extracellular oligomeric-α-synuclein moves in constant equilibrium between the interstitial fluid (ISF) and the CSF. Thus, we expect that continuous depletion of oligomeric-α-synuclein in the CSF will produce a steady clearance of the protein in the ISF, preventing transmission and deposition in the brain.

Genotyping tumour DNA in cerebrospinal fluid and plasma of a HER2-positive breast cancer patient with brain metastases

PubMed Central

Siravegna, Giulia; Geuna, Elena; Mussolin, Benedetta; Crisafulli, Giovanni; Bartolini, Alice; Galizia, Danilo; Casorzo, Laura; Sarotto, Ivana; Scaltriti, Maurizio; Sapino, Anna; Bardelli, Alberto; Montemurro, Filippo

2017-01-01

Background Central nervous system (CNS) involvement contributes to significant morbidity and mortality in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) and represents a major challenge for clinicians. Liquid biopsy of cerebrospinal fluid (CSF)-derived circulating tumour DNA (ctDNA) harbours clinically relevant genomic alterations in patients with CNS metastases and could be effective in tracking tumour evolution. Methods In a HER2-positive mBC patient with brain metastases, we applied droplet digital PCR (ddPCR) and next-generation whole exome sequencing (WES) analysis to measure ctDNA dynamic changes in CSF and plasma collected during treatment. Results Baseline CSF-derived ctDNA analysis revealed TP53 and PIK3CA mutations as well as ERBB2 and cMYC amplification. Post-treatment ctDNA analysis showed decreased markers level in plasma, consistent with extra-CNS disease control, while increased in the CSF, confirming poor treatment benefit in the CNS. Discussion Analysis of ctDNA in the CSF of HER2-positive mBC is feasible and could represent a useful companion for clinical management of brain metastases. PMID:29067216

Cerebrospinal Fluid B Cells Correlate with Early Brain Inflammation in Multiple Sclerosis

PubMed Central

Kuenz, Bettina; Lutterotti, Andreas; Ehling, Rainer; Gneiss, Claudia; Haemmerle, Monika; Rainer, Carolyn; Deisenhammer, Florian; Schocke, Michael; Berger, Thomas; Reindl, Markus

2008-01-01

Background There is accumulating evidence from immunological, pathological and therapeutic studies that B cells are key components in the pathophysiology of multiple sclerosis (MS). Methodology/Principal Findings In this prospective study we have for the first time investigated the differences in the inflammatory response between relapsing and progressive MS by comparing cerebrospinal fluid (CSF) cell profiles from patients at the onset of the disease (clinically isolated syndrome, CIS), relapsing-remitting (RR) and chronic progressive (CP) MS by flow cytometry. As controls we have used patients with other neurological diseases. We have found a statistically significant accumulation of CSF mature B cells (CD19+CD138−) and plasma blasts (CD19+CD138+) in CIS and RRMS. Both B cell populations were, however, not significantly increased in CPMS. Further, this accumulation of B cells correlated with acute brain inflammation measured by magnetic resonance imaging and with inflammatory CSF parameters such as the number of CSF leukocytes, intrathecal immunoglobulin M and G synthesis and intrathecal production of matrix metalloproteinase (MMP)-9 and the B cell chemokine CxCL-13. Conclusions Our data support an important role of CSF B cells in acute brain inflammation in CIS and RRMS. PMID:18596942

Modification in CSF specific gravity in acutely decompensated cirrhosis and acute on chronic liver failure independent of encephalopathy, evidences for an early blood-CSF barrier dysfunction in cirrhosis.

PubMed

Weiss, Nicolas; Rosselli, Matteo; Mouri, Sarah; Galanaud, Damien; Puybasset, Louis; Agarwal, Banwari; Thabut, Dominique; Jalan, Rajiv

2017-04-01

Although hepatic encephalopathy (HE) on the background of acute on chronic liver failure (ACLF) is associated with high mortality rates, it is unknown whether this is due to increased blood-brain barrier permeability. Specific gravity of cerebrospinal fluid measured by CT is able to estimate blood-cerebrospinal fluid-barrier permeability. This study aimed to assess cerebrospinal fluid specific gravity in acutely decompensated cirrhosis and to compare it in patients with or without ACLF and with or without hepatic encephalopathy. We identified all the patients admitted for acute decompensation of cirrhosis who underwent a brain CT-scan. Those patients could present acute decompensation with or without ACLF. The presence of hepatic encephalopathy was noted. They were compared to a group of stable cirrhotic patients and healthy controls. Quantitative brain CT analysis used the Brainview software that gives the weight, the volume and the specific gravity of each determined brain regions. Results are given as median and interquartile ranges and as relative variation compared to the control/baseline group. 36 patients presented an acute decompensation of cirrhosis. Among them, 25 presented with ACLF and 11 without ACLF; 20 presented with hepatic encephalopathy grade ≥ 2. They were compared to 31 stable cirrhosis patients and 61 healthy controls. Cirrhotic patients had increased cerebrospinal fluid specific gravity (CSF-SG) compared to healthy controls (+0.4 %, p < 0.0001). Cirrhotic patients with ACLF have decreased CSF-SG as compared to cirrhotic patients without ACLF (-0.2 %, p = 0.0030) that remained higher than in healthy controls. The presence of hepatic encephalopathy did not modify CSF-SG (-0.09 %, p = 0.1757). Specific gravity did not differ between different brain regions according to the presence or absence of either ACLF or HE. In patients with acute decompensation of cirrhosis, and those with ACLF, CSF specific gravity is modified compared to both stable cirrhotic patients and healthy controls. This pattern is observed even in the absence of hepatic encephalopathy suggesting that blood-CSF barrier impairment is manifest even in absence of overt hepatic encephalopathy.

Evaluation of endothelin-1 and MMPs-2, -9, -14 in cerebrospinal fluid as indirect indicators of blood-brain barrier dysfunction in chronic canine hypothyroidism.

PubMed

Pancotto, Theresa E; Rossmeisl, John H; Huckle, William R; Inzana, Karen D; Zimmerman, Kurt L

2016-04-01

Chronic canine hypothyroidism is associated with blood-brain barrier (BBB) disruption. We hypothesized that this change is mediated by endothelin-1(ET-1) and matrix metalloproteinases (MMP) -2, -9, and -14, as evidenced by increased concentrations of these proteins in cerebrospinal fluid (CSF) compared to controls. CSF from 18 dogs, 9 controls and 9 with experimentally induced hypothyroidism was collected before and 6, 12, and 18 months after induction of hypothyroidism. Concentrations of ET-1 using an ELISA kit, and for MMP-2, -9, and -14 using gelatinase zymography were measured in CSF. ET-1 was undetectable in CSF of control and hypothyroid dogs at all time-points. Constitutively expressed MMP-2 was detectable in CSF samples in all dogs at all time-points. No other MMPs were detectable in CSF. No differences in CSF concentrations of ET-1 and MMP-2, 9, and 14 were found between hypothyroid and euthyroid dogs. Therefore, ET-1 and MMP-2, 9, and 14 are unlikely to be primary mediators of BBB damage in chronically hypothyroid dogs. Copyright © 2016 Elsevier Ltd. All rights reserved.

Biomarkers in Cerebrospinal Fluid: Analysis of Cell-Free Circulating Mitochondrial DNA by Digital PCR.

PubMed

Podlesniy, Petar; Trullas, Ramon

2018-01-01

Cerebrospinal fluid (CSF) contains molecules directly linked with brain function because it permeates brain tissue. The analysis of protein biomarkers in CSF is currently recommended for the diagnosis of neurodegenerative disorders, but the clinical sensitivity and specificity are still being investigated. A major drawback is that most of the currently used biomarkers of neurodegenerative diseases are proteins that are found at very low concentrations in CSF and need to be measured by immunoassays that provide relative values, which sometimes are difficult to reproduce between laboratories. In contrast, the recent availability of digital PCR platforms allows the absolute quantification of nucleic acids at single-molecule resolution, but their presence in CSF has not been characterized. CSF contains cell-free mitochondrial DNA (mtDNA) and changes in the concentration of this nucleic acid are linked to neurodegeneration. Here we describe a method to measure the concentration of cell-free circulating mtDNA directly in unpurified CSF using droplet digital PCR with either hydrolysis probes or fluorescent DNA-binding dye methods. This protocol allows the detection and absolute quantification of mtDNA content in the CSF with high analytical sensitivity, specificity, and accuracy.

Pharmacokinetic modelling of interleukin-1 receptor antagonist in plasma and cerebrospinal fluid of patients following subarachnoid haemorrhage

PubMed Central

Gueorguieva, Ivelina; Clark, Simon R; McMahon, Catherine J; Scarth, Sylvia; Rothwell, Nancy J; Tyrell, Pippa J; Hopkins, Stephen J; Rowland, Malcolm

2008-01-01

Aim The naturally occurring interlukin-1 receptor antagonist (IL-1RA) markedly protects rodents against ischaemic, excitotoxic and traumatic brain injury, suggesting it may be of therapeutic value. The aim was to determine the pharmacokinetics of IL-1RA in cerebrospinal fluid (CSF) of patients, to allow modelling that would aid development of therapeutic regimens. Methods When administered intravenously to patients soon after stroke, IL-1RA is safe and reduces the peripheral inflammatory response. However, IL-1RA is a large protein (17 kDa), which may limit brain penetration, thereby limiting its potential utility in brain injury. In seven patients with subarchnoid haemorrhage (SAH), IL-1RA was administered by intravenous bolus, then infusion for 24 h, and both blood and CSF, via external ventricular drains, were sampled during and after stopping the infusion. Results Plasma steady-state concentrations were rapidly attained and maintained throughout the infusion, whereas CSF concentrations rose slowly towards a plateau during the 24-h infusion, reaching at best only 4% of that in plasma. Plasma kinetic parameters were within the literature range. Modelling of the combined data yielded rate constants entering and leaving the CSF of 0.0019 h−1[relative standard error (RSE) = 19%] and 0.1 h−1 (RSE = 19%), respectively. Conclusions Peripherally administered IL-1RA crosses slowly into and out of the CSF of patients with SAH. However, there is a large concentration gradient of IL-1RA between plasma and CSF. These CSF:plasma data are consistent with very low permeation of IL-1RA into the CSF and elimination kinetics from it controlled by the volumetric turnover of CSF. What is already known about this subject? The naturally occurring interlukin-1 receptor antagonist (IL-1RA) markedly protects rodents against ischaemic, excitotoxic and traumatic brain injury, suggesting it may be of therapeutic value.When administered intravenously to patients soon after stroke, IL-1RA is safe and reduces the peripheral inflammatory response.However, IL-1RA is a large protein (17 kDa), which may limit brain penetration, thereby limiting its potential utility in brain injury. What this study adds The purpose of these experiments was to determine the pharmacokinetics of IL-1RA in cerebrospinal fluid (CSF) of patients, to allow modelling that would aid development of therapeutic regimens.Peripherally administered IL-1RA crosses slowly into and out of the CSF of patients with subarachnoid haemorrhage and, at steady state, CSF IL-1RA concentration (range 115–886 ng ml−1) was similar to that found to be neuroprotective in rats (range 91–232 ng ml−1), although there was considerable variability among patients.However, there is a large concentration gradient of IL-1RA between plasma and CSF.These CSF:plasma data are consistent with very low permeation of IL-1RA into the CSF and elimination kinetics from it controlled by the volumetric turnover of CSF. PMID:17875190

Outer brain barriers in rat and human development

PubMed Central

Brøchner, Christian B.; Holst, Camilla B.; Møllgård, Kjeld

2015-01-01

Complex barriers at the brain's surface, particularly in development, are poorly defined. In the adult, arachnoid blood-cerebrospinal fluid (CSF) barrier separates the fenestrated dural vessels from the CSF by means of a cell layer joined by tight junctions. Outer CSF-brain barrier provides diffusion restriction between brain and subarachnoid CSF through an initial radial glial end feet layer covered with a pial surface layer. To further characterize these interfaces we examined embryonic rat brains from E10 to P0 and forebrains from human embryos and fetuses (6–21st weeks post-conception) and adults using immunohistochemistry and confocal microscopy. Antibodies against claudin-11, BLBP, collagen 1, SSEA-4, MAP2, YKL-40, and its receptor IL-13Rα2 and EAAT1 were used to describe morphological characteristics and functional aspects of the outer brain barriers. Claudin-11 was a reliable marker of the arachnoid blood-CSF barrier. Collagen 1 delineated the subarachnoid space and stained pial surface layer. BLBP defined radial glial end feet layer and SSEA-4 and YKL-40 were present in both leptomeningeal cells and end feet layer, which transformed into glial limitans. IL-13Rα2 and EAAT1 were present in the end feet layer illustrating transporter/receptor presence in the outer CSF-brain barrier. MAP2 immunostaining in adult brain outlined the lower border of glia limitans; remnants of end feet were YKL-40 positive in some areas. We propose that outer brain barriers are composed of at least 3 interfaces: blood-CSF barrier across arachnoid barrier cell layer, blood-CSF barrier across pial microvessels, and outer CSF-brain barrier comprising glial end feet layer/pial surface layer. PMID:25852456

Outer brain barriers in rat and human development.

PubMed

Brøchner, Christian B; Holst, Camilla B; Møllgård, Kjeld

2015-01-01

Complex barriers at the brain's surface, particularly in development, are poorly defined. In the adult, arachnoid blood-cerebrospinal fluid (CSF) barrier separates the fenestrated dural vessels from the CSF by means of a cell layer joined by tight junctions. Outer CSF-brain barrier provides diffusion restriction between brain and subarachnoid CSF through an initial radial glial end feet layer covered with a pial surface layer. To further characterize these interfaces we examined embryonic rat brains from E10 to P0 and forebrains from human embryos and fetuses (6-21st weeks post-conception) and adults using immunohistochemistry and confocal microscopy. Antibodies against claudin-11, BLBP, collagen 1, SSEA-4, MAP2, YKL-40, and its receptor IL-13Rα2 and EAAT1 were used to describe morphological characteristics and functional aspects of the outer brain barriers. Claudin-11 was a reliable marker of the arachnoid blood-CSF barrier. Collagen 1 delineated the subarachnoid space and stained pial surface layer. BLBP defined radial glial end feet layer and SSEA-4 and YKL-40 were present in both leptomeningeal cells and end feet layer, which transformed into glial limitans. IL-13Rα2 and EAAT1 were present in the end feet layer illustrating transporter/receptor presence in the outer CSF-brain barrier. MAP2 immunostaining in adult brain outlined the lower border of glia limitans; remnants of end feet were YKL-40 positive in some areas. We propose that outer brain barriers are composed of at least 3 interfaces: blood-CSF barrier across arachnoid barrier cell layer, blood-CSF barrier across pial microvessels, and outer CSF-brain barrier comprising glial end feet layer/pial surface layer.

Vascular basement membranes as pathways for the passage of fluid into and out of the brain.

PubMed

Morris, Alan W J; Sharp, Matthew MacGregor; Albargothy, Nazira J; Fernandes, Rute; Hawkes, Cheryl A; Verma, Ajay; Weller, Roy O; Carare, Roxana O

2016-05-01

In the absence of conventional lymphatics, drainage of interstitial fluid and solutes from the brain parenchyma to cervical lymph nodes is along basement membranes in the walls of cerebral capillaries and tunica media of arteries. Perivascular pathways are also involved in the entry of CSF into the brain by the convective influx/glymphatic system. The objective of this study is to differentiate the cerebral vascular basement membrane pathways by which fluid passes out of the brain from the pathway by which CSF enters the brain. Experiment 1: 0.5 µl of soluble biotinylated or fluorescent Aβ, or 1 µl 15 nm gold nanoparticles was injected into the mouse hippocampus and their distributions determined at 5 min by transmission electron microscopy. Aβ was distributed within the extracellular spaces of the hippocampus and within basement membranes of capillaries and tunica media of arteries. Nanoparticles did not enter capillary basement membranes from the extracellular spaces. Experiment 2: 2 µl of 15 nm nanoparticles were injected into mouse CSF. Within 5 min, groups of nanoparticles were present in the pial-glial basement membrane on the outer aspect of cortical arteries between the investing layer of pia mater and the glia limitans. The results of this study and previous research suggest that cerebral vascular basement membranes form the pathways by which fluid passes into and out of the brain but that different basement membrane layers are involved. The significance of these findings for neuroimmunology, Alzheimer's disease, drug delivery to the brain and the concept of the Virchow-Robin space are discussed.

Investigating the Relationship between Cerebrospinal Fluid and Magnetic Induction Phase Shift in Rabbit Intracerebral hematoma expansion Monitoring by MRI.

PubMed

Chen, Mingsheng; Yan, Qingguang; Sun, Jian; Jin, Gui; Qin, Mingxin

2017-09-11

In a prior study of intracerebral hemorrhage monitoring using magnetic induction phase shift (MIPS), we found that MIPS signal changes occurred prior to those seen with intracranial pressure. However, the characteristic MIPS alert is not yet fully explained. Combining the brain physiology and MIPS theory, we propose that cerebrospinal fluid (CSF) may be the primary factor that leads to hematoma expansion being alerted by MIPS earlier than with intracranial pressure monitoring. This paper investigates the relationship between CSF and MIPS in monitoring of rabbit intracerebral hemorrhage models, which is based on the MIPS measurements data, the quantified data on CSF from medical images and the amount of injected blood in the rabbit intracerebral hemorrhage model. In the investigated results, a R value of 0.792 with a significance of 0.019 is observed between the MIPS and CSF, which is closer than MIPS and injected blood. Before the reversal point of MIPS, CSF is the leading factor in MIPS signal changing in an early hematoma expansion stage. Under CSF compensation, CSF reduction compensates for hematoma expansion in the brain to keep intracranial pressure stable. MIPS decrease results from the reducing CSF volume. This enables MIPS to detect hematoma expansion earlier than intracranial pressure.

The two-pore domain K+ channel TASK-1 is closely associated with brain barriers and meninges.

PubMed

Kanjhan, Refik; Pow, David V; Noakes, Peter G; Bellingham, Mark C

2010-12-01

Impairment of the blood-brain barrier (BBB), the blood-cerebrospinal fluid (CSF) barrier and brain-CSF barrier has been implicated in neuropathology of several brain disorders, such as amyotrophic lateral sclerosis, cerebral edema, multiple sclerosis, neural inflammation, ischemia and stroke. Two-pore domain weakly inward rectifying K+ channel (TWIK)-related acid-sensitive potassium (TASK)-1 channels (K2p3.1; KCNK3) are among the targets that contribute to the development of these pathologies. For example TASK-1 activity is inhibited by acidification, ischemia, hypoxia and several signaling molecules released under pathologic conditions. We have used immuno-histochemistry to examine the distribution of the TASK-1 protein in structures associated with the BBB, blood-CSF barrier, brain-CSF barrier, and in the meninges of adult rat. Dense TASK-1 immuno-reactivity (TASK-1-IR) was observed in ependymal cells lining the fourth ventricle at the brain-CSF interface, in glial cells that ensheath the walls of blood vessels at the glio-vascular interface, and in the meninges. In these structures, TASK-1-IR often co-localized with glial fibrillary associated protein (GFAP) or vimentin. This study provides anatomical evidence for localization of TASK-1 K+ channels in cells that segregate distinct fluid compartments within and surrounding the brain. We suggest that TASK-1 channels, in coordination with other ion channels (e.g., aquaporins and chloride channels) and transporters (e.g., Na+-K+-ATPase and Na+-K+-2Cl⁻ and by virtue of its heterogeneous distribution, may differentially contribute to the varying levels of K+ vital for cellular function in these compartments. Our findings are likely to be relevant to recently reported roles of TASK-1 in cerebral ischemia, stroke and inflammatory brain disorders.

Cerebrospinal fluid lactate and pyruvate concentrations and their ratio.

PubMed

Zhang, Wan-Ming; Natowicz, Marvin R

2013-05-01

Determinations of cerebrospinal fluid (CSF) lactate and pyruvate concentrations and CSF lactate:pyruvate (L/P) ratios are important in several clinical settings, yet published normative data have significant limitations. We sought to determine a large dataset of stringently-defined normative data for CSF lactate and pyruvate concentrations and CSF L/P ratios. We evaluated data from 627 patients who had determinations of CSF lactate and/or CSF pyruvate from 2001 to 2011 at the Cleveland Clinic. Inclusion in the normal reference population required normal CSF cell counts, glucose and protein and routine serum chemistries and absence of progressive brain disorder, epilepsy, or seizure within 24h. Brain MRI, if done, showed no evidence of tumor, acute changes or basal ganglia abnormality. CSF cytology, CSF alanine and immunoglobulin levels, and oligoclonal band analysis were required to be normal, if done. Various inclusion/exclusion criteria were compared. 92 patients fulfilled inclusion/exclusion criteria for a reference population. The 95% central intervals (2.5%-97.5%) for CSF lactate and pyruvate levels were 1.01-2.09mM and 0.03-0.15mM, respectively, and 9.05-26.37 for CSF L/P. There were no significant gender-related differences of CSF lactate or pyruvate concentrations or of CSF L/P. Weak positive correlations between the concentration of CSF lactate or pyruvate and age were noted. Using stringent inclusion/exclusion criteria, we determined normative data for CSF lactate and pyruvate concentrations and CSF L/P ratios in a large, well-characterized reference population. Normalcy of routine CSF and blood analytes are the most important parameters in determining reference intervals for CSF lactate and pyruvate. Copyright © 2012 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Effect of inhaled nitric oxide on cerebrospinal fluid and blood nitrite concentrations in newborn lambs

PubMed Central

Conahey, George R.; Power, Gordon G.; Hopper, Andrew O.; Terry, Michael H.; Kirby, Laura S.; Blood, Arlin B.

2009-01-01

Inhaled nitric oxide (iNO) has many extrapulmonary effects. As the half-life of NO in blood is orders of magnitude less than the circulation time from lungs to the brain, the mediator of systemic effects of iNO is unknown. We hypothesized that concentrations of nitrite, a circulating byproduct of NO with demonstrated NO bioactivity, would increase in blood and cerebrospinal fluid (CSF) during iNO therapy. iNO (80ppm) was given to six newborn lambs and results compared to six control lambs. Blood and CSF nitrite concentrations increased two-fold in response to iNO. cGMP increased in blood but not CSF suggesting brain guanylate cyclase activity was not increased. When sodium nitrite was infused intravenously blood and CSF nitrite levels increased within 10 min and reached similar levels of 14.6±1.5 µM after 40 min. The reactivity of nitrite in hemoglobin-free brain homogenates was investigated, with the findings that nitrite did not disappear nor did measurable amounts of s-nitroso, n-nitroso, or iron-nitrosyl-species appear. We conclude that although nitrite diffuses freely between blood and CSF, due to its lack of reactivity in the brain, nitrite’s putative role as the mediator of the systemic effects of iNO is limited to intravascular reactions. PMID:18535482

Abnormal cerebrospinal fluid protein indices in schizophrenia.

PubMed

Kirch, D G; Kaufmann, C A; Papadopoulos, N M; Martin, B; Weinberger, D R

1985-10-01

Determinations of albumin and immunoglobulin G (IgG) were performed in paired cerebrospinal fluid (CSF) and serum samples from 24 subjects with schizophrenia. These determinations allowed calculation of two indices, one that is an indicator of integrity of the blood-brain barrier and the other a measure of selective IgG production within the central nervous system (CNS). In comparison with previously determined reference values, 7 of 24 (29%) subjects showed increased blood-brain barrier permeability, and 8 of 24 (33%) demonstrated elevated endogenous CNS IgG production. One of these eight also demonstrated oligoclonal banding on high-resolution protein electrophoresis of the CSF.

Tumor DNA in cerebral spinal fluid reflects clinical course in a patient with melanoma leptomeningeal brain metastases

PubMed Central

Li, Yingmei; Pan, Wenying; Connolly, Ian D.; Reddy, Sunil; Nagpal, Seema

2017-01-01

Cerebral spinal fluid (CSF) from brain tumor patients contains tumor cellular and cell-free DNA (cfDNA), which provides a less-invasive and routinely accessible method to obtain tumor genomic information. In this report, we used droplet digital PCR to test mutant tumor DNA in CSF of a patient to monitor the treatment response of metastatic melanoma leptomeningeal disease (LMD). The primary melanoma was known to have a BRAFV600E mutation, and the patient was treated with whole brain radiotherapy and BRAF inhibitors. We collected 9 CSF samples over 6 months. The mutant cfDNA fraction gradually decreased from 53 % (time of diagnosis) to 0 (time of symptom alleviation) over the first 6 time points. Three months after clinical improvement, the patient returned with severe symptoms and the mutant cfDNA was again detected in CSF at high levels. The mutant DNA fraction corresponded well with the patient’s clinical response. We used whole exome sequencing to examine the mutation profiles of the LMD tumor DNA in CSF before therapeutic response and after disease relapse, and discovered a canonical cancer mutation PTENR130* at both time points. The cellular and cfDNA revealed similar mutation profiles, suggesting cfDNA is representative of LMD cells. This study demonstrates the potential of using cellular or cfDNA in CSF to monitor treatment response for LMD. PMID:26961773

Cerebrospinal fluid concentrations of vemurafenib in patients treated for brain metastatic BRAF-V600 mutated melanoma.

PubMed

Sakji-Dupré, Lilia; Le Rhun, Emilie; Templier, Carole; Desmedt, Eve; Blanchet, Benoit; Mortier, Laurent

2015-08-01

Anti-BRAF agents, including vemurafenib, have modified the prognosis for patients with melanoma. However, a difference can still be observed between extracerebral and cerebral responses. The aim of this study was to investigate the diffusion of vemurafenib in cerebrospinal fluid (CSF) from patients treated for brain metastatic BRAF-V600 mutated melanoma. Six patients treated with vemurafenib 960 mg twice daily were included. These patients had undergone a lumbar puncture because of suspicions of leptomeningeal metastasis, along with simultaneous blood sampling to measure vemurafenib level. The concentrations of vemurafenib in the CSF and the plasma were measured by high-performance liquid chromatography. The mean plasma and CSF concentrations of vemurafenib were 53.4±26.2 and 0.47±0.37 mg/l, respectively. The mean ratio of the CSF : plasma concentration was 0.98±0.84%. No relationship was found between plasma and CSF concentrations (P=0.8). In conclusion, our preliminary results highlight for the first time a low CSF vemurafenib penetration rate associated with a large interindividual variability in patients treated for metastatic BRAF-V600 mutated melanoma and brain metastases. Further investigations with larger cohorts are required to study the relationship between CSF vemurafenib concentrations and cerebral response. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Characterization of individual mouse cerebrospinal fluid proteomes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Smith, Jeffrey S.; Angel, Thomas E.; Chavkin, Charles

2014-03-20

Analysis of cerebrospinal fluid (CSF) offers key insight into the status of the central nervous system. Characterization of murine CSF proteomes can provide a valuable resource for studying central nervous system injury and disease in animal models. However, the small volume of CSF in mice has thus far limited individual mouse proteome characterization. Through non-terminal CSF extractions in C57Bl/6 mice and high-resolution liquid chromatography-mass spectrometry analysis of individual murine samples, we report the most comprehensive proteome characterization of individual murine CSF to date. Utilizing stringent protein inclusion criteria that required the identification of at least two unique peptides (1% falsemore » discovery rate at the peptide level) we identified a total of 566 unique proteins, including 128 proteins from three individual CSF samples that have been previously identified in brain tissue. Our methods and analysis provide a mechanism for individual murine CSF proteome analysis.« less

Characterizing the glymphatic influx by utilizing intracisternal infusion of fluorescently conjugated cadaverine.

PubMed

Zhang, Cui; Lin, Jun; Wei, Fang; Song, Jian; Chen, Wenyue; Shan, Lidong; Xue, Rong; Wang, Guoqing; Tao, Jin; Zhang, Guoxing; Xu, Guang-Yin; Wang, Linhui

2018-05-15

Accumulating evidence supports that cerebrospinal fluid (CSF) in the subarachnoid space (SAS) could reenter the brain parenchyma via the glymphatic influx. The present study was designed to characterize the detailed pathway of subarachnoid CSF influx by using a novel CSF tracer. Fluorescently conjugated cadaverine (A488-ca), for the first time, was employed to investigate CSF movement in the brain. Following intracisternal infusion of CSF tracers, mice brain was sliced and prepared for fluorescence imaging. Some brain sections were immunostained in order to observe tracer distribution and cellular uptake. A488-ca moved into the brain parenchyma rapidly, and the influx was time and region dependent. A488-ca entered the mice brain more readily and spread more widely than another commonly used CSF tracer-fluorescently conjugated ovalbumin (OA-45). Furthermore, A488-ca could enter the brain parenchyma either along the paravascular space or across the pial surface. Suppression of glymphatic transport by administration with acetazolamide strikingly reduced the influx of A488-ca. More importantly, relative to OA-45 largely remained in the extracellular space, A488-ca exhibited obvious cellular uptake by astrocytes surrounding the blood vessels and neurons in the cerebral cortex. Subarachnoid CSF could flow into the brain parenchyma via the glymphatic influx, in which the transcellular pathway was faithfully traced by intracisternal infusion with fluorescently conjugated cadaverine. These observations extend our comprehension on the glymphatic influx pathway. Copyright © 2018 Elsevier Inc. All rights reserved.

Death Is Associated with Complement C3 Depletion in Cerebrospinal Fluid of Patients with Pneumococcal Meningitis

PubMed Central

Goonetilleke, U. R.; Scarborough, M.; Ward, S. A.; Hussain, S.; Kadioglu, A.; Gordon, S. B.

2012-01-01

ABSTRACT Pneumococcal meningitis can lead to death or serious neurological sequelae as a result of the host inflammatory response. We investigated the association between host response protein expression and outcome in patients with pneumococcal meningitis. Cerebrospinal fluid (CSF) was obtained from 80 patients with pneumococcal meningitis (40 nonsurvivors and 40 survivors) and 10 normal controls. Candidate proteins were analyzed for an association with survival. Complement C3 levels were 5-fold lower in nonsurvivors than in survivors (P < 0.05). This C3 reduction was not associated with lower levels in serum, indicating a compartmentalized CSF response. Transferrin levels were significantly higher in CSF (but not serum) from nonsurvivors than in CSF from survivors, suggestive of blood-brain barrier damage. Classical apoptosis proteins caspase 3 and apoptosis-inducing factor were not present in CSF. Expression of creatine kinase BB in clinically infected CSF suggested neuronal necrosis, but there was no clear association between level of expression and clinical outcome. Increased blood-brain barrier permeability and complement C3 depletion may have a role in determining outcome from bacterial meningitis. Therapeutic use of citicoline or caspase inhibitors is unlikely to have beneficial effects in patients with meningitis. PMID:22415003

Understanding Fluid Shifts in the Brain: Choroidal Regulation Involved in the Cerebral Fluid Response to Altered Gravity

NASA Technical Reports Server (NTRS)

Gabrion, Jaqueline; Vasques, Marilyn; Aquilina, Rudy (Technical Monitor)

2002-01-01

Fluid balance and regulation of body fluid production are critical aspects of life and survival on Earth. In space, without gravity exerting its usual downward pulling effect, the fluids of the human body shift in an unnatural, headward direction. After awhile, humans and other mammalian species adapt to the microgravity environment which leads to changes in the regulation and distribution of these body fluids. Previous spaceflight experiments have indicated that production of fluid in the brain and spinal cord, cerebrospinal fluid (CSF), might be reduced in rats exposed to microgravity. In this experiment conducted by Dr. Jacqueline Gabrion (University of Pierre and Marie Curie, France), proteins important for CSF production, and several molecules that regulate water and mineral transport, will be investigated in rats flown on the Shuttle. Dr. Gabrion and her team will determine the amounts of these proteins and molecules present in the brain in order to evaluate whether any changes have taken place during the rats' adaptation to microgravity. The levels of different aquaporins (proteins that act as a channel for water transport in and out of cells) will also be investigated in other areas of the brain and body to better understand the regulatory responses affecting these important water channel proteins. In addition to producing essential and basic information about fluid production in the brain and body, this experiment will reveal fundamental information about the mechanisms involved in cerebral adaptation and fluid balance during spaceflight.

Cerebrospinal Fluid Cortisol and Progesterone Profiles and Outcomes Prognostication after Severe Traumatic Brain Injury

PubMed Central

Santarsieri, Martina; Niyonkuru, Christian; McCullough, Emily H.; Dobos, Julie A.; Dixon, C. Edward; Berga, Sarah L.

2014-01-01

Abstract Despite significant advances in the management of head trauma, there remains a lack of pharmacological treatment options for traumatic brain injury (TBI). While progesterone clinical trials have shown promise, corticosteroid trials have failed. The purpose of this study was to (1) characterize endogenous cerebrospinal fluid (CSF) progesterone and cortisol levels after TBI, (2) determine relationships between CSF and serum profiles, and (3) assess the utility of these hormones as predictors of long-term outcomes. We evaluated 130 adults with severe TBI. Serum samples (n=538) and CSF samples (n=746) were collected for 6 days post-injury, analyzed for cortisol and progesterone, and compared with healthy controls (n=13). Hormone data were linked with clinical data, including Glasgow Outcome Scale (GOS) scores at 6 and 12 months. Group based trajectory (TRAJ) analysis was used to develop temporal hormone profiles delineating distinct subpopulations. Compared with controls, CSF cortisol levels were significantly and persistently elevated during the first week after TBI, and high CSF cortisol levels were associated with poor outcome. As a precursor to cortisol, progesterone mediated these effects. Serum and CSF levels for both cortisol and progesterone were strongly correlated after TBI relative to controls, possibly because of blood–brain barrier disruption. Also, differentially impaired hormone transport and metabolism mechanisms after TBI, potential de novo synthesis of steroids within the brain, and the complex interplay of cortisol and pro-inflammatory cytokines may explain these acute hormone profiles and, when taken together, may help shed light on why corticosteroid trials have previously failed and why progesterone treatment after TBI may be beneficial. PMID:24354775

Impairment of paravascular clearance pathways in the aging brain.

PubMed

Kress, Benjamin T; Iliff, Jeffrey J; Xia, Maosheng; Wang, Minghuan; Wei, Helen S; Zeppenfeld, Douglas; Xie, Lulu; Kang, Hongyi; Xu, Qiwu; Liew, Jason A; Plog, Benjamin A; Ding, Fengfei; Deane, Rashid; Nedergaard, Maiken

2014-12-01

In the brain, protein waste removal is partly performed by paravascular pathways that facilitate convective exchange of water and soluble contents between cerebrospinal fluid (CSF) and interstitial fluid (ISF). Several lines of evidence suggest that bulk flow drainage via the glymphatic system is driven by cerebrovascular pulsation, and is dependent on astroglial water channels that line paravascular CSF pathways. The objective of this study was to evaluate whether the efficiency of CSF-ISF exchange and interstitial solute clearance is impaired in the aging brain. CSF-ISF exchange was evaluated by in vivo and ex vivo fluorescence microscopy and interstitial solute clearance was evaluated by radiotracer clearance assays in young (2-3 months), middle-aged (10-12 months), and old (18-20 months) wild-type mice. The relationship between age-related changes in the expression of the astrocytic water channel aquaporin-4 (AQP4) and changes in glymphatic pathway function was evaluated by immunofluorescence. Advancing age was associated with a dramatic decline in the efficiency of exchange between the subarachnoid CSF and the brain parenchyma. Relative to the young, clearance of intraparenchymally injected amyloid-β was impaired by 40% in the old mice. A 27% reduction in the vessel wall pulsatility of intracortical arterioles and widespread loss of perivascular AQP4 polarization along the penetrating arteries accompanied the decline in CSF-ISF exchange. We propose that impaired glymphatic clearance contributes to cognitive decline among the elderly and may represent a novel therapeutic target for the treatment of neurodegenerative diseases associated with accumulation of misfolded protein aggregates. © 2014 American Neurological Association.

Cerebrospinal Fluid Biomarker and Brain Biopsy Findings in Idiopathic Normal Pressure Hydrocephalus

PubMed Central

Pyykkö, Okko T.; Lumela, Miikka; Rummukainen, Jaana; Nerg, Ossi; Seppälä, Toni T.; Herukka, Sanna-Kaisa; Koivisto, Anne M.; Alafuzoff, Irina; Puli, Lakshman; Savolainen, Sakari; Soininen, Hilkka; Jääskeläinen, Juha E.; Hiltunen, Mikko; Zetterberg, Henrik; Leinonen, Ville

2014-01-01

Background The significance of amyloid precursor protein (APP) and neuroinflammation in idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer's disease (AD) is unknown. Objective To investigate the role of soluble APP (sAPP) and amyloid beta (Aβ) isoforms, proinflammatory cytokines, and biomarkers of neuronal damage in the cerebrospinal fluid (CSF) in relation to brain biopsy Aβ and hyperphosphorylated tau (HPτ) findings. Methods The study population comprised 102 patients with possible NPH with cortical brain biopsies, ventricular and lumbar CSF samples, and DNA available. The final clinical diagnoses were: 53 iNPH (91% shunt-responders), 26 AD (10 mixed iNPH+AD), and 23 others. Biopsy samples were immunostained against Aβ and HPτ. CSF levels of AD-related biomarkers (Aβ42, p-tau, total tau), non-AD-related Aβ isoforms (Aβ38, Aβ40), sAPP isoforms (sAPPα, sAPPβ), proinflammatory cytokines (several interleukins (IL), interferon-gamma, monocyte chemoattractant protein-1, tumor necrosis factor-alpha) and biomarkers of neuronal damage (neurofilament light and myelin basic protein) were measured. All patients were genotyped for APOE. Results Lumbar CSF levels of sAPPα were lower (p<0.05) in patients with shunt-responsive iNPH compared to non-iNPH patients. sAPPβ showed a similar trend (p = 0.06). CSF sAPP isoform levels showed no association to Aβ or HPτ in the brain biopsy. Quantified Aβ load in the brain biopsy showed a negative correlation with CSF levels of Aβ42 in ventricular (r = −0.295, p = 0.003) and lumbar (r = −0.356, p = 0.01) samples, while the levels of Aβ38 and Aβ40 showed no correlation. CSF levels of proinflammatory cytokines and biomarkers of neuronal damage did not associate to the brain biopsy findings, diagnosis, or shunt response. Higher lumbar/ventricular CSF IL-8 ratios (p<0.001) were seen in lumbar samples collected after ventriculostomy compared to the samples collected before the procedure. Conclusions The role of sAPP isoforms in iNPH seems to be independent from the amyloid cascade. No neuroinflammatory background was observed in iNPH or AD. PMID:24638077

Cerebrospinal Fluid Biomarkers for Huntington's Disease.

PubMed

Byrne, Lauren M; Wild, Edward J

2016-01-01

Cerebrospinal fluid (CSF) is enriched in brain-derived components and represents an accessible and appealing means of interrogating the CNS milieu to study neurodegenerative diseases and identify biomarkers to facilitate the development of novel therapeutics. Many such CSF biomarkers have been proposed for Huntington's disease (HD) but none has been validated for clinical trial use. Across many studies proposing dozens of biomarker candidates, there is a notable lack of statistical power, consistency, rigor and validation. Here we review proposed CSF biomarkers including neurotransmitters, transglutaminase activity, kynurenine pathway metabolites, oxidative stress markers, inflammatory markers, neuroendocrine markers, protein markers of neuronal death, proteomic approaches and mutant huntingtin protein itself. We reflect on the need for large-scale, standardized CSF collections with detailed phenotypic data to validate and qualify much-needed CSF biomarkers for clinical trial use in HD.

Prolyl oligopeptidase and dipeptidyl peptidase II/dipeptidyl peptidase IV ratio in the cerebrospinal fluid in Parkinson's disease: historical overview and future prospects.

PubMed

Nagatsu, Toshiharu

2017-06-01

Prolyl oligopeptidase (also named prolyl endopeptidase; PREP) hydrolyzes the Pro-Xaa bonds of biologically active oligopeptides on their carboxyl side. In 1987, we detected PREP activity in human cerebrospinal fluid (CSF) using highly sensitive liquid chromatography-fluorometry with succinyl-Gly-Pro-4-methyl-coumarin amide as a new synthetic substrate, and found a marked decrease in its activity in the cerebrospinal fluid (CSF) from patients with Parkinson's disease (PD) as compared with its level in control patients without neurological diseases. In 2013, Hannula et al. found co-localization of PREP with α-synuclein in the postmortem PD brain. Several recent studies also suggest that the level of PREP in the brain of PD patients may be related to dopamine (DA) cell death via promotion of α-synuclein oligomerization and that inhibitors of PREP may play a neuroprotective role in PD. Although the relationship between another family of prolyl oligopeptidase enzymes, dipeptidyl peptidase II (DPP II) and dipeptidyl peptidase IV (DPP IV), and α-synuclein in the PD brain is not yet clear, we found that the DPP II activity/DPP IV activity ratio in the CSF was significantly increased in PD patients. This review discusses the possibility of PREP as well as the DPP II/DPP IV ratio in the CSF as potential biomarkers of PD.

Association between cerebrospinal fluid and plasma neurodegeneration biomarkers with brain atrophy in Alzheimer's disease.

PubMed

Pereira, Joana B; Westman, Eric; Hansson, Oskar

2017-10-01

The aggregation and deposition of amyloid-β (Aβ) peptides into plaques is an early event in Alzheimer's disease (AD), which is followed by different aspects of neurodegeneration that can be measured in the cerebrospinal fluid (CSF) or plasma using neurofilament light (NFL), neurogranin (Ng), total Tau (T-Tau), and phosphorylated tau (P-Tau) levels. The relationship between these biomarkers and regional brain atrophy across the different stages of AD remains largely unexplored. In this study, we assessed whether NFL, Ng, T-Tau, and P-Tau levels in CSF and NFL in plasma are associated with cortical thinning and subcortical volume loss in cognitively normal, mild cognitive impairment, and AD subjects with and without Aβ pathology. Our main findings showed that CSF NFL levels were associated with brain atrophy in all groups, but plasma NFL only correlated with atrophy in symptomatic cases. In contrast, Ng was associated with regional brain atrophy only in individuals with Aβ pathology. Altogether, our main findings suggest that Ng is strongly associated with Aβ pathology, whereas NFL is more unspecific. Copyright © 2017 Elsevier Inc. All rights reserved.

Identification of the Upward Movement of Human CSF In Vivo and its Relation to the Brain Venous System.

PubMed

Dreha-Kulaczewski, Steffi; Joseph, Arun A; Merboldt, Klaus-Dietmar; Ludwig, Hans-Christoph; Gärtner, Jutta; Frahm, Jens

2017-03-01

CSF flux is involved in the pathophysiology of neurodegenerative diseases and cognitive impairment after traumatic brain injury, all hallmarked by the accumulation of cellular metabolic waste. Its effective disposal via various CSF routes has been demonstrated in animal models. In contrast, the CSF dynamics in humans are still poorly understood. Using novel real-time MRI, forced inspiration has been identified recently as a main driving force of CSF flow in the human brain. Exploiting technical advances toward real-time phase-contrast MRI, the current work analyzed directions, velocities, and volumes of human CSF flow within the brain aqueduct as part of the internal ventricular system and in the spinal canal during respiratory cycles. A consistent upward CSF movement toward the brain in response to forced inspiration was seen in all subjects at the aqueduct, in 11/12 subjects at thoracic level 2, and in 4/12 subjects at thoracic level 5. Concomitant analyses of CSF dynamics and cerebral venous blood flow, that is, in epidural veins at cervical level 3, uniquely demonstrated CSF and venous flow to be closely communicating cerebral fluid systems in which inspiration-induced downward flow of venous blood due to reduced intrathoracic pressure is counterbalanced by an upward movement of CSF. The results extend our understanding of human CSF flux and open important clinical implications, including concepts for drug delivery and new classifications and therapeutic options for various forms of hydrocephalus and idiopathic intracranial hypertension. SIGNIFICANCE STATEMENT Effective disposal of brain cellular waste products via CSF has been demonstrated repeatedly in animal models. However, CSF dynamics in humans are still poorly understood. A novel quantitative real-time MRI technique yielded in vivo CSF flow directions, velocities, and volumes in the human brain and upper spinal canal. CSF moved upward toward the head in response to forced inspiration. Concomitant analysis of brain venous blood flow indicated that CSF and venous flux act as closely communicating systems. The finding of a human CSF-venous network with upward CSF net movement opens new clinical concepts for drug delivery and new classifications and therapeutic options for various forms of hydrocephalus and ideopathic intracranial hypertension. Copyright © 2017 the authors 0270-6474/17/372395-08$15.00/0.

Increased CSF aquaporin-4, and interleukin-6 levels in dogs with idiopathic communicating internal hydrocephalus and a decrease after ventriculo-peritoneal shunting.

PubMed

Schmidt, Martin J; Rummel, Christoph; Hauer, Jessica; Kolecka, Malgorzata; Ondreka, Nele; McClure, Vanessa; Roth, Joachim

2016-06-29

Studies in animal models, in which internal hydrocephalus has been induced by obstructing the cerebrospinal fluid pathways, have documented an up-regulation of the concentrations of aquaporin-4 (AQP4) in the brain. In this study, the concentrations of aquaporin-1 (AQP1), AQP1, AQP4 and interleukin-6 (IL-6) were determined in the CSF of dogs with idiopathic communicating hydrocephalus before and after the reduction of intraventricular volume following ventriculo-peritoneal shunt (VP-shunt) treatment. The concentrations of AQP4 and IL-6 were increased in the cerebrospinal fluid of dogs with hydrocephalus compared to controls. Both parameters significantly decreased after surgical treatment, accompanied by decrease of ventricular size and the clinical recovery of the dogs. AQP1 was not detectable in CSF. Brain AQP4 up-regulation might be a compensatory response in dogs with hydrocephalus. Future determination of AQP4 at the mRNA and protein level in brain tissue is warranted to substantiate this hypothesis.

Numerical simulation of cerebrospinal fluid hydrodynamics in the healing process of hydrocephalus patients

NASA Astrophysics Data System (ADS)

Gholampour, S.; Fatouraee, N.; Seddighi, A. S.; Seddighi, A.

2017-05-01

Three-dimensional computational models of the cerebrospinal fluid (CSF) flow and brain tissue are presented for evaluation of their hydrodynamic conditions before and after shunting for seven patients with non-communicating hydrocephalus. One healthy subject is also modeled to compare deviated patients data to normal conditions. The fluid-solid interaction simulation shows the CSF mean pressure and pressure amplitude (the superior index for evaluation of non-communicating hydrocephalus) in patients at a greater point than those in the healthy subject by 5.3 and 2 times, respectively.

Optimal-mass-transfer-based estimation of glymphatic transport in living brain

NASA Astrophysics Data System (ADS)

Ratner, Vadim; Zhu, Liangjia; Kolesov, Ivan; Nedergaard, Maiken; Benveniste, Helene; Tannenbaum, Allen

2015-03-01

It was recently shown that the brain-wide cerebrospinal fluid (CSF) and interstitial fluid exchange system designated the `glymphatic pathway' plays a key role in removing waste products from the brain, similarly to the lymphatic system in other body organs . It is therefore important to study the flow patterns of glymphatic transport through the live brain in order to better understand its functionality in normal and pathological states. Unlike blood, the CSF does not flow rapidly through a network of dedicated vessels, but rather through para-vascular channels and brain parenchyma in a slower time-domain, and thus conventional fMRI or other blood-flow sensitive MRI sequences do not provide much useful information about the desired flow patterns. We have accordingly analyzed a series of MRI images, taken at different times, of the brain of a live rat, which was injected with a paramagnetic tracer into the CSF via the lumbar intrathecal space of the spine. Our goal is twofold: (a) find glymphatic (tracer) flow directions in the live rodent brain; and (b) provide a model of a (healthy) brain that will allow the prediction of tracer concentrations given initial conditions. We model the liquid flow through the brain by the diffusion equation. We then use the Optimal Mass Transfer (OMT) approach to derive the glymphatic flow vector field, and estimate the diffusion tensors by analyzing the (changes in the) flow. Simulations show that the resulting model successfully reproduces the dominant features of the experimental data. Keywords: inverse problem, optimal mass transport, diffusion equation, cerebrospinal fluid flow in brain, optical flow, liquid flow modeling, Monge Kantorovich problem, diffusion tensor estimation

Brain Gene Expression Signatures From Cerebrospinal Fluid Exosome RNA Profiling

NASA Technical Reports Server (NTRS)

Zanello, S. B.; Stevens, B.; Calvillo, E.; Tang, R.; Gutierrez Flores, B.; Hu, L.; Skog, J.; Bershad, E.

2016-01-01

While the Visual Impairment and Intracranial Pressure (VIIP) syndrome observations have focused on ocular symptoms, spaceflight has been also associated with a number of other performance and neurologic signs, such as headaches, cognitive changes, vertigo, nausea, sleep/circadian disruption and mood alterations, which, albeit likely multifactorial, can also result from elevation of intracranial pressure (ICP). We therefore hypothesize that these various symptoms are caused by disturbances in the neurophysiology of the brain structures and are correlated with molecular markers in the cerebrospinal fluid (CSF) as indicators of neurophysiological changes. Exosomes are 30-200 nm microvesicles shed into all biofluids, including blood, urine, and CSF, carrying a highly rich source of intact protein and RNA cargo. Exosomes have been identified in human CSF, and their proteome and RNA pool is a potential new reservoir for biomarker discovery in neurological disorders. The purpose of this study is to investigate changes in brain gene expression via exosome analysis in patients suffering from ICP elevation of varied severity (idiopathic intracranial hypertension -IIH), a condition which shares some of the neuroophthalmological features of VIIP, as a first step toward obtaining evidence suggesting that cognitive function and ICP levels can be correlated with biomarkers in the CSF. Our preliminary work, reported last year, validated the exosomal technology applicable to CSF analysis and demonstrated that it was possible to obtain gene expression evidence of inflammation processes in traumatic brain injury patients. We are now recruiting patients with suspected IIH requiring lumbar puncture at Baylor College of Medicine. Both CSF (5 ml) and human plasma (10 ml) are being collected in order to compare the pattern of differentially expressed genes observed in CSF and in blood. Since blood is much more accessible than CSF, we would like to determine whether plasma biomarkers for elevated ICP can be identified. This may eventually lead to a blood test to diagnose intracranial hypertension.

The isoform A of reticulon-4 (Nogo-A) in cerebrospinal fluid of primary brain tumor patients: influencing factors.

PubMed

Koper, Olga Martyna; Kamińska, Joanna; Milewska, Anna; Sawicki, Karol; Mariak, Zenon; Kemona, Halina; Matowicka-Karna, Joanna

2018-05-18

The influence of isoform A of reticulon-4 (Nogo-A), also known as neurite outgrowth inhibitor, on primary brain tumor development was reported. Therefore the aim was the evaluation of Nogo-A concentrations in cerebrospinal fluid (CSF) and serum of brain tumor patients compared with non-tumoral individuals. All serum results, except for two cases, obtained both in brain tumors and non-tumoral individuals, were below the lower limit of ELISA detection. Cerebrospinal fluid Nogo-A concentrations were significantly lower in primary brain tumor patients compared to non-tumoral individuals. The univariate linear regression analysis found that if white blood cell count increases by 1 × 10 3 /μL, the mean cerebrospinal fluid Nogo-A concentration value decreases 1.12 times. In the model of multiple linear regression analysis predictor variables influencing cerebrospinal fluid Nogo-A concentrations included: diagnosis, sex, and sodium level. The mean cerebrospinal fluid Nogo-A concentration value was 1.9 times higher for women in comparison to men. In the astrocytic brain tumor group higher sodium level occurs with lower cerebrospinal fluid Nogo-A concentrations. We found the opposite situation in non-tumoral individuals. Univariate linear regression analysis revealed, that cerebrospinal fluid Nogo-A concentrations change in relation to white blood cell count. In the created model of multiple linear regression analysis we found, that within predictor variables influencing CSF Nogo-A concentrations were diagnosis, sex, and sodium level. Results may be relevant to the search for cerebrospinal fluid biomarkers and potential therapeutic targets in primary brain tumor patients. Nogo-A concentrations were tested by means of enzyme-linked immunosorbent assay (ELISA).

Bernoulli's Principle Applied to Brain Fluids: Intracranial Pressure Does Not Drive Cerebral Perfusion or CSF Flow.

PubMed

Schmidt, Eric; Ros, Maxime; Moyse, Emmanuel; Lorthois, Sylvie; Swider, Pascal

2016-01-01

In line with the first law of thermodynamics, Bernoulli's principle states that the total energy in a fluid is the same at all points. We applied Bernoulli's principle to understand the relationship between intracranial pressure (ICP) and intracranial fluids. We analyzed simple fluid physics along a tube to describe the interplay between pressure and velocity. Bernoulli's equation demonstrates that a fluid does not flow along a gradient of pressure or velocity; a fluid flows along a gradient of energy from a high-energy region to a low-energy region. A fluid can even flow against a pressure gradient or a velocity gradient. Pressure and velocity represent part of the total energy. Cerebral blood perfusion is not driven by pressure but by energy: the blood flows from high-energy to lower-energy regions. Hydrocephalus is related to increased cerebrospinal fluid (CSF) resistance (i.e., energy transfer) at various points. Identification of the energy transfer within the CSF circuit is important in understanding and treating CSF-related disorders. Bernoulli's principle is not an abstract concept far from clinical practice. We should be aware that pressure is easy to measure, but it does not induce resumption of fluid flow. Even at the bedside, energy is the key to understanding ICP and fluid dynamics.

Comparison of HIV-1 pol and env sequences of blood, CSF, brain and spleen isolates collected ante-mortem and post-mortem.

PubMed

Caragounis, E-C; Gisslén, M; Lindh, M; Nordborg, C; Westergren, S; Hagberg, L; Svennerholm, B

2008-02-01

HIV-1 infects the central nervous system (CNS) early in the course of infection. However, it is not known to what extent the virus evolves independently within the CNS and whether the HIV-RNA in cerebrospinal fluid (CSF) reflects the viral population replicating within the brain parenchyma or the systemic infection. The aim of this study was to investigate HIV-1 evolution in the CNS and the origin of HIV-1 in CSF. Longitudinally derived paired blood and CSF samples and post-mortem samples from CSF, brain and spleen were collected over a period of up to 63 months from three HIV-1 infected men receiving antiretroviral treatment and presenting with symptoms of AIDS dementia complex (ADC). Phylogenetic analyses of HIV-1 V3, reverse transcriptase (RT) and protease sequences from patient isolates suggest compartmentalization with distinct viral strains in blood, CSF and brain. We found a different pattern of RT and accessory protease mutations in the systemic infection compared to the CNS. We conclude that HIV-1 may to some extent evolve independently in the CNS and the viral population in CSF mainly reflects the infection in the brain parenchyma in patients with ADC. This is of importance in understanding HIV pathogenesis and can have implications on treatment of HIV-1 patients.

Toward a multifactorial model of Alzheimer disease

PubMed Central

Storandt, Martha; Head, Denise; Fagan, Anne M.; Holtzman, David M.; Morris, John C.

2011-01-01

Relations among antecedant biomarkers of AD were evaluated using causal modeling; although correlation cannot be equated to causation, causation does require correlation. Individuals aged 43 to 89 years (N = 220) enrolled as cognitively normal controls in longitudinal studies had clinical and psychometric assessment, structural magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) biomarkers, and brain amyloid imaging via positron emission tomography with Pittsburgh Compound B (PIB) obtained within 1 year. CSF levels of Aβ42 and tau were minimally correlated, indicating they represent independent processes. Aβ42, tau, and their interaction explained 60% of the variance in PIB. Effects of APOE genotype and age on PIB were indirect, operating through CSF markers. Only spurious relations via their common relation with age were found between the biomarkers and regional brain volumes or cognition. Hence, at least two independent hypothesized processes, one reflected by CSF Aβ42 and one by CSF tau, contribute to the development of fibrillar amyloid plaques preclinically. The lack of correlation between these two processes and brain volume in the regions most often affected in AD suggests the operation of a third process related to brain atrophy. PMID:22261556

Major depressive disorder: insight into candidate cerebrospinal fluid protein biomarkers from proteomics studies.

PubMed

Al Shweiki, Mhd Rami; Oeckl, Patrick; Steinacker, Petra; Hengerer, Bastian; Schönfeldt-Lecuona, Carlos; Otto, Markus

2017-06-01

Major Depressive Disorder (MDD) is the leading cause of global disability, and an increasing body of literature suggests different cerebrospinal fluid (CSF) proteins as biomarkers of MDD. The aim of this review is to summarize the suggested CSF biomarkers and to analyze the MDD proteomics studies of CSF and brain tissues for promising biomarker candidates. Areas covered: The review includes the human studies found by a PubMed search using the following terms: 'depression cerebrospinal fluid biomarker', 'major depression biomarker CSF', 'depression CSF biomarker', 'proteomics depression', 'proteomics biomarkers in depression', 'proteomics CSF biomarker in depression', and 'major depressive disorder CSF'. The literature analysis highlights promising biomarker candidates and demonstrates conflicting results on others. It reveals 42 differentially regulated proteins in MDD that were identified in more than one proteomics study. It discusses the diagnostic potential of the biomarker candidates and their association with the suggested pathologies. Expert commentary: One ultimate goal of finding biomarkers for MDD is to improve the diagnostic accuracy to achieve better treatment outcomes; due to the heterogeneous nature of MDD, using bio-signatures could be a good strategy to differentiate MDD from other neuropsychiatric disorders. Notably, further validation studies of the suggested biomarkers are still needed.

Determination of Serotonin and Dopamine Metabolites in Human Brain Microdialysis and Cerebrospinal Fluid Samples by UPLC-MS/MS: Discovery of Intact Glucuronide and Sulfate Conjugates

PubMed Central

Suominen, Tina; Uutela, Päivi; Ketola, Raimo A.; Bergquist, Jonas; Hillered, Lars; Finel, Moshe; Zhang, Hongbo; Laakso, Aki; Kostiainen, Risto

2013-01-01

An UPLC-MS/MS method was developed for the determination of serotonin (5-HT), dopamine (DA), their phase I metabolites 5-HIAA, DOPAC and HVA, and their sulfate and glucuronide conjugates in human brain microdialysis samples obtained from two patients with acute brain injuries, ventricular cerebrospinal fluid (CSF) samples obtained from four patients with obstructive hydrocephalus, and a lumbar CSF sample pooled mainly from patients undergoing spinal anesthesia in preparation for orthopedic surgery. The method was validated by determining the limits of detection and quantification, linearity, repeatability and specificity. The direct method enabled the analysis of the intact phase II metabolites of 5-HT and DA, without hydrolysis of the conjugates. The method also enabled the analysis of the regioisomers of the conjugates, and several intact glucuronide and sulfate conjugates were identified and quantified for the first time in the human brain microdialysis and CSF samples. We were able to show the presence of 5-HIAA sulfate, and that dopamine-3-O-sulfate predominates over dopamine-4-O-sulfate in the human brain. The quantitative results suggest that sulfonation is a more important phase II metabolism pathway than glucuronidation in the human brain. PMID:23826355

Characterization of the rat cerebrospinal fluid proteome following acute cerebral ischemia using an aptamer-based proteomic technology.

PubMed

Simats, Alba; García-Berrocoso, Teresa; Ramiro, Laura; Giralt, Dolors; Gill, Natalia; Penalba, Anna; Bustamante, Alejandro; Rosell, Anna; Montaner, Joan

2018-05-21

The limited accessibility to the brain has turned the cerebrospinal fluid (CSF) into a valuable source that may contribute to the complete understanding of the stroke pathophysiology. Here we have described the CSF proteome in the hyper-acute phase of cerebral ischemia by performing an aptamer-based proteomic assay (SOMAscan) in CSF samples collected before and 30 min after male Wistar rats had undergone a 90 min Middle Cerebral Artery Occlusion (MCAO) or sham-surgery. Proteomic results indicated that cerebral ischemia acutely increased the CSF levels of 716 proteins, mostly overrepresented in leukocyte chemotaxis and neuronal death processes. Seven promising candidates were further evaluated in rat plasma and brain (CKB, CaMK2A, CaMK2B, CaMK2D, PDXP, AREG, CMPK). The 3 CaMK2 family-members and CMPK early decreased in the infarcted brain area and, together with AREG, co-localized with neurons. Conversely, CKB levels remained consistent after the insult and specifically matched with astrocytes. Further exploration of these candidates in human plasma revealed the potential of CKB and CMPK to diagnose stroke, while CaMK2B and CMPK resulted feasible biomarkers of functional stroke outcome. Our findings provided insights into the CSF proteome following cerebral ischemia and identified new outstanding proteins that might be further considered as potential biomarkers of stroke.

Multiple sclerosis patients lacking oligoclonal bands in the cerebrospinal fluid have less global and regional brain atrophy.

PubMed

Ferreira, Daniel; Voevodskaya, Olga; Imrell, Kerstin; Stawiarz, Leszek; Spulber, Gabriela; Wahlund, Lars-Olof; Hillert, Jan; Westman, Eric; Karrenbauer, Virginija Danylaité

2014-09-15

To investigate whether multiple sclerosis (MS) patients with and without cerebrospinal fluid (CSF) oligoclonal immunoglobulin G bands (OCB) differ in brain atrophy. Twenty-eight OCB-negative and thirty-five OCB-positive patients were included. Larger volumes of total CSF and white matter (WM) lesions; smaller gray matter (GM) volume in the basal ganglia, diencephalon, cerebellum, and hippocampus; and smaller WM volume in corpus callosum, periventricular-deep WM, brainstem, and cerebellum, were observed in OCB-positives. OCB-negative patients, known to differ genetically from OCB-positives, are characterized by less global and regional brain atrophy. This finding supports the notion that OCB-negative MS patients may represent a clinically relevant MS subgroup. Copyright © 2014 Elsevier B.V. All rights reserved.

The mediational effects of FDG hypometabolism on the association between cerebrospinal fluid biomarkers and neurocognitive function.

PubMed

Dowling, N Maritza; Johnson, Sterling C; Gleason, Carey E; Jagust, William J

2015-01-15

Positive cerebrospinal fluid (CSF) biomarkers of tau and amyloid beta42 suggest possible active underlying Alzheimer's disease (AD) including neurometabolic dysfunction and neurodegeneration leading to eventual cognitive decline. But the temporal relationship between CSF, imaging markers of neural function, and cognition has not been described. Using a statistical mediation model, we examined relationships between cerebrospinal fluid (CSF) analytes (hyperphosphorylated tau (p-Tau(181p)), β-amyloid peptides 1-42 (Aβ(1-42)), total tau (t-Tau), and their ratios); change in cognitive function; and change in [18F]fluorodeoxyglucose (FDG) uptake using positron emission tomography (PET). We hypothesized that a) abnormal CSF protein values at baseline, result in cognitive declines by decreasing neuronal glucose metabolism across time, and b) the role of altered glucose metabolism in the assumed causal chain varies by brain region and the nature of CSF protein alteration. Data from 412 individuals participating in Alzheimer's Disease Neuroimaging (ADNI) cohort studies were included in analyses. At baseline, individuals were cognitively normal (N = 82), or impaired: 241 with mild cognitive impairment, and 89 with Alzheimer's disease. A parallel-process latent growth curve model was used to test mediational effects of changes in regional FDG-PET uptake over time in relation to baseline CSF biomarkers and changes in cognition, measured with the 13-item Alzheimer Disease's Assessment Scale-cognitive subscale (ADAS-Cog). Findings suggested a causal sequence of events; specifically, FDG hypometabolism acted as a mediator between antecedent CSF biomarker alterations and subsequent cognitive impairment. Higher baseline concentrations of t-Tau, and p-Tau(181p) were more predictive of decline in cerebral glucose metabolism than lower baseline concentrations of Aβ(1-42). FDG-PET changes appeared to mediate t-Tau or t-Tau/Aβ(1-42)-associated cognitive change across all brain regions examined. Significant direct effects of alterations in Aβ(1-42) levels on hypometabolism were observed in a single brain region: middle/inferior temporal gyrus. Results support a temporal framework model in which reduced CSF amyloid-related biomarkers occur earlier in the pathogenic pathway, ultimately leading to detrimental cognitive effects. Also consistent with this temporal framework model, baseline markers of neurofibrillary degeneration predicted changes in brain glucose metabolism in turn causing longitudinal cognitive changes, suggesting that tau-related burden precedes neurometabolic dysfunction. While intriguing, the hypothesized mediational relationships require further validation. Published by Elsevier Inc.

[Effects of pulsed magnetic field on insulin-like growth factor-1 (IGF-1) in cerebrospinal fluid and effects of IGF-1 on functional recovery].

PubMed

Song, Cheng-xian; Fan, Jian-zhong; Wu, Hong-ying; Wei, Yi; Zhen, Jian-rong

2010-10-01

To study the effects of pulsed magnetic field on insulin-like growth factor-1 (IGF-1) level in the cerebrospinal fluid (CSF) and the association of IGF-1 alterations with the activities of daily living (ADL) of patients with brain injury. Sixty-five patients with brain injury were divided randomly into the control group (n=30) and magnetic therapy group (n=35), both receiving conventional therapy and in the latter group, daily pulsed magnetic field treatment (20-40 mT, 50 Hz, 20 min per time, 1 time per day) for 14 consecutive days were administered. On the first and 14th days of the treatment, 2 ml CSF was collected from the cases patients for IGF-1 measurement by radioimmunoassay, and Barthel index (BI) was used to assess the ADL of the patients. After a 14-day treatment, IGF-1 level in the CSF were significantly increased in the magnetic group in comparison with the level before the treatment and with those in the control group (P<0.05). IGF-1 in the CSF underwent no significant changes in the control group (P>0.05). The scores of BI increased significantly in both groups after the treatment (P<0.01), but the increment was more obvious in the magnetic therapy group (P<0.05). A significant positive correlation was found between IGF-1 level in the CSF and BI in these patients (r=0.283, P=0.022). Pulsed magnetic field might increase IGF-1 level in the CSF of patients with brain injury to promote the recovery of the patients ADL, suggesting its potential clinical value in the treatment of brain injury.

Thyroxine transfer from cerebrospinal fluid into choroid plexus and brain is affected by brefeldin A, low sodium, BCH, and phloretin, in ventriculo-cisternal perfused rabbits.

PubMed

Zibara, Kazem; El-Zein, Ali; Joumaa, Wissam; El-Sayyad, Mohammad; Mondello, Stefania; Kassem, Nouhad

2015-01-01

Thyroxine (T4) hormone is synthesized by the thyroid gland and then released into the systemic circulation where it binds to a number of proteins. Dysfunction in T4 transport mechanisms has been demonstrated in multiple central nervous system (CNS) diseases including Alzheimer's disease. In the presence of different compounds that inhibit potential T4 transport mechanisms, this study investigated the transfer of T4 from cerebrospinal fluid (CSF) into Choroid Plexus (CP) and other brain tissues. The compounds used were brefeldin A, low sodium artificial CSF (aCSF), BCH, phloretin, and taurocholate (TA). Radiolabeled T4 ((125)I-T4) was perfused continuously into the CSF and was assessed in several brain compartments with reference molecule (14)C-mannitol and blue dextran, using the in vivo ventriculo-cisternal perfusion (V-C) technique in the rabbit. The aCSF containing the drug of interest was infused after 1 h of perfusion. Drugs were applied independently to the aCSF after 1 h of control perfusion. Of interest, in presence of low sodium or BCH, the percentage recovery of (125)I-T4, was increased compared to controls, with concomitant increase in T4 clearance. Conversely, brefeldin A, phloretin, and TA did not exert any significant effect on the recovery and clearance of (125)I-T4 assessed in aCSF. On the other hand, the uptake of (125)I-T4 into CP was raised by 18 fold compared to controls in the presence of brefeldin A. In addition, low sodium, BCH, or phloretin alone, enhanced the uptake of (125)I-T4 by almost 3-fold, whereas TA did not show any significant effect. Finally, the uptake and distribution of (125)I-T4 into other brain regions including ependymal region (ER) and caudate putamen (CAP) were significantly higher than in controls. Our study suggests the involvement of different mechanisms for the transfer of (125)I-T4 from CSF into CP and other brain regions. This transfer may implicate sodium-dependent mechanisms, amino acid "L" system, or organic anion transporting polypeptide (OATP).

Microdialysis Monitoring of CSF Parameters in Severe Traumatic Brain Injury Patients: A Novel Approach

PubMed Central

Thelin, Eric P.; Nelson, David W.; Ghatan, Per Hamid; Bellander, Bo-Michael

2014-01-01

Background: Neuro-intensive care following traumatic brain injury (TBI) is focused on preventing secondary insults that may lead to irreversible brain damage. Microdialysis (MD) is used to detect deranged cerebral metabolism. The clinical usefulness of the MD is dependent on the regional localization of the MD catheter. The aim of this study was to analyze a new method of continuous cerebrospinal fluid (CSF) monitoring using the MD technique. The method was validated using conventional laboratory analysis of CSF samples. MD-CSF and regional MD-Brain samples were correlated to patient outcome. Materials and Methods: A total of 14 patients suffering from severe TBI were analyzed. They were monitored using (1) a MD catheter (CMA64-iView, n = 7448 MD samples) located in a CSF-pump connected to the ventricular drain and (2) an intraparenchymal MD catheter (CMA70, n = 8358 MD samples). CSF-lactate and CSF-glucose levels were monitored and were compared to MD-CSF samples. MD-CSF and MD-Brain parameters were correlated to favorable (Glasgow Outcome Score extended, GOSe 6–8) and unfavorable (GOSe 1–5) outcome. Results: Levels of glucose and lactate acquired with the CSF-MD technique could be correlated to conventional levels. The median MD recovery using the CMA64 catheter in CSF was 0.98 and 0.97 for glucose and lactate, respectively. Median MD-CSF (CMA 64) lactate (p = 0.0057) and pyruvate (p = 0.0011) levels were significantly lower in the favorable outcome group compared to the unfavorable group. No significant difference in outcome was found using the lactate:pyruvate ratio (LPR), or any of the regional MD-Brain monitoring in our analyzed cohort. Conclusion: This new technique of global MD-CSF monitoring correlates with conventional CSF levels of glucose and lactate, and the MD recovery is higher than previously described. Increase in lactate and pyruvate, without any effect on the LPR, correlates to unfavorable outcome, perhaps related to the presence of erythrocytes in the CSF. PMID:25228896

Regulation of brain copper homeostasis by the brain barrier systems: Effects of Fe-overload and Fe-deficiency

DOE Office of Scientific and Technical Information (OSTI.GOV)

Monnot, Andrew D.; Behl, Mamta; Ho, Sanna

2011-11-15

Maintaining brain Cu homeostasis is vital for normal brain function. The role of systemic Fe deficiency (FeD) or overload (FeO) due to metabolic diseases or environmental insults in Cu homeostasis in the cerebrospinal fluid (CSF) and brain tissues remains unknown. This study was designed to investigate how blood-brain barrier (BBB) and blood-SCF barrier (BCB) regulated Cu transport and how FeO or FeD altered brain Cu homeostasis. Rats received an Fe-enriched or Fe-depleted diet for 4 weeks. FeD and FeO treatment resulted in a significant increase (+ 55%) and decrease (- 56%) in CSF Cu levels (p < 0.05), respectively; however,more » neither treatment had any effect on CSF Fe levels. The FeD, but not FeO, led to significant increases in Cu levels in brain parenchyma and the choroid plexus. In situ brain perfusion studies demonstrated that the rate of Cu transport into the brain parenchyma was significantly faster in FeD rats (+ 92%) and significantly slower (- 53%) in FeO rats than in controls. In vitro two chamber Transwell transepithelial transport studies using primary choroidal epithelial cells revealed a predominant efflux of Cu from the CSF to blood compartment by the BCB. Further ventriculo-cisternal perfusion studies showed that Cu clearance by the choroid plexus in FeD animals was significantly greater than control (p < 0.05). Taken together, our results demonstrate that both the BBB and BCB contribute to maintain a stable Cu homeostasis in the brain and CSF. Cu appears to enter the brain primarily via the BBB and is subsequently removed from the CSF by the BCB. FeD has a more profound effect on brain Cu levels than FeO. FeD increases Cu transport at the brain barriers and prompts Cu overload in the CNS. The BCB plays a key role in removing the excess Cu from the CSF.« less

Identification of Small Peptides in Human Cerebrospinal Fluid upon Amyloid-β Degradation.

PubMed

Mizuta, Naoki; Yanagida, Kanta; Kodama, Takashi; Tomonaga, Takeshi; Takami, Mako; Oyama, Hiroshi; Kudo, Takashi; Ikeda, Manabu; Takeda, Masatoshi; Tagami, Shinji; Okochi, Masayasu

2017-01-01

Amyloid-β (Aβ) degradation in brains of Alzheimer disease patients is a crucial focus for the clarification of disease pathogenesis. Nevertheless, the mechanisms underlying Aβ degradation in the human brain remain unclear. This study aimed to quantify the levels of small C-terminal Aβ fragments generated upon Aβ degradation in human cerebrospinal fluid (CSF). A fraction containing small peptides was isolated and purified from human CSF by high-pressure liquid chromatography. Degradation products of Aβ C termini were identified and measured by liquid chromatography-tandem mass spectrometry. The C-terminal fragments of Aβ in the conditioned medium of cultured cells transfected with the Swedish variant of βAPP (sw βAPP) were analyzed. These fragments in brains of PS1 I213T knock-in transgenic mice, overexpressing sw βAPP, were also analyzed. The peptide fragments GGVV and GVV, produced by the cleavage of Aβ40, were identified in human CSF as well as in the brains of the transgenic mice and in the conditioned medium of the cultured cells. Relative to Aβ40 levels, GGVV and GVV levels were 7.6 ± 0.81 and 1.5 ± 0.18%, respectively, in human CSF. Levels of the GGVV fragment did not increase by the introduction of genes encoding neprilysin and insulin-degrading enzyme to the cultured cells. Our results indicate that a substantial amount of Aβ40 in human brains is degraded via a neprilysin- or insulin-degrading enzyme-independent pathway. © 2017 S. Karger AG, Basel.

Magnetic resonance characteristics and susceptibility weighted imaging of the brain in gadolinium encephalopathy.

PubMed

Samardzic, Dejan; Thamburaj, Krishnamoorthy

2015-01-01

To report the brain imaging features on magnetic resonance imaging (MRI) in inadvertent intrathecal gadolinium administration. A 67-year-old female with gadolinium encephalopathy from inadvertent high dose intrathecal gadolinium administration during an epidural steroid injection was studied with multisequence 3T MRI. T1-weighted imaging shows pseudo-T2 appearance with diffusion of gadolinium into the brain parenchyma, olivary bodies, and membranous labyrinth. Nulling of cerebrospinal fluid (CSF) signal is absent on fluid attenuation recovery (FLAIR). Susceptibility-weighted imaging (SWI) demonstrates features similar to subarachnoid hemorrhage. CT may demonstrate a pseudo-cerebral edema pattern given the high attenuation characteristics of gadolinium. Intrathecal gadolinium demonstrates characteristic imaging features on MRI of the brain and may mimic subarachnoid hemorrhage on susceptibility-weighted imaging. Identifying high dose gadolinium within the CSF spaces on MRI is essential to avoid diagnostic and therapeutic errors. Copyright © 2013 by the American Society of Neuroimaging.

Lymphatic drainage system of the brain: A novel target for intervention of neurological diseases.

PubMed

Sun, Bao-Liang; Wang, Li-Hua; Yang, Tuo; Sun, Jing-Yi; Mao, Lei-Lei; Yang, Ming-Feng; Yuan, Hui; Colvin, Robert A; Yang, Xiao-Yi

2017-09-10

The belief that the vertebrate brain functions normally without classical lymphatic drainage vessels has been held for many decades. On the contrary, new findings show that functional lymphatic drainage does exist in the brain. The brain lymphatic drainage system is composed of basement membrane-based perivascular pathway, a brain-wide glymphatic pathway, and cerebrospinal fluid (CSF) drainage routes including sinus-associated meningeal lymphatic vessels and olfactory/cervical lymphatic routes. The brain lymphatic systems function physiological as a route of drainage for interstitial fluid (ISF) from brain parenchyma to nearby lymph nodes. Brain lymphatic drainage helps maintain water and ion balance of the ISF, waste clearance, and reabsorption of macromolecular solutes. A second physiological function includes communication with the immune system modulating immune surveillance and responses of the brain. These physiological functions are influenced by aging, genetic phenotypes, sleep-wake cycle, and body posture. The impairment and dysfunction of the brain lymphatic system has crucial roles in age-related changes of brain function and the pathogenesis of neurovascular, neurodegenerative, and neuroinflammatory diseases, as well as brain injury and tumors. In this review, we summarize the key component elements (regions, cells, and water transporters) of the brain lymphatic system and their regulators as potential therapeutic targets in the treatment of neurologic diseases and their resulting complications. Finally, we highlight the clinical importance of ependymal route-based targeted gene therapy and intranasal drug administration in the brain by taking advantage of the unique role played by brain lymphatic pathways in the regulation of CSF flow and ISF/CSF exchange. Copyright © 2017. Published by Elsevier Ltd.

Proliferating brain cells are a target of neurotoxic CSF in systemic autoimmune disease

PubMed Central

Sakic, Boris; Kirkham, David L.; Ballok, David A.; Mwanjewe, James; Fearon, Ian M.; Macri, Joseph; Yu, Guanhua; Sidor, Michelle M.; Denburg, Judah A.; Szechtman, Henry; Lau, Jonathan; Ball, Alexander K.; Doering, Laurie C.

2006-01-01

Brain atrophy, neurologic and psychiatric (NP) manifestations are common complications in the systemic autoimmune disease, lupus erythematosus (SLE). Here we show that the cerebrospinal fluid (CSF) from autoimmune MRL-lpr mice and a deceased NP-SLE patient reduce the viability of brain cells which proliferate in vitro. This detrimental effect was accompanied by periventricular neurodegeneration in the brains of autoimmune mice and profound in vivo neurotoxicity when their CSF was administered to the CNS of a rat. Multiple ionic responses with microfluorometry and protein peaks on electropherograms suggest more than one mechanism of cellular demise. Similar to the CSF from diseased MRL-lpr mice, the CSF from a deceased SLE patient with a history of psychosis, memory impairment, and seizures, reduced viability of the C17.2 neural stem cell line. Proposed mechanisms of cytotoxicity involve binding of intrathecally synthesized IgG autoantibodies to target(s) common to different mammalian species and neuronal populations. More importantly, these results indicate that the viability of proliferative neural cells can be compromised in systemic autoimmune disease. Antibody-mediated lesions of germinal layers may impair the regenerative capacity of the brain in NP-SLE and possibly, brain development and function in some forms of CNS disorders in which autoimmune phenomena have been documented. PMID:16198428

Impairment of paravascular clearance pathways in the aging brain

PubMed Central

Kress, Benjamin T.; Iliff, Jeffrey J.; Xia, Maosheng; Wang, Minghuan; Wei, Helen; Zeppenfeld, Douglas; Xie, Lulu; Kang, Hongyi; Xu, Qiwu; Liew, Jason; Plog, Benjamin A.; Ding, Fengfei; Deane, Rashid; Nedergaard, Maiken

2014-01-01

Objective In the brain, protein waste removal is partly performed by paravascular pathways that facilitate convective exchange of water and soluble contents between cerebrospinal and interstitial fluids. Several lines of evidence suggest that bulk flow drainage via the glymphatic system is driven by cerebrovascular pulsation, and is dependent on astroglial water channels that line paravascular cerebrospinal fluid (CSF) pathways. The Objective of this study was to evaluate whether the efficiency of CSF-ISF exchange and interstitial solute clearance is impaired in the aging brain. Methods CSF-ISF exchange was evaluated by in vivo and ex vivo fluorescence microscopy while interstitial solute clearance was evaluated by radio-tracer clearance assays in young (2–3 month), middle age (10–12 month) and old (18–20 month) wild type mice. The relationship between age-related changes in the expression of the astrocytic water channel aquaporin-4 (AQP4) and changes in glymphatic pathway function were evaluated by immunofluorescence. Results Advancing age was associated with a dramatic decline in the efficiency of exchange between the subarachnoid CSF and the brain parenchyma. Relative to the young, clearance of intraparechamally injected amyloid β was impaired by 40% in the old mice. A 27% reduction in the vessel wall pulsatility of intracortical arterioles and widespread loss of perivascular AQP4 polarization along the penetrating arteries accompanied the decline in CSF-ISF exchange. Interpretation We propose that impaired glymphatic clearance contributes to cognitive decline among the elderly and may represent a novel therapeutic target for the treatment of neurodegenerative diseases associated with accumulation of mis-folded protein aggregates. PMID:25204284

Feasibility of using diffuse reflectance spectroscopy for the quantification of brain edema

NASA Astrophysics Data System (ADS)

Rodriguez, Juan G.; Sisson, Cynthia; Hendricks, Chad; Pattillo, Chris; McWaters, Megan; Hardjasudarma, Mardjohan; Quarles, Chad; Yaroslavsky, Anna N.; Yaroslavsky, Ilya V.; Battarbee, Harold

2001-05-01

Many diseased states of the brain can result in the displacement of brain tissues and restrict cerebral blood flow, disrupting function in a life-threatening manner. Clinical examples where displacements are observed include venous thromboses, hematomas, strokes, tumors, abscesses, and, particularly, brain edema. For the latter, the brain tissue swells, displacing the cerebral spinal fluid (CSF) layer that surrounds it, eventually pressing itself against the skull. Under such conditions, catheters are often inserted into the brain's ventricles or the subarachnoid space to monitor increased pressure. These are invasive procedures that incur increased risk of infection and consequently are used reluctantly by clinicians. Recent studies in the field of biomedical optics have suggested that the presence or absence of the CSF layer can lead to dramatic changes in NIR signals obtained from diffuse reflectance measurements around the head. In this study, we consider how this sensitivity of NIR signals to CSF might be exploited to non-invasively monitor the onset and resolution of brain edema.

Cerebrospinal Fluid proNGF: A Putative Biomarker for Early Alzheimer’s Disease

PubMed Central

Counts, Scott E.; He, Bin; Prout, John G.; Michalski, Bernadeta; Farotti, Lucia; Fahnestock, Margaret; Mufson, Elliott J.

2018-01-01

The discovery of biomarkers for the onset of Alzheimer’s disease (AD) is essential for disease modification strategies. To date, AD biomarker studies have focused on brain imaging and cerebrospinal fluid (CSF) changes in amyloid-β (Aβ) peptide and tau proteins. While reliable to an extent, this panel could be improved by the inclusion of novel biomarkers that optimize sensitivity and specificity. In this study, we determined whether CSF levels of the nerve growth factor (NGF) precursor protein, proNGF, increased during the progression of AD, mirroring its up regulation in postmortem brain samples of people who died with a clinical diagnosis of mild cognitive impairment (MCI) or AD. Immunoblot analysis was performed on ventricular CSF harvested from participants in the Rush Religious Orders Study with an antemortem clinical diagnosis of no cognitive impairment (NCI), amnestic MCI (aMCI, a putative prodromal AD stage), or mild/moderate AD. ProNGF levels were increased 55% in aMCI and 70% in AD compared to NCI. Increasing CSF proNGF levels correlated with impairment on cognitive test scores. In a complementary study, we found that proNGF was significantly increased by 30% in lumbar CSF samples derived from patients with a clinical dementia rating (CDR) of 0.5 or 1 compared to those with a CDR = 0. Notably, proNGF/Aβ1-42 levels were 50% higher in CDR 0.5 and CDR 1 compared to CDR 0 controls. By contrast, ELISA measurements of CSF brain-derived neurotrophic factor (BDNF) did not distinguish aMCI from NCI. Taken together, these results suggest that proNGF protein levels may augment the diagnostic accuracy of currently used CSF biomarker panels. PMID:26825093

Imaging review of cerebrospinal fluid leaks

PubMed Central

Vemuri, Naga V; Karanam, Lakshmi S P; Manchikanti, Venkatesh; Dandamudi, Srinivas; Puvvada, Sampath K; Vemuri, Vineet K

2017-01-01

Cerebrospinal fluid (CSF) leak occurs due to a defect in the dura and skull base. Trauma remains the most common cause of CSF leak; however, a significant number of cases are iatrogenic, and result from a complication of functional endoscopic sinus surgery (FESS). Early diagnosis of CSF leak is of paramount importance to prevent life-threatening complications such as brain abscess and meningitis. Imaging plays a crucial role in the detection and characterization of CSF leaks. Three-dimensional, isotropic, high resolution computed tomography (HRCT) accurately detects the site and size of the bony defect. CT cisternography, though invasive, helps accurately identify the site of CSF leak, especially in the presence of multiple bony defects. Magnetic resonance imaging (MRI) accurately detects CSF leaks and associated complications such as the encephaloceles and meningoceles. In this review, we emphasize the importance and usefulness of 3D T2 DRIVE MR cisternography in localizing CSF leaks. This sequence has the advantages of effective bone and fat suppression, decreased artefacts, faster acquisition times, three-dimensional capability, y and high spatial resolution in addition to providing very bright signal from the CSF. PMID:29379240

Imaging review of cerebrospinal fluid leaks.

PubMed

Vemuri, Naga V; Karanam, Lakshmi S P; Manchikanti, Venkatesh; Dandamudi, Srinivas; Puvvada, Sampath K; Vemuri, Vineet K

2017-01-01

Cerebrospinal fluid (CSF) leak occurs due to a defect in the dura and skull base. Trauma remains the most common cause of CSF leak; however, a significant number of cases are iatrogenic, and result from a complication of functional endoscopic sinus surgery (FESS). Early diagnosis of CSF leak is of paramount importance to prevent life-threatening complications such as brain abscess and meningitis. Imaging plays a crucial role in the detection and characterization of CSF leaks. Three-dimensional, isotropic, high resolution computed tomography (HRCT) accurately detects the site and size of the bony defect. CT cisternography, though invasive, helps accurately identify the site of CSF leak, especially in the presence of multiple bony defects. Magnetic resonance imaging (MRI) accurately detects CSF leaks and associated complications such as the encephaloceles and meningoceles. In this review, we emphasize the importance and usefulness of 3D T2 DRIVE MR cisternography in localizing CSF leaks. This sequence has the advantages of effective bone and fat suppression, decreased artefacts, faster acquisition times, three-dimensional capability, y and high spatial resolution in addition to providing very bright signal from the CSF.

Raltegravir cerebrospinal fluid concentrations in HIV-1 infection.

PubMed

Yilmaz, Aylin; Gisslén, Magnus; Spudich, Serena; Lee, Evelyn; Jayewardene, Anura; Aweeka, Francesca; Price, Richard W

2009-09-01

Raltegravir is an HIV-1 integrase inhibitor currently used in treatment-experienced HIV-1-infected patients resistant to other drug classes. In order to assess its central nervous system penetration, we measured raltegravir concentrations in cerebrospinal fluid (CSF) and plasma in subjects receiving antiretroviral treatment regimens containing this drug. Raltegravir concentrations were determined by liquid chromatography tandem mass spectrometry in 25 paired CSF and plasma samples from 16 HIV-1-infected individuals. The lower limit of quantitation was 2.0 ng/ml for CSF and 10 ng/ml for plasma. Twenty-four of the 25 CSF samples had detectable raltegravir concentrations with a median raltegravir concentration of 18.4 ng/ml (range, <2.0-126.0). The median plasma raltegravir concentration was 448 ng/ml (range, 37-5180). CSF raltegravir concentrations correlated with CSF:plasma albumin ratios and CSF albumin concentrations. Approximately 50% of the CSF specimens exceeded the IC(95) levels reported to inhibit HIV-1 strains without resistance to integrase inhibitors. In addition to contributing to control of systemic HIV-1 infection, raltegravir achieves local inhibitory concentrations in CSF in most, but not all, patients. Blood-brain and blood-CSF barriers likely restrict drug entry, while enhanced permeability of these barriers enhances drug entry.

An improved finite element modeling of the cerebrospinal fluid layer in the head impact analysis.

PubMed

Wu, John Z; Pan, Christopher S; Wimer, Bryan M; Rosen, Charles L

2017-01-01

The finite element (FE) method has been widely used to investigate the mechanism of traumatic brain injuries (TBIs), because it is technically difficult to quantify the responses of the brain tissues to the impact in experiments. One of technical challenges to build a FE model of a human head is the modeling of the cerebrospinal fluid (CSF) of the brain. In the current study, we propose to use membrane elements to construct the CSF layer. Using the proposed approach, we demonstrate that a head model can be built by using existing meshes available in commercial databases, without using any advanced meshing software tool, and with the sole use of native functions of the FE package Abaqus. The calculated time histories of the intracranial pressures at frontal, posterior fossa, parietal, and occipital positions agree well with the experimental data and the simulations in the literature, indicating that the physical effects of the CSF layer have been accounted for in the proposed modeling approach. The proposed modeling approach would be useful for bioengineers to solve practical problems.

Oxysterols and Parkinson's disease: evidence that levels of 24S-hydroxycholesterol in cerebrospinal fluid correlates with the duration of the disease.

PubMed

Björkhem, Ingemar; Lövgren-Sandblom, Anita; Leoni, Valerio; Meaney, Steve; Brodin, Lovisa; Salveson, Lisette; Winge, Kristian; Pålhagen, Sven; Svenningsson, Per

2013-10-25

Oxysterols are important for cholesterol homeostasis in the brain and may be affected in neurodegenerative diseases. The levels of the brain-derived oxysterol 24S-hydroxycholesterol (24S-OH) have been reported to be markedly reduced in the circulation of patients with Parkinson's disease (PD) (Lee et al., Antioxid. Redox Signal. 11 (2009) 407-420). The finding is surprising in view of the fact that other neurodegenerative diseases are associated with relatively modest effects on the circulating levels of 24S-OH. We determined the plasma and cerebrospinal fluid (CSF) levels of 24S-OH and 27-hydroxycholesterol (27-OH) in patients with PD with different disease duration using a highly accurate method based on isotope dilution-mass spectrometry. All the patients had plasma levels of the different oxysterols within the normal range. When analyzing CSF, 10% of the PD patients were found to have levels of 24S-OH above the cut-off level and interestingly there was a significant correlation between levels of 24S-OH in CSF and duration of the disease (r=0.40, P<0.05). The CSF level of 27-OH was found to be above the cut-off level in 10% of the patients, indicating a defect blood-brain barrier function. There was no correlation between levels of 27-OH in CSF and duration of the disease. These data indicates that oxysterol levels in CSF may be of value to follow disease progression. Copyright © 2013. Published by Elsevier Ireland Ltd.

Optimal-mass-transfer-based estimation of glymphatic transport in living brain.

PubMed

Ratner, Vadim; Zhu, Liangjia; Kolesov, Ivan; Nedergaard, Maiken; Benveniste, Helene; Tannenbaum, Allen

2015-02-21

It was recently shown that the brain-wide cerebrospinal fluid (CSF) and interstitial fluid exchange system designated the 'glymphatic pathway' plays a key role in removing waste products from the brain, similarly to the lymphatic system in other body organs 1,2 . It is therefore important to study the flow patterns of glymphatic transport through the live brain in order to better understand its functionality in normal and pathological states. Unlike blood, the CSF does not flow rapidly through a network of dedicated vessels, but rather through para-vascular channels and brain parenchyma in a slower time-domain, and thus conventional fMRI or other blood-flow sensitive MRI sequences do not provide much useful information about the desired flow patterns. We have accordingly analyzed a series of MRI images, taken at different times, of the brain of a live rat, which was injected with a paramagnetic tracer into the CSF via the lumbar intrathecal space of the spine. Our goal is twofold: (a) find glymphatic (tracer) flow directions in the live rodent brain; and (b) provide a model of a (healthy) brain that will allow the prediction of tracer concentrations given initial conditions. We model the liquid flow through the brain by the diffusion equation. We then use the Optimal Mass Transfer (OMT) approach 3 to derive the glymphatic flow vector field, and estimate the diffusion tensors by analyzing the (changes in the) flow. Simulations show that the resulting model successfully reproduces the dominant features of the experimental data.

Diagnostic value of creatine kinase activity in canine cerebrospinal fluid.

PubMed

Ferreira, Alexandra

2016-10-01

This study aimed to determine whether creatine kinase (CK) activity in cerebrospinal fluid (CSF) has diagnostic value for various groups of neurological conditions or for different anatomical areas of the nervous system (NS). The age, breed, results of CSF analysis, and diagnosis of 578 canine patients presenting with various neurological conditions between January 2009 and February 2015 were retrospectively collected. The cases were divided according to anatomical areas of the nervous system, i.e., brain, spinal cord, and peripheral nervous system, and into groups according to the nature of the condition diagnosed: vascular, immune/inflammatory/infectious, traumatic, toxic, anomalous, metabolic, idiopathic, neoplastic, and degenerative. Statistical analysis showed that CSF-CK alone cannot be used as a diagnostic tool and that total proteins in the CSF and red blood cells (RBCs) do not have a significant relationship with the CSF-CK activity. CSF-CK did not have a diagnostic value for different disease groups or anatomical areas of the nervous system.

Association of Cerebrospinal Fluid (CSF) Insulin with Cognitive Performance and CSF Biomarkers of Alzheimer's Disease.

PubMed

Geijselaers, Stefan L C; Aalten, Pauline; Ramakers, Inez H G B; De Deyn, Peter Paul; Heijboer, Annemieke C; Koek, Huiberdina L; OldeRikkert, Marcel G M; Papma, Janne M; Reesink, Fransje E; Smits, Lieke L; Stehouwer, Coen D A; Teunissen, Charlotte E; Verhey, Frans R J; van der Flier, Wiesje M; Biessels, Geert Jan

2018-01-01

Abnormal insulin signaling in the brain has been linked to Alzheimer's disease (AD). To evaluate whether cerebrospinal fluid (CSF) insulin levels are associated with cognitive performance and CSF amyloid-β and Tau. Additionally, we explore whether any such association differs by sex or APOE ɛ4 genotype. From 258 individuals participating in the Parelsnoer Institute Neurodegenerative Diseases, a nationwide multicenter memory clinic population, we selected 138 individuals (mean age 66±9 years, 65.2% male) diagnosed with subjective cognitive impairment (n = 45), amnestic mild cognitive impairment (n = 44), or AD (n = 49), who completed a neuropsychological assessment, including tests of global cognition and memory performance, and who underwent lumbar puncture. We measured CSF levels of insulin, amyloid-β1-42, total (t-)Tau, and phosphorylated (p-)Tau. CSF insulin levels did not differ between the diagnostic groups (p = 0.136). Across the whole study population, CSF insulin was unrelated to cognitive performance and CSF biomarkers of AD, after adjustment for age, sex, body mass index, diabetes status, and clinic site (all p≥0.131). Importantly, however, we observed effect modification by sex and APOE ɛ4 genotype. Specifically, among women, higher insulin levels in the CSF were associated with worse global cognition (standardized regression coefficient -0.483; p = 0.008) and higher p-Tau levels (0.353; p = 0.040). Among non-carriers of the APOE ɛ4 allele, higher CSF insulin was associated with higher t-Tau (0.287; p = 0.008) and p-Tau (0.246; p = 0.029). Our findings provide further evidence for a relationship between brain insulin signaling and AD pathology. It also highlights the need to consider sex and APOE ɛ4 genotype when assessing the role of insulin.

General Anesthesia Inhibits the Activity of the “Glymphatic System”

PubMed Central

Gakuba, Clement; Gaberel, Thomas; Goursaud, Suzanne; Bourges, Jennifer; Di Palma, Camille; Quenault, Aurélien; Martinez de Lizarrondo, Sara; Vivien, Denis; Gauberti, Maxime

2018-01-01

INTRODUCTION: According to the “glymphatic system” hypothesis, brain waste clearance is mediated by a continuous replacement of the interstitial milieu by a bulk flow of cerebrospinal fluid (CSF). Previous reports suggested that this cerebral CSF circulation is only active during general anesthesia or sleep, an effect mediated by the dilatation of the extracellular space. Given the controversies regarding the plausibility of this phenomenon and the limitations of currently available methods to image the glymphatic system, we developed original whole-brain in vivo imaging methods to investigate the effects of general anesthesia on the brain CSF circulation. METHODS: We used magnetic resonance imaging (MRI) and near-infrared fluorescence imaging (NIRF) after injection of a paramagnetic contrast agent or a fluorescent dye in the cisterna magna, in order to investigate the impact of general anesthesia (isoflurane, ketamine or ketamine/xylazine) on the intracranial CSF circulation in mice. RESULTS: In vivo imaging allowed us to image CSF flow in awake and anesthetized mice and confirmed the existence of a brain-wide CSF circulation. Contrary to what was initially thought, we demonstrated that the parenchymal CSF circulation is mainly active during wakefulness and significantly impaired during general anesthesia. This effect was especially significant when high doses of anesthetic agent were used (3% isoflurane). These results were consistent across the different anesthesia regimens and imaging modalities. Moreover, we failed to detect a significant change in the brain extracellular water volume using diffusion weighted imaging in awake and anesthetized mice. CONCLUSION: The parenchymal diffusion of small molecular weight compounds from the CSF is active during wakefulness. General anesthesia has a negative impact on the intracranial CSF circulation, especially when using a high dose of anesthetic agent. PMID:29344300

General Anesthesia Inhibits the Activity of the "Glymphatic System".

PubMed

Gakuba, Clement; Gaberel, Thomas; Goursaud, Suzanne; Bourges, Jennifer; Di Palma, Camille; Quenault, Aurélien; de Lizarrondo, Sara Martinez; Vivien, Denis; Gauberti, Maxime

2018-01-01

INTRODUCTION: According to the "glymphatic system" hypothesis, brain waste clearance is mediated by a continuous replacement of the interstitial milieu by a bulk flow of cerebrospinal fluid (CSF). Previous reports suggested that this cerebral CSF circulation is only active during general anesthesia or sleep, an effect mediated by the dilatation of the extracellular space. Given the controversies regarding the plausibility of this phenomenon and the limitations of currently available methods to image the glymphatic system, we developed original whole-brain in vivo imaging methods to investigate the effects of general anesthesia on the brain CSF circulation. METHODS: We used magnetic resonance imaging (MRI) and near-infrared fluorescence imaging (NIRF) after injection of a paramagnetic contrast agent or a fluorescent dye in the cisterna magna, in order to investigate the impact of general anesthesia (isoflurane, ketamine or ketamine/xylazine) on the intracranial CSF circulation in mice. RESULTS: In vivo imaging allowed us to image CSF flow in awake and anesthetized mice and confirmed the existence of a brain-wide CSF circulation. Contrary to what was initially thought, we demonstrated that the parenchymal CSF circulation is mainly active during wakefulness and significantly impaired during general anesthesia. This effect was especially significant when high doses of anesthetic agent were used (3% isoflurane). These results were consistent across the different anesthesia regimens and imaging modalities. Moreover, we failed to detect a significant change in the brain extracellular water volume using diffusion weighted imaging in awake and anesthetized mice. CONCLUSION: The parenchymal diffusion of small molecular weight compounds from the CSF is active during wakefulness. General anesthesia has a negative impact on the intracranial CSF circulation, especially when using a high dose of anesthetic agent.

Traumatic brain injury and recovery mechanisms: peptide modulation of periventricular neurogenic regions by the choroid plexus–CSF nexus

PubMed Central

Stopa, Edward; Baird, Andrew; Sharma, Hari

2010-01-01

In traumatic brain injury (TBI), severe disruptions occur in the choroid plexus (CP)–cerebrospinal fluid (CSF) nexus that destabilize the nearby hippocampal and subventricular neurogenic regions. Following invasive and non-invasive injuries to cortex, several adverse sequelae harm the brain interior: (i) structural damage to CP epithelium that opens the blood–CSF barrier (BCSFB) to protein, (ii) altered CSF dynamics and intracranial pressure (ICP), (iii) augmentation of leukocyte traffic across CP into the CSF–brain, (iv) reduction in CSF sink action and clearance of debris from ventricles, and (v) less efficient provision of micronutritional and hormonal support for the CNS. However, gradual post-TBI restitution of the injured CP epithelium and ependyma, and CSF homeostatic mechanisms, help to restore subventricular/subgranular neurogenesis and the cognitive abilities diminished by CNS damage. Recovery from TBI is faciltated by upregulated choroidal/ependymal growth factors and neurotrophins, and their secretion into ventricular CSF. There, by an endocrine-like mechanism, CSF bulk flow convects the neuropeptides to target cells in injured cortex for aiding repair processes; and to neurogenic niches for enhancing conversion of stem cells to new neurons. In the recovery from TBI and associated ischemia, the modulating neuropeptides include FGF2, EGF, VEGF, NGF, IGF, GDNF, BDNF, and PACAP. Homeostatic correction of TBI-induced neuropathology can be accelerated or amplified by exogenously boosting the CSF concentration of these growth factors and neurotrophins. Such intraventricular supplementation via the CSF route promotes neural restoration through enhanced neurogenesis, angiogenesis, and neuroprotective effects. CSF translational research presents opportunities that involve CP and ependymal manipulations to expedite recovery from TBI. PMID:20936524

Innervation of Ventricular and Periventricular Brain Compartments

PubMed Central

Leak, Rehana K.; Moore, Robert Y.

2012-01-01

Synaptic transmission is divided into two broad categories on the basis of the distance over which neurotransmitters travel. Wiring transmission is the release of transmitter into synaptic clefts in close apposition to receptors. Volume transmission is the release of transmitters or modulators over varying distances before interacting with receptors. One case of volume transmission over potentially long distances involves release into cerebrospinal fluid (CSF). The CSF contains neuroactive substances that affect brain function and range in size from small molecule transmitters to peptides and large proteins. CSF-contacting neurons are a well-known and universal feature of non-mammalian vertebrates, but only supra- and subependymal serotonergic plexuses are a commonly studied feature in mammals. The origin of most other neuroactive substances in CSF is unknown. In order to determine which brain regions communicate with CSF, we describe the distribution of retrograde neuronal labeling in the rat brain following ventricular injection of Cholera toxin, β subunit (CTβ), a tracer frequently used in brain circuit analysis. Within 15 to 30 minutes following intraventricular injection, there is only diffuse, non-specific staining adjacent to the ventricular surface. Within 2 to 10 days, however, there is extensive labeling of neuronal perikarya in specific nuclear groups in the telencephalon, thalamus, hypothalamus and brainstem, many at a considerable distance from the ventricles. These observations support the view that ventricular CSF is a significant channel for volume transmission and identifies those brain regions most likely to be involved in this process. PMID:22575559

Delayed clearance of cerebrospinal fluid tracer from entorhinal cortex in idiopathic normal pressure hydrocephalus: A glymphatic magnetic resonance imaging study.

PubMed

Eide, Per K; Ringstad, Geir

2018-01-01

The glymphatic system plays a key role for clearance of waste solutes from the rodent brain. We recently found evidence of glymphatic circulation in the human brain when using magnetic resonance imaging (MRI) contrast agent as cerebrospinal fluid (CSF) tracer in conjunction with multiple MRI acquisitions (gMRI). The present study explored the hypothesis that reduced glymphatic clearance in entorhinal cortex (ERC) may be instrumental in idiopathic normal pressure hydrocephalus (iNPH) dementia. gMRI acquisitions were obtained over a 24-48 h time span in cognitively affected iNPH patients and non-cognitively affected patients with suspected CSF leaks. The CSF tracer enrichment was determined as changes in normalized MRI T1 signal units. The study included 30 patients with iNPH and 8 individuals with suspected CSF leaks (i.e. reference individuals). Compared to reference individuals, iNPH patients presented with higher medial temporal lobe atrophy score and Evan's index and inferior ERC thickness. We found delayed clearance of the intrathecal CSF tracer gadobutrol from CSF, the ERC and adjacent white matter, suggesting impaired glymphatic circulation. Reduced clearance and accumulation of toxic waste product such as amyloid-β may be a mechanism behind dementia in iNPH. Glymphatic MRI (gMRI) may become a tool for assessment of early dementia.

Cerebrospinal Fluid Metabolomics After Natural Product Treatment in an Experimental Model of Cerebral Ischemia.

PubMed

Huan, Tao; Xian, Jia Wen; Leung, Wing Nang; Li, Liang; Chan, Chun Wai

2016-11-01

Cerebrospinal fluid (CSF) is an important biofluid for diagnosis of and research on neurological diseases. However, in-depth metabolomic profiling of CSF remains an analytical challenge due to the small volume of samples, particularly in small animal models. In this work, we report the application of a high-performance chemical isotope labeling (CIL) liquid chromatography-mass spectrometry (LC-MS) workflow for CSF metabolomics in Gastrodia elata and Uncaria rhynchophylla water extract (GUW)-treated experimental cerebral ischemia model of rat. The GUW is a commonly used Traditional Chinese Medicine (TCM) for hypertension and brain disease. This study investigated the amine- and phenol-containing biomarkers in the CSF metabolome. After GUW treatment for 7 days, the neurological deficit score was significantly improved with infarct volume reduction, while the integrity of brain histological structure was preserved. Over 1957 metabolites were quantified in CSF by dansylation LC-MS. The analysis of this comprehensive list of metabolites suggests that metabolites associated with oxidative stress, inflammatory response, and excitotoxicity change during GUW-induced alleviation of ischemic injury. This work is significant in that (1) it shows CIL LC-MS can be used for in-depth profiling of the CSF metabolome in experimental ischemic stroke and (2) identifies several potential molecular targets (that might mediate the central nervous system) and associate with pharmacodynamic effects of some frequently used TCMs.

Superficial subarachnoid cerebrospinal fluid space expansion after surgical drainage of chronic subdural hematoma.

PubMed

Tosaka, Masahiko; Tsushima, Yoshito; Watanabe, Saiko; Sakamoto, Kazuya; Yodonawa, Masahiko; Kunimine, Hideo; Fujita, Haruyasu; Fujii, Takashi

2015-07-01

The present study examined the computed tomography (CT) findings after surgery and overnight drainage for chronic subdural hematoma (CSDH) to clear the significance of inner superficial subarachnoid CSF space and outer subdural hematoma cavity between the brain surface and the inner skull. A total of 73 sides in 60 patients were evaluated. Head CT was performed on the day after surgery and overnight drainage (1st CT), within 3 weeks of surgery (2nd CT), and more than 3 weeks after surgery (3rd CT). Subdural and subarachnoid spaces were identified to focus on density of fluid, shape of air collection, and location of silicone drainage tube, etc. Cases with subdural space larger than the subarachnoid CSF space were classified as Group SD between the brain and the skull. Cases with subarachnoid CSF space larger than the subdural space were classified as Group SA. Cases with extremely thin (<3 mm) spaces between the brain and the skull were classified as Group NS. Group SA, SD, and NS accounted for 31.9, 55.6 and 12.5% of cases on the 1st CT. No statistical differences were found between Groups SA, SD, and NS in any clinical factors, including recurrence. Group SA were found significantly more on 1st CT than on 2nd and 3rd CT. Subarachnoid CSF space sometimes expands between the brain and skull on CT after surgical overnight drainage. Expansion of the arachnoid space may be a passive phenomenon induced by overnight drainage and delayed re-expansion of the brain parenchyma.

Evaluating glymphatic pathway function utilizing clinically relevant intrathecal infusion of CSF tracer.

PubMed

Yang, Lijun; Kress, Benjamin T; Weber, Harris J; Thiyagarajan, Meenakshisundaram; Wang, Baozhi; Deane, Rashid; Benveniste, Helene; Iliff, Jeffrey J; Nedergaard, Maiken

2013-05-01

Neurodegenerative diseases such as Alzheimer's are associated with the aggregation of endogenous peptides and proteins that contribute to neuronal dysfunction and loss. The glymphatic system, a brain-wide perivascular pathway along which cerebrospinal fluid (CSF) and interstitial fluid (ISF) rapidly exchange, has recently been identified as a key contributor to the clearance of interstitial solutes from the brain, including amyloid β. These findings suggest that measuring changes in glymphatic pathway function may be an important prognostic for evaluating neurodegenerative disease susceptibility or progression. However, no clinically acceptable approach to evaluate glymphatic pathway function in humans has yet been developed. Time-sequenced ex vivo fluorescence imaging of coronal rat and mouse brain slices was performed at 30-180 min following intrathecal infusion of CSF tracer (Texas Red- dextran-3, MW 3 kD; FITC- dextran-500, MW 500 kD) into the cisterna magna or lumbar spine. Tracer influx into different brain regions (cortex, white matter, subcortical structures, and hippocampus) in rat was quantified to map the movement of CSF tracer following infusion along both routes, and to determine whether glymphatic pathway function could be evaluated after lumbar intrathecal infusion. Following lumbar intrathecal infusions, small molecular weight TR-d3 entered the brain along perivascular pathways and exchanged broadly with the brain ISF, consistent with the initial characterization of the glymphatic pathway in mice. Large molecular weight FITC-d500 remained confined to the perivascular spaces. Lumbar intrathecal infusions exhibited a reduced and delayed peak parenchymal fluorescence intensity compared to intracisternal infusions. Lumbar intrathecal contrast delivery is a clinically useful approach that could be used in conjunction with dynamic contrast enhanced MRI nuclear imaging to assess glymphatic pathway function in humans.

Evaluating glymphatic pathway function utilizing clinically relevant intrathecal infusion of CSF tracer

PubMed Central

2013-01-01

Background Neurodegenerative diseases such as Alzheimer’s are associated with the aggregation of endogenous peptides and proteins that contribute to neuronal dysfunction and loss. The glymphatic system, a brain-wide perivascular pathway along which cerebrospinal fluid (CSF) and interstitial fluid (ISF) rapidly exchange, has recently been identified as a key contributor to the clearance of interstitial solutes from the brain, including amyloid β. These findings suggest that measuring changes in glymphatic pathway function may be an important prognostic for evaluating neurodegenerative disease susceptibility or progression. However, no clinically acceptable approach to evaluate glymphatic pathway function in humans has yet been developed. Methods Time-sequenced ex vivo fluorescence imaging of coronal rat and mouse brain slices was performed at 30–180 min following intrathecal infusion of CSF tracer (Texas Red- dextran-3, MW 3 kD; FITC- dextran-500, MW 500 kD) into the cisterna magna or lumbar spine. Tracer influx into different brain regions (cortex, white matter, subcortical structures, and hippocampus) in rat was quantified to map the movement of CSF tracer following infusion along both routes, and to determine whether glymphatic pathway function could be evaluated after lumbar intrathecal infusion. Results Following lumbar intrathecal infusions, small molecular weight TR-d3 entered the brain along perivascular pathways and exchanged broadly with the brain ISF, consistent with the initial characterization of the glymphatic pathway in mice. Large molecular weight FITC-d500 remained confined to the perivascular spaces. Lumbar intrathecal infusions exhibited a reduced and delayed peak parenchymal fluorescence intensity compared to intracisternal infusions. Conclusion Lumbar intrathecal contrast delivery is a clinically useful approach that could be used in conjunction with dynamic contrast enhanced MRI nuclear imaging to assess glymphatic pathway function in humans. PMID:23635358

Spirocyclic β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors: from hit to lowering of cerebrospinal fluid (CSF) amyloid β in a higher species.

PubMed

Hunt, Kevin W; Cook, Adam W; Watts, Ryan J; Clark, Christopher T; Vigers, Guy; Smith, Darin; Metcalf, Andrew T; Gunawardana, Indrani W; Burkard, Michael; Cox, April A; Geck Do, Mary K; Dutcher, Darrin; Thomas, Allen A; Rana, Sumeet; Kallan, Nicholas C; DeLisle, Robert K; Rizzi, James P; Regal, Kelly; Sammond, Douglas; Groneberg, Robert; Siu, Michael; Purkey, Hans; Lyssikatos, Joseph P; Marlow, Allison; Liu, Xingrong; Tang, Tony P

2013-04-25

A hallmark of Alzheimer's disease is the brain deposition of amyloid beta (Aβ), a peptide of 36-43 amino acids that is likely a primary driver of neurodegeneration. Aβ is produced by the sequential cleavage of APP by BACE1 and γ-secretase; therefore, inhibition of BACE1 represents an attractive therapeutic target to slow or prevent Alzheimer's disease. Herein we describe BACE1 inhibitors with limited molecular flexibility and molecular weight that decrease CSF Aβ in vivo, despite efflux. Starting with spirocycle 1a, we explore structure-activity relationships of core changes, P3 moieties, and Asp binding functional groups in order to optimize BACE1 affinity, cathepsin D selectivity, and blood-brain barrier (BBB) penetration. Using wild type guinea pig and rat, we demonstrate a PK/PD relationship between free drug concentrations in the brain and CSF Aβ lowering. Optimization of brain exposure led to the discovery of (R)-50 which reduced CSF Aβ in rodents and in monkey.

Effects of spatial variation of skull and cerebrospinal fluid layers on optical mapping of brain activities

NASA Astrophysics Data System (ADS)

Wang, Shuping; Shibahara, Nanae; Kuramashi, Daishi; Okawa, Shinpei; Kakuta, Naoto; Okada, Eiji; Maki, Atsushi; Yamada, Yukio

2010-07-01

In order to investigate the effects of anatomical variation in human heads on the optical mapping of brain activity, we perform simulations of optical mapping by solving the photon diffusion equation for layered-models simulating human heads using the finite element method (FEM). Particularly, the effects of the spatial variations in the thicknesses of the skull and cerebrospinal fluid (CSF) layers on mapping images are investigated. Mapping images of single active regions in the gray matter layer are affected by the spatial variations in the skull and CSF layer thicknesses, although the effects are smaller than those of the positions of the active region relative to the data points. The increase in the skull thickness decreases the sensitivity of the images to active regions, while the increase in the CSF layer thickness increases the sensitivity in general. The images of multiple active regions are also influenced by their positions relative to the data points and by their depths from the skin surface.

Molecular forms of C-type natriuretic peptide in cerebrospinal fluid and plasma reflect differential processing in brain and pituitary tissues.

PubMed

Wilson, Michele O; Barrell, Graham K; Prickett, Timothy C R; Espiner, Eric A

2018-01-01

C-type natriuretic peptide (CNP) is a paracrine growth factor widely expressed within tissues of the central nervous system. Consistent with this is the high concentration of CNP in cerebrospinal fluid (CSF), exceeding levels in the systemic circulation. CNP abundance is high in hypothalamus and especially enriched in pituitary tissue where - in contrast to hypothalamus - processing to CNP-22 is minimal. Recently we have shown that dexamethasone acutely raises CNP peptides throughout the brain as well as in CSF and plasma. Postulating that molecular forms of CNP would differ in central tissues compared to forms in pituitary and plasma, we have characterized the molecular forms of CNP in tissues (hypothalamus, anterior and posterior pituitary gland) and associated fluids (CSF and plasma) using size-exclusion high performance liquid chromatography (SE-HPLC) and radioimmunoassay in control (saline-treated) and dexamethasone-treated adult sheep. Three immunoreactive-CNP components were identified which were consistent with proCNP (1-103), CNP-53 and CNP-22, but the presence and proportions of these different fragments differed among tissues. Peaks consistent with CNP-53 were the dominant form in all tissues and fluids. Peaks consistent with proCNP, conspicuous in hypothalamic extracts, were negligible in CSF whereas proportions of low molecular weight immunoreactivity (IR) consistent with CNP-22 were similar in hypothalamus, posterior pituitary gland and CSF. In contrast, in both plasma and the anterior pituitary gland, proportions of higher molecular weight IR, consistent with CNP-53 and proCNP, predominated, and low molecular weight IR consistent with CNP-22 was very low. After dexamethasone, proCNP like material - but not other forms - was increased in all samples except CSF, consistent with increased synthesis and secretion. In conclusion, immunoreactive forms of CNP in central tissues differ from those identified in anterior pituitary tissue and plasma - suggesting that the anterior pituitary gland may contribute to systemic levels of CNP in some physiological settings. Copyright © 2017 Elsevier Inc. All rights reserved.

Quantification of Transporter and Receptor Proteins in Dog Brain Capillaries and Choroid Plexus: Relevance for the Distribution in Brain and CSF of Selected BCRP and P-gp Substrates.

PubMed

Braun, Clemens; Sakamoto, Atsushi; Fuchs, Holger; Ishiguro, Naoki; Suzuki, Shinobu; Cui, Yunhai; Klinder, Klaus; Watanabe, Michitoshi; Terasaki, Tetsuya; Sauer, Achim

2017-10-02

Transporters at the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) play a pivotal role as gatekeepers for efflux or uptake of endogenous and exogenous molecules. The protein expression of a number of them has already been determined in the brains of rodents, nonhuman primates, and humans using quantitative targeted absolute proteomics (QTAP). The dog is an important animal model for drug discovery and development, especially for safety evaluations. The purpose of the present study was to clarify the relevance of the transporter protein expression for drug distribution in the dog brain and CSF. We used QTAP to examine the protein expression of 17 selected transporters and receptors at the dog BBB and BCSFB. For the first time, we directly linked the expression of two efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), to regional brain and CSF distribution using specific substrates. Two cocktails, each containing one P-gp substrate (quinidine or apafant) and one BCRP substrate (dantrolene or daidzein) were infused intravenously prior to collection of the brain. Transporter expression varied only slightly between the capillaries of different brain regions and did not result in region-specific distribution of the investigated substrates. There were, however, distinct differences between brain capillaries and choroid plexus. Largest differences were observed for BCRP and P-gp: both were highly expressed in brain capillaries, but no BCRP and only low amounts of P-gp were detected in the choroid plexus. K p,uu,brain and K p,uu,CSF of both P-gp substrates were indicative of drug efflux. Also, K p,uu,brain for the BCRP substrates was low. In contrast, K p,uu,CSF for both BCRP substrates was close to unity, resulting in K p,uu,CSF /K p,uu,brain ratios of 7 and 8, respectively. We conclude that the drug transporter expression profiles differ between the BBB and BCSFB in dogs, that there are species differences in the expression profiles, and that CSF is not a suitable surrogate for unbound brain concentrations of BCRP substrates in dogs.

Enantioselective distribution of albendazole metabolites in cerebrospinal fluid of patients with neurocysticercosis

PubMed Central

Takayanagui, O M; Bonato, P S; Dreossi, S A C; Lanchote, V L

2002-01-01

Aims Albendazole (ABZ) is effective in the treatment of neurocysticercosis. ABZ undergoes extensive metabolism to (+) and (−)-albendazole sulphoxide (ASOX), which are further metabolized to albendazole sulphone (ASON). We have investigated the distribution of (+)-ASOX (−)-ASOX, and ASON in cerebrospinal fluid (CSF) of patients with neurocysticercosis. Methods Twelve patients with a diagnosis of active brain parenchymal neurocysticercosis treated with albendazole for 8 days (15 mg kg−1 day−1) were investigated. On day 8, serial blood samples were collected during the dose interval (0–12 h) and one CSF sample was taken from each patient by lumbar puncture at different time points up to 12 h after the last albendazole dose. Albendazole metabolites were determined in CSF and plasma samples by h.p.l.c. using a Chiralpak AD column and fluorescence detection. Population curves for CSF albendazole metabolite concentration vs time were constructed. Results The mean plasma/CSF ratios were 2.6 (95% CI: 1.9, 3.3) for (+)-ASOX and 2.7 (95% CI: 1.8, 3.7) for (−)-ASOX, with the two-tailed P value of 0.9873 being non-significant. These data indicate that the transport of ASOX through the blood–brain barrier is not enantioselective, but rather depends on passive diffusion. The present results suggest the accumulation of the (+)-ASOX metabolite in the CSF of patients with neurocysticercosis. The CSF AUC(+)/AUC(−) ratio was 3.4 for patients receiving albendazole every 12 h. The elimination half-life of both ASOX enantiomers in CSF was 2.5 h. ASOX was the predominant metabolite in the CSF compared with ASON; the CSF AUCASOX/AUCASON ratio was approximately 20 and the elimination half-life of ASON in CSF was 2.6 h. Conclusions We have demonstrated accumulation of the (+)-ASOX metabolite in CSF, which was about three times greater than the (−) antipode. ASOX concentrations were approximately 20 times higher than those observed for the ASON metabolite. PMID:12207631

Effects of sustained i.c.v. infusion of lupus CSF and autoantibodies on behavioral phenotype and neuronal calcium signaling.

PubMed

Kapadia, Minesh; Bijelić, Dunja; Zhao, Hui; Ma, Donglai; Stojanovich, Ljudmila; Milošević, Milena; Andjus, Pavle; Šakić, Boris

2017-09-07

Systemic lupus erythematosus (SLE) is a potentially fatal autoimmune disease that is often accompanied by brain atrophy and diverse neuropsychiatric manifestations of unknown origin. More recently, it was observed that cerebrospinal fluid (CSF) from patients and lupus-prone mice can be neurotoxic and that acute administration of specific brain-reactive autoantibodies (BRAs) can induce deficits in isolated behavioral tasks. Given the chronic and complex nature of CNS SLE, the current study examines broad behavioral performance and neuronal Ca 2+ signaling in mice receiving a sustained infusion of cerebrospinal fluid (CSF) from CNS SLE patients and putative BRAs (anti-NR2A, anti-ribosomal P, and anti-α-tubulin). A 2-week intracerebroventricular (i.c.v.) infusion of CSF altered home-cage behavior and induced olfactory dysfunction, excessive immobility in the forced swim test, and perseveration in a learning task. Conversely, sustained administration of purified BRAs produced relatively mild, both inhibitory and stimulatory effects on olfaction, spatial learning/memory, and home-cage behavior. In vitro studies revealed that administration of some CSF samples induces a rapid influx of extracellular Ca 2+ into murine neurons, an effect that could be partially mimicked with the commercial anti-NR2A antibody and blocked with selective N-methyl-D-aspartate (NMDA) receptor antagonists. The current findings confirm that the CSF from CNS SLE patients can be neuroactive and support the hypothesis that intrathecal BRAs induce synergistically diverse effects on all domains of behavior. In addition, anti-NMDA receptor antibodies may alter Ca 2+ homeostasis of central neurons, thus accounting for excitotoxicity and contributing to the heterogeneity of psychiatric manifestations in CNS SLE and other autoantibody-related brain disorders.

Raltegravir Cerebrospinal Fluid Concentrations in HIV-1 Infection

PubMed Central

Yilmaz, Aylin; Gisslén, Magnus; Spudich, Serena; Lee, Evelyn; Jayewardene, Anura; Aweeka, Francesca; Price, Richard W.

2009-01-01

Introduction Raltegravir is an HIV-1 integrase inhibitor currently used in treatment-experienced HIV-1-infected patients resistant to other drug classes. In order to assess its central nervous system penetration, we measured raltegravir concentrations in cerebrospinal fluid (CSF) and plasma in subjects receiving antiretroviral treatment regimens containing this drug. Methods Raltegravir concentrations were determined by liquid chromatography tandem mass spectrometry in 25 paired CSF and plasma samples from 16 HIV-1-infected individuals. The lower limit of quantitation was 2.0 ng/ml for CSF and 10 ng/ml for plasma. Results Twenty-four of the 25 CSF samples had detectable raltegravir concentrations with a median raltegravir concentration of 18.4 ng/ml (range, <2.0–126.0). The median plasma raltegravir concentration was 448 ng/ml (range, 37–5180). CSF raltegravir concentrations correlated with CSF:plasma albumin ratios and CSF albumin concentrations. Conclusions Approximately 50% of the CSF specimens exceeded the IC95 levels reported to inhibit HIV-1 strains without resistance to integrase inhibitors. In addition to contributing to control of systemic HIV-1 infection, raltegravir achieves local inhibitory concentrations in CSF in most, but not all, patients. Blood-brain and blood-CSF barriers likely restrict drug entry, while enhanced permeability of these barriers enhances drug entry. PMID:19721718

The evaluation of oxidative DNA damage in children with brain damage using 8-hydroxydeoxyguanosine levels.

PubMed

Fukuda, Miho; Yamauchi, Hiroshi; Yamamoto, Hitoshi; Aminaka, Masahito; Murakami, Hiroshi; Kamiyama, Noriko; Miyamoto, Yusaku; Koitabashi, Yasushi

2008-02-01

Urinary and cerebrospinal fluid (CSF) levels of 8-hydroxydeoxyguanosine (8-OHdG) were examined to estimate the relevance of oxidative stress in children with brain damage. Urinary 8-OHdG levels were measured in 51 children with various forms of central nervous system (CNS) disorders (status epilepticus [SE], hypoxic-ischemic encephalopathy [HIE], CNS infections and chronic epilepsy) and these levels were compared with those in 51 healthy children. CSF 8-OHdG levels were measured in 25 children with brain damage and in 19 control subjects. In addition, urinary and CSF levels of 8-OHdG were compared between the children with brain damage and healthy children. Finally, the relationship between urinary and CSF levels of 8-OHdG was determined in 12 children that provided both urinary and CSF samples. Our results showed that urinary 8-OHdG levels in children with HIE and CNS infections were higher than those of controls (Steel test; p < 0.05 and p < 0.05, respectively) and that CSF 8-OHdG levels were higher in children with SE, HIE, and CNS infections than in control subjects (Steel test; p < 0.01, 0.05 and 0.05, respectively). In addition, a positive correlation between the levels of urinary and CSF 8-OHdG was noted in the 12 children that provided both CSF and urinary samples (Spearman's rank correlation; rho = 0.82, p < 0.01). Further, we observed changes in the urinary 8-OHdG in a patient with HHV-6 encephalopathy, and found that the changes correlated well with the patient's clinical condition. These results suggest that oxidative stress is strongly related to acute brain damage in children, and that 8-OHdG is a useful marker of brain damage. Therefore, repeated measurements of urinary 8-OHdG may be helpful in estimating the extent of brain damage.

Addressing the need for biomarker liquid chromatography/mass spectrometry assays: a protocol for effective method development for the bioanalysis of endogenous compounds in cerebrospinal fluid.

PubMed

Benitex, Yulia; McNaney, Colleen A; Luchetti, David; Schaeffer, Eric; Olah, Timothy V; Morgan, Daniel G; Drexler, Dieter M

2013-08-30

Research on disorders of the central nervous system (CNS) has shown that an imbalance in the levels of specific endogenous neurotransmitters may underlie certain CNS diseases. These alterations in neurotransmitter levels may provide insight into pathophysiology, but can also serve as disease and pharmacodynamic biomarkers. To measure these potential biomarkers in vivo, the relevant sample matrix is cerebrospinal fluid (CSF), which is in equilibrium with the brain's interstitial fluid and circulates through the ventricular system of the brain and spinal cord. Accurate analysis of these potential biomarkers can be challenging due to low CSF sample volume, low analyte levels, and potential interferences from other endogenous compounds. A protocol has been established for effective method development of bioanalytical assays for endogenous compounds in CSF. Database searches and standard-addition experiments are employed to qualify sample preparation and specificity of the detection thus evaluating accuracy and precision. This protocol was applied to the study of the histaminergic neurotransmitter system and the analysis of histamine and its metabolite 1-methylhistamine in rat CSF. The protocol resulted in a specific and sensitive novel method utilizing pre-column derivatization ultra high performance liquid chromatography/tandem mass spectrometry (UHPLC/MS/MS), which is also capable of separating an endogenous interfering compound, identified as taurine, from the analytes of interest. Copyright © 2013 John Wiley & Sons, Ltd.

Optimal-mass-transfer-based estimation of glymphatic transport in living brain

PubMed Central

Zhu, Liangjia; Kolesov, Ivan; Nedergaard, Maiken; Benveniste, Helene; Tannenbaum, Allen

2016-01-01

It was recently shown that the brain-wide cerebrospinal fluid (CSF) and interstitial fluid exchange system designated the ‘glymphatic pathway’ plays a key role in removing waste products from the brain, similarly to the lymphatic system in other body organs1,2. It is therefore important to study the flow patterns of glymphatic transport through the live brain in order to better understand its functionality in normal and pathological states. Unlike blood, the CSF does not flow rapidly through a network of dedicated vessels, but rather through para-vascular channels and brain parenchyma in a slower time-domain, and thus conventional fMRI or other blood-flow sensitive MRI sequences do not provide much useful information about the desired flow patterns. We have accordingly analyzed a series of MRI images, taken at different times, of the brain of a live rat, which was injected with a paramagnetic tracer into the CSF via the lumbar intrathecal space of the spine. Our goal is twofold: (a) find glymphatic (tracer) flow directions in the live rodent brain; and (b) provide a model of a (healthy) brain that will allow the prediction of tracer concentrations given initial conditions. We model the liquid flow through the brain by the diffusion equation. We then use the Optimal Mass Transfer (OMT) approach3 to derive the glymphatic flow vector field, and estimate the diffusion tensors by analyzing the (changes in the) flow. Simulations show that the resulting model successfully reproduces the dominant features of the experimental data. PMID:26877579

Influence of peptide transporter 2 (PEPT2) on the distribution of cefadroxil in mouse brain: A microdialysis study.

PubMed

Chen, Xiaomei; Keep, Richard F; Liang, Yan; Zhu, Hao-Jie; Hammarlund-Udenaes, Margareta; Hu, Yongjun; Smith, David E

2017-05-01

Peptide transporter 2 (PEPT2) is a high-affinity low-capacity transporter belonging to the proton-coupled oligopeptide transporter family. Although many aspects of PEPT2 structure-function are known, including its localization in choroid plexus and neurons, its regional activity in brain, especially extracellular fluid (ECF), is uncertain. In this study, the pharmacokinetics and regional brain distribution of cefadroxil, a β-lactam antibiotic and PEPT2 substrate, were investigated in wildtype and Pept2 null mice using in vivo intracerebral microdialysis. Cefadroxil was infused intravenously over 4h at 0.15mg/min/kg, and samples obtained from plasma, brain ECF, cerebrospinal fluid (CSF) and brain tissue. A permeability-surface area experiment was also performed in which 0.15mg/min/kg cefadroxil was infused intravenously for 10min, and samples obtained from plasma and brain tissues. Our results showed that PEPT2 ablation significantly increased the brain ECF and CSF levels of cefadroxil (2- to 2.5-fold). In contrast, there were no significant differences between wildtype and Pept2 null mice in the amount of cefadroxil in brain cells. The unbound volume of distribution of cefadroxil in brain was 60% lower in Pept2 null mice indicating an uptake function for PEPT2 in brain cells. Finally, PEPT2 did not affect the influx clearance of cefadroxil, thereby, ruling out differences between the two genotypes in drug entry across the blood-brain barriers. These findings demonstrate, for the first time, the impact of PEPT2 on brain ECF as well as the known role of PEPT2 in removing peptide-like drugs, such as cefadroxil, from the CSF to blood. Copyright © 2017 Elsevier Inc. All rights reserved.

White matter lesion extension to automatic brain tissue segmentation on MRI.

PubMed

de Boer, Renske; Vrooman, Henri A; van der Lijn, Fedde; Vernooij, Meike W; Ikram, M Arfan; van der Lugt, Aad; Breteler, Monique M B; Niessen, Wiro J

2009-05-01

A fully automated brain tissue segmentation method is optimized and extended with white matter lesion segmentation. Cerebrospinal fluid (CSF), gray matter (GM) and white matter (WM) are segmented by an atlas-based k-nearest neighbor classifier on multi-modal magnetic resonance imaging data. This classifier is trained by registering brain atlases to the subject. The resulting GM segmentation is used to automatically find a white matter lesion (WML) threshold in a fluid-attenuated inversion recovery scan. False positive lesions are removed by ensuring that the lesions are within the white matter. The method was visually validated on a set of 209 subjects. No segmentation errors were found in 98% of the brain tissue segmentations and 97% of the WML segmentations. A quantitative evaluation using manual segmentations was performed on a subset of 6 subjects for CSF, GM and WM segmentation and an additional 14 for the WML segmentations. The results indicated that the automatic segmentation accuracy is close to the interobserver variability of manual segmentations.

Cilia induced cerebrospinal fluid flow in the third ventricle of brain

NASA Astrophysics Data System (ADS)

Wang, Yong; Westendorf, Christian; Faubel, Regina; Eichele, Gregor; Bodenschatz, Eberhard

2016-11-01

Cerebrospinal fluid (CSF) conveys many physiologically important signaling factors through the ventricles of the mammalian brain. The walls of the ventricles are covered with motile cilia that were thought to generate a laminar flow purely following the curvature of walls. However, we recently discovered that cilia of the ventral third ventricle (v3V) generate a complex flow network along the wall, leading to subdivision of the v3V. The contribution of such cilia induced flow to the overall three dimensional volume flow remains to be investigated by using numerical simulation, arguably the best approach for such investigations. The lattice Boltzmann method is used to study the CFS flow in a reconstructed geometry of the v3V. Simulation of CSF flow neglecting cilia in this geometry confirmed that the previous idea about pure confined flow does not reflect the reality observed in experiment. The experimentally recorded ciliary flow network along the wall was refined with the smoothed particle hydrodynamics and then adapted as boundary condition in simulation. We study the contribution of the ciliary network to overall CSF flow and identify site-specific delivery of CSF constituents with respect to the temporal changes.

Dynamics of Viral and Proviral Loads of Feline Immunodeficiency Virus within the Feline Central Nervous System during the Acute Phase following Intravenous Infection

PubMed Central

Ryan, G.; Klein, D.; Knapp, E.; Hosie, M. J.; Grimes, T.; Mabruk, M. J. E. M. F.; Jarrett, O.; Callanan, J. J.

2003-01-01

Animal models of human immunodeficiency virus 1, such as feline immunodeficiency virus (FIV), provide the opportunities to dissect the mechanisms of early interactions of the virus with the central nervous system (CNS). The aims of the present study were to evaluate viral loads within CNS, cerebrospinal fluid (CSF), ocular fluid, and the plasma of cats in the first 23 weeks after intravenous inoculation with FIVGL8. Proviral loads were also determined within peripheral blood mononuclear cells (PBMCs) and brain tissue. In this acute phase of infection, virus entered the brain in the majority of animals. Virus distribution was initially in a random fashion, with more diffuse brain involvement as infection progressed. Virus in the CSF was predictive of brain parenchymal infection. While the peak of virus production in blood coincided with proliferation within brain, more sustained production appeared to continue in brain tissue. In contrast, proviral loads in the brain decreased to undetectable levels in the presence of a strengthening PBMC load. A final observation in this study was that there was no direct correlation between viral loads in regions of brain or ocular tissue and the presence of histopathology. PMID:12805447

Hydrocephalus: the role of cerebral aquaporin-4 channels and computational modeling considerations of cerebrospinal fluid.

PubMed

Desai, Bhargav; Hsu, Ying; Schneller, Benjamin; Hobbs, Jonathan G; Mehta, Ankit I; Linninger, Andreas

2016-09-01

Aquaporin-4 (AQP4) channels play an important role in brain water homeostasis. Water transport across plasma membranes has a critical role in brain water exchange of the normal and the diseased brain. AQP4 channels are implicated in the pathophysiology of hydrocephalus, a disease of water imbalance that leads to CSF accumulation in the ventricular system. Many molecular aspects of fluid exchange during hydrocephalus have yet to be firmly elucidated, but review of the literature suggests that modulation of AQP4 channel activity is a potentially attractive future pharmaceutical therapy. Drug therapy targeting AQP channels may enable control over water exchange to remove excess CSF through a molecular intervention instead of by mechanical shunting. This article is a review of a vast body of literature on the current understanding of AQP4 channels in relation to hydrocephalus, details regarding molecular aspects of AQP4 channels, possible drug development strategies, and limitations. Advances in medical imaging and computational modeling of CSF dynamics in the setting of hydrocephalus are summarized. Algorithmic developments in computational modeling continue to deepen the understanding of the hydrocephalus disease process and display promising potential benefit as a tool for physicians to evaluate patients with hydrocephalus.

Evaluation of a deep learning approach for the segmentation of brain tissues and white matter hyperintensities of presumed vascular origin in MRI.

PubMed

Moeskops, Pim; de Bresser, Jeroen; Kuijf, Hugo J; Mendrik, Adriënne M; Biessels, Geert Jan; Pluim, Josien P W; Išgum, Ivana

2018-01-01

Automatic segmentation of brain tissues and white matter hyperintensities of presumed vascular origin (WMH) in MRI of older patients is widely described in the literature. Although brain abnormalities and motion artefacts are common in this age group, most segmentation methods are not evaluated in a setting that includes these items. In the present study, our tissue segmentation method for brain MRI was extended and evaluated for additional WMH segmentation. Furthermore, our method was evaluated in two large cohorts with a realistic variation in brain abnormalities and motion artefacts. The method uses a multi-scale convolutional neural network with a T 1 -weighted image, a T 2 -weighted fluid attenuated inversion recovery (FLAIR) image and a T 1 -weighted inversion recovery (IR) image as input. The method automatically segments white matter (WM), cortical grey matter (cGM), basal ganglia and thalami (BGT), cerebellum (CB), brain stem (BS), lateral ventricular cerebrospinal fluid (lvCSF), peripheral cerebrospinal fluid (pCSF), and WMH. Our method was evaluated quantitatively with images publicly available from the MRBrainS13 challenge ( n  = 20), quantitatively and qualitatively in relatively healthy older subjects ( n  = 96), and qualitatively in patients from a memory clinic ( n  = 110). The method can accurately segment WMH (Overall Dice coefficient in the MRBrainS13 data of 0.67) without compromising performance for tissue segmentations (Overall Dice coefficients in the MRBrainS13 data of 0.87 for WM, 0.85 for cGM, 0.82 for BGT, 0.93 for CB, 0.92 for BS, 0.93 for lvCSF, 0.76 for pCSF). Furthermore, the automatic WMH volumes showed a high correlation with manual WMH volumes (Spearman's ρ  = 0.83 for relatively healthy older subjects). In both cohorts, our method produced reliable segmentations (as determined by a human observer) in most images (relatively healthy/memory clinic: tissues 88%/77% reliable, WMH 85%/84% reliable) despite various degrees of brain abnormalities and motion artefacts. In conclusion, this study shows that a convolutional neural network-based segmentation method can accurately segment brain tissues and WMH in MR images of older patients with varying degrees of brain abnormalities and motion artefacts.

The nonlinear relationship between cerebrospinal fluid Aβ42 and tau in preclinical Alzheimer's disease.

PubMed

de Leon, Mony J; Pirraglia, Elizabeth; Osorio, Ricardo S; Glodzik, Lidia; Saint-Louis, Les; Kim, Hee-Jin; Fortea, Juan; Fossati, Silvia; Laska, Eugene; Siegel, Carole; Butler, Tracy; Li, Yi; Rusinek, Henry; Zetterberg, Henrik; Blennow, Kaj

2018-01-01

Cerebrospinal fluid (CSF) studies consistently show that CSF levels of amyloid-beta 1-42 (Aβ42) are reduced and tau levels increased prior to the onset of cognitive decline related to Alzheimer's disease (AD). However, the preclinical prediction accuracy for low CSF Aβ42 levels, a surrogate for brain Aβ42 deposits, is not high. Moreover, the pathology data suggests a course initiated by tauopathy contradicting the contemporary clinical view of an Aβ initiated cascade. CSF Aβ42 and tau data from 3 normal aging cohorts (45-90 years) were combined to test both cross-sectional (n = 766) and longitudinal (n = 651) hypotheses: 1) that the relationship between CSF levels of Aβ42 and tau are not linear over the adult life-span; and 2) that non-linear models improve the prediction of cognitive decline. Supporting the hypotheses, the results showed that a u-shaped quadratic fit (Aβ2) best describes the relationship for CSF Aβ42 with CSF tau levels. Furthermore we found that the relationship between Aβ42 and tau changes with age-between 45 and 70 years there is a positive linear association, whereas between 71 and 90 years there is a negative linear association between Aβ42 and tau. The quadratic effect appears to be unique to Aβ42, as Aβ38 and Aβ40 showed only positive linear relationships with age and CSF tau. Importantly, we observed the prediction of cognitive decline was improved by considering both high and low levels of Aβ42. Overall, these data suggest an earlier preclinical stage than currently appreciated, marked by CSF elevations in tau and accompanied by either elevations or reductions in Aβ42. Future studies are needed to examine potential mechanisms such as failing CSF clearance as a common factor elevating CSF Aβxx analyte levels prior to Aβ42 deposition in brain.

Association of Cerebrospinal Fluid Neurofilament Light Concentration With Alzheimer Disease Progression.

PubMed

Zetterberg, Henrik; Skillbäck, Tobias; Mattsson, Niklas; Trojanowski, John Q; Portelius, Erik; Shaw, Leslie M; Weiner, Michael W; Blennow, Kaj

2016-01-01

The extent to which large-caliber axonal degeneration contributes to Alzheimer disease (AD) progression is unknown. Cerebrospinal fluid (CSF) neurofilament light (NFL) concentration is a general marker of damage to large-caliber myelinated axons. To test whether CSF NFL concentration is associated with cognitive decline and imaging evidence of neurodegeneration and white matter change in AD. A commercially available immunoassay was used to analyze CSF NFL concentration in a cohort of patients with AD (n = 95) or mild cognitive impairment (MCI) (n = 192) and in cognitively normal individuals (n = 110) from the Alzheimer's Disease Neuroimaging Initiative. The study dates were January 2005 to December 2007. The NFL analysis was performed in November 2014. Correlation was investigated among baseline CSF NFL concentration and longitudinal cognitive impairment, white matter change, and regional brain atrophy within each diagnostic group. Cerebrospinal fluid NFL concentration (median [interquartile range]) was higher in the AD dementia group (1479 [1134-1842] pg/mL), stable MCI group (no progression to AD during follow-up; 1182 [923-1687] pg/mL), and progressive MCI group (MCI with progression to AD dementia during follow-up; 1336 [1061-1693] pg/mL) compared with control participants (1047 [809-1265] pg/mL) (P < .001 for all) and in the AD dementia group compared with the stable MCI group (P = .01). In the MCI group, a higher CSF NFL concentration was associated with faster brain atrophy over time as measured by changes in whole-brain volume (β = -4177, P = .003), ventricular volume (β = 1835, P < .001), and hippocampus volume (β = -54.22, P < .001); faster disease progression as reflected by decreased Mini-Mental State Examination scores (β = -1.077, P < .001) and increased Alzheimer Disease Assessment Scale cognitive subscale scores (β = 2.30, P < .001); and faster white matter intensity change (β = 598.7, P < .001). Cerebrospinal fluid NFL concentration is increased by the early clinical stage of AD and is associated with cognitive deterioration and structural brain changes over time. This finding corroborates the contention that degeneration of large-caliber axons is an important feature of AD neurodegeneration.

Blood-brain barrier permeability during the development of experimental bacterial meningitis in the rat.

PubMed

Kim, K S; Wass, C A; Cross, A S

1997-05-01

In an attempt to examine whether routes of bacterial entry into the central nervous system have any bearing on subsequent changes in blood-brain barrier permeability, we examined cerebrospinal fluid (CSF) penetration of circulating 125I-albumin in two different models of experimental meningitis due to K1 Escherichia coli, type III group B streptococcus, or Haemophilus influenzae type b in infant rats: hematogenous meningitis subsequent to subcutaneous inoculation of bacteria vs meningitis induced by direct inoculation of bacteria into the CSF via the cisterna magna. In the model of hematogenous meningitis, the mean CSF penetration was significantly greater in animals with H. influenzae type b meningitis than in those with meningitis due to K1 E. coli or type III group B streptococcus. In contrast, the mean CSF penetration was significantly enhanced in all animals with meningitis induced by intracisternal inoculation regardless of infecting pathogens. Tumor necrosis factor activity in CSF appeared to correlate with the functional penetration of circulating albumin across the blood-brain barrier in both models of experimental meningitis. These findings suggest that the alterations of blood-brain barrier permeability during development of experimental meningitis may vary for different models of inducing meningitis and that the mechanisms responsible for these different permeability changes may be multifactorial.

Permeability and route of entry for lipid-insoluble molecules across brain barriers in developing Monodelphis domestica

PubMed Central

Ek, C Joakim; Habgood, Mark D; Dziegielewska, Katarzyna M; Potter, Ann; Saunders, Norman R

2001-01-01

We have studied the permeability of blood-brain barriers to small molecules such as [14C]sucrose, [3H]inulin, [14C]l-glucose and [3H]glycerol from early stages of development (postnatal day 6, P6) in South American opossums (Monodelphis domestica), using a litter-based method for estimating steady-state cerebrospinal fluid (CSF)/plasma and brain/plasma ratios of markers that were injected i.p.. Steady-state ratios for l-glucose, sucrose and inulin all showed progressive decreases during development. The rate of uptake of l-glucose into the brain and CSF, in short time course experiments (7–24 min) when age-related differences in CSF production can be considered negligible also decreased during development. These results indicate that there is a significant decrease in the permeability of brain barriers to small lipid-insoluble molecules during brain development. The steady-state blood/CSF ratio for 3000 Da lysine-fixable biotin-dextran following i.p. injection was shown to be consistent with diffusion from blood to CSF. It was therefore used to visualise the route of penetration for small lipid-insoluble molecules across brain barriers at P 0–30. The proportion of biotin-dextran-positive cells in the choroid plexuses declined in parallel with the age-related decline in permeability to the small-molecular-weight markers; the paracellular (tight junction) pathway for biotin-dextran appeared to be blocked, but biotin-dextran was easily detectable in the CSF. A transcellular route from blood to CSF was suggested by the finding that some choroid plexus epithelial cells contained biotin-dextran. Biotin-dextran was also taken up by cerebral endothelial cells in the youngest brains studied (P0), but in contrast to the CSF, could not be detected in the brain extracellular space (i.e. a significant blood-brain barrier to small-sized lipid-insoluble compounds was already present). However, in immature brains (P0–13) biotin-dextran was taken up by some cells in the brain. These cells generally had contact with the CSF, suggesting that it is likely to have been the 2source of their biotin-dextran. Since the quantitative permeability data suggest that biotin-dextran behaves similarly to the radiolabelled markers used in this study, it is suggested that these markers in the more immature brains were also present intracellularly. Thus, brain/plasma ratios may be a misleading indicator of blood-brain barrier permeability in very immature animals. The immunocytochemical staining for biotin-dextran in the CSF, in contrast to the lack of staining in the brain extracellular space, together with the quantitative permeability data showing that the radiolabelled markers penetrated more rapidly and to a much higher steady-state level in CSF than in the brain, suggests that lipid-insoluble molecules such as sucrose and inulin reach the immature brain predominantly via the CSF rather than directly across the very few blood vessels that are present at that time. PMID:11691876

Complications of pediatric auditory brain stem implantation via retrosigmoid approach.

PubMed

Bayazit, Yildirim A; Abaday, Ayça; Dogulu, Fikret; Göksu, Nebil

2011-01-01

We aimed to present the complications of auditory brain stem implantations (ABI) in pediatric patients which were performed via retrosigmoid approach. Between March 2007 and February 2010, five prelingually deaf children underwent ABI (Medel device) operation via retrosigmoid approach. All children had severe cochlear malformations. The ages ranged from 20 months to 5 years. The perioperative complications encountered in 2 patients were evaluated retrospectively. No intraoperative complication was observed in the patients. Cerebrospinal fluid (CSF) leakage was the most common postoperative complication that was seen in 2 patients. The CSF leak triggered a cascade of comorbidities, and elongated the hospitalization. Pediatric ABI surgery can lead to morbidity. The CSF leak is the most common complication encountered in retrosigmoid approach. The other complications usually result from long-term hospital stay during treatment period of the CSF leak. Therefore, every attempt must be made to prevent occurrence of CSF leaks in pediatric ABI operations. Copyright © 2011 S. Karger AG, Basel.

Convective influx/glymphatic system: tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways.

PubMed

Albargothy, Nazira J; Johnston, David A; MacGregor-Sharp, Matthew; Weller, Roy O; Verma, Ajay; Hawkes, Cheryl A; Carare, Roxana O

2018-05-12

Tracers injected into CSF pass into the brain alongside arteries and out again. This has been recently termed the "glymphatic system" that proposes tracers enter the brain along periarterial "spaces" and leave the brain along the walls of veins. The object of the present study is to test the hypothesis that: (1) tracers from the CSF enter the cerebral cortex along pial-glial basement membranes as there are no perivascular "spaces" around cortical arteries, (2) tracers leave the brain along smooth muscle cell basement membranes that form the Intramural Peri-Arterial Drainage (IPAD) pathways for the elimination of interstitial fluid and solutes from the brain. 2 μL of 100 μM soluble, fluorescent fixable amyloid β (Aβ) were injected into the CSF of the cisterna magna of 6-10 and 24-30 month-old male mice and their brains were examined 5 and 30 min later. At 5 min, immunocytochemistry and confocal microscopy revealed Aβ on the outer aspects of cortical arteries colocalized with α-2 laminin in the pial-glial basement membranes. At 30 min, Aβ was colocalised with collagen IV in smooth muscle cell basement membranes in the walls of cortical arteries corresponding to the IPAD pathways. No evidence for drainage along the walls of veins was found. Measurements of the depth of penetration of tracer were taken from 11 regions of the brain. Maximum depths of penetration of tracer into the brain were achieved in the pons and caudoputamen. Conclusions drawn from the present study are that tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways. The exit route is along IPAD pathways in which Aβ accumulates in cerebral amyloid angiopathy (CAA) in Alzheimer's disease. Results from this study suggest that CSF may be a suitable route for delivery of therapies for neurological diseases, including CAA.

Absorption kinetics of flurbiprofen axetil microspheres in cerebrospinal fluid: A pilot study
.

PubMed

Zhang, Hong; Gu, Jian; Feng, Yi; An, Haiyan

2017-11-01

The purpose of this study is to investigate the absorption dynamics of flurbiprofen axetil in cerebrospinal fluid. We analyzed the concentrations of flurbiprofen in peripheral venous blood and cerebrospinal fluid (CSF) to explore the absorption dynamics of flurbiprofen axetil loaded in lipid microspheres in CSF. 72 adult patients who planned to undergo selective operations under spinal anesthesia or combined spinal-epidural anesthesia were intravenously injected with flurbiprofen axetil (1 mg/kg) and randomly divided into nine groups according to the sampling time after administration: 5 (T5), 10 (T10), 15 (T15), 20 (T20), 25 (T25), 30 (T30), 35 (T35), 40 (T40), and 45 minutes (T45). The CSF and venous blood samples collected from patients were analyzed by reverse-phase high-performance liquid chromatography to determine the concentrations of flurbiprofen. With the exception of 3 CSF samples in T5 and 4 CSF samples in T10, flurbiprofen was detected in all CSF and blood specimens. Significant differences between the CSF concentrations and CSF/plasma drug concentration ratios were observed among the nine time points (p < 0.001), whereas no significant difference in plasma concentration was found (p > 0.05). The findings suggest that lipid microspheres loaded with flurbiprofen can penetrate through the blood-brain barrier into CSF after intravenous injection. The fact that the flurbiprofen concentration rose continuously for 45 minutes after injection indicates that flurbiprofen-loaded lipid microspheres may exert analgesic action via the central nervous system.
.

Photoacoustic and photothermal detection of circulating tumor cells, bacteria and nanoparticles in cerebrospinal fluid in vivo and ex vivo.

PubMed

Nedosekin, Dmitry A; Juratli, Mazen A; Sarimollaoglu, Mustafa; Moore, Christopher L; Rusch, Nancy J; Smeltzer, Mark S; Zharov, Vladimir P; Galanzha, Ekaterina I

2013-06-01

Circulating cells, bacteria, proteins, microparticles, and DNA in cerebrospinal fluid (CSF) are excellent biomarkers of many diseases, including cancer and infections. However, the sensitivity of existing methods is limited in their ability to detect rare CSF biomarkers at the treatable, early-stage of diseases. Here, we introduce novel CSF tests based on in vivo photoacoustic flow cytometry (PAFC) and ex vivo photothermal scanning cytometry. In the CSF of tumor-bearing mice, we molecularly detected in vivo circulating tumor cells (CTCs) before the development of breast cancer brain metastasis with 20-times higher sensitivity than with current assays. For the first time, we demonstrated assessing three pathways (i.e., blood, lymphatic, and CSF) of CTC dissemination, tracking nanoparticles in CSF in vivo and their imaging ex vivo. In label-free CSF samples, we counted leukocytes, erythrocytes, melanoma cells, and bacteria and imaged intracellular cytochromes, hemoglobin, melanin, and carotenoids, respectively. Taking into account the safety of PAFC, its translation for use in humans is expected to improve disease diagnosis beyond conventional detection limits. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

[Use of the methods of mathematical modeling for evaluation of the data of cerebrospinal fluid examination in patients with bacterial meningoencephalitis].

PubMed

Iarosh, O A; Iarosh, A A

1991-01-01

As many as 300 patients of different age groups underwent a probability statistical analysis of cytosis and CSF protein depending on the outcome of bacterial meningoencephalitis. The clinical and CSF interrelations discovered reflect the function of the blood-brain barrier and can be used as an additional test for predicting the disease outcome.

Drowning stars: Reassessing the role of astrocytes in brain edema

PubMed Central

Thrane, Alexander S.; Thrane, Vinita Rangroo; Nedergaard, Maiken

2014-01-01

Edema formation frequently complicates brain infarction, tumors and trauma. Despite the significant mortality of this condition, current treatment options are often ineffective or incompletely understood. Recent studies have revealed the existence of a brain-wide paravascular pathway for cerebrospinal (CSF) and interstitial fluid (ISF) exchange. The current review critically examines the contribution of this ‘glymphatic’ system to the main types of brain edema. We propose that in cytotoxic edema, energy depletion enhances glymphatic CSF influx, whilst suppressing ISF efflux. We also argue that paravascular inflammation or ‘paravasculitis’ plays a critical role in vasogenic edema. Finally, recent advances in diagnostic imaging of glymphatic function may hold the key to defining the edema profile of individual patients and thus enable more targeted therapy. PMID:25236348

A Robust Two-Dimensional Separation of Intact Proteins for Bottom-Up Tandem Mass Spectrometry of the Human CSF Proteome

PubMed Central

Bora, Adriana; Anderson, Carol; Bachani, Muznabanu; Nath, Avindra; Cotter, Robert J.

2012-01-01

The cerebrospinal fluid (CSF) is produced in the brain by cells in the choroid plexus at a rate of 500mL/day. It is the only body fluid in direct contact with the brain. Thus, any changes in the CSF composition will reflect pathological processes and make CSF a potential source of biomarkers for different disease states. Proteomics offers a comprehensive view of the proteins found in CSF. In this study, we use a recently developed non-gel based method of sample preparation of CSF followed by liquid chromatography high accuracy mass spectrometry (LC-MS) for MS and MS/MS analyses, allowing unambiguous identification of peptides/proteins. Gel-eluted liquid fraction entrapment electrophoresis (Gelfree) is used to separate a CSF complex protein mixture in 12 user-selectable liquid-phase molecular weight fractions. Using this high throughput workflow we have been able to separate CSF intact proteins over a broad mass range 3.5 kDa-100 kDa with high resolution between 15 kDa and 100 kDa in 2 hours and 40 min. We have completely eliminated albumin and were able to interrogate the low abundance CSF proteins in a highly reproducible manner from different CSF samples in the same time. Using LC-MS as a downstream analysis, we identified 368 proteins using MidiTrap G-10 desalting columns and 166 proteins (including 57 unique proteins) using Zeba spin columns with 5% false discovery rate (FDR). Prostaglandin D2 synthase, Chromogranin A, Apolipoprotein E, Chromogranin B, Secretogranin III, Cystatin C, VGF nerve growth factor, Cadherin 2 are a few of the proteins that were characterized. The Gelfree-LC-MS is a robust method for the analysis of the human proteome that we will use to develop biomarkers for several neurodegenerative diseases and to quantitate these markers using multiple reaction monitoring. PMID:22537003

The effect of perinatal anoxia on amino acid metabolism in the developing brain. Part II: The effect of perinatal anoxia on the free amino acid patterns in CSF of infants and children.

PubMed

Kaneko, K

1985-01-01

To clarify the effects of perinatal anoxia on the subsequent amino acid metabolism in the brain of children, free amino acid levels in the cerebrospinal fluid (CSF) were determined in 15 children diagnosed as having cerebral palsy and/or mental retardation with perinatal anoxia, and 58 control children without anoxia, aged from 4 days to 12 yrs. There was no significant difference in total amino acid levels between anoxic children and the controls. In the controls, the Gln level in CSF was high, Arg, Asp and Glu levels in CSF were almost the same during infancy and childhood, and the levels of Orn, Lys, His, Tau, Thr, Ser, Asn, Gly, Ala, Val, Met, Ile, Leu, Tyr and Phe in CSF decreased with age until pre-school age. In the newborns and infants among the anoxic children, the levels of most free amino acids in CSF were relatively high compared with those of the controls and, except Glu and Gln, decreased with age during infancy. The Orn, His, Gly, Tyr and Phe levels in CSF of anoxic children were lower than those of the controls in older infants. These results suggest that perinatal anoxia affected free amino acid patterns in CSF of newborns and infants and that the subsequent disturbance of amino acid metabolism in their brains remained after birth.

The Brain Response to Peripheral Insulin Declines with Age: A Contribution of the Blood-Brain Barrier?

PubMed Central

Heni, Martin; Maetzler, Walter; Fritsche, Andreas; Häring, Hans-Ulrich; Hennige, Anita M.

2015-01-01

Objectives It is a matter of debate whether impaired insulin action originates from a defect at the neural level or impaired transport of the hormone into the brain. In this study, we aimed to investigate the effect of aging on insulin concentrations in the periphery and the central nervous system as well as its impact on insulin-dependent brain activity. Methods Insulin, glucose and albumin concentrations were determined in 160 paired human serum and cerebrospinal fluid (CSF) samples. Additionally, insulin was applied in young and aged mice by subcutaneous injection or intracerebroventricularly to circumvent the blood-brain barrier. Insulin action and cortical activity were assessed by Western blotting and electrocorticography radiotelemetric measurements. Results In humans, CSF glucose and insulin concentrations were tightly correlated with the respective serum/plasma concentrations. The CSF/serum ratio for insulin was reduced in older subjects while the CSF/serum ratio for albumin increased with age like for most other proteins. Western blot analysis in murine whole brain lysates revealed impaired phosphorylation of AKT (P-AKT) in aged mice following peripheral insulin stimulation whereas P-AKT was comparable to levels in young mice after intracerebroventricular insulin application. As readout for insulin action in the brain, insulin-mediated cortical brain activity instantly increased in young mice subcutaneously injected with insulin but was significantly reduced and delayed in aged mice during the treatment period. When insulin was applied intracerebroventricularly into aged animals, brain activity was readily improved. Conclusions This study discloses age-dependent changes in insulin CSF/serum ratios in humans. In the elderly, cerebral insulin resistance might be partially attributed to an impaired transport of insulin into the central nervous system. PMID:25965336

Human Cerebrospinal Fluid Promotes Neuronal Viability and Activity of Hippocampal Neuronal Circuits In Vitro

PubMed Central

Perez-Alcazar, Marta; Culley, Georgia; Lyckenvik, Tim; Mobarrez, Kristoffer; Bjorefeldt, Andreas; Wasling, Pontus; Seth, Henrik; Asztely, Frederik; Harrer, Andrea; Iglseder, Bernhard; Aigner, Ludwig; Hanse, Eric; Illes, Sebastian

2016-01-01

For decades it has been hypothesized that molecules within the cerebrospinal fluid (CSF) diffuse into the brain parenchyma and influence the function of neurons. However, the functional consequences of CSF on neuronal circuits are largely unexplored and unknown. A major reason for this is the absence of appropriate neuronal in vitro model systems, and it is uncertain if neurons cultured in pure CSF survive and preserve electrophysiological functionality in vitro. In this article, we present an approach to address how human CSF (hCSF) influences neuronal circuits in vitro. We validate our approach by comparing the morphology, viability, and electrophysiological function of single neurons and at the network level in rat organotypic slice and primary neuronal cultures cultivated either in hCSF or in defined standard culture media. Our results demonstrate that rodent hippocampal slices and primary neurons cultured in hCSF maintain neuronal morphology and preserve synaptic transmission. Importantly, we show that hCSF increases neuronal viability and the number of electrophysiologically active neurons in comparison to the culture media. In summary, our data indicate that hCSF represents a physiological environment for neurons in vitro and a superior culture condition compared to the defined standard media. Moreover, this experimental approach paves the way to assess the functional consequences of CSF on neuronal circuits as well as suggesting a novel strategy for central nervous system (CNS) disease modeling. PMID:26973467

A Customized Quantitative PCR MicroRNA Panel Provides a Technically Robust Context for Studying Neurodegenerative Disease Biomarkers and Indicates a High Correlation Between Cerebrospinal Fluid and Choroid Plexus MicroRNA Expression.

PubMed

Wang, Wang-Xia; Fardo, David W; Jicha, Gregory A; Nelson, Peter T

2017-12-01

MicroRNA (miRNA) expression varies in association with different tissue types and in diseases. Having been found in body fluids including blood and cerebrospinal fluid (CSF), miRNAs constitute potential biomarkers. CSF miRNAs have been proposed as biomarkers for neurodegenerative diseases; however, there is a lack of consensus about the best candidate miRNA biomarkers and there has been variability in results from different research centers, perhaps due to technical factors. Here, we sought to optimize technical parameters for CSF miRNA studies. We examined different RNA isolation methods and performed miRNA expression profiling with TaqMan® miRNA Arrays. More specifically, we developed a customized CSF-miRNA low-density array (TLDA) panel that contains 47 targets: miRNAs shown previously to be relevant to neurodegenerative disease, miRNAs that are abundant in CSF, data normalizers, and controls for potential blood and tissue contamination. The advantages of using this CSF-miRNA TLDA panel include specificity, sensitivity, fast processing and data analysis, and cost effectiveness. We optimized technical parameters for this assay. Further, the TLDA panel can be tailored to other specific purposes. We tested whether the profile of miRNAs in the CSF resembled miRNAs isolated from brain tissue (hippocampus or cerebellum), blood, or the choroid plexus. We found that the CSF miRNA expression profile most closely resembles that of choroid plexus tissue, underscoring the potential importance of choroid plexus-derived signaling through CSF miRNAs. In summary, the TLDA miRNA array panel will enable evaluation and discovery of CSF miRNA biomarkers and can potentially be utilized in clinical diagnosis and disease stage monitoring.

A mutation in Ccdc39 causes neonatal hydrocephalus with abnormal motile cilia development in mice.

PubMed

Abdelhamed, Zakia; Vuong, Shawn M; Hill, Lauren; Shula, Crystal; Timms, Andrew; Beier, David; Campbell, Kenneth; Mangano, Francesco T; Stottmann, Rolf W; Goto, June

2018-01-09

Pediatric hydrocephalus is characterized by an abnormal accumulation of cerebrospinal fluid (CSF) and is one of the most common congenital brain abnormalities. However, little is known about the molecular and cellular mechanisms regulating CSF flow in the developing brain. Through whole-genome sequencing analysis, we report that a homozygous splice site mutation in coiled-coil domain containing 39 ( Ccdc39 ) is responsible for early postnatal hydrocephalus in the progressive hydrocephal us ( prh ) mouse mutant. Ccdc39 is selectively expressed in embryonic choroid plexus and ependymal cells on the medial wall of the forebrain ventricle, and the protein is localized to the axoneme of motile cilia. The Ccdc39 prh/prh ependymal cells develop shorter cilia with disorganized microtubules lacking the axonemal inner arm dynein. Using high-speed video microscopy, we show that an orchestrated ependymal ciliary beating pattern controls unidirectional CSF flow on the ventricular surface, which generates bulk CSF flow in the developing brain. Collectively, our data provide the first evidence for involvement of Ccdc39 in hydrocephalus and suggest that the proper development of medial wall ependymal cilia is crucial for normal mouse brain development. © 2018. Published by The Company of Biologists Ltd.

Cannula Implantation into the Cisterna Magna of Rodents.

PubMed

Xavier, Anna L R; Hauglund, Natalie Linea; von Holstein-Rathlou, Stephanie; Li, Qianliang; Sanggaard, Simon; Lou, Nanhong; Lundgaard, Iben; Nedergaard, Maiken

2018-05-23

Cisterna magna cannulation (CMc) is a straightforward procedure that enables direct access to the cerebrospinal fluid (CSF) without operative damage to the skull or the brain parenchyma. In anesthetized rodents, the exposure of the dura mater by blunt dissection of the neck muscles allows the insertion of a cannula into the cisterna magna (CM). The cannula, composed either by a fine beveled needle or borosilicate capillary, is attached via a polyethylene (PE) tube to a syringe. Using a syringe pump, molecules can then be injected at controlled rates directly into the CM, which is continuous with the subarachnoid space. From the subarachnoid space, we can trace CSF fluxes by convective flow into the perivascular space around penetrating arterioles, where solute exchange with the interstitial fluid (ISF) occurs. CMc can be performed for acute injections immediately following the surgery, or for chronic implantation, with later injection in anesthetized or awake, freely moving rodents. Quantitation of tracer distribution in the brain parenchyma can be performed by epifluorescence, 2-photon microscopy, and magnetic resonance imaging (MRI), depending on the physico-chemical properties of the injected molecules. Thus, CMc in conjunction with various imaging techniques offers a powerful tool for assessment of the glymphatic system and CSF dynamics and function. Furthermore, CMc can be utilized as a conduit for fast, brain-wide delivery of signaling molecules and metabolic substrates that could not otherwise cross the blood brain barrier (BBB).

Blood-brain barrier and foetal-onset hydrocephalus, with a view on potential novel treatments beyond managing CSF flow.

PubMed

Guerra, M; Blázquez, J L; Rodríguez, E M

2017-07-13

Despite decades of research, no compelling non-surgical therapies have been developed for foetal hydrocephalus. So far, most efforts have pointed to repairing disturbances in the cerebrospinal fluid (CSF) flow and to avoid further brain damage. There are no reports trying to prevent or diminish abnormalities in brain development which are inseparably associated with hydrocephalus. A key problem in the treatment of hydrocephalus is the blood-brain barrier that restricts the access to the brain for therapeutic compounds or systemically grafted cells. Recent investigations have started to open an avenue for the development of a cell therapy for foetal-onset hydrocephalus. Potential cells to be used for brain grafting include: (1) pluripotential neural stem cells; (2) mesenchymal stem cells; (3) genetically-engineered stem cells; (4) choroid plexus cells and (5) subcommissural organ cells. Expected outcomes are a proper microenvironment for the embryonic neurogenic niche and, consequent normal brain development.

Normal brain tissue volumes after long-term recovery in anorexia and bulimia nervosa.

PubMed

Wagner, Angela; Greer, Phil; Bailer, Ursula F; Frank, Guido K; Henry, Shannan E; Putnam, Karen; Meltzer, Carolyn C; Ziolko, Scott K; Hoge, Jessica; McConaha, Claire; Kaye, Walter H

2006-02-01

Individuals who are ill with anorexia (AN) and bulimia nervosa (BN) often have increased cerebrospinal fluid (CSF) volumes and decreased total gray and white matter volumes. It is unclear whether such disturbances persist after recovery from an eating disorder. Magnetic resonance imaging was performed on 40 women who were long-term recovered (>1 year no binging, purging, or restricting behaviors, normal weight, and menstrual cycles, not on medication) from restricting or binge/purging type AN or BN and 31 healthy control women (CW). Voxel-based morphometry (VBM) was used for data analysis. Recovered AN and BN subgroups were similar to CW in terms of cerebrospinal fluid (CSF) volume as well as total or regional gray or white matter volume. These findings suggest that structural brain abnormalities are reversible in individuals with eating disorders after long-term recovery.

The circulation of the cerebrospinal fluid (CSF) in the spinal canal

NASA Astrophysics Data System (ADS)

Sanchez, Antonio L.; Martinez-Bazan, Carlos; Lasheras, Juan C.

2016-11-01

Cerebrospinal Fluid (CSF) is secreted in the choroid plexus in the lateral sinuses of the brain and fills the subarachnoid space bathing the external surfaces of the brain and the spinal canal. Absence of CSF circulation has been shown to impede its physiological function that includes, among others, supplying nutrients to neuronal and glial cells and removing the waste products of cellular metabolism. Radionuclide scanning images published by Di Chiro in 1964 showed upward migration of particle tracers from the lumbar region of the spinal canal, thereby suggesting the presence of an active bulk circulation responsible for bringing fresh CSF into the spinal canal and returning a portion of it to the cranial vault. However, the existence of this slow moving bulk circulation in the spinal canal has been a subject of dispute for the last 50 years. To date, there has been no physical explanation for the mechanism responsible for the establishment of such a bulk motion. We present a perturbation analysis of the flow in an idealized model of the spinal canal and show how steady streaming could be responsible for the establishment of such a circulation. The results of this analysis are compared to flow measurements conducted on in-vitro models of the spinal canal of adult humans.

Clinical assessment of cerebrospinal fluid dynamics in hydrocephalus. Guide to interpretation based on observational study.

PubMed

Weerakkody, R A; Czosnyka, M; Schuhmann, M U; Schmidt, E; Keong, N; Santarius, T; Pickard, J D; Czosnyka, Z

2011-08-01

The term hydrocephalus encompasses a range of disorders characterised by clinical symptoms, abnormal brain imaging and derangement of cerebrospinal fluid (CSF) dynamics. The ability to elucidate which patients would benefit from CSF diversion (a shunt or third ventriculostomy) is often unclear. Similar difficulties are often encountered in shunted patients to predict the scope for improvement by shunt re-adjustment or revision. In this study we aimed to update our knowledge of how key quantitative parameters describing CSF dynamics may be used in diagnosis of shunt-responsive hydrocephalus and in the assessment of shunt function. A number of quantitative parameters [including resistance to CSF outflow (Rcsf), pulse amplitude of intracranial pressure waveform (AMP), RAP index and slow vasogenic waves] were studies in 1423 patients with 2665 CSF infusion tests and 305 overnight intracranial pressure (ICP)-monitoring sessions over a 17 year period. We demonstrate our observations for typical values of Pb, Rcsf, AMP, slow vasogenic waves derived from infusion studies or overnight ICP monitoring in differentiating atrophy from shunt-responsive normal pressure hydrocephalus or acute hydrocephalus. From the same variables tested on shunted patients we demonstrate a standardised approach to help differentiate a properly-functioning shunt from underdrainage or overdrainage. Quantitative variables derived from CSF dynamics allow differentiation between clinically overlapping entities such as shunt-responsive normal pressure hydrocephalus and brain atrophy (not shunt responsive) as well as allowing the detection of shunt malfunction (partial or complete blockage) or overdrainage. This observational study is intended to serve as an update for our understanding of quantitative testing of CSF dynamics. © 2011 John Wiley & Sons A/S.

Cerebrospinal Fluid Concentration of Key Autophagy Protein Lamp2 Changes Little During Normal Aging

PubMed Central

Loeffler, David A.; Klaver, Andrea C.; Coffey, Mary P.; Aasly, Jan O.

2018-01-01

Autophagy removes both functional and damaged intracellular macromolecules from cells via lysosomal degradation. Three autophagic mechanisms, namely macroautophagy, chaperone-mediated autophagy (CMA), and microautophagy, have been described in mammals. Studies in experimental systems have found macroautophagy and CMA to decrease with normal aging, despite the fact that oxidative stress, which can activate both processes, increases with normal aging. Whether autophagic mechanisms decrease in the human brain during normal aging is unclear. The primary objective of this study was to examine the association of a major autophagy protein, lysosome-associated membrane glycoprotein (lamp2), with age in cerebrospinal fluid (CSF) samples from healthy subjects. Lamp2 consists of three isoforms, lamp2a, 2b and 2c, all of which participate in autophagy. Lamp2’s CSF concentration decreases in Parkinson’s disease (PD) and increases in Alzheimer’s disease (AD), but whether its CSF concentration changes during normal aging has not been investigated. Our secondary objectives were to examine the associations of lamp2’s CSF concentration with CSF levels of the molecular chaperone heat shock 70-kDa protein (HSPA8), which interacts with lamp2a in CMA, and oxidative stress markers 8-hydroxy-2′-deoxyguanosine (8-OHdG), 8-isoprostane (8-ISO) and Total Antioxidant Capacity (TAC) in healthy subjects. We found lamp2’s observed associations with these variables to be weak, with all Kendall’s tau-b absolute values ≤0.20. These results suggest that CSF lamp2 concentration changes little during normal aging and does not appear to be associated with HSPA8 or oxidative stress. Further studies are indicated to determine the relationship between CSF lamp2 concentration and brain autophagic processes.

Spaceflight-induced changes in white matter hyperintensity burden in astronauts.

PubMed

Alperin, Noam; Bagci, Ahmet M; Lee, Sang H

2017-11-21

To assess the effect of weightlessness and the respective roles of CSF and vascular fluid on changes in white matter hyperintensity (WMH) burden in astronauts. We analyzed prespaceflight and postspaceflight brain MRI scans from 17 astronauts, 10 who flew a long-duration mission on the International Space Station (ISS) and 7 who flew a short-duration mission on the Space Shuttle. Automated analysis methods were used to determine preflight to postflight changes in periventricular and deep WMH, CSF, and brain tissue volumes in fluid-attenuated inversion recovery and high-resolution 3-dimensional T1-weighted imaging. Differences between cohorts and associations between individual measures were assessed. The short-term reversibility of the identified preflight to postflight changes was tested in a subcohort of 5 long-duration astronauts who had a second postflight MRI scan 1 month after the first postflight scan. Significant preflight to postflight changes were measured only in the long-duration cohort and included only the periventricular WMH and ventricular CSF volumes. Changes in deep WMH and brain tissue volumes were not significant in either cohort. The increase in periventricular WMH volume was significantly associated with an increase in ventricular CSF volume (ρ = 0.63, p = 0.008). A partial reversal of these increases was observed in the long-duration subcohort with a 1-month follow-up scan. Long-duration exposure to microgravity is associated with an increase in periventricular WMH in astronauts. This increase was linked to an increase in ventricular CSF volume documented in ISS astronauts. There was no associated change in or abnormal levels of WMH volumes in deep white matter as reported in U-2 high-altitude pilots. © 2017 American Academy of Neurology.

Drug concentrations in the serum and cerebrospinal fluid of patients treated with cefoperazone/sulbactam after craniotomy.

PubMed

Wang, Qiang; Wu, Yuanxing; Chen, Biyao; Zhou, Jianxin

2015-01-01

To identify changes in cefoperazone/sulbactam penetration into cerebrospinal fluid (CSF) after craniotomy and to investigate preliminarily whether cefoperazone/sulbactam CSF concentration can reach therapeutic level when administered intravenously after neurosurgical operation. Neurosurgical patients with an indwelling ventricular drainage pipe who received prophylactic cefoperazone/sulbactam for the treatment of intracranial infection were received a cefoperazone/sulbactam 2:1, 3.0-g infusion for 3 hours every 6 hours for 24 h. Venous blood and CSF specimens were collected to determine cefoperazone/sulbactam concentrations. The cefoperazone and sulbactam concentrations in serum were highest at the second hour (237.54 ± 336.72 mg/L and 66.52 ± 80.38 mg/L, respectively) and then decreased. The cefoperazone and sulbactam concentrations in CSF were highest at the 4th hour (39.22 ± 75.55 mg/L and 6.24 ± 8.35 mg/L, respectively) and then decreased. CSF penetration measured by the ratio of peak concentrations (CSF/serum) was 8.6% ± 7.2% for cefoperazone and 13.5% ± 11.9% for sulbactam, CSF penetration measured by the ratio of trough concentrations (CSF/serum) was 13.4% ± 5.3% for cefoperazone and 106.5% ± 87.5% for sulbactam. CSF penetration represented by the ratio of area under the curve (AUC) of CSF and serum was 14.5% for cefoperazone and 22.6% for sulbactam. Neurosurgical impairment of the blood-brain barrier may improve the CSF penetration of these drugs, but it is difficult to reach the MIC90 of resistant bacteria. If single intravenous administration time was extended to 3 hours, the serum concentrations of drugs were able to meet the PK/PD standard (T> MIC%> 50%) for treating common, highly resistant bacteria. The CSF penetration of cefoperazone/sulbactam may be enhanced after neurosurgical impairment of the blood-brain barrier. This study is a pilot research of cefoperazone/sulbactam using in neurosurgical individuals, However, it needs to be confirmed by further large-scale studies.

Central nervous system immune activation characterizes primary human immunodeficiency virus 1 infection even in participants with minimal cerebrospinal fluid viral burden.

PubMed

Spudich, Serena; Gisslen, Magnus; Hagberg, Lars; Lee, Evelyn; Liegler, Teri; Brew, Bruce; Fuchs, Dietmar; Tambussi, Giuseppe; Cinque, Paola; Hecht, Frederick M; Price, Richard W

2011-09-01

Central nervous system (CNS) human immunodeficiency virus (HIV) infection and immune activation lead to brain injury and neurological impairment. Although HIV enters the nervous system soon after transmission, the magnitude of infection and immunoactivation within the CNS during primary HIV infection (PHI) has not been characterized. This cross-sectional study analyzed cerebrospinal fluid (CSF) and blood from 96 participants with PHI and compared them with samples from neuroasymptomatic participants with chronic infection and ≥ 200 or < 200 blood CD4 T cells/μL, and with samples from HIV-seronegative participants with respect to CSF and plasma HIV RNA, CSF to serum albumin ratio, and CSF white blood cell counts (WBC), neopterin levels, and concentrations of chemokines CXCL10 and CCL2. The PHI participants (median 77 days post transmission) had CSF HIV RNA, WBC, neopterin, and CXCL10 concentrations similar to the chronic infection participants but uniquely high albumin ratios. 18 participants had ≤ 100 copies/mL CSF HIV RNA, which was associated with low CSF to plasma HIV ratios and levels of CSF inflammation lower than in other PHI participants but higher than in HIV-seronegative controls. Prominent CNS infection and immune activation is evident during the first months after HIV transmission, though a proportion of PHI patients demonstrate relatively reduced CSF HIV RNA and inflammation during this early period.

Decreased levels of guanosine 3', 5'-monophosphate (cGMP) in cerebrospinal fluid (CSF) are associated with cognitive decline and amyloid pathology in Alzheimer's disease.

PubMed

Ugarte, Ana; Gil-Bea, Francisco; García-Barroso, Carolina; Cedazo-Minguez, Ángel; Ramírez, M Javier; Franco, Rafael; García-Osta, Ana; Oyarzabal, Julen; Cuadrado-Tejedor, Mar

2015-06-01

Levels of the cyclic nucleotides guanosine 3', 5'-monophosphate (cGMP) or adenosine 3', 5'-monophosphate (cAMP) that play important roles in memory processes are not characterized in Alzheimer's disease (AD). The aim of this study was to analyse the levels of these nucleotides in cerebrospinal fluid (CSF) samples from patients diagnosed with clinical and prodromal stages of AD and study the expression level of the enzymes that hydrolyzed them [phosphodiesterases (PDEs)] in the brain of AD patients vs. For cGMP and cAMP CSF analysis, the cohort (n = 79) included cognitively normal participants (subjective cognitive impairment), individuals with stable mild cognitive impairment or AD converters (sMCI and cMCI), and mild AD patients. A high throughput liquid chromatography-tandem mass spectrometry method was used. Interactions between CSF cGMP or cAMP with mini-mental state examination (MMSE) score, CSF Aβ(1-42) and CSF p-tau were analysed. For PDE4, 5, 9 and 10 expression analysis, brains of AD patients vs. controls (n = 7 and n = 8) were used. cGMP, and not cAMP levels, were significantly lower in the CSF of patients diagnosed with mild AD when compared with nondemented controls. CSF levels of cGMP showed a significant association with MMSE-diagnosed clinical dementia and with CSF biomarker Aβ42 in AD patients. Significant increase in PDE5 expression was detected in temporal cortex of AD patients compared with that of age-matched healthy control subjects. No changes in the expression of others PDEs were detected. These results support the potential involvement of cGMP in the pathological and clinical development of AD. The cGMP reduction in early stages of AD might participate in the aggravation of amyloid pathology and cognitive decline. © 2014 British Neuropathological Society.

Cerebrospinal Fluid Clearance in Alzheimer Disease Measured with Dynamic PET.

PubMed

de Leon, Mony J; Li, Yi; Okamura, Nobuyuki; Tsui, Wai H; Saint-Louis, Les A; Glodzik, Lidia; Osorio, Ricardo S; Fortea, Juan; Butler, Tracy; Pirraglia, Elizabeth; Fossati, Silvia; Kim, Hee-Jin; Carare, Roxana O; Nedergaard, Maiken; Benveniste, Helene; Rusinek, Henry

2017-09-01

Evidence supporting the hypothesis that reduced cerebrospinal fluid (CSF) clearance is involved in the pathophysiology of Alzheimer disease (AD) comes primarily from rodent models. However, unlike rodents, in which predominant extracranial CSF egress is via olfactory nerves traversing the cribriform plate, human CSF clearance pathways are not well characterized. Dynamic PET with 18 F-THK5117, a tracer for tau pathology, was used to estimate the ventricular CSF time-activity as a biomarker for CSF clearance. We tested 3 hypotheses: extracranial CSF is detected at the superior turbinates; CSF clearance is reduced in AD; and CSF clearance is inversely associated with amyloid deposition. Methods: Fifteen subjects, 8 with AD and 7 normal control volunteers, were examined with 18 F-THK5117. Ten subjects additionally underwent 11 C-Pittsburgh compound B ( 11 C-PiB) PET scanning, and 8 were 11 C-PiB-positive. Ventricular time-activity curves of 18 F-THK5117 were used to identify highly correlated time-activity curves from extracranial voxels. Results: For all subjects, the greatest density of CSF-positive extracranial voxels was in the nasal turbinates. Tracer concentration analyses validated the superior nasal turbinate CSF signal intensity. AD patients showed ventricular tracer clearance reduced by 23% and 66% fewer superior turbinate CSF egress sites. Ventricular CSF clearance was inversely associated with amyloid deposition. Conclusion: The human nasal turbinate is part of the CSF clearance system. Lateral ventricle and superior nasal turbinate CSF clearance abnormalities are found in AD. Ventricular CSF clearance reductions are associated with increased brain amyloid depositions. These data suggest that PET-measured CSF clearance is a biomarker of potential interest in AD and other neurodegenerative diseases. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

Monochloroacetic acid lethality in the rat in relation to lactic acid accumulation in the cerebrospinal fluid

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mitroka, J.G.

1989-01-01

Potential antidotes for human exposure to monochloroacetic acid (MCA) were evaluated using a rodent model. Dichloroacetic acid (DCA) and phenobarbital (PB) but not ethanol or phenytoin, were found to be effective antidotes to monochloroacetic acid (MCA) in rats. DCA (110 mg/kg, ip), administered to rats 15 minutes after a LD-80 of MCA (80 mg/kg, iv), consistently reduced mortality to 0%, while PB reduced mortality to less than 20%. Both DCA and PB were found to be similarly effective in mice. The hypothesis that PB reduces mortality in MCA treated rats by altering the metabolic disposition of MCA was evaluated andmore » rejected. Administration of PB to rats treated with a lethal dose of ({sup 14}C)MCA did not alter the concentrations of MCA or its metabolites in plasma or cerebrospinal fluid (CSF), or the extent of covalent binding between radioactivity equivalent to ({sup 14}C)MCA and brain proteins. The relationship between altered blood-brain barrier permeability and death in MCA treated rats was investigated. Treatment with MCA (80 mg/kg, iv) was associated with a significant (50%) increase in the permeability of the rat blood-brain barrier to ({sup 125}I)BSA. The effect was not altered by treatment with PB, however, suggesting that altered blood-brain barrier permeability does not have an important role in the lethal effect of MCA in rats. The effect of MCA on brain carbohydrate metabolism in vivo was investigated. CSF and blood lactic acid concentrations increased in MCA treated rats, and the increase in CSF levels was dose related. In individual MCA treated rats, CSF lactate concentrations paralleled the time course of ataxia and a discrete threshold for death (18 mmol/L) was observed. The relationship between excess brain lactate levels and death in MCA treated rats was investigated further.« less

Drowning stars: reassessing the role of astrocytes in brain edema.

PubMed

Thrane, Alexander S; Rangroo Thrane, Vinita; Nedergaard, Maiken

2014-11-01

Edema formation frequently complicates brain infarction, tumors, and trauma. Despite the significant mortality of this condition, current treatment options are often ineffective or incompletely understood. Recent studies have revealed the existence of a brain-wide paravascular pathway for cerebrospinal (CSF) and interstitial fluid (ISF) exchange. The current review critically examines the contribution of this 'glymphatic' system to the main types of brain edema. We propose that in cytotoxic edema, energy depletion enhances glymphatic CSF influx, whilst suppressing ISF efflux. We also argue that paravascular inflammation or 'paravasculitis' plays a critical role in vasogenic edema. Finally, recent advances in diagnostic imaging of glymphatic function may hold the key to defining the edema profile of individual patients, and thus enable more targeted therapy. Copyright © 2014 Elsevier Ltd. All rights reserved.

An Antidepressant Decreases CSF Aβ Production in Healthy Individuals and in Transgenic AD Mice

PubMed Central

Sheline, Yvette I.; West, Tim; Yarasheski, Kevin; Swarm, Robert; Jasielec, Mateusz S.; Fisher, Jonathan R.; Ficker, Whitney D.; Yan, Ping; Xiong, Chengjie; Frederiksen, Christine; Grzelak, Monica V.; Chott, Robert; Bateman, Randall J.; Morris, John C.; Mintun, Mark A.; Lee, Jin-Moo; Cirrito, John R.

2014-01-01

Serotonin signaling suppresses generation of amyloid-β (Aβ) in vitro and in animal models of Alzheimer’s disease (AD). We show that in an aged transgenic AD mouse model (APP/PS1 plaque-bearing mice), the antidepressant citalopram, a selective serotonin reuptake inhibitor (SSRI), decreased Aβ in brain interstitial fluid (ISF) in a dose-dependent manner. Growth of individual amyloid plaques was assessed in plaque-bearing mice that were chronically administered citalopram. Citalopram arrested the growth of pre-existing plaques and reduced the appearance of new plaques by 78%. In healthy human volunteers, citalopram’s effects on Aβ production and Aβ concentrations in cerebrospinal fluid (CSF) were measured prospectively using stable-isotope labeling kinetics (SILK), with CSF sampling during acute dosing of citalopram. Aβ production in CSF was slowed by 37% in the citalopram group compared to placebo. This change was associated with a 38% decrease in total CSF Aβ concentrations in the drug-treated group. The ability to safely decrease Aβ concentrations is potentially important as a preventive strategy for AD. This study demonstrates key target engagement for future AD prevention trials. PMID:24828079

Vitamin B6 in plasma and cerebrospinal fluid of children.

PubMed

Albersen, Monique; Bosma, Marjolein; Jans, Judith J M; Hofstede, Floris C; van Hasselt, Peter M; de Sain-van der Velden, Monique G M; Visser, Gepke; Verhoeven-Duif, Nanda M

2015-01-01

Over the past years, the essential role of vitamin B6 in brain development and functioning has been recognized and genetic metabolic disorders resulting in functional vitamin B6 deficiency have been identified. However, data on B6 vitamers in children are scarce. B6 vitamer concentrations in simultaneously sampled plasma and cerebrospinal fluid (CSF) of 70 children with intellectual disability were determined by ultra performance liquid chromatography-tandem mass spectrometry. For ethical reasons, CSF samples could not be obtained from healthy children. The influence of sex, age, epilepsy and treatment with anti-epileptic drugs, were investigated. The B6 vitamer composition of plasma (pyridoxal phosphate (PLP) > pyridoxic acid > pyridoxal (PL)) differed from that of CSF (PL > PLP > pyridoxic acid > pyridoxamine). Strong correlations were found for B6 vitamers in and between plasma and CSF. Treatment with anti-epileptic drugs resulted in decreased concentrations of PL and PLP in CSF. We provide concentrations of all B6 vitamers in plasma and CSF of children with intellectual disability (±epilepsy), which can be used in the investigation of known and novel disorders associated with vitamin B6 metabolism as well as in monitoring of the biochemical effects of treatment with vitamin B6.

A novel liquid chromatography/tandem mass spectrometry method for the quantification of glycine as biomarker in brain microdialysis and cerebrospinal fluid samples within 5min.

PubMed

Voehringer, Patrizia; Fuertig, René; Ferger, Boris

2013-11-15

Glycine is an important amino acid neurotransmitter in the central nervous system (CNS) and a useful biomarker to indicate biological activity of drugs such as glycine reuptake inhibitors (GRI) in the brain. Here, we report how a liquid chromatography/tandem mass spectrometry (LC-MS/MS) method for the fast and reliable analysis of glycine in brain microdialysates and cerebrospinal fluid (CSF) samples has been established. Additionally, we compare this method with the conventional approach of high performance liquid chromatography (HPLC) coupled to fluorescence detection (FD). The present LC-MS/MS method did not require any derivatisation step. Fifteen microliters of sample were injected for analysis. Glycine was detected by a triple quadrupole mass spectrometer in the positive electrospray ionisation (ESI) mode. The total running time was 5min. The limit of quantitation (LOQ) was determined as 100nM, while linearity was given in the range from 100nM to 100μM. In order to demonstrate the feasibility of the LC-MS/MS method, we measured glycine levels in striatal in vivo microdialysates and CSF of rats after administration of the commercially available glycine transporter 1 (GlyT1) inhibitor LY 2365109 (10mg/kg, p.o.). LY 2365109 produced 2-fold and 3-fold elevated glycine concentrations from 1.52μM to 3.6μM in striatal microdialysates and from 10.38μM to 36μM in CSF, respectively. In conclusion, we established a fast and reliable LC-MS/MS method, which can be used for the quantification of glycine in brain microdialysis and CSF samples in biomarker studies. Copyright © 2013 Elsevier B.V. All rights reserved.

Virchow-Robin space and aquaporin-4: new insights on an old friend.

PubMed

Nakada, Tsutomu

2014-08-28

Recent studies have strongly indicated that the classic circulation model of cerebrospinal fluid (CSF) is no longer valid. The production of CSF is not only dependent on the choroid plexus but also on water flux in the peri-capillary (Virchow Robin) space. Historically, CSF flow through the Virchow Robin space is known as interstitial flow, the physiological significance of which is now fully understood. This article briefly reviews the modern concept of CSF physiology and the Virchow-Robin space, in particular its functionalities critical for central nervous system neural activities. Water influx into the Virchow Robin space and, hence, interstitial flow is regulated by aquaporin-4 (AQP-4) localized in the endfeet of astrocytes, connecting the intracellular cytosolic fluid space of astrocytes and the Virchow Robin space. Interstitial flow has a functionality equivalent to systemic lymphatics, on which clearance of β-amyloid is strongly dependent. Autoregulation of brain blood flow serves to maintain a constant inner capillary fluid pressure, allowing fluid pressure of the Virchow Robin space to regulate regional cerebral blood flow (rCBF) based on AQP-4 gating. Excess heat produced by neural activities is effectively removed from the area of activation by increased rCBF by closing AQP-4 channels. This neural flow coupling (NFC) is likely mediated by heat generated proton channels.

An integrated mechanism of pediatric pseudotumor cerebri syndrome: evidence of bioenergetic and hormonal regulation of cerebrospinal fluid dynamics

PubMed Central

Sheldon, Claire A.; Kwon, Young Joon; Liu, Grant T.; McCormack, Shana E.

2015-01-01

Pseudotumor cerebri syndrome (PTCS) is defined by the presence of elevated intracranial pressure (ICP) in the setting of normal brain parenchyma and cerebrospinal fluid (CSF). Headache, vision changes, and papilledema are common presenting features. Up to 10% of appropriately treated patients may experience permanent visual loss. The mechanism(s) underlying PTCS is unknown. PTCS occurs in association with a variety of conditions, including kidney disease, obesity, and adrenal insufficiency, suggesting endocrine and/or metabolic derangements may occur. Recent studies suggest that fluid and electrolyte balance in renal epithelia is regulated by a complex interaction of metabolic and hormonal factors; these cells share many of the same features as the choroid plexus cells in the central nervous system (CNS) responsible for regulation of CSF dynamics. Thus, we posit that similar factors may influence CSF dynamics in both types of fluid-sensitive tissues. Specifically, we hypothesize that, in patients with PTCS, mitochondrial metabolites (glutamate, succinate) and steroid hormones (cortisol, aldosterone) regulate CSF production and/or absorption. In this integrated mechanism review, we consider the clinical and molecular evidence for each metabolite and hormone in turn. We illustrate how related intracellular signaling cascades may converge in the choroid plexus, drawing on evidence from functionally similar tissues. PMID:25420176

Pseudo-polar drive patterns for brain electrical impedance tomography.

PubMed

Shi, Xuetao; Dong, Xiuzhen; Shuai, Wanjun; You, Fusheng; Fu, Feng; Liu, Ruigang

2006-11-01

Brain electrical impedance tomography (EIT) is a difficult task as brain tissues are enclosed by the skull of high resistance and cerebrospinal fluid (CSF) of low resistance, which makes internal resistivity information more difficult to extract. In order to seek a single source drive pattern that is more suitable for brain EIT, we built a more realistic experimental setting that simulates a head with the resistivity of the scalp, skull, CSF and brain, and compared the performance of adjacent, cross, polar and pseudo-polar drive patterns in terms of the boundary voltage dynamic range, independent measurement number, total boundary voltage changes and anti-noise performance based on it. The results demonstrate that the pseudo-polar drive pattern is optimal in all the aspects except for the dynamic range. The polar and cross drive patterns come next, and the adjacent drive pattern is the worst. Therefore, the pseudo-polar drive pattern should be chosen for brain EIT.

First demonstration of cerebrospinal fluid and plasma A beta lowering with oral administration of a beta-site amyloid precursor protein-cleaving enzyme 1 inhibitor in nonhuman primates.

PubMed

Sankaranarayanan, Sethu; Holahan, Marie A; Colussi, Dennis; Crouthamel, Ming-Chih; Devanarayan, Viswanath; Ellis, Joan; Espeseth, Amy; Gates, Adam T; Graham, Samuel L; Gregro, Allison R; Hazuda, Daria; Hochman, Jerome H; Holloway, Katharine; Jin, Lixia; Kahana, Jason; Lai, Ming-tain; Lineberger, Janet; McGaughey, Georgia; Moore, Keith P; Nantermet, Philippe; Pietrak, Beth; Price, Eric A; Rajapakse, Hemaka; Stauffer, Shaun; Steinbeiser, Melissa A; Seabrook, Guy; Selnick, Harold G; Shi, Xiao-Ping; Stanton, Matthew G; Swestock, John; Tugusheva, Katherine; Tyler, Keala X; Vacca, Joseph P; Wong, Jacky; Wu, Guoxin; Xu, Min; Cook, Jacquelynn J; Simon, Adam J

2009-01-01

beta-Site amyloid precursor protein (APP)-cleaving enzyme (BACE) 1 cleavage of amyloid precursor protein is an essential step in the generation of the potentially neurotoxic and amyloidogenic A beta 42 peptides in Alzheimer's disease. Although previous mouse studies have shown brain A beta lowering after BACE1 inhibition, extension of such studies to nonhuman primates or man was precluded by poor potency, brain penetration, and pharmacokinetics of available inhibitors. In this study, a novel tertiary carbinamine BACE1 inhibitor, tertiary carbinamine (TC)-1, was assessed in a unique cisterna magna ported rhesus monkey model, where the temporal dynamics of A beta in cerebrospinal fluid (CSF) and plasma could be evaluated. TC-1, a potent inhibitor (IC(50) approximately 0.4 nM), has excellent passive membrane permeability, low susceptibility to P-glycoprotein transport, and lowered brain A beta levels in a mouse model. Intravenous infusion of TC-1 led to a significant but transient lowering of CSF and plasma A beta levels in conscious rhesus monkeys because it underwent CYP3A4-mediated metabolism. Oral codosing of TC-1 with ritonavir, a potent CYP3A4 inhibitor, twice daily over 3.5 days in rhesus monkeys led to sustained plasma TC-1 exposure and a significant and sustained reduction in CSF sAPP beta, A beta 40, A beta 42, and plasma A beta 40 levels. CSF A beta 42 lowering showed an EC(50) of approximately 20 nM with respect to the CSF [TC-1] levels, demonstrating excellent concordance with its potency in a cell-based assay. These results demonstrate the first in vivo proof of concept of CSF A beta lowering after oral administration of a BACE1 inhibitor in a nonhuman primate.

Development of a diagnostic system for bilirubin detection in cerebral spinal fluid

NASA Astrophysics Data System (ADS)

Bhadri, Prashant R.; Salgaonkar, Vasant A.; Majumdar, Anindya; Morgan, Chad J.; Zuccarello, Mario; Pyne, Gail J.; Dulaney, Elizabeth; Caffery, James, Jr.; Shukla, Rakesh; Beyette, Fred R., Jr.

2004-11-01

A weakened portion of an artery in the brain leads to a medical condition known as a cerebral aneurysm. A subarachnoid hemorrhage (SAH) occurs when an aneurysm ruptures. For those individuals suspected of having a SAH, a computerized tomography (CT) scan of the brain usually demonstrates evidence of the bleeding. However, in a considerable portion of people, the CT scan is unable to detect the blood that has escaped from the blood vessel. Recent studies have indicated nearly 30% of patients with a SAH are initially misdiagnosed. For circumstances when a SAH is suspected despite a normal CT scan, physicians make the diagnosis of SAH by performing a spinal tap. A spinal tap uses a needle to sample the cerebrospinal fluid (CSF) collected from the patient"s lumbar spine. However, it is also possible for blood to be introduced into the CSF as a result of the spinal tap procedure. Therefore, an effective solution is required to help medical personnel differentiate between the blood that results from a tap and that from a ruptured aneurysm. In this paper, the development of a prototype is described which is sensitive and specific for measuring bilirubin in CSF, hemorrhagic-CSF and CSF-like solutions. To develop this instrument a combination of spectrophotometric analysis, custom data analysis software and other hardware interfaces are assembled that lay the foundation for the development of portable and user-friendly equipment suitable for assisting trained medical personnel with the diagnosis of a ruptured cerebral aneurysm.

Afferent vagal stimulation, vasopressin, and nitroprusside alter cerebrospinal fluid kinin.

PubMed

Thomas, G R; Thibodeaux, H; Margolius, H S; Webb, J G; Privitera, P J

1987-07-01

The effects of afferent vagal stimulation, cerebroventricular vasopressin, and intravenous nitroprusside on cerebrospinal fluid (CSF) kinin levels, mean arterial pressure (MAP), and heart rate (HR) were determined in anesthetized dogs in which a ventriculocisternal perfusion system (VP) was established. Following bilateral vagotomy, stimulation of the central ends of both vagi for 60 min significantly increased MAP and CSF perfusate levels of kinin and norepinephrine (NE). MAP was increased a maximum of 32 +/- 4 mmHg, and the rates of kinin and NE appearance into the CSF perfusate increased from 4.2 +/- 1.4 to 22.1 +/- 6.9 and from 28 +/- 5 to 256 +/- 39 pg/min, respectively. A significant correlation was found between CSF kinin and NE levels in these experiments. In other experiments the addition of arginine vasopressin to the VP system caused a significant increase in CSF perfusate kinin without affecting MAP or HR. Intravenous infusion of nitroprusside lowered MAP without affecting kinin levels in the CSF. However, on cessation of nitroprusside infusion, CSF kinin increased significantly in association with the return in MAP to predrug level. Collectively the data are consistent with the hypothesis that central nervous system kinins have some role in cardiovascular regulation, and furthermore that this role may involve an interaction between brain kinin and central noradrenergic neuronal pathways.

Vanishing calcification associated with a spontaneous ventral spinal cerebrospinal fluid leak.

PubMed

Schievink, Wouter I; Ross, Lindsey; Prasad, Ravi S; Maya, M Marcel

2016-12-01

Some patients with spontaneous intracranial hypotension have a ventral spinal cerebrospinal fluid (CSF) leak and these CSF leaks may be associated with calcified disk herniations. Identifying these calcifications is helpful in directing treatment. We report here the unusual case of a patient with a ventral CSF leak in whom the associated calcification absorbed over a five-month period. A 42-year-old woman developed orthostatic headaches and bilateral abducens nerve palsies. Magnetic resonance imaging of her brain showed typical findings of spontaneous intracranial hypotension. Magnetic resonance imaging of her spine showed an extensive cervicothoracic CSF leak. Computed tomographic myelography showed calcification at the Th1-2 disk space. Three epidural blood patches were performed, but her symptoms persisted. Digital subtraction myelography performed five months later showed an upper thoracic ventral CSF, but the calcification was no longer present. A dural tear, found at surgery at the Th1-2 level, was repaired and the patient made an uneventful recovery. The resorption of calcifications at the level of a ventral spinal CSF leak could explain the absence of any calcifications in at least some patients with such leaks and demonstrates the usefulness of reviewing previous imaging in patients with ventral CSF leaks if the exact site of the leak remains unknown. © International Headache Society 2016.

Comparison of 4D Phase-Contrast MRI Flow Measurements to Computational Fluid Dynamics Simulations of Cerebrospinal Fluid Motion in the Cervical Spine

PubMed Central

Yiallourou, Theresia I.; Kröger, Jan Robert; Stergiopulos, Nikolaos; Maintz, David

2012-01-01

Cerebrospinal fluid (CSF) dynamics in the cervical spinal subarachnoid space (SSS) have been thought to be important to help diagnose and assess craniospinal disorders such as Chiari I malformation (CM). In this study we obtained time-resolved three directional velocity encoded phase-contrast MRI (4D PC MRI) in three healthy volunteers and four CM patients and compared the 4D PC MRI measurements to subject-specific 3D computational fluid dynamics (CFD) simulations. The CFD simulations considered the geometry to be rigid-walled and did not include small anatomical structures such as nerve roots, denticulate ligaments and arachnoid trabeculae. Results were compared at nine axial planes along the cervical SSS in terms of peak CSF velocities in both the cranial and caudal direction and visual interpretation of thru-plane velocity profiles. 4D PC MRI peak CSF velocities were consistently greater than the CFD peak velocities and these differences were more pronounced in CM patients than in healthy subjects. In the upper cervical SSS of CM patients the 4D PC MRI quantified stronger fluid jets than the CFD. Visual interpretation of the 4D PC MRI thru-plane velocity profiles showed greater pulsatile movement of CSF in the anterior SSS in comparison to the posterior and reduction in local CSF velocities near nerve roots. CFD velocity profiles were relatively uniform around the spinal cord for all subjects. This study represents the first comparison of 4D PC MRI measurements to CFD of CSF flow in the cervical SSS. The results highlight the utility of 4D PC MRI for evaluation of complex CSF dynamics and the need for improvement of CFD methodology. Future studies are needed to investigate whether integration of fine anatomical structures and gross motion of the brain and/or spinal cord into the computational model will lead to a better agreement between the two techniques. PMID:23284970

Precursors and metabolites of phenylethylamine, m and p-tyramine and tryptamine in human lumbar and cisternal cerebrospinal fluid.

PubMed Central

Young, S N; Davis, B A; Gauthier, S

1982-01-01

Phenylacetic acid, p-hydroxyphenylacetic acid, m-hydroxyphenylacetic acid, phenylalanine, indoleacetic acid, 5-hydroxyindoleacetic acid and tryptophan were measured in lumbar and cisternal cerebrospinal fluid (CSF) taken during pneumoencephalography. The data suggest that the concentration of the acid metabolites of the trace amines tryptamine, phenylethylamine, p-tyramine and m-tyramine in lumbar CSF are influenced by the system that transports these acids out of CSF. In cisternal CSF this mechanism does not operate and more information can be obtained on the metabolism of the parent amines in the CNS. Our data indicate that (1) m-tyramine is relatively unimportant quantitatively (2) the rate of metabolism of phenylethylamine in human brain is similar to that of 5-hydroxytryptamine (3) the most important variable controlling the synthesis of phenylethylamine is the activity of aromatic amino acid decarboxylase (4) p-tyramine is synthesised at about half the rate of phenylethylamine and is thus quantitatively important in metabolic terms. PMID:6181210

Magnetic resonance imaging provides evidence of glymphatic drainage from human brain to cervical lymph nodes.

PubMed

Eide, Per Kristian; Vatnehol, Svein Are Sirirud; Emblem, Kyrre Eeg; Ringstad, Geir

2018-05-08

Pre-clinical research in rodents provides evidence that the central nervous system (CNS) has functional lymphatic vessels. In-vivo observations in humans, however, are not demonstrated. We here show data on CNS lymphatic drainage to cervical lymph nodes in-vivo by magnetic resonance imaging (MRI) enhanced with an intrathecal contrast agent as a cerebrospinal fluid (CSF) tracer. Standardized MRI of the intracranial compartment and the neck were acquired before and up to 24-48 hours following intrathecal contrast agent administration in 19 individuals. Contrast enhancement was radiologically confirmed by signal changes in CSF nearby inferior frontal gyrus, brain parenchyma of inferior frontal gyrus, parahippocampal gyrus, thalamus and pons, and parenchyma of cervical lymph node, and with sagittal sinus and neck muscle serving as reference tissue for cranial and neck MRI acquisitions, respectively. Time series of changes in signal intensity shows that contrast enhancement within CSF precedes glymphatic enhancement and peaks at 4-6 hours following intrathecal injection. Cervical lymph node enhancement coincides in time with peak glymphatic enhancement, with peak after 24 hours. Our findings provide in-vivo evidence of CSF tracer drainage to cervical lymph nodes in humans. The time course of lymph node enhancement coincided with brain glymphatic enhancement rather than with CSF enhancement.

Leukemic meningitis in a patient with hairy cell leukemia. A case report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wolfe, D.W.; Scopelliti, J.A.; Boselli, B.D.

1984-09-15

Central nervous system involvement has not previously been described in patients with hairy cell leukemia (HCL). A patient is reported who presented with meningeal involvement as his initial symptom of HCL. Diagnosis was established by morphologic and cytochemical studies of his cerebrospinal fluid (CSF) and bone marrow. Treatment with whole-brain irradiation and intrathecal chemotherapy was successful in clearing leukemic cells from the CSF with resolution of symptoms.

The Connected Steady State Model and the Interdependence of the CSF Proteome and CSF Flow Characteristics.

PubMed

Metzger, Fabian; Mischek, Daniel; Stoffers, Frédéric

2017-01-01

Here we show that the hydrodynamic radii-dependent entry of blood proteins into cerebrospinal fluid (CSF) can best be modeled with a diffusional system of consecutive interdependent steady states between barrier-restricted molecular flux and bulk flow of CSF. The connected steady state model fits precisely to experimental results and provides the theoretical backbone to calculate the in-vivo hydrodynamic radii of blood-derived proteins as well as individual barrier characteristics. As the experimental reference set we used a previously published large-scale patient cohort of CSF to serum quotient ratios of immunoglobulins in relation to the respective albumin quotients. We related the inter-individual variances of these quotient relationships to the individual CSF flow time and barrier characteristics. We claim that this new concept allows the diagnosis of inflammatory processes with Reibergrams derived from population-based thresholds to be shifted to individualized judgment, thereby improving diagnostic sensitivity. We further use the source-dependent gradient patterns of proteins in CSF as intrinsic tracers for CSF flow characteristics. We assume that the rostrocaudal gradient of blood-derived proteins is a consequence of CSF bulk flow, whereas the slope of the gradient is a consequence of the unidirectional bulk flow and bidirectional pulsatile flow of CSF. Unlike blood-derived proteins, the influence of CSF flow characteristics on brain-derived proteins in CSF has been insufficiently discussed to date. By critically reviewing existing experimental data and by reassessing their conformity to CSF flow assumptions we conclude that the biomarker potential of brain-derived proteins in CSF can be improved by considering individual subproteomic dynamics of the CSF system.

Impact of whole brain radiation therapy on CSF penetration ability of Icotinib in EGFR-mutated non-small cell lung cancer patients with brain metastases: Results of phase I dose-escalation study.

PubMed

Zhou, Lin; He, Jiazhuo; Xiong, Weijie; Liu, Yongmei; Xiang, Jing; Yu, Qin; Liang, Maozhi; Zhou, Xiaojuan; Ding, Zhenyu; Huang, Meijuan; Ren, Li; Zhu, Jiang; Li, Lu; Hou, Mei; Ding, Lieming; Tan, Fenlai; Lu, You

2016-06-01

Whole-brain radiation therapy (WBRT) and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are both treatment options for EGFR-mutated non-small cell lung cancer (NSCLC) patients with brain metastases. However, the dose-escalation toxicity and efficacy of combination therapy, and the effect of WBRT on cerebrospinal fluid (CSF) penetration of EGFR-TKIs are still unclear. EGFR-mutated NSCLC patients with brain metastases were enrolled in this study, and the cohorts were constructed with a 3+3 design. The patients received icotinib with escalating doses (125-625mg, tid), and the concurrent WBRT (37.5Gy/15f/3weeks) started a week later. The CSF penetration rates of icotinib were tested before, immediately after, and 4 weeks after WBRT, respectively. Potential toxicities and benefits from dose-escalation treatment were analyzed. Fifteen patients were included in this study, 3 at each dose level from 125mg-375mg and 6 at 500mg with 3 occurred dose-limiting toxicities. The maximal tolerated dose of icotinib was 375mg tid in this combination therapy. There was a significant correlation between icotinib concentration in the CSF and plasma (R(2)=0.599, P<0.001). The CSF penetration rate of icotinib, from 1.2% to 9.7%, reached a maximum at 375mg (median, 6.1%). There was no significant difference for CSF penetration rates among the three test points (median, 4.1% vs. 2.8% vs. 2.8%, P=0.16). The intracranial objective response rate and median intracranial progression free survival are 80% and 18.9 months. WBRT plus concurrent icotinib is well tolerated in EGFR-mutated NSCLC patients with brain metastases, up to an icotinib dose of 375mg tid. The icotinib CSF concentration seemed to have a potential ceiling effect with the dose escalation, and WBRT seemed to have no significant impact on CSF penetration of icotinib till 4 weeks after the treatment. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Brain-derived neurotrophic factor and interleukin-6 levels in the serum and cerebrospinal fluid of children with viral infection-induced encephalopathy.

PubMed

Morichi, Shinichiro; Yamanaka, Gaku; Ishida, Yu; Oana, Shingo; Kashiwagi, Yasuyo; Kawashima, Hisashi

2014-11-01

We investigated changes in the brain-derived neurotrophic factor (BDNF) and interleukin (IL)-6 levels in pediatric patients with central nervous system (CNS) infections, particularly viral infection-induced encephalopathy. Over a 5-year study period, 24 children hospitalized with encephalopathy were grouped based on their acute encephalopathy type (the excitotoxicity, cytokine storm, and metabolic error types). Children without CNS infections served as controls. In serum and cerebrospinal fluid (CSF) samples, BDNF and IL-6 levels were increased in all encephalopathy groups, and significant increases were noted in the influenza-associated and cytokine storm encephalopathy groups. Children with sequelae showed higher BDNF and IL-6 levels than those without sequelae. In pediatric patients, changes in serum and CSF BDNF and IL-6 levels may serve as a prognostic index of CNS infections, particularly for the diagnosis of encephalopathy and differentiation of encephalopathy types.

The Glymphatic System in Central Nervous System Health and Disease: Past, Present, and Future.

PubMed

Plog, Benjamin A; Nedergaard, Maiken

2018-01-24

The central nervous system (CNS) is unique in being the only organ system lacking lymphatic vessels to assist in the removal of interstitial metabolic waste products. Recent work has led to the discovery of the glymphatic system, a glial-dependent perivascular network that subserves a pseudolymphatic function in the brain. Within the glymphatic pathway, cerebrospinal fluid (CSF) enters the brain via periarterial spaces, passes into the interstitium via perivascular astrocytic aquaporin-4, and then drives the perivenous drainage of interstitial fluid (ISF) and its solute. Here, we review the role of the glymphatic pathway in CNS physiology, the factors known to regulate glymphatic flow, and the pathologic processes in which a breakdown of glymphatic CSF-ISF exchange has been implicated in disease initiation and progression. Important areas of future research, including manipulation of glymphatic activity aiming to improve waste clearance and therapeutic agent delivery, are also discussed.

Brain-Specific Cytoskeletal Damage Markers in Cerebrospinal Fluid: Is There a Common Pattern between Amyotrophic Lateral Sclerosis and Primary Progressive Multiple Sclerosis?

PubMed

Abdelhak, Ahmed; Junker, Andreas; Brettschneider, Johannes; Kassubek, Jan; Ludolph, Albert C; Otto, Markus; Tumani, Hayrettin

2015-07-31

Many neurodegenerative disorders share a common pathophysiological pathway involving axonal degeneration despite different etiological triggers. Analysis of cytoskeletal markers such as neurofilaments, protein tau and tubulin in cerebrospinal fluid (CSF) may be a useful approach to detect the process of axonal damage and its severity during disease course. In this article, we review the published literature regarding brain-specific CSF markers for cytoskeletal damage in primary progressive multiple sclerosis and amyotrophic lateral sclerosis in order to evaluate their utility as a biomarker for disease progression in conjunction with imaging and histological markers which might also be useful in other neurodegenerative diseases associated with affection of the upper motor neurons. A long-term benefit of such an approach could be facilitating early diagnostic and prognostic tools and assessment of treatment efficacy of disease modifying drugs.

Brain-Specific Cytoskeletal Damage Markers in Cerebrospinal Fluid: Is There a Common Pattern between Amyotrophic Lateral Sclerosis and Primary Progressive Multiple Sclerosis?

PubMed Central

Abdelhak, Ahmed; Junker, Andreas; Brettschneider, Johannes; Kassubek, Jan; Ludolph, Albert C.; Otto, Markus; Tumani, Hayrettin

2015-01-01

Many neurodegenerative disorders share a common pathophysiological pathway involving axonal degeneration despite different etiological triggers. Analysis of cytoskeletal markers such as neurofilaments, protein tau and tubulin in cerebrospinal fluid (CSF) may be a useful approach to detect the process of axonal damage and its severity during disease course. In this article, we review the published literature regarding brain-specific CSF markers for cytoskeletal damage in primary progressive multiple sclerosis and amyotrophic lateral sclerosis in order to evaluate their utility as a biomarker for disease progression in conjunction with imaging and histological markers which might also be useful in other neurodegenerative diseases associated with affection of the upper motor neurons. A long-term benefit of such an approach could be facilitating early diagnostic and prognostic tools and assessment of treatment efficacy of disease modifying drugs. PMID:26263977

The glymphatic system in CNS health and disease: past, present and future

PubMed Central

Plog, Benjamin A.; Nedergaard, Maiken

2018-01-01

The central nervous system (CNS) is unique in being the only organ system lacking lymphatic vessels to assist in the removal of interstitial metabolic waste products. Recent work has led to the discovery of the glymphatic system, a glial-dependent perivascular network that subserves a pseudo-lymphatic function in the brain. Within the glymphatic pathway, cerebrospinal fluid (CSF) enters brain via periarterial spaces, passes into the interstitium via perivascular astrocytic aquaporin-4, and then drives the perivenous drainage of interstitial fluid (ISF) and its solute. Here we review the role of the glymphatic pathway in CNS physiology, factors known to regulate glymphatic flow, and pathologic processes where a breakdown of glymphatic CSF-ISF exchange has been implicated in disease initiation and progression. Important areas of future research, including manipulation of glymphatic activity aiming to improve waste clearance and therapeutic agent delivery, will also be discussed. PMID:29195051

Intra-Blood-Brain Barrier Synthesis of Human Immunodeficiency Virus Antigen and Antibody in Humans and Chimpanzees

NASA Astrophysics Data System (ADS)

Goudsmit, Jaap; Epstein, Leon G.; Paul, Deborah A.; van der Helm, Hayo J.; Dawson, George J.; Asher, David M.; Yanagihara, Richard; Wolff, Axel V.; Gibbs, Clarence J.; Carleton Gajdusek, D.

1987-06-01

The presence of human immunodeficiency virus (HIV) antigens in cerebrospinal fluid (CSF) was associated with progressive encephalopathy in adult and pediatric patients with acquired immunodeficiency syndrome (AIDS). HIV antigen was detected in CSF from 6 of 7 AIDS patients with progressive encephalopathy. By contrast, HIV antigen, whether free or complexed, was detected in CSF from only 1 of 18 HIV antibody seropositive patients without progressive encephalopathy and from 0 of 8 experimentally infected chimpanzees without clinical signs. Intra-blood-brain barrier synthesis of HIV-specific antibody was demonstrated in the majority of patients with AIDS (9/12) or at risk for AIDS (8/13) as well as in the experimentally infected chimpanzees, indicating HIV-specific B-cell reactivity in the brain without apparent neurological signs. In 6 of 11 patients with HIV infection, antibodies synthesized in the central nervous system were directed against HIV envelope proteins. Active viral expression appears to be necessary for both the immunodeficiency and progressive encephalopathy associated with HIV infection.

Validity and Normative Data for the Biber Figure Learning Test: A Visual Supraspan Memory Measure.

PubMed

Gifford, Katherine A; Liu, Dandan; Neal, Jacquelyn E; Acosta, Lealani Mae Y; Bell, Susan P; Wiggins, Margaret E; Wisniewski, Kristi M; Godfrey, Mary; Logan, Laura A; Hohman, Timothy J; Pechman, Kimberly R; Libon, David J; Blennow, Kaj; Zetterberg, Henrik; Jefferson, Angela L

2018-05-01

The Biber Figure Learning Test (BFLT), a visuospatial serial figure learning test, was evaluated for biological correlates and psychometric properties, and normative data were generated. Nondemented individuals ( n = 332, 73 ± 7, 41% female) from the Vanderbilt Memory & Aging Project completed a comprehensive neuropsychological protocol. Adjusted regression models related BFLT indices to structural brain magnetic resonance imaging and cerebrospinal fluid (CSF) markers of brain health. Regression-based normative data were generated. Lower BFLT performances (Total Learning, Delayed Recall, Recognition) related to smaller medial temporal lobe volumes and higher CSF tau concentrations but not CSF amyloid. BFLT indices were most strongly correlated with other measures of verbal and nonverbal memory and visuospatial skills. The BFLT provides a comprehensive assessment of all aspects of visuospatial learning and memory and is sensitive to biomarkers of unhealthy brain aging. Enhanced normative data enriches the clinical utility of this visual serial figure learning test for use with older adults.

Paradoxical Brain Herniation After Decompressive Craniectomy Provoked by Drainage of Subdural Hygroma.

PubMed

Nasi, Davide; Dobran, Mauro; Iacoangeli, Maurizio; Di Somma, Lucia; Gladi, Maurizio; Scerrati, Massimo

2016-07-01

Paradoxical brain herniation (PBH) is a rare and potentially life-threatening complication of decompressive craniectomy (DC) and results from the combined effects of brain gravity, atmospheric pressure and intracranial hypotension causing herniation in the direction opposite to the site of the DC with subsequent brainstem compression. To date, the cases of PBH reported in literature are spontaneous or provoked by a lumbar puncture, a cerebrospinal fluid (CSF) shunt, or ventriculostomy. We present an uncommon case of PBH provoked by percutaneous drainage of a huge subdural hygroma (SH) ipsilateral to the decompressive craniectomy causing mass effect and neurologic deterioration. After percutaneous evacuation of SH, the patient became unresponsive with dilated and fixed left pupil. A brain computed tomography scan showed marked midline shift in the direction opposite to the craniectomy site with subfalcine herniation and effacement of the peripontine cisterns. Paradoxical brain herniation (PBH) was diagnosed. Conservative treatment failed, and the patient required an emergency cranioplasty for reverse PBH. The present case highlights the possibility that all forms of CSF depletion, including percutaneous drainage of subdural CSF collection and not only CSF shunting and/or lumbar puncture, can be dangerous for patients with large craniotomies and result in PBH. Moreover, an emergency cranioplasty could represent a safe and effective procedure in patients not responding to conservative treatment. Copyright © 2016 Elsevier Inc. All rights reserved.

The importance of the cortical subarachnoid space in understanding hydrocephalus.

PubMed

Rekate, Harold L; Nadkarni, Trimurti D; Wallace, Donna

2008-07-01

In this paper the authors define the role of the cortical subarachnoid space (CSAS) in poorly understood forms of hydrocephalus to cerebrospinal fluid (CSF) dynamics to improve understanding of the importance of the CSAS and its role in selecting patients for endoscopic third ventriculostomy (ETV). The secondary purpose of this work was to define testable hypotheses to explain enigmatic disorders of CSF dynamics and to suggest how these concepts could be tested. The magnitude of the contribution of the CSAS is explored using the solid geometry of concentric spheres. With this starting point, clinical conditions in which CSF dynamics are not easily understood are explored regarding the potential role of the CSAS. Overall, problems of CSF dynamics are easily understood. Insights may be gained when the results of a pathological process or its treatment vary from what has been expected. Acute changes in ventricular volume at the time that hydrocephalus develops, the failure of shunts, and the changes in ventricular volume with shunt repair may occur very rapidly. Changes in the volume of water in the brain, especially in the brain substance itself, are unlikely to occur at this rapid rate and may be interpreted as a simple redistribution of the CSF between the ventricle and CSAS with no initial change in the actual volume of brain parenchyma. Problems such as pseudotumor cerebri, shunt failure with nonresponsive ventricles, and negative-pressure hydrocephalus can be explained by assessing the ability of ventricular CSF to flow to the CSAS and the ability of this fluid to exit this compartment. Ventricular enlargement at the time of shunt failure implies a failure of flow between the ventricles and CSAS, implying that all patients who show this phenomenon are potential candidates for ETV. The important role of the CSAS in the pathophysiology of various forms of hydrocephalus has been largely ignored. Attention to the dynamics of the CSF in this compartment will improve understanding of enigmatic conditions of hydrocephalus and improve selection criteria for treatment paradigms such as ETV. These concepts lead to clearly defined problems that may be solved by the creation of a central database to address these issues.

Phase-contrast cerebrospinal fluid flow magnetic resonance imaging in qualitative evaluation of patency of CSF flow pathways prior to infusion of chemotherapeutic and other agents into the fourth ventricle.

PubMed

Patel, Rajan P; Sitton, Clark W; Ketonen, Leena M; Hou, Ping; Johnson, Jason M; Romo, Seferino; Fletcher, Stephen; Shah, Manish N; Kerr, Marcia; Zaky, Wafik; Rytting, Michael E; Khatua, Soumen; Sandberg, David I

2018-03-01

Nuclear medicine studies have previously been utilized to assess for blockage of cerebrospinal fluid (CSF) flow prior to intraventricular chemotherapy infusions. To assess CSF flow without nuclear medicine studies, we obtained cine phase-contrast MRI sequences that assess CSF flow from the fourth ventricle down to the sacrum. In three clinical trials, 18 patients with recurrent malignant posterior fossa tumors underwent implantation of a ventricular access device (VAD) into the fourth ventricle, either with or without simultaneous tumor resection. Prior to infusing therapeutic agents into the VAD, cine MRI phase-contrast CSF flow sequences of the brain and total spine were performed. Velocity encoding (VENC) of 5 and 10 cm/s was used to confirm CSF flow from the fourth ventricular outlets to the cervical, thoracic, and lumbar spine. Qualitative CSF flow was characterized by neuroradiologists as present or absent. All 18 patients demonstrated CSF flow from the outlets of the fourth ventricle down to the sacrum with no evidence of obstruction. One of these patients, after disease progression, subsequently showed obstruction of CSF flow. No patient required a nuclear medicine study to assess CSF flow prior to initiation of infusions. Fourteen patients have received infusions to date, and none has had neurological toxicity. CSF flow including the fourth ventricle and the total spine can be assessed noninvasively with phase-contrast MRI sequences. Advantages over nuclear medicine studies include avoiding both an invasive procedure and radiation exposure.

Associations between biomarkers and age in the presenilin 1 E280A autosomal dominant Alzheimer disease kindred: a cross-sectional study.

PubMed

Fleisher, Adam S; Chen, Kewei; Quiroz, Yakeel T; Jakimovich, Laura J; Gutierrez Gomez, Madelyn; Langois, Carolyn M; Langbaum, Jessica B S; Roontiva, Auttawut; Thiyyagura, Pradeep; Lee, Wendy; Ayutyanont, Napatkamon; Lopez, Liliana; Moreno, Sonia; Muñoz, Claudia; Tirado, Victoria; Acosta-Baena, Natalia; Fagan, Anne M; Giraldo, Margarita; Garcia, Gloria; Huentelman, Matthew J; Tariot, Pierre N; Lopera, Francisco; Reiman, Eric M

2015-03-01

Age-associated changes in brain imaging and fluid biomarkers are characterized and compared in presenilin 1 (PSEN1)E280A mutation carriers and noncarriers from the world's largest known autosomal dominant Alzheimer disease (AD) kindred. To characterize and compare age-associated changes in brain imaging and fluid biomarkers in PSEN1 E280A mutation carriers and noncarriers. Cross-sectional measures of 18F-florbetapir positron emission tomography, 18F-fludeoxyglucose positron emission tomography, structural magnetic resonance imaging, cerebrospinal fluid (CSF), and plasma biomarkers of AD were assessed from 54 PSEN1 E280A kindred members (age range, 20-59 years). We used brain mapping algorithms to compare regional cerebral metabolic rates for glucose and gray matter volumes in cognitively unimpaired mutation carriers and noncarriers. We used regression analyses to characterize associations between age and the mean cortical to pontine 18F-florbetapir standard uptake value ratios, precuneus cerebral metabolic rates for glucose, hippocampal gray matter volume, CSF Aβ1-42, total tau and phosphorylated tau181, and plasma Aβ measurements. Age at onset of progressive biomarker changes that distinguish carriers from noncarriers was estimated using best-fitting regression models. Compared with noncarriers, cognitively unimpaired mutation carriers had significantly lower precuneus cerebral metabolic rates for glucose, smaller hippocampal volume, lower CSF Aβ1-42, higher CSF total tau and phosphorylated tau181, and higher plasma Aβ1-42 measurements. Sequential changes in biomarkers were seen at age 20 years (95% CI, 14-24 years) for CSF Aβ1-42, age 16 years (95% CI, 11-24 years) for the mean cortical 18F-florbetapir standard uptake value ratio, age 15 years (95% CI, 10-24 years) for precuneus cerebral metabolic rate for glucose, age 15 years (95% CI, 7-20 years) for CSF total tau, age 13 years (95% CI, 8-19 years) for phosphorylated tau181, and age 6 years (95% CI, 1-10 years) for hippocampal volume, with cognitive decline up to 6 years before the kindred's estimated median age of 44 years (95% CI, 43-45 years) at mild cognitive impairment diagnosis. No age-associated findings were seen in plasma Aβ1-42 or Aβ1-40. This cross-sectional study provides additional information about the course of different AD biomarkers in the preclinical and clinical stages of autosomal dominant AD.

Neurologic Deterioration Due to Brain Sag After Bilateral Craniotomy for Subdural Hematoma Evacuation.

PubMed

Liu, James K C

2018-06-01

Intracranial hypotension from cerebrospinal fluid (CSF) hypovolemia resulting in cerebral herniation is a rare but known complication that can occur after neurosurgical procedures, usually encountered in correlation with perioperative placement of a lumbar subarachnoid drain. Decrease in CSF volume resulting in loss of buoyancy results in downward herniation of the brain without contributing mass effect, causing a phenomenon known as brain sag. Unreported previously is brain sag occurring without concomitant occult CSF leak or lumbar drainage. This case report describes a patient who underwent bilateral craniotomies for subacute on chronic subdural hematoma with successful decompression but experienced acute neurologic deterioration secondary to brain sag. Despite an initial improvement in neurologic function, he subsequently experienced progressive neurologic deterioration with evidence of cerebral herniation on neuroimaging, without evidence of continued mass effect on the brain parenchyma. After a diagnosis of brain sag was determined based on imaging criteria, the patient was placed in a flat position, which resulted in rapid improvement in his neurologic function without any further intervention. This case is unique in comparison with previous reports of intracranial hypotension after craniotomy in that the symptoms were completely reversed with positioning alone, without any evidence of active or occult CSF drainage. This report emphasizes that the diagnosis of brain sag should be taken into consideration when there is an unknown reason for neurologic decline after craniotomy, particularly bilateral craniotomies, if the imaging indicates herniation with imaging findings consistent with intracranial hypotension, without evidence of overlying mass effect. Copyright © 2018 Elsevier Inc. All rights reserved.

[Disturbances of cerebral perfusion in patients with bacterial meningoencephalitis].

PubMed

Garlicki, Aleksander; Podsiadło-Kleinrok, Beata; Bociaga-Jasik, Monika; Kleinrok, Krzysztof; Tomik, Barbara

2003-01-01

The investigations were done in acute and reconvalescent phase in 34 patients with bacterial meningoencephalitis. Neurologic condition, degree of the brain injury on the basis of Glasgow Coma Scale (GCS), protein level and pleocytosis in cerebrospinal fluid (CSF), and regional cerebral blood flow on dynamic computed tomography (CT) were assessed. The brain blood flow was measured in the white matter of the frontal and occipital horns of lateral ventricles, symmetrically in both hemispheres. Statistically significant reduction of the brain perfusion in acute phase of illness was improved. In reconvalescent phase normalisation of the brain blood supply was observed. 56% of patients had changes of consciousness. There was no significant correlation between these symptoms and parameters describing blood supply. The rest of patients had neurologic abnormalities: seizure, pyramidal syndrome, injury of the central nerves due to the reduction of blood flow in selected regions of the brain. Patients who aggregated low GCS score had high inflow of the blood. In patients who were in better condition, inflow was smaller. High pleocytosis in CSF was associated with small blood inflow and perfusion in investigated regions of the brain. Whereas high protein concentration correlated with higher inflow and increase in regional perfusion. We consider, that the brain blood supply correlate with intensification of inflammatory response in CSF.

Increased levels of cerebrospinal fluid JNK3 associated with amyloid pathology: links to cognitive decline

PubMed Central

Gourmaud, Sarah; Paquet, Claire; Dumurgier, Julien; Pace, Clarisse; Bouras, Constantin; Gray, Françoise; Laplanche, Jean-Louis; Meurs, Eliane F.; Mouton-Liger, François; Hugon, Jacques

2015-01-01

Background Alzheimer disease is characterized by cognitive decline, senile plaques of β-amyloid (Aβ) peptides, neurofibrillary tangles composed of hyperphosphorylated τ proteins and neuronal loss. Aβ and τ are useful markers in the cerebrospinal fluid (CSF). C-Jun N-terminal kinases (JNKs) are serine-threonine protein kinases activated by phosphorylation and involved in neuronal death. Methods In this study, Western blots, enzyme-linked immunosorbent assay and histological approaches were used to assess the concentrations of Aβ, τ and JNK isoforms in postmortem brain tissue samples (10 Alzheimer disease and 10 control) and in CSF samples from 30 living patients with Alzheimer disease and 27 controls with neurologic disease excluding Alzheimer disease. Patients with Alzheimer disease were followed for 1–3 years and assessed using Mini–Mental State Examination scores. Results The biochemical and morphological results showed a significant increase of JNK3 and phosphorylated JNK levels in patients with Alzheimer disease, and JNK3 levels correlated with Aβ42 levels. Confocal microscopy revealed that JNK3 was associated with Aβ in senile plaques. The JNK3 levels in the CSF were significantly elevated in patients with Alzheimer disease and correlated statistically with the rate of cognitive decline in a mixed linear model. Limitations The study involved different samples grouped into 3 small cohorts. Evaluation of JNK3 in CSF was possible only with immunoblot analysis. Conclusion We found that JNK3 levels are increased in brain tissue and CSF from patients with Alzheimer disease. The finding that increased JNK3 levels in CSF could reflect the rate of cognitive decline is new and merits further investigation. PMID:25455349

Effect of Buyang Huanwu decoction on amino acid content in cerebrospinal fluid of rats during ischemic/reperfusion injury.

PubMed

Wang, Lisheng; Huang, Yuwei; Wu, Junhong; Lv, Gengbin; Zhou, Liling; Jia, Jie

2013-12-01

The inhibitory effect of Buyang Huanwu decoction (BYHWD) on ischemic injury has been proven, but it is not clear how amino acid levels in cerebrospinal fluid (CSF) are associated with BYHWD treatment, nor the mechanism by which BYHWD protects the brain from ischemia/reperfusion injury. We investigated the effect of BYHWD on the amino acid content of CSF in rats during ischemia-reperfusion injury. Ischemia was imposed by right middle cerebral artery occlusion (MCAO). CSF was continuously collected from the striatum via brain microdialysis before and after ischemia/reperfusion. We used on-line derivatization combined with high-performance liquid chromatography with fluorescence detection (HPLC-FD) to determine levels of glutamate (Glu), aspartate (Asp), glycine (Gly), taurine (Tau), and γ-aminobutyric acid (GABA) in CSF. The MCAO model displayed an infarct lesion in the ipsilateral hemisphere and nerve injuries, as the left upper limb was unable to extend and turn leftward. Significant increases in excitatory and inhibitory amino acids were observed in the CSF of the ischemic rats relative to the sham-operated group (P<0.01). Treatment with BYHWD reduced the areas of cerebral infarction and improved the neurological behavior scores of rats after MCAO. BYHWD treatment was also associated with a significant decrease in excitatory amino acids and increase in inhibitory amino acids in the CSF. Only the higher dose of BYHWD (20mg/kg) affected all these levels significantly. Attenuated excitatory toxicity and reduced areas of cerebral infarction associated with BYHWD treatment might be due to a protective mechanism induced by BYHWD against ischemia/reperfusion injury. Copyright © 2013 Elsevier B.V. All rights reserved.

A Low-Molecular-Weight Ferroxidase Is Increased in the CSF of sCJD Cases: CSF Ferroxidase and Transferrin as Diagnostic Biomarkers for sCJD

PubMed Central

Haldar, Swati; Beveridge, ’Alim J.; Wong, Joseph; Singh, Ajay; Galimberti, Daniela; Borroni, Barbara; Zhu, Xiongwei; Blevins, Janis; Greenlee, Justin; Perry, George; Mukhopadhyay, Chinmay K.; Schmotzer, Christine

2013-01-01

Abstract Aims: Most biomarkers used for the premortem diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) are surrogate in nature, and provide suboptimal sensitivity and specificity. Results: We report that CJD-associated brain iron dyshomeostasis is reflected in the cerebrospinal fluid (CSF), providing disease-specific diagnostic biomarkers. Analysis of 290 premortem CSF samples from confirmed cases of CJD, Alzheimer's disease, and other dementias (DMs), and 52 non-DM (ND) controls revealed a significant difference in ferroxidase (Frx) activity and transferrin (Tf) levels in sporadic Creutzfeldt-Jakob disease (sCJD) relative to other DM and ND controls. A combination of CSF Frx and Tf discriminated sCJD from other DMs with a sensitivity of 86.8%, specificity of 92.5%, accuracy of 88.9%, and area-under-the receiver-operating-characteristic (ROC) curve of 0.94. This combination provided a similar diagnostic accuracy in discriminating CJD from rapidly progressing cases who died within 6 months of sample collection. Surprisingly, ceruloplasmin and amyloid precursor protein, the major brain Frxs, displayed minimal activity in the CSF. Most of the Frx activity was concentrated in the <3-kDa fraction in normal and diseased CSF, and resisted heat and proteinase-K treatment. Innovation: (i) A combination of CSF Frx and Tf provides disease-specific premortem diagnostic biomarkers for sCJD. (ii) A novel, nonenzymatic, nonprotein Frx predominates in human CSF that is distinct from the currently known CSF Frxs. Conclusion: The underlying cause of iron imbalance is distinct in sCJD relative to other DMs associated with the brain iron imbalance. Thus, change in the CSF levels of iron-management proteins can provide disease-specific biomarkers and insight into the cause of iron imbalance in neurodegenerative conditions. Antioxid. Redox Signal. 19, 1662–1675. PMID:23379482

Enhanced Delivery of Galanin Conjugates to the Brain through Bioengineering of the Anti-Transferrin Receptor Antibody OX26.

PubMed

Thom, George; Burrell, Matthew; Haqqani, Arsalan S; Yogi, Alvaro; Lessard, Etienne; Brunette, Eric; Delaney, Christie; Baumann, Ewa; Callaghan, Deborah; Rodrigo, Natalia; Webster, Carl I; Stanimirovic, Danica B

2018-04-02

The blood-brain barrier (BBB) is a formidable obstacle for brain delivery of therapeutic antibodies. However, antibodies against the transferrin receptor (TfR), enriched in brain endothelial cells, have been developed as delivery carriers of therapeutic cargoes into the brain via a receptor-mediated transcytosis pathway. In vitro and in vivo studies demonstrated that either a low-affinity or monovalent binding of these antibodies to the TfR improves their release on the abluminal side of the BBB and target engagement in brain parenchyma. However, these studies have been performed with mouse-selective TfR antibodies that recognize different TfR epitopes and have varied binding characteristics. In this study, we evaluated serum pharmacokinetics and brain and CSF exposure of the rat TfR-binding antibody OX26 affinity variants, having K D s of 5 nM, 76 nM, 108 nM, and 174 nM, all binding the same epitope in bivalent format. Pharmacodynamic responses were tested in the Hargreaves chronic pain model after conjugation of OX26 affinity variants with the analgesic and antiepileptic peptide, galanin. OX26 variants with affinities of 76 nM and 108 nM showed enhanced brain and cerebrospinal fluid (CSF) exposure and higher potency in the Hargreaves model, compared to a 5 nM affinity variant; lowering affinity to 174 nM resulted in prolonged serum pharmacokinetics, but reduced brain and CSF exposure. The study demonstrates that binding affinity optimization of TfR-binding antibodies could improve their brain and CSF exposure even in the absence of monovalent TfR engagement.

Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy

PubMed Central

Haurigot, Virginia; Marcó, Sara; Ribera, Albert; Garcia, Miguel; Ruzo, Albert; Villacampa, Pilar; Ayuso, Eduard; Añor, Sònia; Andaluz, Anna; Pineda, Mercedes; García-Fructuoso, Gemma; Molas, Maria; Maggioni, Luca; Muñoz, Sergio; Motas, Sandra; Ruberte, Jesús; Mingozzi, Federico; Pumarola, Martí; Bosch, Fatima

2013-01-01

For most lysosomal storage diseases (LSDs) affecting the CNS, there is currently no cure. The BBB, which limits the bioavailability of drugs administered systemically, and the short half-life of lysosomal enzymes, hamper the development of effective therapies. Mucopolysaccharidosis type IIIA (MPS IIIA) is an autosomic recessive LSD caused by a deficiency in sulfamidase, a sulfatase involved in the stepwise degradation of glycosaminoglycan (GAG) heparan sulfate. Here, we demonstrate that intracerebrospinal fluid (intra-CSF) administration of serotype 9 adenoassociated viral vectors (AAV9s) encoding sulfamidase corrects both CNS and somatic pathology in MPS IIIA mice. Following vector administration, enzymatic activity increased throughout the brain and in serum, leading to whole body correction of GAG accumulation and lysosomal pathology, normalization of behavioral deficits, and prolonged survival. To test this strategy in a larger animal, we treated beagle dogs using intracisternal or intracerebroventricular delivery. Administration of sulfamidase-encoding AAV9 resulted in transgenic expression throughout the CNS and liver and increased sulfamidase activity in CSF. High-titer serum antibodies against AAV9 only partially blocked CSF-mediated gene transfer to the brains of dogs. Consistently, anti-AAV antibody titers were lower in CSF than in serum collected from healthy and MPS IIIA–affected children. These results support the clinical translation of this approach for the treatment of MPS IIIA and other LSDs with CNS involvement. PMID:23863627

Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy.

PubMed

Haurigot, Virginia; Marcó, Sara; Ribera, Albert; Garcia, Miguel; Ruzo, Albert; Villacampa, Pilar; Ayuso, Eduard; Añor, Sònia; Andaluz, Anna; Pineda, Mercedes; García-Fructuoso, Gemma; Molas, Maria; Maggioni, Luca; Muñoz, Sergio; Motas, Sandra; Ruberte, Jesús; Mingozzi, Federico; Pumarola, Martí; Bosch, Fatima

2013-07-01

For most lysosomal storage diseases (LSDs) affecting the CNS, there is currently no cure. The BBB, which limits the bioavailability of drugs administered systemically, and the short half-life of lysosomal enzymes, hamper the development of effective therapies. Mucopolysaccharidosis type IIIA (MPS IIIA) is an autosomic recessive LSD caused by a deficiency in sulfamidase, a sulfatase involved in the stepwise degradation of glycosaminoglycan (GAG) heparan sulfate. Here, we demonstrate that intracerebrospinal fluid (intra-CSF) administration of serotype 9 adenoassociated viral vectors (AAV9s) encoding sulfamidase corrects both CNS and somatic pathology in MPS IIIA mice. Following vector administration, enzymatic activity increased throughout the brain and in serum, leading to whole body correction of GAG accumulation and lysosomal pathology, normalization of behavioral deficits, and prolonged survival. To test this strategy in a larger animal, we treated beagle dogs using intracisternal or intracerebroventricular delivery. Administration of sulfamidase-encoding AAV9 resulted in transgenic expression throughout the CNS and liver and increased sulfamidase activity in CSF. High-titer serum antibodies against AAV9 only partially blocked CSF-mediated gene transfer to the brains of dogs. Consistently, anti-AAV antibody titers were lower in CSF than in serum collected from healthy and MPS IIIA-affected children. These results support the clinical translation of this approach for the treatment of MPS IIIA and other LSDs with CNS involvement.

Reduced Cerebrospinal Fluid Levels of Brain-Derived Neurotrophic Factor Is Associated With Cognitive Impairment in Late-Life Major Depression

PubMed Central

Teixeira, Antonio L.; Machado-Vieira, Rodrigo; Talib, Leda L.; Radanovic, Marcia; Gattaz, Wagner F.; Forlenza, Orestes V.

2014-01-01

Objectives. Late-life depression (LLD) is associated with reduced neurotrophic support and abnormalities in neurodegenerative cascades. The aim of the present study is to determine the concentrations of brain-derived neurotrophic factor (BDNF), amyloid-β42, total Tau, and phosphorylated Tau in the cerebrospinal fluid (CSF) of patients with LLD and cognitive impairment compared to healthy older adults. Method. We included 25 antidepressant-free patients with LLD (10 with mild cognitive impairment [LLD + MCI] and 15 with no cognitive decline [LLD + NCD]) and 25 healthy older adults as a comparison group. Depressive symptoms were assessed by the 21-item Hamilton Depression Rating Scale (HDRS-21) and cognitive performance by a comprehensive cognitive battery. Results. Patients with LLD + MCI showed significantly lower CSF BDNF levels compared to LLD + NCD and healthy controls (p = .003). There were no significant differences in Alzheimer’s disease–related CSF biomarkers between groups. CSF BDNF concentrations were positively correlated with Cambridge Cognitive Test (CAMCOG) scores (r = .36, p = .02). Discussion. The present study adds to the growing body of evidence that abnormalities in the BDNF system are involved in the pathophysiology of LLD. The reduction of the availability of BDNF in the central nervous system may indicate increased vulnerability to the development of several age-related neuropsychiatric disorders as well as to adverse cognitive outcomes. PMID:25149921

Alzheimer CSF biomarkers may be misleading in normal-pressure hydrocephalus

PubMed Central

2014-01-01

Objective: This article discusses why CSF biomarkers found in normal-pressure hydrocephalus (NPH) can be misleading when distinguishing NPH from comorbid NPH with Alzheimer disease (AD). Methods: We describe NPH CSF biomarkers and how shunt surgery can change them. We hypothesize the effects that hydrocephalus may play on interstitial fluid space and amyloid precursor protein (APP) fragment drainage into the CSF based on a recent report and how this may explain the misleading CSF NPH biomarker findings. Results: In NPH, β-amyloid protein 42 (Aβ42) is low (as in AD), but total tau (t-tau) and phospho-tau (p-tau) levels are normal, providing conflicting biomarker findings. Low Aβ42 supports an AD diagnosis but tau findings do not. Importantly, not only Aβ42, but all APP fragments and tau proteins are low in NPH CSF. Further, these proteins increase after shunting. An increase in interstitial space and APP fragment drainage into the CSF during sleep was reported recently. Conclusions: In the setting of hydrocephalus when the brain is compressed, a decrease in interstitial space and APP protein fragment drainage into the CSF may be impeded, resulting in low levels of all APP fragments and tau proteins, which has been reported. Shunting, which decompresses the brain, would create more room for the interstitial space to increase and protein waste fragments to drain into the CSF. In fact, CSF proteins increase after shunting. CSF biomarkers in pre-shunt NPH have low Aβ42 and tau protein levels, providing misleading information to distinguish NPH from comorbid NPH plus AD. PMID:25332445

A new glaucoma hypothesis: a role of glymphatic system dysfunction.

PubMed

Wostyn, Peter; Van Dam, Debby; Audenaert, Kurt; Killer, Hanspeter Esriel; De Deyn, Peter Paul; De Groot, Veva

2015-06-29

In a recent review article titled "A new look at cerebrospinal fluid circulation", Brinker et al. comprehensively described novel insights from molecular and cellular biology as well as neuroimaging research, which indicate that cerebrospinal fluid (CSF) physiology is much more complex than previously believed. The glymphatic system is a recently defined brain-wide paravascular pathway for CSF and interstitial fluid exchange that facilitates efficient clearance of interstitial solutes, including amyloid-β, from the brain. Although further studies are needed to substantiate the functional significance of the glymphatic concept, one implication is that glymphatic pathway dysfunction may contribute to the deficient amyloid-β clearance in Alzheimer's disease. In this paper, we review several lines of evidence suggesting that the glymphatic system may also have potential clinical relevance for the understanding of glaucoma. As a clinically acceptable MRI-based approach to evaluate glymphatic pathway function in humans has recently been developed, a unique opportunity now exists to investigate whether suppression of the glymphatic system contributes to the development of glaucoma. The observation of a dysfunctional glymphatic system in patients with glaucoma would provide support for the hypothesis recently proposed by our group that CSF circulatory dysfunction may play a contributory role in the pathogenesis of glaucomatous damage. This would suggest a new hypothesis for glaucoma, which, just like Alzheimer's disease, might be considered then as an imbalance between production and clearance of neurotoxins, including amyloid-β.

Review: Tau in biofluids - relation to pathology, imaging and clinical features.

PubMed

Zetterberg, H

2017-04-01

Tau is a microtubule-binding protein that is important for the stability of neuronal axons. It is normally expressed within neurons and is also secreted into the brain interstitial fluid that communicates freely with cerebrospinal fluid (CSF) and, in a more restricted manner, blood via the glymphatic clearance system of the brain. In Alzheimer's disease (AD), neuroaxonal degeneration results in increased release of tau from neurons. Furthermore, tau is truncated and phosphorylated, which leads to aggregation of tau in neurofibrillary tangles of the proximal axoplasm. Neuroaxonal degeneration and tangle formation are reflected by increased concentrations of total tau (T-tau, measured using assays that detect most forms of tau) and phospho-tau (P-tau, measured using assays with antibodies specific to phosphorylated forms of tau). In AD CSF, both T-tau and P-tau concentrations are increased. In stroke and other CNS disorders with neuroaxonal injury but without tangles, T-tau is selectively increased, whereas P-tau concentration often stays normal. In tauopathies (diseases with both neurodegeneration and neurofibrillary tangles) other than AD, CSF T-tau and P-tau concentrations are typically unaltered, which is a puzzling result that warrants further investigation. In the current review, I discuss the association of T-tau and P-tau concentrations in body fluids with neuropathological changes, imaging findings and clinical features in AD and other CNS diseases. © 2017 British Neuropathological Society.

Elevated levels of kynurenic acid in the cerebrospinal fluid of patients with bipolar disorder

PubMed Central

Olsson, Sara K.; Samuelsson, Martin; Saetre, Peter; Lindström, Leif; Jönsson, Erik G.; Nordin, Conny; Engberg, Göran; Erhardt, Sophie; Landén, Mikael

2010-01-01

Background Patients with schizophrenia show elevated brain levels of the neuroactive tryptophan metabolite kynurenic acid (KYNA). This astrocyte-derived mediator acts as a neuroprotectant and modulates sensory gating and cognitive function. We measured the levels of KYNA in the cerebrospinal fluid (CSF) of patients with bipolar disorder and healthy volunteers to investigate the putative involvement of KYNA in bipolar disorder. Methods We obtained CSF by lumbar puncture from 23 healthy men and 31 euthymic men with bipolar disorder. We analyzed the samples using high-performance liquid chromatography. Results Patients with bipolar disorder had increased levels of KYNA in their CSF compared with healthy volunteers (1.71 nM, standard error of the mean [SEM] 0.13 v. 1.13 nM, SEM 0.09; p = 0.002. The levels of KYNA were positively correlated with age among bipolar patients but not healthy volunteers. Limitations The influence of ongoing drug treatment among patients cannot be ruled out. We conducted our study during the euthymic phase of the disease. Conclusion Brain KYNA levels are increased in euthymic men with bipolar disorder. In addition, KYNA levels increased with age in these patients. These findings indicate shared mechanisms between bipolar disorder and schizophrenia. Elevated levels of brain KYNA may provide further insight to the pathophysiology and progression of bipolar disorder. PMID:20420770

Measurement of cerebral biomarkers proving traumatic brain injuries in post-mortem body fluids.

PubMed

Ondruschka, Benjamin; Sieber, Monique; Kirsten, Holger; Franke, Heike; Dressler, Jan

2018-05-05

Until now, it is impossible to identify a fatal traumatic brain injury (TBI) before post-mortem radiological investigations or an autopsy take place. It would be preferable to have an additional diagnostic tool like post-mortem biochemistry to get greater insight into the pathological pathways and survival times after sustaining TBI. Cerebrospinal fluid (CSF) and serum samples of 84 autopsy cases were collected from forensic autopsies with post-mortem intervals (PMI) of up to 148 h. The cases were categorized into a fatal TBI case group (n=42) and non-TBI controls (n=42). The values of glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF) and neutrophil gelatinase-associated lipocalin (NGAL) were analyzed by means of quantitative chemiluminescent multiplex immunoassays. The main results indicate that the usage of liquid samples with good macroscopic quality is more relevant for meaningful biomarker analyses than the length of the PMI. All three proteins were shown to differentiate TBI fatalities from the controls in CSF. In serum, only GFAP could be shown to be able to identify TBI cases. This study is the first approach to measure the three proteins together in CSF and serum in autopsy cases. Determined threshold values may differentiate between fatal TBI and control cases. The presented results emphasize the possible use of post-mortem biochemistry as a supplemental tool in everyday forensic routine.

Spaceflight-Induced Visual Impairment and Globe Deformations in Astronauts Are Linked to Orbital Cerebrospinal Fluid Volume Increase.

PubMed

Alperin, Noam; Bagci, Ahmet M

2018-01-01

Most of the astronauts onboard the International Space Station (ISS) develop visual impairment and ocular structural changes that are not fully reversible upon return to earth. Current understanding assumes that the so-called visual impairments/intracranial pressure (VIIP) syndrome is caused by cephalad vascular fluid shift. This study assesses the roles of cerebrospinal fluid (CSF) and intracranial pressure (ICP) in VIIP. Seventeen astronauts, 9 who flew a short-duration mission on the space shuttle (14.1 days [SD 1.6]) and 7 who flew a long-duration mission on the ISS (188 days [SD 22]) underwent MRI of the brain and orbits to assess the pre-to-post spaceflight changes in four categories: VIIP severity measures: globe flattening and nerve protrusion; orbital and ventricular CSF volumes; cortical gray and white matter volumes; and MR-derived ICP (MRICP). Significant pre-to-post-flight increase in globe flattening and optic nerve protrusion occurred only in the long-duration cohort (0.031 [SD 0.019] vs -0.001 [SD 0.006], and 0.025 [SD 0.013] vs 0.001 [SD 0.006]; p < 0.00002 respectively). The increased globe deformations were associated with significant increases in orbital and ventricular CSF volumes, but not with increased tissue vascular fluid content. Additionally, a moderate increase in MRICP of 6 mmHg was observed in only two ISS astronauts with large ocular structure changes. These findings are evidence for the primary role of CSF and a lesser role for intracranial cephalad fluid-shift in the formation of VIIP. VIIP is caused by a prolonged increase in orbital CSF spaces that compress the globes' posterior pole, even without a large increase in ICP.

[Acid-base equilibrium and the brain].

PubMed

Rabary, O; Boussofara, M; Grimaud, D

1994-01-01

In physiological conditions, the regulation of acid-base balance in brain maintains a noteworthy stability of cerebral pH. During systemic metabolic acid-base imbalances cerebral pH is well controlled as the blood/brain barrier is slowly and poorly permeable to electrolytes (HCO3- and H+). Cerebral pH is regulated by a modulation of the respiratory drive, triggered by the early alterations of interstitial fluid pH, close to medullary chemoreceptors. As blood/brain barrier is highly permeable to Co2, CSF pH is corrected in a few hours, even in case of severe metabolic acidosis and alkalosis. Conversely, during ventilatory acidosis and alkalosis the cerebral pH varies in the same direction and in the same range than blood pH. Therefore, the brain is better protected against metabolic than ventilatory acid-base imbalances. Ventilatory acidosis and alkalosis are able to impair cerebral blood flow and brain activity through interstitial pH alterations. During respiratory acidosis, [HCO3-] increases in extracellular fluids to control cerebral pH by two main ways: a carbonic anhydrase activation at the blood/brain and blood/CSF barriers level and an increase in chloride shift in glial cells (HCO3- exchanged for Cl-). During respiratory alkalosis, [HCO3-] decreases in extracellular fluids by the opposite changes in HCO3- transport and by an increase in lactic acid synthesis by cerebral cells. The treatment of metabolic acidosis with bicarbonates may induce a cerebral acidosis and worsen a cerebral oedema during ketoacidosis. Moderate hypocapnia carried out to treat intracranial hypertension is mainly effective when cerebral blood flow is high and vascular CO2 reactivity maintained. Hypocapnia may restore an altered cerebral blood flow autoregulation. Instrumental hypocapnia requires a control of cerebral perfusion pressure and cerebral arteriovenous difference for oxygen, to select patients for whom this kind of treatment may be of benefit, to choose the optimal level of hypocapnia and to avoid any deleterious effect. If hypocapnia is maintained over several days, an adaptation of CSF pH may limit the therapeutic effect on the cerebral blood flow and the intracranial pressure.

An integrated workflow for multiplex CSF proteomics and peptidomics-identification of candidate cerebrospinal fluid biomarkers of Alzheimer's disease.

PubMed

Hölttä, Mikko; Minthon, Lennart; Hansson, Oskar; Holmén-Larsson, Jessica; Pike, Ian; Ward, Malcolm; Kuhn, Karsten; Rüetschi, Ulla; Zetterberg, Henrik; Blennow, Kaj; Gobom, Johan

2015-02-06

Many disease processes in the brain are reflected in the protein composition of the cerebrospinal fluid (CSF). In addition to proteins, CSF also contains a large number of endogenous peptides whose potential as disease biomarkers largely remains to be explored. We have developed a novel workflow in which multiplex isobaric labeling is used for simultaneous quantification of endogenous CSF peptides and proteins by liquid chromatography coupled with mass spectrometry. After the labeling of CSF samples, endogenous peptides are separated from proteins by ultrafiltration. The proteins retained on the filters are trypsinized, and the tryptic peptides are collected separately. We evaluated this technique in a comparative pilot study of CSF peptide and protein profiles in eight patients with Alzheimer's disease (AD) and eight nondemented controls. We identified several differences between the AD and control group among endogenous peptides derived from proteins known to be associated with AD, including neurosecretory protein VGF (ratios AD/controls 0.45-0.81), integral membrane protein 2B (ratios AD/controls 0.72-0.84), and metallothionein-3 (ratios AD/controls 0.51-0.61). Analysis of tryptic peptides identified several proteins that were altered in the AD group, some of which have previously been reported as changed in AD, for example, VGF (ratio AD/controls 0.70).

Raltegravir Treatment Intensification Does Not Alter Cerebrospinal Fluid HIV-1 Infection or Immunoactivation in Subjects on Suppressive Therapy

PubMed Central

Dahl, Viktor; Lee, Evelyn; Peterson, Julia; Spudich, Serena S.; Leppla, Idris; Sinclair, Elizabeth; Fuchs, Dietmar; Palmer, Sarah

2011-01-01

Background. Despite suppression of plasma human immunodeficiency virus type 1 (HIV-1) RNA by antiretroviral therapy to levels below clinical assay detection, infection and immune activation may persist within the central nervous system and possibly lead to continued brain injury. We hypothesized that intensifying therapy would decrease cerebrospinal fluid (CSF) infection and immune activation. Methods. This was a 12-week, randomized, open-label pilot study comparing addition of the integrase inhibitor raltegravir to no treatment augmentation, with an option for rollover to raltegravir. CSF and plasma were analyzed for HIV-1 RNA using a single-copy assay. CSF and blood immune activation was assessed by neopterin concentrations and CD4+ and CD8+ T-cell surface antigen expression. Results. Primary analysis compared 14 intensified (including rollovers) to 9 nonintensified subject experiences. Median HIV-1 RNA levels in all samples were lower in CSF (<.3 copies/mL) than in plasma (<.9 copies/mL; P < .0001), and raltegravir did not reduce HIV-1 RNA, CSF neopterin, or CD4+ and CD8+ T-cell activation. Conclusions. Raltegravir intensification did not reduce intrathecal immunoactivation or alter CSF HIV-1 RNA levels in subjects with baseline viral suppression. With and without raltegravir intensification, HIV RNA levels in CSF were very low in the enrolled subjects. Clinical Trials Registration. NCT00672932. PMID:22021620

The choroid plexus: function, pathology and therapeutic potential of its transplantation.

PubMed

Emerich, Dwaine F; Vasconcellos, Alfred V; Elliott, Robert B; Skinner, Stephen J M; Borlongan, Cesario V

2004-08-01

The choroid plexus (CP) produces cerebrospinal fluid (CSF) and forms the blood-CSF barrier. However, the CP may have additional functions in the CNS beyond these traditional roles. Preclinical and clinical studies in ageing and neurodegeneration demonstrate anatomical and physiological changes in CP, suggesting roles in normal and pathological conditions and potentially endogenous repair processes following trauma. One of the broadest functions of the CP is establishing and maintaining the extracellular milieu throughout the brain and spinal cord, in part by secreting numerous growth factors into the CSF. The endogenous secretion of growth factors raises the possibility that transplantable CP might enable delivery of these molecules to the brain, while avoiding the conventional molecular and genetic alterations associated with modifying cells to secrete selected products. This review describes some of the anatomical and functional changes of CP in ageing and neurodegeneration, and recent demonstrations of the therapeutic potential of transplanted CP for neural trauma.

Brain Barrier Disruption and Region-Specific Neuronal Degeneration during Necrotizing Enterocolitis in Preterm Pigs.

PubMed

Brunse, Anders; Abbaspour, Afrouz; Sangild, Per Torp

2018-06-06

Necrotizing enterocolitis (NEC) increases the risk of brain injury and impaired neurodevelopment. Rapid brain maturation prior to birth may explain why preterm brains are particularly vulnerable to serious infections. Using pigs as models, we hypothesized that preterm birth was associated with altered blood-cerebrospinal fluid (CSF) barrier (BCSFB) function and cerebral structural deficits, and that NEC was associated with systemic inflammation, BCSFB disruption, and neuroinflammation. First, cesarean-delivered preterm and term pigs (n = 43-44) were euthanized at birth to investigate BCSFB function and markers of brain structural maturation, or on day 5 to measure markers of blood-brain barrier maturation in the hippocampus and striatum (experiment 1). Next, preterm pigs (n = 162) were fed increasing volumes of infant formula to assess NEC lesions, systemic inflammation, BCSFB permeability, cerebral histopathology, hippocampal micro-glial density, and cytokine levels on day 5 (experiments 2 and 3). In experiment 1, preterm newborns had increased CSF-plasma ratios of albumin and raffinose, reduced CSF glucose levels, as well as increased cerebral hydration and reduced white matter myelination compared with term animals. We observed lower hippocampal (but not striatal) perivascular astrocyte coverage for the first 5 days after preterm birth, accompanied by altered cell junction protein levels. In experiments 2 and- 3, piglets with severe NEC lesions showed reduced blood thrombocytes and increased plasma C-reactive protein and interleukin-6 levels. NEC was associated with increased CSF-plasma albumin and raffinose ratios, reduced CSF leukocyte numbers, and increased cerebral hydration. In the hippocampus, NEC was associated with pyramidal neuron loss and increased interleukin-6 levels. In the short term, NEC did not affect cerebral myelination or microglia density. In conclusion, altered BCSFB properties and brain structural deficits were observed in pigs after preterm birth. Acute gastrointestinal NEC lesions were associated with systemic inflammation, increased BCSFB permeability and region-specific neuronal damage. The results demonstrate the importance of early interventions against NEC to prevent brain injury in preterm infants. © 2018 S. Karger AG, Basel.

Spontaneous spinal cerebrospinal fluid leak as a cause of coma after craniotomy for clipping of an unruptured intracranial aneurysm.

PubMed

Schievink, Wouter I; Palestrant, David; Maya, M Marcel; Rappard, George

2009-03-01

Spontaneous spinal CSF leaks are best known as a cause of orthostatic headache, but may also be the cause of coma. The authors encountered a unique case of a spontaneous spinal CSF leak causing coma 2 days after craniotomy for clipping of an unruptured aneurysm. This 44-year-old woman with autosomal dominant polycystic kidney disease underwent an uneventful craniotomy for an incidental anterior choroidal artery aneurysm. No intraoperative spinal CSF drainage was used. Two days after surgery the patient became comatose with a left oculomotor nerve palsy. Computed tomography scanning revealed a right extraceberal hematoma and loss of gray-white matter differentiation. The hematoma was evacuated and a diagnosis of hemodialysis disequilibrium syndrome was made. Continuous hemodialysis and hyperosmolar therapy were instituted without any improvement. The CT scans were then reinterpreted as showing sagging of the brain, and the patient was placed in the Trendelenburg position which resulted in prompt improvement in her level of consciousness. A CT myelogram demonstrated an upper thoracic CSF leak that eventually required surgical correction. The patient made a complete neurological recovery. Neurological deterioration after craniotomy may be caused by brain sagging caused by a spontaneous spinal CSF leak, similar to intracranial hypotension due to intraoperative lumbar CSF drainage.

Human Cerebrospinal Fluid Fatty Acid Levels Differ between Supernatant Fluid and Brain-Derived Nanoparticle Fractions, and Are Altered in Alzheimer's Disease

PubMed Central

Fonteh, Alfred N.; Cipolla, Matthew; Chiang, Jiarong; Arakaki, Xianghong; Harrington, Michael G.

2014-01-01

Background Although saturated (SAFA), monounsaturated (MUFA), and polyunsaturated (PUFA) fatty acids are important structural components of neuronal membranes and precursors of signaling molecules, knowledge of their metabolism in Alzheimer's disease (AD) is limited. Based on recent discovery that lipids in cerebrospinal fluid (CSF) are distributed in both brain-derived nanoparticles (NP) and supernatant fluid (SF), we hypothesized that fatty acid (FA) abundance and distribution into these compartments is altered in early AD pathology. Methodology and Findings We assayed the FA composition and abundance in CSF fractions from cognitively healthy (CH), mild cognitive impairment (MCI), and AD study participants using gas chromatography - mass spectrometry. In the SF fraction, concentration of docosahexaenoic acid [DHA, (C22:6n-3)] was less in AD compared with CH, while alpha linolenic acid [α-LNA, (C18:3n-3)] was lower in MCI compared with CH. In the NP fraction, levels of SAFAs (C15:0, C16:0) and a MUFA (C15:1) differentiated CH from MCI, while two MUFAs (C15:1, C19:1) and four PUFAs (C20:2n-6, C20:3n-3, C22:4n-6, C22:5n-3) were higher in AD compared with CH. Levels of even-chain free SAFA and total free FA levels were higher in AD, levels of odd-chain free SAFAs, MUFAs, n-3 PUFAs, and total PUFA, were lower in AD compared with CH. Free n-6 PUFA levels were similar in all three groups. Conclusions and Significance FA metabolism is compartmentalized differently in NP versus SF fractions of CSF, and altered FA levels reflect the importance of abnormal metabolism and oxidative pathways in AD. Depleted DHA in CSF fractions in AD is consistent with the importance of n-3 PUFAs in cognitive function, and suggests that disturbed PUFA metabolism contributes to AD pathology. This study of FA levels in CSF fractions from different cognitive stages shows potential AD biomarkers, and provides further insight into cell membrane dysfunctions, including mechanisms leading to amyloid production. PMID:24956173

Insulin transport into the brain.

PubMed

Gray, Sarah M; Barrett, Eugene J

2018-05-30

While there is a growing consensus that insulin has diverse and important regulatory actions on the brain, seemingly important aspects of brain insulin physiology are poorly understood. Examples include: what is the insulin concentration within brain interstitial fluid under normal physiologic conditions; whether insulin is made in the brain and acts locally; does insulin from the circulation cross the blood-brain barrier or the blood-CSF barrier in a fashion that facilitates its signaling in brain; is insulin degraded within the brain; do privileged areas with a "leaky" blood-brain barrier serve as signaling nodes for transmitting peripheral insulin signaling; does insulin action in the brain include regulation of amyloid peptides; whether insulin resistance is a cause or consequence of processes involved in cognitive decline. Heretofore, nearly all studies examining brain insulin physiology have employed techniques and methodologies that do not appreciate the complex fluid compartmentation and flow throughout the brain. This review attempts to provide a status report on historical and recent work that begins to address some of these issues. It is undertaken in an effort to suggest a framework for studies going forward. Such studies are inevitably influenced by recent physiologic and genetic studies of insulin accessing and acting in brain, discoveries relating to brain fluid dynamics and the interplay of cerebrospinal fluid, brain interstitial fluid, and brain lymphatics, and advances in clinical neuroimaging that underscore the dynamic role of neurovascular coupling.

Dopamine-related genes and their relationships to monoamine metabolites in CSF.

PubMed

Jönsson, E; Sedvall, G; Brené, S; Gustavsson, J P; Geijer, T; Terenius, L; Crocq, M A; Lannfelt, L; Tylec, A; Sokoloff, P; Schwartz, J C; Wiesel, F A

1996-11-15

Monoamine metabolite (MM) levels in lumbar cerebrospinal fluid (CSF) are extensively used as indirect estimates of monoamine turnover in the brain. In this study we investigated genotypes for DNA polymorphisms in the D2 (DRD2), D3 (DRD3), and D4 (DRD4) dopamine receptor and tyrosine hydroxylase (TH) genes and their relationships to CSF MM in healthy volunteers (n = 66). Concentrations of homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) were corrected for back length, a confounding variable. Corrected MM levels were not related to age, gender, height, weight heredity, season or atmospheric pressure at sampling. Individuals with specific DRD2 and TH allele and genotype configurations significantly differed in HVA and MHPG concentrations. DRD3 homo- and heterozygotic genotypes had significantly different CSF 5-HIAA levels. DRD4 genotypes were not related to MM concentrations. The results suggest that specific DRD2, DRD3, and TH genotypes participate in the regulation of monoamine turnover in the central nervous system. Accordingly monoamine receptors and synthesizing enzyme genotypes appear to be variance factors influencing MM concentrations in CSF. The relationships found in this study support MM concentrations as markers for monoamine transmission in the human brain.

Changes in Oxidative Damage, Inflammation and [NAD(H)] with Age in Cerebrospinal Fluid

PubMed Central

Guest, Jade; Grant, Ross; Mori, Trevor A.; Croft, Kevin D.

2014-01-01

An extensive body of evidence indicates that oxidative stress and inflammation play a central role in the degenerative changes of systemic tissues in aging. However a comparatively limited amount of data is available to verify whether these processes also contribute to normal aging within the brain. High levels of oxidative damage results in key cellular changes including a reduction in available nicotinamide adenine dinucleotide (NAD+), an essential molecule required for a number of vital cellular processes including DNA repair, immune signaling and epigenetic processing. In this study we quantified changes in [NAD(H)] and markers of inflammation and oxidative damage (F2-isoprostanes, 8-OHdG, total antioxidant capacity) in the cerebrospinal fluid (CSF) of healthy humans across a wide age range (24–91 years). CSF was collected from consenting patients who required a spinal tap for the administration of anesthetic. CSF of participants aged >45 years was found to contain increased levels of lipid peroxidation (F2-isoprostanes) (p = 0.04) and inflammation (IL-6) (p = 0.00) and decreased levels of both total antioxidant capacity (p = 0.00) and NAD(H) (p = 0.05), compared to their younger counterparts. A positive association was also observed between plasma [NAD(H)] and CSF NAD(H) levels (p = 0.03). Further analysis of the data identified a relationship between alcohol intake and CSF [NAD(H)] and markers of inflammation. The CSF of participants who consumed >1 standard drink of alcohol per day contained lower levels of NAD(H) compared to those who consumed no alcohol (p<0.05). An increase in CSF IL-6 was observed in participants who reported drinking >0–1 (p<0.05) and >1 (p<0.05) standard alcoholic drinks per day compared to those who did not drink alcohol. Taken together these data suggest a progressive age associated increase in oxidative damage, inflammation and reduced [NAD(H)] in the brain which may be exacerbated by alcohol intake. PMID:24454842

Bulk derivatization and direct injection of human cerebrospinal fluid for trace-level quantification of endogenous estrogens using trap-and-elute liquid chromatography with tandem mass spectrometry.

PubMed

Fan, Hui; Papouskova, Barbora; Lemr, Karel; Wigginton, Jane G; Schug, Kevin A

2014-08-01

Although there are existing methods for determining estrogen in human bodily fluids including blood plasma and serum, very little information is available regarding estrogen levels in human cerebrospinal fluid (CSF), which is critical to assess in studies of neuroprotective functions and diffusion of neuroprotective estrogens across the blood-brain barrier. To address this problem, a liquid chromatography with tandem mass spectrometry method for the simultaneous quantification of four endogenous estrogens (estrone, 17α-estradiol, 17β-estradiol, and estriol) in human CSF was developed. An aliquot (300 μL) of human CSF was bulk derivatized using dansyl chloride in the sample and 10 μL was directly injected onto a restricted-access media trap column for protein removal. No off-line sample extraction or cleanup was needed. The limits of detection of estrone, 17α-estradiol, 17β-estradiol, and estriol were 17, 28, 13, and 30 pg/mL, respectively, which is in the parts-per-trillion regime. The method was then applied to human CSF collected from ischemic trauma patients. Endogenous estrogens were detected and quantified, demonstrating the effectiveness of this method. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Intraoperative Tumoral Bleeding of Hypervascular Medulloblastoma after Ventricular Drainage: A Case Report.

PubMed

Ryu, Han-Seung; Jung, Tae-Young; Han, Moon-Soo; Kim, Seul-Ki; Lee, Kyung-Hwa

2017-01-01

We report a rare case of intraoperative tumoral bleeding of a hypervascular medulloblastoma. A 12-year-old girl presented with dizziness and nausea. Brain magnetic resonance (MR) images revealed an approximately 4.2-cm enhanced mass on the cerebellar vermis associated with mild perilesional edema and increased cerebral blood volume. Angiography showed tumoral staining and developed occipital and circular dural sinuses in the venous phase. A suboccipital craniotomy was performed. To relieve the intracranial pressure, cerebrospinal fluid (CSF) was drained via a lateral ventricular catheter in the occipital horn. During the opening of the dura, the brain swelling had progressed, and brain computed tomography revealed an intratumoral hemorrhage with brainstem compression. The patient was in a stuporous mental state. A reoperation was performed, and the mass was totally removed. The pathologic findings revealed a medulloblastoma with abnormal enlarged arterial vascular structures. Postoperatively, the patient recovered to an alert mental state. She underwent chemotherapy and radiotherapy. There was no recurrence after 1 year. Pre-resectional CSF drainage should not be routinely performed in posterior fossa tumors, especially with increased cerebral blood volume on MR perfusion images. Complete removal should be performed quickly while CSF drainage should be performed slowly. An intratumoral hemorrhage should be considered in posterior fossa tumors when severe brain swelling suddenly develops after CSF drainage. © 2016 S. Karger AG, Basel.

Antioxidants for Alzheimer disease: a randomized clinical trial with cerebrospinal fluid biomarker measures.

PubMed

Galasko, Douglas R; Peskind, Elaine; Clark, Christopher M; Quinn, Joseph F; Ringman, John M; Jicha, Gregory A; Cotman, Carl; Cottrell, Barbara; Montine, Thomas J; Thomas, Ronald G; Aisen, Paul

2012-07-01

To evaluate whether antioxidant supplements presumed to target specific cellular compartments affected cerebrospinal fluid (CSF) biomarkers. Double-blind, placebo-controlled clinical trial. Academic medical centers. Subjects with mild to moderate Alzheimer disease. Random assignment to treatment for 16 weeks with 800 IU/d of vitamin E (α-tocopherol) plus 500 mg/d of vitamin C plus 900 mg/d of α-lipoic acid (E/C/ALA); 400 mg of coenzyme Q 3 times/d; or placebo. Changes from baseline to 16 weeks in CSF biomarkers related to Alzheimer disease and oxidative stress, cognition (Mini-Mental State Examination), and function (Alzheimer's Disease Cooperative Study Activities of Daily Living Scale). Seventy-eight subjects were randomized; 66 provided serial CSF specimens adequate for biochemical analyses. Study drugs were well tolerated, but accelerated decline in Mini-Mental State Examination scores occurred in the E/C/ALA group, a potential safety concern. Changes in CSF Aβ42, tau, and P-tau(181) levels did not differ between the 3 groups. Cerebrospinal fluid F2-isoprostane levels, an oxidative stress biomarker, decreased on average by 19% from baseline to week 16 in the E/C/ALA group but were unchanged in the other groups. Antioxidants did not influence CSF biomarkers related to amyloid or tau pathology. Lowering of CSF F2-isoprostane levels in the E/C/ALA group suggests reduction of oxidative stress in the brain. However, this treatment raised the caution of faster cognitive decline, which would need careful assessment if longer-term clinical trials are conducted. clinicaltrials.gov Identifier: NCT00117403.

Brain-Derived Neurotrophic Factor (BDNF) in Traumatic Brain Injury-Related Mortality: Interrelationships Between Genetics and Acute Systemic and Central Nervous System BDNF Profiles.

PubMed

Failla, Michelle D; Conley, Yvette P; Wagner, Amy K

2016-01-01

Older adults have higher mortality rates after severe traumatic brain injury (TBI) compared to younger adults. Brain-derived neurotrophic factor (BDNF) signaling is altered in aging and is important to TBI given its role in neuronal survival/plasticity and autonomic function. Following experimental TBI, acute BDNF administration has not been efficacious. Clinically, genetic variation in BDNF (reduced signaling alleles: rs6265, Met-carriers; rs7124442, C-carriers) can be protective against acute mortality. Postacutely, these genotypes carry lower mortality risk in older adults and greater mortality risk among younger adults. Investigate BDNF levels in mortality/outcome following severe TBI in the context of age and genetic risk. Cerebrospinal fluid (CSF) and serum BDNF were assessed prospectively during the first week following severe TBI (n = 203) and in controls (n = 10). Age, BDNF genotype, and BDNF levels were assessed as mortality/outcome predictors. CSF BDNF levels tended to be higher post-TBI (P = .061) versus controls and were associated with time until death (P = .042). In contrast, serum BDNF levels were reduced post-TBI versus controls (P < .0001). Both gene * BDNF serum and gene * age interactions were mortality predictors post-TBI in the same multivariate model. CSF and serum BDNF tended to be negatively correlated post-TBI (P = .07). BDNF levels predicted mortality, in addition to gene * age interactions, suggesting levels capture additional mortality risk. Higher CSF BDNF post-TBI may be detrimental due to injury and age-related increases in pro-apoptotic BDNF target receptors. Negative CSF and serum BDNF correlations post-TBI suggest blood-brain barrier transit alterations. Understanding BDNF signaling in neuronal survival, plasticity, and autonomic function may inform treatment. © The Author(s) 2015.

Fast CSF MRI for brain segmentation; Cross-validation by comparison with 3D T1-based brain segmentation methods

PubMed Central

de Bresser, Jeroen; Hendrikse, Jeroen; Siero, Jeroen C. W.; Petersen, Esben T.; De Vis, Jill B.

2018-01-01

Objective In previous work we have developed a fast sequence that focusses on cerebrospinal fluid (CSF) based on the long T2 of CSF. By processing the data obtained with this CSF MRI sequence, brain parenchymal volume (BPV) and intracranial volume (ICV) can be automatically obtained. The aim of this study was to assess the precision of the BPV and ICV measurements of the CSF MRI sequence and to validate the CSF MRI sequence by comparison with 3D T1-based brain segmentation methods. Materials and methods Ten healthy volunteers (2 females; median age 28 years) were scanned (3T MRI) twice with repositioning in between. The scan protocol consisted of a low resolution (LR) CSF sequence (0:57min), a high resolution (HR) CSF sequence (3:21min) and a 3D T1-weighted sequence (6:47min). Data of the HR 3D-T1-weighted images were downsampled to obtain LR T1-weighted images (reconstructed imaging time: 1:59 min). Data of the CSF MRI sequences was automatically segmented using in-house software. The 3D T1-weighted images were segmented using FSL (5.0), SPM12 and FreeSurfer (5.3.0). Results The mean absolute differences for BPV and ICV between the first and second scan for CSF LR (BPV/ICV: 12±9/7±4cc) and CSF HR (5±5/4±2cc) were comparable to FSL HR (9±11/19±23cc), FSL LR (7±4, 6±5cc), FreeSurfer HR (5±3/14±8cc), FreeSurfer LR (9±8, 12±10cc), and SPM HR (5±3/4±7cc), and SPM LR (5±4, 5±3cc). The correlation between the measured volumes of the CSF sequences and that measured by FSL, FreeSurfer and SPM HR and LR was very good (all Pearson’s correlation coefficients >0.83, R2 .67–.97). The results from the downsampled data and the high-resolution data were similar. Conclusion Both CSF MRI sequences have a precision comparable to, and a very good correlation with established 3D T1-based automated segmentations methods for the segmentation of BPV and ICV. However, the short imaging time of the fast CSF MRI sequence is superior to the 3D T1 sequence on which segmentation with established methods is performed. PMID:29672584

Fast CSF MRI for brain segmentation; Cross-validation by comparison with 3D T1-based brain segmentation methods.

PubMed

van der Kleij, Lisa A; de Bresser, Jeroen; Hendrikse, Jeroen; Siero, Jeroen C W; Petersen, Esben T; De Vis, Jill B

2018-01-01

In previous work we have developed a fast sequence that focusses on cerebrospinal fluid (CSF) based on the long T2 of CSF. By processing the data obtained with this CSF MRI sequence, brain parenchymal volume (BPV) and intracranial volume (ICV) can be automatically obtained. The aim of this study was to assess the precision of the BPV and ICV measurements of the CSF MRI sequence and to validate the CSF MRI sequence by comparison with 3D T1-based brain segmentation methods. Ten healthy volunteers (2 females; median age 28 years) were scanned (3T MRI) twice with repositioning in between. The scan protocol consisted of a low resolution (LR) CSF sequence (0:57min), a high resolution (HR) CSF sequence (3:21min) and a 3D T1-weighted sequence (6:47min). Data of the HR 3D-T1-weighted images were downsampled to obtain LR T1-weighted images (reconstructed imaging time: 1:59 min). Data of the CSF MRI sequences was automatically segmented using in-house software. The 3D T1-weighted images were segmented using FSL (5.0), SPM12 and FreeSurfer (5.3.0). The mean absolute differences for BPV and ICV between the first and second scan for CSF LR (BPV/ICV: 12±9/7±4cc) and CSF HR (5±5/4±2cc) were comparable to FSL HR (9±11/19±23cc), FSL LR (7±4, 6±5cc), FreeSurfer HR (5±3/14±8cc), FreeSurfer LR (9±8, 12±10cc), and SPM HR (5±3/4±7cc), and SPM LR (5±4, 5±3cc). The correlation between the measured volumes of the CSF sequences and that measured by FSL, FreeSurfer and SPM HR and LR was very good (all Pearson's correlation coefficients >0.83, R2 .67-.97). The results from the downsampled data and the high-resolution data were similar. Both CSF MRI sequences have a precision comparable to, and a very good correlation with established 3D T1-based automated segmentations methods for the segmentation of BPV and ICV. However, the short imaging time of the fast CSF MRI sequence is superior to the 3D T1 sequence on which segmentation with established methods is performed.

Hypertension from chronic central sodium chloride in mice is mediated by the ouabain-binding site on the Na,K-ATPase α2-isoform

PubMed Central

Dostanic, Iva; Lingrel, Jerry B.; Hou, Xiaohong; Wu, Hengwei

2011-01-01

A chronic increase in the concentration of sodium chloride in the cerebrospinal fluid (CSF) (↑CSF [NaCl]) appears to be critically important for the development of salt-dependent hypertension. In agreement with this concept, increasing CSF [NaCl] chronically by intracerebroventricular (icv) infusion of NaCl-rich artificial CSF (aCSF-HiNaCl) in rats produces hypertension by the same mechanisms (i.e., aldosterone-ouabain pathway in the brain) as that produced by dietary sodium in salt-sensitive strains. We first demonstrate here that icv aCSF-HiNaCl for 10 days also causes hypertension in wild-type (WT) mice. We then used both WT and gene-targeted mice to explore the mechanisms. In WT mice with a ouabain-sensitive Na,K-ATPase α2-isoform (α2S/S), mean arterial pressure rose by ∼25 mmHg within 2 days of starting aCSF-HiNaCl (0.6 nmol Na/min) and remained elevated throughout the study. Ouabain (171 pmol/day icv) increased blood pressure to a similar extent. aCSF-HiNaCl or ouabain given at the same rates subcutaneously instead of intracerebroventricularly had no effect on blood pressure. The pressor response to icv aCSF-HiNaCl was abolished by an anti-ouabain antibody given intracerebroventricularly but not subcutaneously, indicating that it is mediated by an endogenous ouabain-like substance in the brain. We compared the effects of icv aCSF-HiNaCl or icv ouabain on blood pressure in α2S/S versus knockout/knockin mice with a ouabain-resistant endogenous α2-subunit (α2R/R). In α2R/R, there was no pressor response to icv aCSF-HiNaCl in contrast to WT mice. The α2R/R genotype also lacked a pressor response to icv ouabain. These data demonstrate that chronic ↑CSF [NaCl] causes hypertension in mice and that the blood pressure response is mediated by the ouabain-like substance in the brain, specifically by its binding to the α2-isoform of the Na,K-ATPase. PMID:21856907

Inverse association between CSF Aβ 42 levels and years of education in mild form of Alzheimer's disease: the cognitive reserve theory.

PubMed

Dumurgier, Julien; Paquet, Claire; Benisty, Sarah; Kiffel, Claire; Lidy, Claude; Mouton-Liger, François; Chabriat, Hugues; Laplanche, Jean-Louis; Hugon, Jacques

2010-11-01

In Alzheimer's disease (AD), the cognitive reserve theory predicts that at any level of assessed clinical severity, the underlying brain pathology is more advanced in patients with more cognitive reserve. Recent evidences suggest that cerebrospinal fluid (CSF) biomarkers may reflect the brain pathology in AD. We investigated the relationship between education level and CSF concentrations of β-amyloid, total tau and phosphorylated tau (ptau-181) in a cohort of 70 subjects newly diagnosed with AD. We report that CSF concentration of β-amyloid was inversely associated with years of education, after adjustment for age, sex, and severity of the disease. We further demonstrate in stratified analysis that this relation was mainly present in mild form of the disease (CDR1), and was attenuated in more advanced forms of the disease. These results are consistent with the cognitive reserve theory, and suggest that cognitive reserve may be protective against amyloid related cognitive impairment at the onset of the clinical dementia. Copyright © 2010 Elsevier Inc. All rights reserved.

Leukocyte attraction by CCL20 and its receptor CCR6 in humans and mice with pneumococcal meningitis.

PubMed

Klein, Matthias; Brouwer, Matthijs C; Angele, Barbara; Geldhoff, Madelijn; Marquez, Gabriel; Varona, Rosa; Häcker, Georg; Schmetzer, Helga; Häcker, Hans; Hammerschmidt, Sven; van der Ende, Arie; Pfister, Hans-Walter; van de Beek, Diederik; Koedel, Uwe

2014-01-01

We previously identified CCL20 as an early chemokine in the cerebrospinal fluid (CSF) of patients with pneumococcal meningitis but its functional relevance was unknown. Here we studied the role of CCL20 and its receptor CCR6 in pneumococcal meningitis. In a prospective nationwide study, CCL20 levels were significantly elevated in the CSF of patients with pneumococcal meningitis and correlated with CSF leukocyte counts. CCR6-deficient mice with pneumococcal meningitis and WT mice with pneumococcal meningitis treated with anti-CCL20 antibodies both had reduced CSF white blood cell counts. The reduction in CSF pleocytosis was also accompanied by an increase in brain bacterial titers. Additional in vitro experiments showed direct chemoattractant activity of CCL20 for granulocytes. In summary, our results identify the CCL20-CCR6 axis as an essential component of the innate immune defense against pneumococcal meningitis, controlling granulocyte recruitment.

Leukocyte Attraction by CCL20 and Its Receptor CCR6 in Humans and Mice with Pneumococcal Meningitis

PubMed Central

Angele, Barbara; Geldhoff, Madelijn; Marquez, Gabriel; Varona, Rosa; Häcker, Georg; Schmetzer, Helga; Häcker, Hans; Hammerschmidt, Sven; van der Ende, Arie; Pfister, Hans-Walter

2014-01-01

We previously identified CCL20 as an early chemokine in the cerebrospinal fluid (CSF) of patients with pneumococcal meningitis but its functional relevance was unknown. Here we studied the role of CCL20 and its receptor CCR6 in pneumococcal meningitis. In a prospective nationwide study, CCL20 levels were significantly elevated in the CSF of patients with pneumococcal meningitis and correlated with CSF leukocyte counts. CCR6-deficient mice with pneumococcal meningitis and WT mice with pneumococcal meningitis treated with anti-CCL20 antibodies both had reduced CSF white blood cell counts. The reduction in CSF pleocytosis was also accompanied by an increase in brain bacterial titers. Additional in vitro experiments showed direct chemoattractant activity of CCL20 for granulocytes. In summary, our results identify the CCL20-CCR6 axis as an essential component of the innate immune defense against pneumococcal meningitis, controlling granulocyte recruitment. PMID:24699535

T-Lymphocytes Traffic into the Brain across the Blood-CSF Barrier: Evidence Using a Reconstituted Choroid Plexus Epithelium

PubMed Central

Strazielle, Nathalie; Creidy, Rita; Malcus, Christophe; Boucraut, José; Ghersi-Egea, Jean-François

2016-01-01

An emerging concept of normal brain immune surveillance proposes that recently and moderately activated central memory T lymphocytes enter the central nervous system (CNS) directly into the cerebrospinal fluid (CSF) via the choroid plexus. Within the CSF space, T cells inspect the CNS environment for cognate antigens. This gate of entry into the CNS could also prevail at the initial stage of neuroinflammatory processes. To actually demonstrate T cell migration across the choroidal epithelium forming the blood-CSF barrier, an in vitro model of the rat blood-CSF barrier was established in an “inverse” configuration that enables cell transmigration studies in the basolateral to apical, i.e. blood/stroma to CSF direction. Structural barrier features were evaluated by immunocytochemical analysis of tight junction proteins, functional barrier properties were assessed by measuring the monolayer permeability to sucrose and the active efflux transport of organic anions. The migratory behaviour of activated T cells across the choroidal epithelium was analysed in the presence and absence of chemokines. The migration pathway was examined by confocal microscopy. The inverse rat BCSFB model reproduces the continuous distribution of tight junction proteins at cell margins, the restricted paracellular permeability, and polarized active transport mechanisms, which all contribute to the barrier phenotype in vivo. Using this model, we present experimental evidence of T cell migration across the choroidal epithelium. Cell migration appears to occur via a paracellular route without disrupting the restrictive barrier properties of the epithelial interface. Apical chemokine addition strongly stimulates T cell migration across the choroidal epithelium. The present data provide evidence for the controlled migration of T cells across the blood-CSF barrier into brain. They further indicate that this recruitment route is sensitive to CSF-borne chemokines, extending the relevance of this migration pathway to neuroinflammatory and neuroinfectious disorders which are typified by elevated chemokine levels in CSF. PMID:26942913

T-Lymphocytes Traffic into the Brain across the Blood-CSF Barrier: Evidence Using a Reconstituted Choroid Plexus Epithelium.

PubMed

Strazielle, Nathalie; Creidy, Rita; Malcus, Christophe; Boucraut, José; Ghersi-Egea, Jean-François

2016-01-01

An emerging concept of normal brain immune surveillance proposes that recently and moderately activated central memory T lymphocytes enter the central nervous system (CNS) directly into the cerebrospinal fluid (CSF) via the choroid plexus. Within the CSF space, T cells inspect the CNS environment for cognate antigens. This gate of entry into the CNS could also prevail at the initial stage of neuroinflammatory processes. To actually demonstrate T cell migration across the choroidal epithelium forming the blood-CSF barrier, an in vitro model of the rat blood-CSF barrier was established in an "inverse" configuration that enables cell transmigration studies in the basolateral to apical, i.e. blood/stroma to CSF direction. Structural barrier features were evaluated by immunocytochemical analysis of tight junction proteins, functional barrier properties were assessed by measuring the monolayer permeability to sucrose and the active efflux transport of organic anions. The migratory behaviour of activated T cells across the choroidal epithelium was analysed in the presence and absence of chemokines. The migration pathway was examined by confocal microscopy. The inverse rat BCSFB model reproduces the continuous distribution of tight junction proteins at cell margins, the restricted paracellular permeability, and polarized active transport mechanisms, which all contribute to the barrier phenotype in vivo. Using this model, we present experimental evidence of T cell migration across the choroidal epithelium. Cell migration appears to occur via a paracellular route without disrupting the restrictive barrier properties of the epithelial interface. Apical chemokine addition strongly stimulates T cell migration across the choroidal epithelium. The present data provide evidence for the controlled migration of T cells across the blood-CSF barrier into brain. They further indicate that this recruitment route is sensitive to CSF-borne chemokines, extending the relevance of this migration pathway to neuroinflammatory and neuroinfectious disorders which are typified by elevated chemokine levels in CSF.

The Alzheimer’s Disease Neuroimaging Initiative: Progress report and future plans

PubMed Central

Weiner, Michael W.; Aisen, Paul S.; Jack, Clifford R.; Jagust, William J.; Trojanowski, John Q.; Shaw, Leslie; Saykin, Andrew J.; Morris, John C.; Cairns, Nigel; Beckett, Laurel A.; Toga, Arthur; Green, Robert; Walter, Sarah; Soares, Holly; Snyder, Peter; Siemers, Eric; Potter, William; Cole, Patricia E.; Schmidt, Mark

2010-01-01

The Alzheimer’s Disease Neuroimaging Initiative (ADNI) beginning in October 2004, is a 6-year re-search project that studies changes of cognition, function, brain structure and function, and biomarkers in elderly controls, subjects with mild cognitive impairment, and subjects with Alzheimer’s disease (AD). A major goal is to determine and validate MRI, PET images, and cerebrospinal fluid (CSF)/blood biomarkers as predictors and outcomes for use in clinical trials of AD treatments. Structural MRI, FDG PET, C-11 Pittsburgh compound B (PIB) PET, CSF measurements of amyloid β (Aβ) and species of tau, with clinical/cognitive measurements were performed on elderly controls, subjects with mild cognitive impairment, and subjects with AD. Structural MRI shows high rates of brain atrophy, and has high statistical power for determining treatment effects. FDG PET, C-11 Pittsburgh compound B PET, and CSF measurements of Aβ and tau were significant predictors of cognitive decline and brain atrophy. All data are available at UCLA/LONI/ADNI, without embargo. ADNI-like projects started in Australia, Europe, Japan, and Korea. ADNI provides significant new information concerning the progression of AD. PMID:20451868

Optimized Standard Operating Procedures for the Analysis of Cerebrospinal Fluid Aβ42 and the Ratios of Aβ Isoforms Using Low Protein Binding Tubes.

PubMed

Vanderstichele, Hugo Marcel Johan; Janelidze, Shorena; Demeyer, Leentje; Coart, Els; Stoops, Erik; Herbst, Victor; Mauroo, Kimberley; Brix, Britta; Hansson, Oskar

2016-05-31

Reduced cerebrospinal fluid (CSF) concentration of amyloid-β1-42 (Aβ1-42) reflects the presence of amyloidopathy in brains of subjects with Alzheimer's disease (AD). To qualify the use of Aβ1-42/Aβ1-40 for improvement of standard operating procedures (SOP) for measurement of CSF Aβ with a focus on CSF collection, storage, and analysis. Euroimmun ELISAs for CSF Aβ isoforms were used to set up a SOP with respect to recipient properties (low binding, polypropylene), volume of tubes, freeze/thaw cycles, addition of detergents (Triton X-100, Tween-20) in collection or storage tubes or during CSF analysis. Data were analyzed with linear repeated measures and mixed effects models. Optimization of CSF analysis included a pre-wash of recipients (e.g., tubes, 96-well plates) before sample analysis. Using the Aβ1-42/Aβ1-40 ratio, in contrast to Aβ1-42, eliminated effects of tube type, additional freeze/thaw cycles, or effect of CSF volumes for polypropylene storage tubes. 'Low binding' tubes reduced the loss of Aβ when aliquoting CSF or in function of additional freeze/thaw cycles. Addition of detergent in CSF collection tubes resulted in an almost complete absence of variation in function of collection procedures, but affected the concentration of Aβ isoforms in the immunoassay. The ratio of Aβ1-42/Aβ1-40 is a more robust biomarker than Aβ1-42 toward (pre-) analytical interfering factors. Further, 'low binding' recipients and addition of detergent in collection tubes are able to remove effects of SOP-related confounding factors. Integration of the Aβ1-42/Aβ1-40 ratio and 'low-binding tubes' into guidance criteria may speed up worldwide standardization of CSF biomarker analysis.

The plasma and cerebrospinal fluid pharmacokinetics of erlotinib and its active metabolite (OSI-420) after intravenous administration of erlotinib in non-human primates.

PubMed

Meany, Holly J; Fox, Elizabeth; McCully, Cynthia; Tucker, Chris; Balis, Frank M

2008-08-01

Erlotinib hydrochloride is a small molecule inhibitor of epidermal growth factor receptor (EGFR). EGFR is over-expressed in primary brain tumors and solid tumors that metastasize to the central nervous system. We evaluated the plasma and cerebrospinal fluid (CSF) pharmacokinetics of erlotinib and its active metabolite OSI-420 after an intravenous (IV) dose in a non-human primate model. Erlotinib was administered as a 1 h IV infusion to four adult rhesus monkeys. Serial blood and CSF samples were drawn over 48 h and erlotinib and OSI-420 were quantified with an HPLC/tandem mass spectroscopic assay. Pharmacokinetic parameters were estimated using non-compartmental and compartmental methods. CSF penetration was calculated from the AUC(CSF):AUC(plasma). Erlotinib disappearance from plasma after a short IV infusion was biexponential with a mean terminal half-life of 5.2 h and a mean clearance of 128 ml/min per m(2). OSI-420 exposure (AUC) in plasma was 30% (range 12-59%) of erlotinib, and OSI-420 clearance was more than 5-fold higher than erlotinib. Erlotinib and OSI-420 were detectable in CSF. The CSF penetration (AUC(CSF):AUC(plasma)) of erlotinib and OSI-420 was <5% relative to total plasma concentration, but CSF drug exposure was approximately 30% of plasma free drug exposure, which was calculated from published plasma protein binding values. The IV administration of erlotinib was well tolerated. Erlotinib and its active metabolite OSI-420 are measurable in CSF after an IV dose. The drug exposure (AUC) in the CSF is limited relative to total plasma concentrations but is substantial relative the free drug exposure in plasma.

Cerebrospinal fluid neopterin: an informative biomarker of central nervous system immune activation in HIV-1 infection.

PubMed

Hagberg, Lars; Cinque, Paola; Gisslen, Magnus; Brew, Bruce J; Spudich, Serena; Bestetti, Arabella; Price, Richard W; Fuchs, Dietmar

2010-06-03

HIV-1 invades the central nervous system (CNS) in the context of acute infection, persists thereafter in the absence of treatment, and leads to chronic intrathecal immunoactivation that can be measured by the macrophage activation marker, neopterin, in cerebrospinal fluid (CSF). In this review we describe our experience with CSF neopterin measurements in 382 untreated HIV-infected patients across the spectrum of immunosuppression and HIV-related neurological diseases, in 73 untreated AIDS patients with opportunistic CNS infections, and in 233 treated patients.In untreated patients, CSF neopterin concentrations are almost always elevated and increase progressively as immunosuppression worsens and blood CD4 cell counts fall. However, patients with HIV dementia exhibit particularly high CSF neopterin concentrations, above those of patients without neurological disease, though patients with CNS opportunistic infections, including CMV encephalitis and cryptococcal meningitis, also exhibit high levels of CSF neopterin. Combination antiretroviral therapy, with its potent effect on CNS HIV infection and CSF HIV RNA, mitigates both intrathecal immunoactivation and lowers CSF neopterin. However, despite suppression of plasma and CSF HIV RNA to below the detection limits of clinical assays (<50 copies HIV RNA/mL), CSF neopterin often remains mildly elevated, indicating persistent low-level intrathecal immune activation and raising the important questions of whether this elevation is driven by continued CNS infection and whether it causes continued indolent CNS injury.Although nonspecific, CSF neopterin can serve as a useful biomarker in the diagnosis of HIV dementia in the setting of confounding conditions, in monitoring the CNS inflammatory effects of antiretroviral treatment, and give valuable information to the cause of ongoing brain injury.

Operation Brain Trauma Therapy Extended Studies

DTIC Science & Technology

2015-05-01

peaks in the TBI models. It is also possible that the use of a craniotomy in all 3 models results in an under- estimation of the potential benefit of...traditional strategies, namely, osmolar therapy (mannitol or hypertonic saline administration), CSF drainage , craniectomy, limitation of fluid administration

Preclinical cerebrospinal fluid and volumetric magnetic resonance imaging biomarkers in Swedish familial Alzheimer's disease.

PubMed

Thordardottir, Steinunn; Ståhlbom, Anne Kinhult; Ferreira, Daniel; Almkvist, Ove; Westman, Eric; Zetterberg, Henrik; Eriksdotter, Maria; Blennow, Kaj; Graff, Caroline

2015-01-01

It is currently believed that therapeutic interventions will be most effective when introduced at the preclinical stage of Alzheimer's disease (AD). This underlines the importance of biomarkers to detect AD pathology in vivo before clinical disease onset. To examine the evolution of cerebrospinal fluid (CSF) biomarker and brain structure changes in the preclinical phase of familial AD. The study included members from four Swedish families at risk for carrying an APPswe, APParc, PSEN1 H163Y, or PSEN1 I143T mutation. Magnetic resonance imaging (MRI) scans were obtained from 13 mutation carriers (MC) and 20 non-carriers (NC) and analyzed using vertex-based analyses of cortical thickness and volume. CSF was collected from 10 MC and 12 NC from familial AD families and analyzed for Aβ42, total tau (T-tau) and phospho-tau (P-tau). The MC had significantly lower levels of CSF Aβ42 and higher levels T-tau and P-tau than the NC. There was a trend for a decrease in Aβ42 15-20 years before expected onset of clinical symptoms, while increasing T-tau and P-tau was not found until close to the expected clinical onset. The MC had decreased volume on MRI in the left precuneus, superior temporal gyrus, and fusiform gyrus. Aberrant biomarker levels in CSF as well as regional brain atrophy are present in preclinical familial AD, several years before the expected onset of clinical symptoms.

Focal Solute Trapping and Global Glymphatic Pathway Impairment in a Murine Model of Multiple Microinfarcts

PubMed Central

Wang, Minghuan; Ding, Fengfei; Deng, SaiYue; Guo, Xuequn; Wang, Wei

2017-01-01

Microinfarcts occur commonly in the aging brain as a consequence of diffuse embolic events and are associated with the development of vascular dementia and Alzheimer's disease. However, the manner in which disperse microscopic lesions reduce global cognitive function and increase the risk for Alzheimer's disease is unclear. The glymphatic system, which is a brain-wide perivascular network that supports the recirculation of CSF through the brain parenchyma, facilitates the clearance of interstitial solutes including amyloid β and tau. We investigated whether glymphatic pathway function is impaired in a murine model of multiple microinfarcts induced by intraarterial injection of cholesterol crystals. The analysis showed that multiple microinfarcts markedly impaired global influx of CSF along the glymphatic pathway. Although suppression of global glymphatic function was transient, resolving within 2 weeks of injury, CSF tracers also accumulated within tissue associated with microinfarcts. The effect of diffuse microinfarcts on global glymphatic pathway function was exacerbated in the mice aged 12 months compared with the 2- to 3-month-old mice. These findings indicate that glymphatic function is focally disrupted around microinfarcts and that the aging brain is more vulnerable to this disruption than the young brain. These observations suggest that microlesions may trap proteins and other interstitial solutes within the brain parenchyma, increasing the risk of amyloid plaque formation. SIGNIFICANCE STATEMENT Microinfarcts, small (<1 mm) ischemic lesions, are strongly associated with age-related dementia. However, how these microscopic lesions affect global cognitive function and predispose to Alzheimer's disease is unclear. The glymphatic system is a brain-wide network of channels surrounding brain blood vessels that allows CSF to exchange with interstitial fluid, clearing away cellular wastes such as amyloid β. We observed that, in mice, microinfarcts impaired global glymphatic function and solutes from the CSF became trapped in tissue associated with microinfarcts. These data suggest that small, disperse ischemic lesions can impair glymphatic function across the brain and trapping of solutes in these lesions may promote protein aggregation and neuroinflammation and eventually lead to neurodegeneration, especially in the aging brain. PMID:28188218

Focal Solute Trapping and Global Glymphatic Pathway Impairment in a Murine Model of Multiple Microinfarcts.

PubMed

Wang, Minghuan; Ding, Fengfei; Deng, SaiYue; Guo, Xuequn; Wang, Wei; Iliff, Jeffrey J; Nedergaard, Maiken

2017-03-15

Microinfarcts occur commonly in the aging brain as a consequence of diffuse embolic events and are associated with the development of vascular dementia and Alzheimer's disease. However, the manner in which disperse microscopic lesions reduce global cognitive function and increase the risk for Alzheimer's disease is unclear. The glymphatic system, which is a brain-wide perivascular network that supports the recirculation of CSF through the brain parenchyma, facilitates the clearance of interstitial solutes including amyloid β and tau. We investigated whether glymphatic pathway function is impaired in a murine model of multiple microinfarcts induced by intraarterial injection of cholesterol crystals. The analysis showed that multiple microinfarcts markedly impaired global influx of CSF along the glymphatic pathway. Although suppression of global glymphatic function was transient, resolving within 2 weeks of injury, CSF tracers also accumulated within tissue associated with microinfarcts. The effect of diffuse microinfarcts on global glymphatic pathway function was exacerbated in the mice aged 12 months compared with the 2- to 3-month-old mice. These findings indicate that glymphatic function is focally disrupted around microinfarcts and that the aging brain is more vulnerable to this disruption than the young brain. These observations suggest that microlesions may trap proteins and other interstitial solutes within the brain parenchyma, increasing the risk of amyloid plaque formation. SIGNIFICANCE STATEMENT Microinfarcts, small (<1 mm) ischemic lesions, are strongly associated with age-related dementia. However, how these microscopic lesions affect global cognitive function and predispose to Alzheimer's disease is unclear. The glymphatic system is a brain-wide network of channels surrounding brain blood vessels that allows CSF to exchange with interstitial fluid, clearing away cellular wastes such as amyloid β. We observed that, in mice, microinfarcts impaired global glymphatic function and solutes from the CSF became trapped in tissue associated with microinfarcts. These data suggest that small, disperse ischemic lesions can impair glymphatic function across the brain and trapping of solutes in these lesions may promote protein aggregation and neuroinflammation and eventually lead to neurodegeneration, especially in the aging brain. Copyright © 2017 the authors 0270-6474/17/372870-08$15.00/0.

Associations Between Biomarkers and Age in the Presenilin 1 E280A Autosomal Dominant Alzheimer Disease Kindred A Cross-sectional Study

PubMed Central

Fleisher, Adam S.; Chen, Kewei; Quiroz, Yakeel T.; Jakimovich, Laura J.; Gomez, Madelyn Gutierrez; Langois, Carolyn M.; Langbaum, Jessica B. S.; Roontiva, Auttawut; Thiyyagura, Pradeep; Lee, Wendy; Ayutyanont, Napatkamon; Lopez, Liliana; Moreno, Sonia; Muñoz, Claudia; Tirado, Victoria; Acosta-Baena, Natalia; Fagan, Anne M.; Giraldo, Margarita; Garcia, Gloria; Huentelman, Matthew J.; Tariot, Pierre N.; Lopera, Francisco; Reiman, Eric M.

2015-01-01

IMPORTANCE Age-associated changes in brain imaging and fluid biomarkers are characterized and compared in presenilin 1 (PSEN1) E280A mutation carriers and noncarriers from the world’s largest known autosomal dominant Alzheimer disease (AD) kindred. OBJECTIVE To characterize and compare age-associated changes in brain imaging and fluid biomarkers in PSEN1 E280A mutation carriers and noncarriers. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional measures of 18F-florbetapir positron emission tomography, 18F-fludeoxyglucose positron emission tomography, structural magnetic resonance imaging, cerebrospinal fluid (CSF), and plasma biomarkers of AD were assessed from 54 PSEN1 E280A kindred members (age range, 20-59 years). MAIN OUTCOMES AND MEASURES We used brain mapping algorithms to compare regional cerebral metabolic rates for glucose and gray matter volumes in cognitively unimpaired mutation carriers and noncarriers. We used regression analyses to characterize associations between age and the mean cortical to pontine 18F-florbetapir standard uptake value ratios, precuneus cerebral metabolic rates for glucose, hippocampal gray matter volume, CSF Aβ1-42, total tau and phosphorylated tau181, and plasma Aβ measurements. Age at onset of progressive biomarker changes that distinguish carriers from noncarriers was estimated using best-fitting regression models. RESULTS Compared with noncarriers, cognitively unimpaired mutation carriers had significantly lower precuneus cerebral metabolic rates for glucose, smaller hippocampal volume, lower CSF Aβ1-42, higher CSF total tau and phosphorylated tau181, and higher plasma Aβ1-42 measurements. Sequential changes in biomarkers were seen at age 20 years (95% CI, 14-24 years) for CSF Aβ1-42, age 16 years (95% CI, 11-24 years) for the mean cortical 18F-florbetapir standard uptake value ratio, age 15 years (95% CI, 10-24 years) for precuneus cerebral metabolic rate for glucose, age 15 years (95% CI, 7-20 years) for CSF total tau, age 13 years (95% CI, 8-19 years) for phosphorylated tau181, and age 6 years (95% CI, 1-10 years) for hippocampal volume, with cognitive decline up to 6 years before the kindred’s estimated median age of 44 years (95% CI, 43-45 years) at mild cognitive impairment diagnosis. No age-associated findings were seen in plasma Aβ1-42 or Aβ1-40. CONCLUSIONS AND RELEVANCE This cross-sectional study provides additional information about the course of different AD biomarkers in the preclinical and clinical stages of autosomal dominant AD. PMID:25580592

Tau Phosphorylation Pathway Genes and Cerebrospinal Fluid Tau Levels in Alzheimer’s Disease

PubMed Central

Bekris, Lynn M.; Millard, Steve; Lutz, Franziska; Li, Gail; Galasko, Doug R.; Farlow, Martin R.; Quinn, Joseph F.; Kaye, Jeffrey A.; Leverenz, James B.; Tsuang, Debby W.; Yu, Chang-En; Peskind, Elaine R.

2013-01-01

Alzheimer’s disease (AD) is characterized by the presence in the brain of amyloid plaques, consisting predominately of the amyloid β peptide (Aβ), and neurofibrillary tangles, consisting primarily of tau. Hyper-phosphorylated-tau (p-tau) contributes to neuronal damage, and both p-tau and total-tau (t-tau) levels are elevated in AD cerebrospinal fluid (CSF) compared to cognitively normal controls. Our hypothesis was that increased ratios of CSF phosphorylated-tau levels relative to total-tau levels correlate with regulatory region genetic variation of kinase or phosphatase genes biologically associated with the phosphorylation status of tau. Eighteen SNPs located within 5′ and 3′ regions of 5 kinase and 4 phosphatase genes, as well as two SNPs within regulatory regions of the MAPT gene were chosen for this analysis. The study sample consisted of 101 AD patients and 169 cognitively normal controls. Rs7768046 in the FYN kinase gene and rs913275 in the PPP2R4 phosphatase gene were both associated with CSF p-tau and t-tau levels in AD. These SNPs were also differentially associated with either CSF t-tau (rs7768046) or CSF p-tau (rs913275) relative to t-tau levels in AD compared to controls. These results suggest that rs7768046 and rs913275 both influence CSF tau levels in an AD-associated manner. PMID:22927204

Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia — significance for activation of the kynurenine pathway

PubMed Central

Schwieler, Lilly; Larsson, Markus K.; Skogh, Elisabeth; Kegel, Magdalena E.; Orhan, Funda; Abdelmoaty, Sally; Finn, Anja; Bhat, Maria; Samuelsson, Martin; Lundberg, Kristina; Dahl, Marja-Liisa; Sellgren, Carl; Schuppe-Koistinen, Ina; Svensson, Camilla I.; Erhardt, Sophie; Engberg, Göran

2015-01-01

Background Accumulating evidence indicates that schizophrenia is associated with brain immune activation. While a number of reports suggest increased cytokine levels in patients with schizophrenia, many of these studies have been limited by their focus on peripheral cytokines or confounded by various antipsychotic treatments. Here, well-characterized patients with schizophrenia, all receiving olanzapine treatment, and healthy volunteers were analyzed with regard to cerebrospinal fluid (CSF) levels of cytokines. We correlated the CSF cytokine levels to previously analyzed metabolites of the kynurenine (KYN) pathway. Methods We analyzed the CSF from patients and controls using electrochemiluminescence detection with regard to cytokines. Cell culture media from human cortical astrocytes were analyzed for KYN and kynurenic acid (KYNA) using high-pressure liquid chromatography or liquid chromatography/mass spectrometry. Results We included 23 patients and 37 controls in our study. Patients with schizophrenia had increased CSF levels of interleukin (IL)-6 compared with healthy volunteers. In patients, we also observed a positive correlation between IL-6 and the tryptophan:KYNA ratio, indicating that IL-6 activates the KYN pathway. In line with this, application of IL-6 to cultured human astrocytes increased cell medium concentration of KYNA. Limitations The CSF samples had been frozen and thawed twice before analysis of cytokines. Median age differed between patients and controls. When appropriate, all present analyses were adjusted for age. Conclusion We have shown that IL-6, KYN and KYNA are elevated in patients with chronic schizophrenia, strengthening the idea of brain immune activation in patients with this disease. Our concurrent cell culture and clinical findings suggest that IL-6 induces the KYN pathway, leading to increased production of the N-methyl-d-aspartate receptor antagonist KYNA in patients with schizophrenia. PMID:25455350

Transfer of omega-3 fatty acids across the blood-brain barrier after dietary supplementation with a docosahexaenoic acid-rich omega-3 fatty acid preparation in patients with Alzheimer's disease: the OmegAD study.

PubMed

Freund Levi, Y; Vedin, I; Cederholm, T; Basun, H; Faxén Irving, G; Eriksdotter, M; Hjorth, E; Schultzberg, M; Vessby, B; Wahlund, L-O; Salem, N; Palmblad, J

2014-04-01

Little is known about the transfer of essential fatty acids (FAs) across the human blood-brain barrier (BBB) in adulthood. In this study, we investigated whether oral supplementation with omega-3 (n-3) FAs would change the FA profile of the cerebrospinal fluid (CSF). A total of 33 patients (18 receiving the n-3 FA supplement and 15 receiving placebo) were included in the study. These patients were participants in the double-blind, placebo-controlled randomized OmegAD study in which 204 patients with mild Alzheimer's disease (AD) received 2.3 g n-3 FA [high in docosahexaenoic acid (DHA)] or placebo daily for 6 months. CSF FA levels were related to changes in plasma FA and to CSF biomarkers of AD and inflammation. At 6 months, the n-3 FA supplement group displayed significant increases in CSF (and plasma) eicosapentaenoic acid (EPA), DHA and total n-3 FA levels (P < 0.01), whereas no changes were observed in the placebo group. Changes in CSF and plasma levels of EPA and n-3 docosapentaenoic acid were strongly correlated, in contrast to those of DHA. Changes in DHA levels in CSF were inversely correlated with CSF levels of total and phosphorylated tau, and directly correlated with soluble interleukin-1 receptor type II. Thus, the more DHA increased in CSF, the greater the change in CSF AD/inflammatory biomarkers. Oral supplementation with n-3 FAs conferred changes in the n-3 FA profile in CSF, suggesting transfer of these FAs across the BBB in adults. © 2013 The Association for the Publication of the Journal of Internal Medicine.

Comparison of lacosamide concentrations in cerebrospinal fluid and serum in patients with epilepsy.

PubMed

May, Theodor W; Brandt, Christian; Helmer, Renate; Bien, Christian G; Cawello, Willi

2015-07-01

This study was carried out to estimate the exposure of the central nervous system (CNS) to the antiepileptic drug (AED) lacosamide, under steady state conditions, in patients with epilepsy who take oral lacosamide alongside up to three other AEDs. Twenty-seven serum and cerebral spinal fluid (CSF) samples were collected from 21 patients receiving lacosamide for the treatment of epilepsy (50-600 mg/day over two or three doses). This included 23 time-matched pairs of serum and CSF samples from 19 patients. The concentration of lacosamide in each sample was determined using high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). Linear regression was used to characterize the relationship between the CSF-to-serum ratio of lacosamide concentration and the time since dosing, the daily lacosamide dose, or the daily dose normalized by volume of distribution (Vd , approximated to total body water), and between the drug concentrations in each compartment (CSF vs. serum). Concentrations of lacosamide in CSF (mean ± standard deviation [SD] 7.37 ± 3.73 μg/ml, range 1.24-14.95, n = 27) and serum (mean ± SD 8.16 ± 3.82 μg/ml, range 2.29-15.45, n = 27) samples showed a good correlation over the dose range investigated. The mean CSF-to-serum ratio of lacosamide concentrations was 0.897 ± 0.193 (range 0.492-1.254, n = 23 time-matched pairs) and was independent of lacosamide dose. Drug concentrations in the CSF are often used to indicate those in the brain interstitial fluid. In patients with epilepsy who follow a stable oral AED dosing regimen, lacosamide concentration in CSF is approximately 85% of that found in serum, suggesting that serum may be a valuable indicator of lacosamide concentration in the CNS. Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.

Brain tissue volumes in the general elderly population. The Rotterdam Scan Study.

PubMed

Ikram, M Arfan; Vrooman, Henri A; Vernooij, Meike W; van der Lijn, Fedde; Hofman, Albert; van der Lugt, Aad; Niessen, Wiro J; Breteler, Monique M B

2008-06-01

We investigated how volumes of cerebrospinal fluid (CSF), grey matter (GM) and white matter (WM) varied with age, sex, small vessel disease and cardiovascular risk factors in the Rotterdam Scan Study. Participants (n=490; 60-90 years) were non-demented and 51.0% had hypertension, 4.9% had diabetes mellitus, 17.8% were current smoker and 54.0% were former smoker. We segmented brain MR-images into GM, normal WM, white matter lesion (WML) and CSF. Brain infarcts were rated visually. Volumes were expressed as percentage of intra-cranial volume. With increasing age, volumes of total brain, normal WM and total WM decreased; that of GM remained unchanged; and that of WML increased, in both men and women. Excluding persons with infarcts did not alter these results. Persons with larger load of small vessel disease had smaller brain volume, especially normal WM volume. Diastolic blood pressure, diabetes mellitus and current smoking were also related to smaller brain volume. In the elderly, higher age, small vessel disease and cardiovascular risk factors are associated with smaller brain volume, especially WM volume.

Analytical variables affecting analysis of F2-isoprostanes and F4-neuroprostanes in human cerebrospinal fluid by gas chromatography/mass spectrometry.

PubMed

Yen, Hsiu-Chuan; Wei, Hsing-Ju; Chen, Ting-Wei

2013-01-01

F2-isoprostanes (F2-IsoPs) are a gold marker of lipid peroxidation in vivo, whereas F4-neuroprostanes (F4-NPs) measured in cerebrospinal fluid (CSF) or brain tissue selectively indicate neuronal oxidative damage. Gas chromatography/negative-ion chemical-ionization mass spectrometry (GC/NICI-MS) is the most sensitive and robust method for quantifying these compounds, which is essential for CSF samples because abundance of these compounds in CSF is very low. The present study revealed potential interferences on the analysis of F2-IsoPs and F4-NPs in CSF by GC/NICI-MS due to the use of improper analytical methods that have been employed in the literature. First, simultaneous quantification of F2-IsoPs and F4-NPs in CSF samples processed for F4-NPs analysis could cause poor chromatographic separation and falsely higher F2-IsoPs values for CSF samples with high levels of F2-IsoPs and F4-NPs. Second, retention of unknown substances in GC columns from CSF samples during F4-NPs analysis and from plasma samples during F2-IsoPs analysis might interfere with F4-NPs analysis of subsequent runs, which could be solved by holding columns at a high temperature for a period of time after data acquisition. Therefore, these special issues should be taken into consideration when performing analysis of F2-IsoPs and F4-NPs in CSF to avoid misleading results.

Analytical Variables Affecting Analysis of F2-Isoprostanes and F4-Neuroprostanes in Human Cerebrospinal Fluid by Gas Chromatography/Mass Spectrometry

PubMed Central

Yen, Hsiu-Chuan; Wei, Hsing-Ju; Chen, Ting-Wei

2013-01-01

F2-isoprostanes (F2-IsoPs) are a gold marker of lipid peroxidation in vivo, whereas F4-neuroprostanes (F4-NPs) measured in cerebrospinal fluid (CSF) or brain tissue selectively indicate neuronal oxidative damage. Gas chromatography/negative-ion chemical-ionization mass spectrometry (GC/NICI-MS) is the most sensitive and robust method for quantifying these compounds, which is essential for CSF samples because abundance of these compounds in CSF is very low. The present study revealed potential interferences on the analysis of F2-IsoPs and F4-NPs in CSF by GC/NICI-MS due to the use of improper analytical methods that have been employed in the literature. First, simultaneous quantification of F2-IsoPs and F4-NPs in CSF samples processed for F4-NPs analysis could cause poor chromatographic separation and falsely higher F2-IsoPs values for CSF samples with high levels of F2-IsoPs and F4-NPs. Second, retention of unknown substances in GC columns from CSF samples during F4-NPs analysis and from plasma samples during F2-IsoPs analysis might interfere with F4-NPs analysis of subsequent runs, which could be solved by holding columns at a high temperature for a period of time after data acquisition. Therefore, these special issues should be taken into consideration when performing analysis of F2-IsoPs and F4-NPs in CSF to avoid misleading results. PMID:23957004

Serum and cerebrospinal fluid levels of visinin-like protein-1 in acute encephalopathy with biphasic seizures and late reduced diffusion.

PubMed

Hasegawa, Shunji; Matsushige, Takeshi; Inoue, Hirofumi; Takahara, Midori; Kajimoto, Madoka; Momonaka, Hiroshi; Oka, Momoko; Isumi, Hiroshi; Emi, Sakie; Hayashi, Megumi; Ichiyama, Takashi

2014-08-01

Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) has recently been recognized as an encephalopathy subtype. Typical clinical symptoms of AESD are biphasic seizures, and MRI findings show reduced subcortical diffusion during clustering seizures with unconsciousness after the acute phase. Visinin-like protein-1 (VILIP-1) is a recently discovered protein that is abundant in the central nervous system, and some reports have shown that VILIP-1 may be a prognostic biomarker of conditions such as Alzheimer's disease, stroke, and brain injury. However, there have been no reports regarding serum and cerebrospinal fluid (CSF) levels of VILIP-1 in patients with AESD. We measured the serum and CSF levels of VILIP-1 in patients with AESD, and compared the levels to those in patients with prolonged febrile seizures (FS). Both serum and CSF levels of VILIP-1 were significantly higher in patients with AESD than in patients with prolonged FS. Serum and CSF VILIP-1 levels were normal on day 1 of AESD. Our results suggest that both serum and CSF levels of VILIP-1 may be one of predictive markers of AESD. Copyright © 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Increased insulin-like growth factor-1 levels in cerebrospinal fluid of advanced subacute sclerosing panencephalitis patients.

PubMed

Yılmaz, Deniz; Yüksel, Deniz; Gökkurt, Didem; Oguz, Hava; Anlar, Banu

2016-07-01

Subacute sclerosing panencephalitis (SSPE) is a progressive, lethal disease. Brain histopathology in certain SSPE patients shows, neurofibrillary tangles composed of abnormally phosphorylated, microtubule-associated protein tau (PHF-tau). Because the, phosphorylation of tau is inhibited by insulin and insulin-like growth factor-1 (IGF-1), we investigated cerebrospinal fluid (CSF) insulin and IGF-1 levels in SSPE patients. In this study CSF IGF-1 and insulin levels of 45 SSPE and 25 age-matched control patients were investigated. CSF IGF-1 levels were significantly higher in SSPE patients at stage 4, compared to other stages (p 0.05). CSF insulin and IGF-1 levels were both positively correlated with serum measles IgG. The correlation between CSF insulin and IGF-1 levels and serum measles virus IgG titer may be the result of, insulin activating IGF-1 receptors, and consequently, IGF-1 stimulating, plasma cells and enhancing IgG production. Increased IGF-1 may also, inhibit the phosphorylation of tau. Further studies examining the, correlation between IGF-1, insulin, tau, and PHF-tau levels in the same, patients may clarify any possible pathogenetic relation between these, pathways. Copyright © 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Application of Quantitative MRI for Brain Tissue Segmentation at 1.5 T and 3.0 T Field Strengths

PubMed Central

West, Janne; Blystad, Ida; Engström, Maria; Warntjes, Jan B. M.; Lundberg, Peter

2013-01-01

Background Brain tissue segmentation of white matter (WM), grey matter (GM), and cerebrospinal fluid (CSF) are important in neuroradiological applications. Quantitative Mri (qMRI) allows segmentation based on physical tissue properties, and the dependencies on MR scanner settings are removed. Brain tissue groups into clusters in the three dimensional space formed by the qMRI parameters R1, R2 and PD, and partial volume voxels are intermediate in this space. The qMRI parameters, however, depend on the main magnetic field strength. Therefore, longitudinal studies can be seriously limited by system upgrades. The aim of this work was to apply one recently described brain tissue segmentation method, based on qMRI, at both 1.5 T and 3.0 T field strengths, and to investigate similarities and differences. Methods In vivo qMRI measurements were performed on 10 healthy subjects using both 1.5 T and 3.0 T MR scanners. The brain tissue segmentation method was applied for both 1.5 T and 3.0 T and volumes of WM, GM, CSF and brain parenchymal fraction (BPF) were calculated on both field strengths. Repeatability was calculated for each scanner and a General Linear Model was used to examine the effect of field strength. Voxel-wise t-tests were also performed to evaluate regional differences. Results Statistically significant differences were found between 1.5 T and 3.0 T for WM, GM, CSF and BPF (p<0.001). Analyses of main effects showed that WM was underestimated, while GM and CSF were overestimated on 1.5 T compared to 3.0 T. The mean differences between 1.5 T and 3.0 T were -66 mL WM, 40 mL GM, 29 mL CSF and -1.99% BPF. Voxel-wise t-tests revealed regional differences of WM and GM in deep brain structures, cerebellum and brain stem. Conclusions Most of the brain was identically classified at the two field strengths, although some regional differences were observed. PMID:24066153

CNS Langerhans cell histiocytosis: Common hematopoietic origin for LCH-associated neurodegeneration and mass lesions.

PubMed

McClain, Kenneth L; Picarsic, Jennifer; Chakraborty, Rikhia; Zinn, Daniel; Lin, Howard; Abhyankar, Harshal; Scull, Brooks; Shih, Albert; Lim, Karen Phaik Har; Eckstein, Olive; Lubega, Joseph; Peters, Tricia L; Olea, Walter; Burke, Thomas; Ahmed, Nabil; Hicks, M John; Tran, Brandon; Jones, Jeremy; Dauser, Robert; Jeng, Michael; Baiocchi, Robert; Schiff, Deborah; Goldman, Stanton; Heym, Kenneth M; Wilson, Harry; Carcamo, Benjamin; Kumar, Ashish; Rodriguez-Galindo, Carlos; Whipple, Nicholas S; Campbell, Patrick; Murdoch, Geoffrey; Kofler, Julia; Heales, Simon; Malone, Marian; Woltjer, Randy; Quinn, Joseph F; Orchard, Paul; Kruer, Michael C; Jaffe, Ronald; Manz, Markus G; Lira, Sergio A; Parsons, D Williams; Merad, Miriam; Man, Tsz-Kwong; Allen, Carl E

2018-06-15

Central nervous system Langerhans cell histiocytosis (CNS-LCH) brain involvement may include mass lesions and/or a neurodegenerative disease (LCH-ND) of unknown etiology. The goal of this study was to define the mechanisms of pathogenesis that drive CNS-LCH. Cerebrospinal fluid (CSF) biomarkers including CSF proteins and extracellular BRAFV600E DNA were analyzed in CSF from patients with CNS-LCH lesions compared with patients with brain tumors and other neurodegenerative conditions. Additionally, the presence of BRAFV600E was tested in peripheral mononuclear blood cells (PBMCs) as well as brain biopsies from LCH-ND patients, and the response to BRAF-V600E inhibitor was evaluated in 4 patients with progressive disease. Osteopontin was the only consistently elevated CSF protein in patients with CNS-LCH compared with patients with other brain pathologies. BRAFV600E DNA was detected in CSF of only 2/20 (10%) cases, both with LCH-ND and active lesions outside the CNS. However, BRAFV600E + PBMCs were detected with significantly higher frequency at all stages of therapy in LCH patients who developed LCH-ND. Brain biopsies of patients with LCH-ND demonstrated diffuse perivascular infiltration by BRAFV600E + cells with monocyte phenotype (CD14 + CD33 + CD163 + P2RY12 - ) and associated osteopontin expression. Three of 4 patients with LCH-ND treated with BRAF-V600E inhibitor experienced significant clinical and radiologic improvement. In LCH-ND patients, BRAFV600E + cells in PBMCs and infiltrating myeloid/monocytic cells in the brain is consistent with LCH-ND as an active demyelinating process arising from a mutated hematopoietic precursor from which LCH lesion CD207 + cells are also derived. Therapy directed against myeloid precursors with activated MAPK signaling may be effective for LCH-ND. Cancer 2018;124:2607-20. © 2018 American Cancer Society. © 2018 American Cancer Society.

Cerebrospinal fluid and behavioral changes after methyltestosterone administration: preliminary findings.

PubMed

Daly, R C; Su, T P; Schmidt, P J; Pickar, D; Murphy, D L; Rubinow, D R

2001-02-01

Anabolic androgen steroid abuse is associated with multiple psychiatric symptoms and is a significant public health problem. The biological mechanisms underlying behavioral symptom development are poorly understood. We examined levels of monoamine metabolites, neurohormones, and neuropeptides in the cerebrospinal fluid (CSF) of 17 healthy men, at baseline and following 6 days of methyltestosterone (MT) administration (3 days of 40 mg/d, then 3 days of 240 mg/d). Subjects received MT or placebo in a fixed sequence, with neither subjects nor raters aware of the order. Potential relationships were examined between CSF measures, CSF MT levels, and behavioral changes measured on a visual analog scale. Following MT administration, levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) were significantly lower (mean +/- SD, 103.8 +/- 47 vs 122.0 +/- 50.7 pmol/mL; P<.01), and 5-hydroxyindoleacetic acid (5-HIAA) levels were significantly higher (mean +/- SD, 104.7 +/- 31.3 vs 86.9 +/- 23.6 pmol/mL; P<.01). No significant MT-related changes were observed in CSF levels of corticotropin, norepinephrine, cortisol, arginine vasopressin, prolactin, corticotropin-releasing hormone, beta-endorphin, and somatotropin release-inhibiting factor. Changes in CSF 5-HIAA significantly correlated with increases in "activation" symptoms (energy, sexual arousal, and diminished sleep) (r = 0.55; P =.02). No significant correlation was observed between changes in CSF and plasma MT, CSF MHPG, and behavioral symptoms. Short-term anabolic androgenic steroid use affects brain neurochemistry, increasing CSF 5-HIAA and decreasing MHPG. Changes in 5-HIAA levels caused by anabolic androgenic steroids are related to the behavioral changes we observed. In this small sample, we did not observe a significant relationship between behavioral measures and either dose of MT or CSF and plasma levels of MT.

Cerebrospinal fluid kynurenine and kynurenic acid concentrations are associated with coma duration and long-term neurocognitive impairment in Ugandan children with cerebral malaria.

PubMed

Holmberg, Dag; Franzén-Röhl, Elisabeth; Idro, Richard; Opoka, Robert O; Bangirana, Paul; Sellgren, Carl M; Wickström, Ronny; Färnert, Anna; Schwieler, Lilly; Engberg, Göran; John, Chandy C

2017-07-28

One-fourth of children with cerebral malaria (CM) retain cognitive sequelae up to 2 years after acute disease. The kynurenine pathway of the brain, forming neuroactive metabolites, e.g. the NMDA-receptor antagonist kynurenic acid (KYNA), has been implicated in long-term cognitive dysfunction in other CNS infections. In the present study, the association between the kynurenine pathway and neurologic/cognitive complications in children with CM was investigated. Cerebrospinal fluid (CSF) concentrations of KYNA and its precursor kynurenine in 69 Ugandan children admitted for CM to Mulago Hospital, Kampala, Uganda, between 2008 and 2013 were assessed. CSF kynurenine and KYNA were compared to CSF cytokine levels, acute and long-term neurologic complications, and long-term cognitive impairments. CSF kynurenine and KYNA from eight Swedish children without neurological or infectious disease admitted to Astrid Lindgren's Children's Hospital were quantified and used for comparison. Children with CM had significantly higher CSF concentration of kynurenine and KYNA than Swedish children (P < 0.0001 for both), and CSF kynurenine and KYNA were positively correlated. In children with CM, CSF kynurenine and KYNA concentrations were associated with coma duration in children of all ages (P = 0.003 and 0.04, respectively), and CSF kynurenine concentrations were associated with worse overall cognition (P = 0.056) and attention (P = 0.003) at 12-month follow-up in children ≥5 years old. CSF KYNA and kynurenine are elevated in children with CM, indicating an inhibition of glutamatergic and cholinergic signaling. This inhibition may lead acutely to prolonged coma and long-term to impairment of attention and cognition.

Transcriptomic Profiling of Extracellular RNAs Present in Cerebrospinal Fluid Identifies Differentially Expressed Transcripts in Parkinson’s Disease

PubMed Central

Hossein-nezhad, Arash; Fatemi, Roya Pedram; Ahmad, Rili; Peskind, Elaine R.; Zabetian, Cyrus P.; Hu, Shu-Ching; Shi, Min; Wahlestedt, Claes; Zhang, Jing; Faghihi, Mohammad Ali

2016-01-01

Background: Parkinson’s disease (PD) is a debilitating neurological disorder for which prognostic and diagnostic biomarkers are lacking. Cerebrospinal fluid (CSF) is an accessible body fluid that comes into direct contact with the central nervous system (CNS) and acts as a nuclease-free repository where RNA transcripts shed by brain tissues can reside for extended periods of time. Objective: We studied the RNA species present in the CSF of PD patients to identify novel diagnostic biomarkers. Methods: Small volumes of CSF from 27 PD patients and 30 healthy age- and sex-matched controls were used for RNA extraction followed by next-generation sequencing (RNA-seq) using the Illumina platform. CSF contains a number of fragmented RNA species that were individually sequenced and analyzed. Comparing PD to control subjects, we observed a pool of dysregulated sequencing tags that were further analyzed and validated by quantitative real-time PCR (qRT-PCR). Results: A total of 201 differentially expressed sequencing tags (DETs), including 92 up-regulated and 109 down-regulated DETs were identified. We validated the following DETs by real time PCR in the patient samples: Dnmt1, Ezh2, CCR3, SSTR5,PTPRC, UBC, NDUFV2, BMP7, SCN9, SCN9 antisense (AC010127.3), and long noncoding RNAs AC079630 and UC001lva.4 (close to the LRRK2 gene locus), as potential PD biomarkers. Conclusions: The CSF is a unique environment that contains many species of RNA. Our work demonstrates that CSF can potentially be used to identify biomarkers for the detection and tracking of disease progression and evaluation of therapeutic outcomes. PMID:26889637

Postprandial changes in leptin concentrations of cerebrospinal fluid in dogs during development of obesity.

PubMed

Nishii, Naohito; Nodake, Hiroyuki; Takasu, Masaki; Soe, Okkar; Ohba, Yasunori; Maeda, Sadatoshi; Ohtsuka, Yoshihiko; Honjo, Tsutomu; Saito, Masayuki; Kitagawa, Hitoshi

2006-12-01

To evaluate postprandial changes in the leptin concentration of CSF in dogs during development of obesity. 4 male Beagles. Weight gain was induced and assessments were made when the dogs were in thin, optimal, and obese body conditions (BCs). The fat area at the level of the L3 vertebra was measured via computed tomography to assess the degree of obesity. Dogs were evaluated in fed and unfed states. Dogs in the fed state received food at 9 AM. Blood and CSF samples were collected at 8 AM, 4 PM, and 10 PM. Baseline CSF leptin concentrations in the thin, optimal, and obese dogs were 24.3 +/- 2.7 pg/mL, 86.1 +/- 14.7 pg/mL, and 116.2 +/- 47.3 pg/mL, respectively. In the thin BC, CSF leptin concentration transiently increased at 4 PM. In the optimal BC, baseline CSF leptin concentration was maintained until 10 PM. In the obese BC, CSF leptin concentration increased from baseline value at 4 PM and 10 PM. Correlation between CSF leptin concentration and fat area was good at all time points. There was a significant negative correlation between the CSF leptin concentration-to-serum leptin concentration ratio and fat area at 4 PM; this correlation was not significant at 8 AM and 10 PM. Decreased transport of leptin at the blood-brain barrier may be 1 mechanism of leptin resistance in dogs. However, leptin resistance at the blood-brain barrier may not be important in development of obesity in dogs.

Inorganic phosphorus (Pi) in CSF is a biomarker for SLC20A2-associated idiopathic basal ganglia calcification (IBGC1).

PubMed

Hozumi, Isao; Kurita, Hisaka; Ozawa, Kazuhiro; Furuta, Nobuyuki; Inden, Masatoshi; Sekine, Shin-Ichiro; Yamada, Megumi; Hayashi, Yuichi; Kimura, Akio; Inuzuka, Takashi; Seishima, Mitsuru

2018-05-15

Idiopathic basal ganglia calcification (IBGC), also called Fahr's disease or recently primary familial brain calcification (PFBC), is characterized by abnormal deposits of minerals including calcium mainly and phosphate in the brain. Mutations in SLC20A2 (IBGC1 (merged with former IBGC2 and IBGC3)), which encodes PiT-2, a phosphate transporter, is the major cause of IBGC. Recently, Slc20a2-KO mice have been showed to have elevated levels of inorganic phosphorus (Pi) in cerebrospinal fluid (CSF); however, CSF Pi levels in patients with IBGC have not been fully examined. We investigated the cases of 29 patients with IBGC including six patients with SLC20A2 mutation and three patients with PDGFB mutation, and 13 controls. The levels of sodium (Na), potassium (K), chloride (Cl), calcium (Ca), and Pi in sera and CSF were determined by potentiometry and colorimetry. Moreover, clinical manifestations were investigated in the IBGC patients with high Pi levels in CSF. The study revealed that the average level of Pi in the CSF of the total group of patients with IBGC is significantly higher than that of the control group, and the levels of Pi in CSF of the IBGC patients with SLC20A2 mutations are significantly higher than those of the IBGC patients with PDGFB mutations, the other IBGC patients and controls. Results of this study suggest that the levels of CSF Pi will be a good biomarker for IBGC1. Copyright © 2018 Elsevier B.V. All rights reserved.

Brain tissue segmentation based on DTI data

PubMed Central

Liu, Tianming; Li, Hai; Wong, Kelvin; Tarokh, Ashley; Guo, Lei; Wong, Stephen T.C.

2008-01-01

We present a method for automated brain tissue segmentation based on the multi-channel fusion of diffusion tensor imaging (DTI) data. The method is motivated by the evidence that independent tissue segmentation based on DTI parametric images provides complementary information of tissue contrast to the tissue segmentation based on structural MRI data. This has important applications in defining accurate tissue maps when fusing structural data with diffusion data. In the absence of structural data, tissue segmentation based on DTI data provides an alternative means to obtain brain tissue segmentation. Our approach to the tissue segmentation based on DTI data is to classify the brain into two compartments by utilizing the tissue contrast existing in a single channel. Specifically, because the apparent diffusion coefficient (ADC) values in the cerebrospinal fluid (CSF) are more than twice that of gray matter (GM) and white matter (WM), we use ADC images to distinguish CSF and non-CSF tissues. Additionally, fractional anisotropy (FA) images are used to separate WM from non-WM tissues, as highly directional white matter structures have much larger fractional anisotropy values. Moreover, other channels to separate tissue are explored, such as eigenvalues of the tensor, relative anisotropy (RA), and volume ratio (VR). We developed an approach based on the Simultaneous Truth and Performance Level Estimation (STAPLE) algorithm that combines these two-class maps to obtain a complete tissue segmentation map of CSF, GM, and WM. Evaluations are provided to demonstrate the performance of our approach. Experimental results of applying this approach to brain tissue segmentation and deformable registration of DTI data and spoiled gradient-echo (SPGR) data are also provided. PMID:17804258

Sex-Related Differences in Rat Choroid Plexus and Cerebrospinal Fluid: A cDNA Microarray and Proteomic Analysis.

PubMed

Quintela, T; Marcelino, H; Deery, M J; Feret, R; Howard, J; Lilley, K S; Albuquerque, T; Gonçalves, I; Duarte, A C; Santos, C R A

2016-01-01

The choroid plexus (CP) epithelium is a unique structure in the brain that forms an interface between the peripheral blood and the cerebrospinal fluid (CSF), which is mostly produced by the CP itself. Because the CP transcriptome is regulated by the sex hormone background, the present study compared gene/protein expression profiles in the CP and CSF from male and female rats aiming to better understand sex-related differences in CP functions and brain physiology. We used data previously obtained by cDNA microarrays to compare the CP transcriptome between male and female rats, and complemented these data with the proteomic analysis of the CSF of castrated and sham-operated males and females. Microarray analysis showed that 17 128 and 17 002 genes are expressed in the male and female CP, which allowed the functional annotation of 141 and 134 pathways, respectively. Among the most expressed genes, canonical pathways associated with mitochondrial dysfunctions and oxidative phosphorylation were the most prominent, whereas the most relevant molecular and cellular functions annotated were protein synthesis, cellular growth and proliferation, cell death and survival, molecular transport, and protein trafficking. No significant differences were found between males and females regarding these pathways. Seminal functions of the CP differentially regulated between sexes were circadian rhythm signalling, as well as several canonical pathways related to stem cell differentiation, metabolism and the barrier function of the CP. The proteomic analysis identified five down-regulated proteins in the CSF samples from male rats compared to females and seven proteins exhibiting marked variation in the CSF of gonadectomised males compared to sham animals, whereas no differences were found between sham and ovariectomised females. These data clearly show sex-related differences in CP gene expression and CSF protein composition that may impact upon neurological diseases. © 2015 British Society for Neuroendocrinology.

The blood-cerebrospinal fluid barrier: structure and functional significance.

PubMed

Johanson, Conrad E; Stopa, Edward G; McMillan, Paul N

2011-01-01

The choroid plexus (CP) of the blood-CSF barrier (BCSFB) displays fundamentally different properties than blood-brain barrier (BBB). With brisk blood flow (10 × brain) and highly permeable capillaries, the human CP provides the CNS with a high turnover rate of fluid (∼400,000 μL/day) containing micronutrients, peptides, and hormones for neuronal networks. Renal-like basement membranes in microvessel walls and underneath the epithelium filter large proteins such as ferritin and immunoglobulins. Type IV collagen (α3, α4, and α5) in the subepithelial basement membrane confers kidney-like permselectivity. As in the glomerulus, so also in CP, the basolateral membrane utrophin A and colocalized dystrophin impart structural stability, transmembrane signaling, and ion/water homeostasis. Extensive infoldings of the plasma-facing basal labyrinth together with lush microvilli at the CSF-facing membrane afford surface area, as great as that at BBB, for epithelial solute and water exchange. CSF formation occurs by basolateral carrier-mediated uptake of Na+, Cl-, and HCO3-, followed by apical release via ion channel conductance and osmotic flow of water through AQP1 channels. Transcellular epithelial active transport and secretion are energized and channeled via a highly dense organelle network of mitochondria, endoplasmic reticulum, and Golgi; bleb formation occurs at the CSF surface. Claudin-2 in tight junctions helps to modulate the lower electrical resistance and greater permeability in CP than at BBB. Still, ratio analyses of influx coefficients (Kin) for radiolabeled solutes indicate that paracellular diffusion of small nonelectrolytes (e.g., urea and mannitol) through tight junctions is restricted; molecular sieving is proportional to solute size. Protein/peptide movement across BCSFB is greatly limited, occurring by paracellular leaks through incomplete tight junctions and low-capacity transcellular pinocytosis/exocytosis. Steady-state concentration ratios, CSF/plasma, ranging from 0.003 for IgG to 0.80 for urea, provide insight on plasma solute penetrability, barrier permeability, and CSF sink action to clear substances from CNS.

Cross-sectional and longitudinal relationships between cerebrospinal fluid biomarkers and cognitive function in people without cognitive impairment from across the adult life span.

PubMed

Li, Ge; Millard, Steven P; Peskind, Elaine R; Zhang, Jing; Yu, Chang-En; Leverenz, James B; Mayer, Cynthia; Shofer, Jane S; Raskind, Murray A; Quinn, Joseph F; Galasko, Douglas R; Montine, Thomas J

2014-06-01

Age-related cognitive decline among older individuals with normal cognition is a complex trait that potentially derives from processes of aging, inherited vulnerabilities, environmental factors, and common latent diseases that can progress to cause dementia, such as Alzheimer disease and vascular brain injury. To use cerebrospinal fluid (CSF) biomarkers to gain insight into this complex trait. Secondary analyses of an academic multicenter cross-sectional (n = 315) and longitudinal (n = 158) study of 5 neuropsychological tests (Immediate Recall, Delayed Recall, Trail Making Test Parts A and B, and Category Fluency) in cognitively normal individuals aged 21 to 100 years. To investigate the association of these cognitive function test results with age, sex, educational level, inheritance of the ε4 allele of the apolipoprotein E gene, and CSF concentrations of β-amyloid 42 (Aβ42) and tau (biomarkers of Alzheimer disease) as well as F2-isoprostanes (measures of free radical injury). Age and educational level were broadly predictive of cross-sectional cognitive performance; of the genetic and CSF measures, only greater CSF F2-isoprostane concentration was significantly associated with poorer executive function (adjusted R2 ≤0.31). Longitudinal measures of cognitive abilities, except Category Fluency, also were associated broadly with age; of the genetic and CSF measures, only lower baseline CSF Aβ42 concentration was associated with longitudinal measures of immediate and delayed recall (marginal R2 ≤0.31). Our results suggest that age and educational level accounted for a substantial minority of variance in cross-sectional or longitudinal cognitive test performance in this large group of cognitively normal adults. Latent Alzheimer disease and other diseases that produce free radical injury, such as vascular brain injury, accounted for a small amount of variation in cognitive test performance across the adult human life span. Additional genetic and environmental factors likely contribute substantially to age-related cognitive decline.

Cellular Specificity of the Blood–CSF Barrier for Albumin Transfer across the Choroid Plexus Epithelium

PubMed Central

Liddelow, Shane A.; Dzięgielewska, Katarzyna M.; Møllgård, Kjeld; Whish, Sophie C.; Noor, Natassya M.; Wheaton, Benjamin J.; Gehwolf, Renate; Wagner, Andrea; Traweger, Andreas; Bauer, Hannelore; Bauer, Hans-Christian; Saunders, Norman R.

2014-01-01

To maintain the precise internal milieu of the mammalian central nervous system, well-controlled transfer of molecules from periphery into brain is required. Recently the soluble and cell-surface albumin-binding glycoprotein SPARC (secreted protein acidic and rich in cysteine) has been implicated in albumin transport into developing brain, however the exact mechanism remains unknown. We postulate that SPARC is a docking site for albumin, mediating its uptake and transfer by choroid plexus epithelial cells from blood into cerebrospinal fluid (CSF). We used in vivo physiological measurements of transfer of endogenous (mouse) and exogenous (human) albumins, in situ Proximity Ligation Assay (in situ PLA), and qRT-PCR experiments to examine the cellular mechanism mediating protein transfer across the blood–CSF interface. We report that at all developmental stages mouse albumin and SPARC gave positive signals with in situ PLAs in plasma, CSF and within individual plexus cells suggesting a possible molecular interaction. In contrast, in situ PLA experiments in brain sections from mice injected with human albumin showed positive signals for human albumin in the vascular compartment that were only rarely identifiable within choroid plexus cells and only at older ages. Concentrations of both endogenous mouse albumin and exogenous (intraperitoneally injected) human albumin were estimated in plasma and CSF and expressed as CSF/plasma concentration ratios. Human albumin was not transferred through the mouse blood–CSF barrier to the same extent as endogenous mouse albumin, confirming results from in situ PLA. During postnatal development Sparc gene expression was higher in early postnatal ages than in the adult and changed in response to altered levels of albumin in blood plasma in a differential and developmentally regulated manner. Here we propose a possible cellular route and mechanism by which albumin is transferred from blood into CSF across a sub-population of specialised choroid plexus epithelial cells. PMID:25211495

Is cerebral glucose metabolism related to blood-brain barrier dysfunction and intrathecal IgG synthesis in Alzheimer disease?: A 18F-FDG PET/CT study.

PubMed

Chiaravalloti, Agostino; Fiorentini, Alessandro; Ursini, Francesco; Martorana, Alessandro; Koch, Giacomo; Belli, Lorena; Toniolo, Sofia; Di Pietro, Barbara; Motta, Caterina; Schillaci, Orazio

2016-09-01

The aim of this study was to investigate the relationships between blood-brain barrier (BBB) dysfunction, intrathecal IgG synthesis, and brain glucose consumption as detectable by means of serum/cerebrospinal fluid (CSF) albumin index (Qalb) and IgG index [(CSF IgG/serum IgG) × Serum albumin/CSF albumin)] and 2-deoxy-2-(F) fluoro-D-glucose (F-FDG) positron emission tomography/computed tomography (PET/CT) in a selected population affected by Alzheimer disease (AD). The study included 134 newly diagnosed AD patients according to the NINCDS-ADRDA criteria. The mean (±SD) age of the patients was 70 (±6) years; 60 were male and 64 were female. Mini mental State Examination was equal to 18.9 (±7.2). All patients underwent a CSF assay and magnetic resonance before F-FDG PET scanning. The relationships were evaluated by means of statistical parametric mapping (SPM8). We found a significant negative correlation between the increase of Qalb and F-FDG uptake in the Brodmann Area 42 and 22 that corresponds to the left superior temporal gyrus, with higher Qalb values being related to a reduced glucose consumption in these areas. No significant relationships have been found between brain glucose consumption and IgG index. The results of our study suggest that BBB dysfunction is related to reduction of cortical activity in the left temporal cortex in AD subjects.

Multicenter Study of Brain Volume Abnormalities in Children and Adolescent-Onset Psychosis

PubMed Central

Reig, Santiago; Parellada, Mara; Castro-Fornieles, Josefina; Janssen, Joost; Moreno, Dolores; Baeza, Inmaculada; Bargalló, Nuria; González-Pinto, Ana; Graell, Montserrat; Ortuño, Felipe; Otero, Soraya; Arango, Celso; Desco, Manuel

2011-01-01

The goal of the study is to determine the extent of structural brain abnormalities in a multicenter sample of children and adolescents with a recent-onset first episode of psychosis (FEP), compared with a sample of healthy controls. Total brain and lobar volumes and those of gray matter (GM), white matter, and cerebrospinal fluid (CSF) were measured in 92 patients with a FEP and in 94 controls, matched for age, gender, and years of education. Male patients (n = 64) showed several significant differences when compared with controls (n = 61). GM volume in male patients was reduced in the whole brain and in frontal and parietal lobes compared with controls. Total CSF volume and frontal, temporal, and right parietal CSF volumes were also increased in male patients. Within patients, those with a further diagnosis of “schizophrenia” or “other psychosis” showed a pattern similar to the group of all patients relative to controls. However, bipolar patients showed fewer differences relative to controls. In female patients, only the schizophrenia group showed differences relative to controls, in frontal CSF. GM deficit in male patients with a first episode correlated with negative symptoms. Our study suggests that at least part of the GM deficit in children and adolescent-onset schizophrenia and in other psychosis occurs before onset of the first positive symptoms and that, contrary to what has been shown in children-onset schizophrenia, frontal GM deficits are probably present from the first appearance of positive symptoms in children and adolescents. PMID:20478821

The role of glycogen, glucose and lactate in neuronal activity during hypoxia in the hooded seal (Cystophora cristata) brain.

PubMed

Czech-Damal, N U; Geiseler, S J; Hoff, M L M; Schliep, R; Ramirez, J-M; Folkow, L P; Burmester, T

2014-09-05

The brains of diving mammals are repeatedly exposed to hypoxic conditions during diving. Brain neurons of the hooded seal (Cystophora cristata) have been shown to be more hypoxia tolerant than those of mice, but the underlying mechanisms are not clear. Here we investigated the roles of different metabolic substrates for maintenance of neuronal activity and integrity, by comparing the in vitro spontaneous neuronal activity of brain slices from layer V of the visual cortex of hooded seals with those in mice (Mus musculus). Studies were conducted by manipulating the composition of the artificial cerebrospinal fluid (aCSF), containing either 10 mM glucose, or 20 mM lactate, or no external carbohydrate supply (aglycemia). Normoxic, hypoxic and ischemic conditions were applied. The lack of glucose or the application of lactate in the aCSF containing no glucose had little effect on the neuronal activity of seal neurons in either normoxia or hypoxia, while neurons from mice survived in hypoxia only few minutes regardless of the composition of the aCSF. We propose that seal neurons have higher intrinsic energy stores. Indeed, we found about three times higher glycogen stores in the seal brain (∼4.1 ng per μg total protein in the seal cerebrum) than in the mouse brain. Notably, in aCSF containing no glucose, seal neurons can tolerate 20 mM lactate while in mouse neuronal activity vanished after few minutes even in normoxia. This can be considered as an adaptation to long dives, during which lactate accumulates in the blood. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Neuropathogenesis of a highly pathogenic avian influenza virus (H7N1) in experimentally infected chickens.

PubMed

Chaves, Aida J; Busquets, Núria; Valle, Rosa; Rivas, Raquel; Vergara-Alert, Júlia; Dolz, Roser; Ramis, Antonio; Darji, Ayub; Majó, Natàlia

2011-10-07

In order to understand the mechanism of neuroinvasion of a highly pathogenic avian influenza virus (HPAIV) into the central nervous system (CNS) of chickens, specific pathogen free chickens were inoculated with a H7N1 HPAIV. Blood, cerebrospinal fluid (CSF), nasal cavity and brain tissue samples were obtained from 1 to 4 days post-inoculation (dpi) of infected and control chickens. Viral antigen topographical distribution, presence of influenza A virus receptors in the brain, as well as, the role of the olfactory route in virus CNS invasion were studied using different immunohistochemistry techniques. Besides, viral RNA load in CSF and blood was quantified by means of a quantitative real-time reverse transcription-polymerase chain reaction. Viral antigen was observed widely distributed in the CNS, showing bilateral and symmetrical distribution in the nuclei of the diencephalon, mesencephalon and rhombencephalon. Viral RNA was detected in blood and CSF at one dpi, indicating that the virus crosses the blood-CSF-barrier early during infection. This early dissemination is possibly favoured by the presence of Siaα2,3 Gal and Siaα2,6 Gal receptors in brain vascular endothelial cells, and Siaα2,3 Gal receptors in ependymal and choroid plexus cells. No viral antigen was observed in olfactory sensory neurons, while the olfactory bulb showed only weak staining, suggesting that the virus did not use this pathway to enter into the brain. The sequence of virus appearance and the topographical distribution of this H7N1 HPAIV indicate that the viral entry occurs via the haematogenous route, with early and generalized spreading through the CSF.

Neuropathogenesis of a highly pathogenic avian influenza virus (H7N1) in experimentally infected chickens

PubMed Central

2011-01-01

In order to understand the mechanism of neuroinvasion of a highly pathogenic avian influenza virus (HPAIV) into the central nervous system (CNS) of chickens, specific pathogen free chickens were inoculated with a H7N1 HPAIV. Blood, cerebrospinal fluid (CSF), nasal cavity and brain tissue samples were obtained from 1 to 4 days post-inoculation (dpi) of infected and control chickens. Viral antigen topographical distribution, presence of influenza A virus receptors in the brain, as well as, the role of the olfactory route in virus CNS invasion were studied using different immunohistochemistry techniques. Besides, viral RNA load in CSF and blood was quantified by means of a quantitative real-time reverse transcription-polymerase chain reaction. Viral antigen was observed widely distributed in the CNS, showing bilateral and symmetrical distribution in the nuclei of the diencephalon, mesencephalon and rhombencephalon. Viral RNA was detected in blood and CSF at one dpi, indicating that the virus crosses the blood-CSF-barrier early during infection. This early dissemination is possibly favoured by the presence of Siaα2,3 Gal and Siaα2,6 Gal receptors in brain vascular endothelial cells, and Siaα2,3 Gal receptors in ependymal and choroid plexus cells. No viral antigen was observed in olfactory sensory neurons, while the olfactory bulb showed only weak staining, suggesting that the virus did not use this pathway to enter into the brain. The sequence of virus appearance and the topographical distribution of this H7N1 HPAIV indicate that the viral entry occurs via the haematogenous route, with early and generalized spreading through the CSF. PMID:21982125

Structural magnetic resonance imaging in patients with first-episode schizophrenia, psychotic and severe non-psychotic depression and healthy controls. Results of the schizophrenia and affective psychoses (SAP) project.

PubMed

Salokangas, R K R; Cannon, T; Van Erp, T; Ilonen, T; Taiminen, T; Karlsson, H; Lauerma, H; Leinonen, K M; Wallenius, E; Kaljonen, A; Syvälahti, E; Vilkman, H; Alanen, A; Hietala, J

2002-09-01

Structural brain abnormalities are prevalent in patients with schizophrenia and affective disorders. To study how regional brain volumes and their ratios differ between patients with schizophrenia, psychotic depression, severe non-psychotic depression and healthy controls. Magnetic resonance imaging scans of the brain on first-episode patients and on healthy controls. Patients with schizophrenia had a smaller left frontal grey matter volume than the other three groups. Patients with psychotic depression had larger ventricular and posterior sulcal cerebrospinal fluid (CSF) volumes than controls. Patients with depression had larger white matter volumes than the other patients. Left frontal lobe, especially its grey matter volume, seems to be specifically reduced in first-episode schizophrenia. Enlarged cerebral ventricles and sulcal CSF volumes are prevalent in psychotic depression. Preserved or expanded white matter is typical of non-psychotic depression.

Alterations in the Balance of Amyloid-β Protein Precursor Species in the Cerebrospinal Fluid of Alzheimer's Disease Patients.

PubMed

Lopez-Font, Inmaculada; Boix, Claudia P; Zetterberg, Henrik; Blennow, Kaj; Sáez-Valero, Javier

2017-01-01

We recently demonstrated that soluble forms of the amyloid-β protein precursor (sAβPP) assemble into multimeric complexes in cerebrospinal fluid (CSF), which contributes to the underestimation of specific sAβPP species when assessed by ELISA. To circumvent this issue, we analyzed by SDS-PAGE large fragments of sAβPP and their variants in the CSF from Alzheimer's disease (AD; n = 20) and control (n = 20) subjects, probing with specific antibodies against particular domains. Similar levels of sAβPPα and sAβPPβ protein were found in CSF samples from AD and controls, yet there appeared to be a shift in the balance of the soluble full-length AβPP (sAβPPf) species in AD samples, with a decrease in the proportion of the lower (∼100 kDa) band relative to the upper (∼120 kDa) band. Similar differences were observed in the contribution of the major KPI-immunoreactive AβPP species. CSF samples also displayed differences in the correlations of AβPP species with classical AD biomarkers, particularly with respect to the Aβ42 peptide. The differences reveal alterations that probably reflect pathophysiological changes in the brain.

Antibodies in Cerebrospinal Fluid of Some Alzheimer Disease Patients Recognize Cholinergic Neurons in the Rat Central Nervous System

NASA Astrophysics Data System (ADS)

McRae-Degueurce, Amanda; Booj, Serney; Haglid, Kenneth; Rosengren, Lars; Karlsson, Jan Erik; Karlsson, Ingvar; Wallin, Anders; Svennerholm, Lars; Gottfries, Carl-Gerhard; Dahlstrom, Annica

1987-12-01

The etiology of Alzheimer disease is unclear. However, immunological aberrations have been suggested to be critical factors in the pathogenesis of this neurodegenerative disease. This study was carried out to investigate if cerebrospinal fluid (CSF) from Alzheimer disease patients contains antibodies that recognize specific neuronal populations in the rat central nervous system. The results indicate that in a subgroup of patients this is indeed the case. The antibodies reported in this study have the following properties: (i) they recognize neuronal populations and components in the medial septum and spinal motor neurons in rats perfused with a mixture that fixes small neurotransmitter molecules; (ii) adsorption of the patient CSF with staphylococcal protein A-Sepharose and using a polyclonal antiserum against human IgG3 indicates that the immunocytochemical reaction in these brain regions is mainly due to the subclass IgG3; and (iii) the CSF immunocytochemical reaction is blocked by preincubation of the sections with a rabbit anti-acetylcholine antiserum. These results provide evidence that antibodies in the CSF of some, but not all, Alzheimer disease patients recognize acetylcholine-like epitopes in cholinergic neurons in the rat central nervous system.

Cerebrospinal fluid circulation and hydrocephalus.

PubMed

Leinonen, Ville; Vanninen, Ritva; Rauramaa, Tuomas

2017-01-01

Hydrocephalus (HC) is classically defined as dynamic imbalance between the production and absorption of cerebrospinal fluid (CSF) leading to enlarged ventricles. Potential causative factors include various brain disorders like tumors causing obstruction of CSF flow within the ventricular system or the subarachnoid space. Classification of HC is based on the site of CSF flow obstruction guiding optimal treatment, with endoscopic third ventriculostomy in intraventricular obstruction and CSF shunt in communicating HC. Another clinically relevant classification is acute and chronic; the most frequent chronic form is idiopathic normal-pressure hydrocephalus (iNPH). The reported incidence of HC varies according to the study population and classification used. The incidence of congenital HC is approximately 0.4-0.6/1,000 newborns and the annual incidence of iNPH varies from 0.5/100,000 to 5.5/100,000. Radiologically, ventricular dilatation may be nonspecific, and differentiation of iNPH from other neurodegenerative diseases may be ambiguous. There are no known specific microscopic findings of HC but a systematic neuropathologic examination is needed to detect comorbid diseases and possible etiologic factors of HC. Depending on the etiology of HC, there are several nonspecific signs potentially to be seen. Copyright © 2017 Elsevier B.V. All rights reserved.

Post-craniotomy intracranial infection in patients with brain tumors: a retrospective analysis of 5723 consecutive patients.

PubMed

Shi, Zhong-Hua; Xu, Ming; Wang, Yong-Zhi; Luo, Xu-Ying; Chen, Guang-Qiang; Wang, Xin; Wang, Tao; Tang, Ming-Zhong; Zhou, Jian-Xin

2017-02-01

To determine the risk factors for and the incidence, outcomes, and causative pathogens of post-craniotomy intracranial infection (PCII) in patients with brain tumors. A retrospective study was performed of 5723 patients with brain tumors who were surgically treated between January 2012 and December 2013 in Beijing Tiantan Hospital. The patients' demographics, pathohistological diagnoses, surgical procedures, postoperative variables, causative pathogens, and outcomes were evaluated. The overall incidence of PCII was 6.8%, and 82.1% of all cases were diagnosed within two weeks after the craniotomy. Postoperative administration of antibiotics reduced the incidence of PCII. Independent risk factors included clean-contaminated craniotomy, prolonged operation (> 7 h), external cerebrospinal fluid (CSF) drainage/monitoring device placement, and postoperative CSF leakage. Patients ≤ 45 years old were more susceptible to infection. Compared with supratentorial tumors, tumors located in the infratentorial or intraventricular regions were more vulnerable to PCII. Gram-positive bacteria were the most common causative pathogens isolated from the CSF samples, accounting for 82.0% of the PCII cases. Risk factors for PCII can be identified early in the perioperative period. These findings raise the possibility of improving the clinical outcomes of patients with brain tumors who undergo craniotomy.

Occurrence of Leishmania infantum in the central nervous system of naturally infected dogs: Parasite load, viability, co-infections and histological alterations.

PubMed

Oliveira, Valéria da Costa; Boechat, Viviane Cardoso; Mendes Junior, Artur Augusto Velho; Madeira, Maria de Fátima; Ferreira, Luiz Claudio; Figueiredo, Fabiano Borges; Campos, Monique Paiva; de Carvalho Rodrigues, Francisco das Chagas; Carvalhaes de Oliveira, Raquel de Vasconcellos; Amendoeira, Maria Regina Reis; Menezes, Rodrigo Caldas

2017-01-01

Zoonotic visceral leishmaniasis is caused by the protozoan Leishmania infantum and little is known about the occurrence and pathogenesis of this parasite in the CNS. The aims of this study were to evaluate the occurrence, viability and load of L. infantum in the CNS, and to identify the neurological histological alterations associated with this protozoan and its co-infections in naturally infected dogs. Forty-eight Leishmania-seropositive dogs from which L. infantum was isolated after necropsy were examined. Cerebrospinal fluid (CSF) samples were analyzed by parasitological culture, quantitative real-time PCR (qPCR) and the rapid immunochromatographic Dual Path Platform test. Brain, spinal cord and spleen samples were submitted to parasitological culture, qPCR, and histological techniques. Additionally, anti-Toxoplasma gondii and anti-Ehrlichia canis antibodies in serum and distemper virus antigens in CSF were investigated. None of the dogs showed neurological signs. All dogs tested positive for L. infantum in the CNS. Viable forms of L. infantum were isolated from CSF, brain and spinal cord in 25% of the dogs. Anti-L. infantum antibodies were detected in CSF in 61% of 36 dogs. Inflammatory histological alterations were observed in the CNS of 31% of the animals; of these, 66% were seropositive for E. canis and/or T. gondii. Amastigote forms were associated with granulomatous non-suppurative encephalomyelitis in a dog without evidence of co-infections. The highest frequency of L. infantum DNA was observed in the brain (98%), followed by the spinal cord (96%), spleen (95%), and CSF (50%). The highest L. infantum load in CNS was found in the spinal cord. These results demonstrate that L. infantum can cross the blood-brain barrier, spread through CSF, and cause active infection in the entire CNS of dogs. Additionally, L. infantum can cause inflammation in the CNS that can lead to neurological signs with progression of the disease.

Occurrence of Leishmania infantum in the central nervous system of naturally infected dogs: Parasite load, viability, co-infections and histological alterations

PubMed Central

Oliveira, Valéria da Costa; Boechat, Viviane Cardoso; Mendes Junior, Artur Augusto Velho; Madeira, Maria de Fátima; Ferreira, Luiz Claudio; Figueiredo, Fabiano Borges; Campos, Monique Paiva; de Carvalho Rodrigues, Francisco das Chagas; Carvalhaes de Oliveira, Raquel de Vasconcellos; Amendoeira, Maria Regina Reis

2017-01-01

Zoonotic visceral leishmaniasis is caused by the protozoan Leishmania infantum and little is known about the occurrence and pathogenesis of this parasite in the CNS. The aims of this study were to evaluate the occurrence, viability and load of L. infantum in the CNS, and to identify the neurological histological alterations associated with this protozoan and its co-infections in naturally infected dogs. Forty-eight Leishmania-seropositive dogs from which L. infantum was isolated after necropsy were examined. Cerebrospinal fluid (CSF) samples were analyzed by parasitological culture, quantitative real-time PCR (qPCR) and the rapid immunochromatographic Dual Path Platform test. Brain, spinal cord and spleen samples were submitted to parasitological culture, qPCR, and histological techniques. Additionally, anti-Toxoplasma gondii and anti-Ehrlichia canis antibodies in serum and distemper virus antigens in CSF were investigated. None of the dogs showed neurological signs. All dogs tested positive for L. infantum in the CNS. Viable forms of L. infantum were isolated from CSF, brain and spinal cord in 25% of the dogs. Anti-L. infantum antibodies were detected in CSF in 61% of 36 dogs. Inflammatory histological alterations were observed in the CNS of 31% of the animals; of these, 66% were seropositive for E. canis and/or T. gondii. Amastigote forms were associated with granulomatous non-suppurative encephalomyelitis in a dog without evidence of co-infections. The highest frequency of L. infantum DNA was observed in the brain (98%), followed by the spinal cord (96%), spleen (95%), and CSF (50%). The highest L. infantum load in CNS was found in the spinal cord. These results demonstrate that L. infantum can cross the blood-brain barrier, spread through CSF, and cause active infection in the entire CNS of dogs. Additionally, L. infantum can cause inflammation in the CNS that can lead to neurological signs with progression of the disease. PMID:28419136

Analysis of glycosaminoglycans in cerebrospinal fluid from patients with mucopolysaccharidoses by isotope-dilution ultra-performance liquid chromatography-tandem mass spectrometry.

PubMed

Zhang, Haoyue; Young, Sarah P; Auray-Blais, Christiane; Orchard, Paul J; Tolar, Jakub; Millington, David S

2011-07-01

New therapies for the treatment of mucopolysaccharidoses that target the brain, including intrathecal enzyme replacement, are being explored. Quantitative analysis of the glycosaminoglycans (GAGs) that accumulate in these disorders is required to assess the disease burden and monitor the effect of therapy in affected patients. Because current methods lack the required limit of quantification and specificity to analyze GAGs in small volumes of cerebrospinal fluid (CSF), we developed a method based on ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Samples of CSF (25 μL) were evaporated to dryness and subjected to methanolysis. The GAGs were degraded to uronic acid-N-acetylhexosamine dimers and mixed with internal standards derived from deuteriomethanolysis of GAG standards. Specific dimers derived from heparan, dermatan and chondroitin sulfates (HS, DS and CS) were separated by UPLC and analyzed by electrospray ionization MS/MS using selected reaction monitoring for each targeted GAG product and its corresponding internal standard. CSF from control pediatric subjects (n = 22) contained <0.38 mg/L HS, 0.26 mg/L DS, and 2.8 mg/L CS, whereas CSF from patients with Hurler syndrome (n = 7) contained concentrations of DS and HS that were at least 6-fold greater than the upper control limits. These concentrations were reduced by 17.5% to 82.5% after allogeneic transplantation and treatment with intrathecal and intravenous enzyme replacement therapy. The method described here has potential value in monitoring patients with mucopolysaccharidoses receiving treatment targeted to the brain.

Long-term survival in a dog with meningoencephalitis and epidural abscessation due to Actinomyces species.

PubMed

Song, Rachel B; Vitullo, Carina A; da Costa, Ronaldo C; Daniels, Joshua B

2015-07-01

A 2-year-old, female spayed Golden Retriever dog was presented to The Ohio State University Veterinary Medical Center for evaluation of ataxia, cervical pain, 1 episode of acute collapse, dull mentation, and inappetence. Physical examination revealed an elevated temperature of 39.7°C and severe cervical pain. Blood work revealed a mature neutrophilia. Cerebrospinal fluid (CSF) analysis revealed nondegenerative neutrophilic pleocytosis with no infectious agents. A presumptive diagnosis of steroid-responsive meningitis-arteritis was made, and corticosteroid therapy was started. The patient improved initially but experienced a vestibular episode characterized by falling and vertical nystagmus. A magnetic resonance imaging of the brain revealed an epidural abscess in the cervical vertebral canal and diffuse meningeal enhancement in the brain and cranial cervical spine. Abscess drainage revealed degenerate neutrophils and several filamentous, branching organisms. Culture of the initial CSF using an enrichment broth revealed growth of a Gram-positive organism 5 days after fluid collection. The isolate was identified by partial 16S ribosomal DNA sequencing as Actinomyces spp. The patient was successfully treated with long-term antibiotics. Our study reports the long-term survival after medical treatment of bacterial meningoencephalitis and epidural abscessation due to Actinomyces sp. infection in a dog. Bacterial meningoencephalitis should be included as a differential diagnosis in patients with cervical pain and fever, even when a nondegenerative neutrophilic pleocytosis is found on CSF analysis. Culture of the CSF with use of an enrichment broth should be considered in all cases of neutrophilic pleocytosis to rule out infections of the central nervous system. © 2015 The Author(s).

Automatic brain tissue segmentation based on graph filter.

PubMed

Kong, Youyong; Chen, Xiaopeng; Wu, Jiasong; Zhang, Pinzheng; Chen, Yang; Shu, Huazhong

2018-05-09

Accurate segmentation of brain tissues from magnetic resonance imaging (MRI) is of significant importance in clinical applications and neuroscience research. Accurate segmentation is challenging due to the tissue heterogeneity, which is caused by noise, bias filed and partial volume effects. To overcome this limitation, this paper presents a novel algorithm for brain tissue segmentation based on supervoxel and graph filter. Firstly, an effective supervoxel method is employed to generate effective supervoxels for the 3D MRI image. Secondly, the supervoxels are classified into different types of tissues based on filtering of graph signals. The performance is evaluated on the BrainWeb 18 dataset and the Internet Brain Segmentation Repository (IBSR) 18 dataset. The proposed method achieves mean dice similarity coefficient (DSC) of 0.94, 0.92 and 0.90 for the segmentation of white matter (WM), grey matter (GM) and cerebrospinal fluid (CSF) for BrainWeb 18 dataset, and mean DSC of 0.85, 0.87 and 0.57 for the segmentation of WM, GM and CSF for IBSR18 dataset. The proposed approach can well discriminate different types of brain tissues from the brain MRI image, which has high potential to be applied for clinical applications.

Hyperdynamic CSF motion profiles found in idiopathic normal pressure hydrocephalus and Alzheimer's disease assessed by fluid mechanics derived from magnetic resonance images.

PubMed

Takizawa, Ken; Matsumae, Mitsunori; Hayashi, Naokazu; Hirayama, Akihiro; Yatsushiro, Satoshi; Kuroda, Kagayaki

2017-10-18

Magnetic resonance imaging (MRI) does not only ascertain morphological features, but also measures physiological properties such as fluid velocity or pressure gradient. The purpose of this study was to investigate cerebrospinal fluid (CSF) dynamics in patients with morphological abnormalities such as enlarged brain ventricles and subarachnoid spaces. We used a time-resolved three dimensional phase contrast (3D-PC) MRI technique to quantitatively evaluate CSF dynamics in the Sylvian aqueduct of healthy elderly individuals and patients with either idiopathic normal pressure hydrocephalus (iNPH) or Alzheimer's disease (AD) presenting with ventricular enlargement. Nineteen healthy elderly individuals, ten iNPH patients, and seven AD patients (all subjects ≥ 60 years old) were retrospectively evaluated 3D-PC MRI. The CSF velocity, pressure gradient, and rotation in the Sylvian aqueduct were quantified and compared between the three groups using Kolmogorov-Smirnov and Mann-Whitney U tests. There was no statistically significant difference in velocity among the three groups. The pressure gradient was not significantly different between the iNPH and AD groups, but was significantly different between the iNPH group and the healthy controls (p < 0.001), and similarly, between the AD group and the healthy controls (p < 0.001). Rotation was not significantly different between the iNPH and AD groups, but was significantly different between the iNPH group and healthy controls (p < 0.001), and similarly, between the AD group and the healthy controls (p < 0.001). Quantitative analysis of CSF dynamics with time resolved 3D-PC MRI revealed differences and similarities in the Sylvian aqueduct between healthy elderly individuals, iNPH patients, and AD patients. The results showed that CSF motion is in a hyperdynamic state in both iNPH and AD patient groups compared to healthy elderly individuals, and that iNPH patients and AD patients display similar CSF motion profiles.

Choroid plexus-cerebrospinal fluid route for monocyte-derived macrophages after stroke.

PubMed

Ge, Ruimin; Tornero, Daniel; Hirota, Masao; Monni, Emanuela; Laterza, Cecilia; Lindvall, Olle; Kokaia, Zaal

2017-07-28

Choroid plexus (CP) supports the entry of monocyte-derived macrophages (MDMs) to the central nervous system in animal models of traumatic brain injury, spinal cord injury, and Alzheimer's disease. Whether the CP is involved in the recruitment of MDMs to the injured brain after ischemic stroke is unknown. Adult male C57BL/6 mice were subjected to focal cortical ischemia by permanent occlusion of the distal branch of the right middle cerebral artery. Choroid plexus tissues were collected and analyzed for Vcam1, Madcam1, Cx 3 cl1, Ccl2, Nt5e, and Ifnγ expression at different timepoints after stroke using qPCR. Changes of MDMs in CP and cerebrospinal fluid (CSF) at 1 day and 3 days after stroke were analyzed using flow cytometry. Infiltration of MDMs into CP and CSF were validated using β-actin-GFP chimeric mice and Fgd5-CreERT2 x Lox-stop-lox-Tomato mice. CD115+ monocytes were isolated using a magnetic cell separation system from bone marrow of Cx 3 cr1-GFP or wild-type C57BL/6 donor mice. The freshly isolated monocytes or M2-like MDMs primed in vitro with IL4 and IL13 were stereotaxically injected into the lateral ventricle of stroke-affected mice to trace for their migration into ischemic hemisphere or to assess their effect on post-stroke recovery using open field, corridor, and active avoidance behavioral tests. We found that CP responded to cortical stroke by upregulation of gene expression for several possible mediators of MDM trafficking and, concomitantly, MDMs increased in CP and cerebrospinal fluid (CSF). We then confirmed that MDMs infiltrated from blood into CP and CSF after the insult using β-actin-GFP chimeric mice and Fgd5-CreERT2 x Lox-stop-lox-Tomato mice. When MDMs were directly administered into CSF following stroke, they homed to the ischemic hemisphere. If they had been primed in vitro prior to their administration to become M2-like macrophages, they promoted post-stroke recovery of motor and cognitive function without influencing infarct volume. Our findings suggest the possibility that autologous transplantation of M2-like MDMs into CSF might be developed into a new strategy for promoting recovery also in patients with stroke.

Experimental Investigation of Cavitation as a Possible Damage Mechanism in Blast-Induced Traumatic Brain Injury in Post-Mortem Human Subject Heads.

PubMed

Salzar, Robert S; Treichler, Derrick; Wardlaw, Andrew; Weiss, Greg; Goeller, Jacques

2017-04-15

The potential of blast-induced traumatic brain injury from the mechanism of localized cavitation of the cerebrospinal fluid (CSF) is investigated. While the mechanism and criteria for non-impact blast-induced traumatic brain injury is still unknown, this study demonstrates that local cavitation in the CSF layer of the cranial volume could contribute to these injuries. The cranial contents of three post-mortem human subject (PMHS) heads were replaced with both a normal saline solution and a ballistic gel mixture with a simulated CSF layer. Each were instrumented with multiple pressure transducers and placed inside identical shock tubes at two different research facilities. Sensor data indicates that cavitation may have occurred in the PMHS models at pressure levels below those for a 50% risk of blast lung injury. This study points to skull flexion, the result of the shock wave on the front of the skull leading to a negative pressure in the contrecoup, as a possible mechanism that contributes to the onset of cavitation. Based on observation of intracranial pressure transducer data from the PMHS model, cavitation onset is thought to occur from approximately a 140 kPa head-on incident blast.

[The early diagnosis of juvenile germinoma originating from the basal ganglia and thalamus].

PubMed

Wang, Xian-Ling; Li, Cun-Jiang

2011-04-01

To explore the early diagnosis of germinoma originating from the basal ganglia (BG) and thalamus during juveniles. Retrospective analysis was done with the clinical cases of germinomas in BG and thalamus from 2000 to 2009. The symptoms, signs, neuroimaging, cerebrospinal fluid (CSF) findings were analyzed and related literature were reviewed. Eight patents were collected. The main symptoms were hemiplegia, associated with aphasia and/or impaired cognition. Brain CT showed high density and calcification. Abnormal T1 and T2 signal were found in brain MRI frequently associated with ipsilateral hemisphere atrophy. MRS showed increased choline and decreased N-acetylaspartate level. Elevated CSF human chorionic gonadotrophin level were found in two of them. Germinoma in BG and thalamus predominates in a boy. The neuroimaging features are very informative for early diagnosis.

Intrasphenoidal encephalocele and spontaneous CSF rhinorrhoea.

PubMed

Daniilidis, J; Vlachtsis, K; Ferekidis, E; Dimitriadis, A

1999-12-01

Intrasphenoidal encephalocele is a rare clinical entity. In the international literature only 16 cases have been reported up today, with female predominance. Clinically they manifest at middle and advanced ages (40-67 years), when spontaneous CSF rhinorrhoea or recurrent meningitis occurs. We present our case, a 46 years old female, who had CSF rhinorrhoea from the right vestibule for 10 months. The diagnosis was based on the history and the high-resolution brain and skull base CT-scanning in conjunction with opaque fluid injection in the subarachnoidal space through a lumbar puncture. She was successfully treated with an operation, through an endonasal trans-ethmoid microendoscopic approach, using the Draf and Stammberger technique. We discuss the pathogenesis of the intrasphenoidal encephalocele, the existence of small occult defects in the skull base, which cause, at the middle and advanced ages, CSF fistula with spontaneous CSF rhinorrhoea and/or recurrent meningitis. Finally we emphasize the advantages of the endonasal surgical approach for the treatment of this condition.

CSF GABA is reduced in first-episode psychosis and associates to symptom severity

PubMed Central

Orhan, F; Fatouros-Bergman, H; Goiny, M; Malmqvist, A; Piehl, F; Engberg, Göran; Erhardt, Sophie; Schwieler, Lilly; Orhan, Funda; Malmqvist, Anna; Hedberg, Mikael; Farde, Lars; Cervenka, Simon; Flyckt, Lena; Collste, Karin; Ikonen, Pauliina; Piehl, Fredrik; Agartz, Ingrid; Cervenka, S; Collste, K; Victorsson, P; Sellgren, C M; Flyckt, L; Erhardt, S; Engberg, G

2018-01-01

Schizophrenia is characterized by a multiplicity of symptoms arising from almost all domains of mental function. γ-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the brain and is increasingly recognized to have a significant role in the pathophysiology of the disorder. In the present study, cerebrospinal fluid (CSF) concentrations of GABA were analyzed in 41 first-episode psychosis (FEP) patients and 21 age- and sex-matched healthy volunteers by high-performance liquid chromatography. We found lower CSF GABA concentration in FEP patients compared with that in the healthy volunteers, a condition that was unrelated to antipsychotic and/or anxiolytic medication. Moreover, lower CSF GABA levels were associated with total and general score of Positive and Negative Syndrome Scale, illness severity and probably with a poor performance in a test of attention. This study offers clinical in vivo evidence for a potential role of GABA in early-stage schizophrenia. PMID:28289277

Safety of Lumbar Puncture Procedures in Patients with Alzheimer's Disease

PubMed Central

Peskind, E.; Nordberg, A.; Darreh-Shori, T.; Soininen, H.

2014-01-01

Changes in cerebrospinal fluid (CSF) biomarkers are representative of biochemical changes in the brain. Collection of CSF by lumbar puncture (LP) is essential for biomarker analysis, which is important for research in neurodegenerative disorders. However, LP for research purposes has been controversial due to a reported high incidence of severe LP headache when using standard 18g or 20g Quincke needles with a beveled cutting tip. A procedural safety analysis was performed using the database of a multicenter, 13-week study of CSF cholinesterase activity. A 24g Sprotte atraumatic needle was used to collect CSF at baseline and at Week 13 from 63 older patients with mild to moderate Alzheimer's disease. There was a < 2% LP headache incidence, and a favorable safety profile was reported. In conclusion, LP performed with a 24g Sprotte atraumatic needle (blunt, “bullet” tip) was a well-tolerated procedure, with good acceptability. PMID:19519311

Kynurenine 3-monooxygenase polymorphisms: relevance for kynurenic acid synthesis in patients with schizophrenia and healthy controls.

PubMed

Holtze, Maria; Saetre, Peter; Engberg, Göran; Schwieler, Lilly; Werge, Thomas; Andreassen, Ole A; Hall, Håkan; Terenius, Lars; Agartz, Ingrid; Jönsson, Erik G; Schalling, Martin; Erhardt, Sophie

2012-01-01

Patients with schizophrenia show increased brain and cerebrospinal fluid (CSF) concentrations of the endogenous N-methyl-D-aspartate receptor antagonist kynurenic acid (KYNA). This compound is an end-metabolite of the kynurenine pathway, and its formation indirectly depends on the activity of kynurenine 3-monooxygenase (KMO), the enzyme converting kynurenine to 3-hydroxykynurenine. We analyzed the association between KMO gene polymorphisms and CSF concentrations of KYNA in patients with schizophrenia and healthy controls. Fifteen single nucleotide polymorphisms (SNPs) were selected covering KMO and were analyzed in UNPHASED. We included 17 patients with schizophrenia and 33 controls in our study. We found an association between a KMO SNP (rs1053230), encoding an amino acid change of potential importance for substrate interaction, and CSF concentrations of KYNA. Given the limited sample size, the results are tentative until replication. Our results suggest that the nonsynonymous KMO SNP rs1053230 influences CSF concentrations of KYNA.

[Primary central nervous system lymphoma mimicking ventriculitis].

PubMed

Yamamoto, Shiro; Nagano, Seiji; Shibata, Sumiya; Kunieda, Takeharu; Imai, Yukihiro; Kohara, Nobuo

2013-01-01

A 66-year-old man presented with deteriorated bradykinesia, gait disturbance, disorientation, and urinary incontinence for three weeks. Magnetic resonance imaging (MRI) showed dilatation of the ventricles. Cerebrospinal fluid (CSF) examination demonstrated lymphocytic pleocytosis, elevation of protein levels, and decreased of glucose levels. A gadolinium-enhanced MRI revealed lesions in the ventricular wall and choroid plexus, mimicking ventriculitis. No evidence of bacterial, fungal, mycobacterial, or viral infections were observed in the CSF. Flow cytometry of CSF showed predominance of CD20+, λ+ cells. PCR examination of CSF revealed positive IgH gene rearrangement, suggesting B cell lymphoma. Endoscopic brain biopsy showed diffuse large B cell lymphoma. As the patient had no evidence of lymphoma in the other organs, we made a diagnosed of primary central nervous system lymphoma (PCNSL). A limited intraventricular spread of PCNSL is rare but important as one of differential diagnosis of ventriculitis.

CSF-Biomarkers in Olympic Boxing: Diagnosis and Effects of Repetitive Head Trauma

PubMed Central

Neselius, Sanna; Brisby, Helena; Theodorsson, Annette; Blennow, Kaj; Zetterberg, Henrik; Marcusson, Jan

2012-01-01

Background Sports-related head trauma is common but still there is no established laboratory test used in the diagnostics of minimal or mild traumatic brain injuries. Further the effects of recurrent head trauma on brain injury markers are unknown. The purpose of this study was to investigate the relationship between Olympic (amateur) boxing and cerebrospinal fluid (CSF) brain injury biomarkers. Methods The study was designed as a prospective cohort study. Thirty Olympic boxers with a minimum of 45 bouts and 25 non-boxing matched controls were included in the study. CSF samples were collected by lumbar puncture 1–6 days after a bout and after a rest period for at least 14 days. The controls were tested once. Biomarkers for acute and chronic brain injury were analysed. Results NFL (mean ± SD, 532±553 vs 135±51 ng/L p = 0.001), GFAP (496±238 vs 247±147 ng/L p<0.001), T-tau (58±26 vs 49±21 ng/L p<0.025) and S-100B (0.76±0.29 vs 0.60±0.23 ng/L p = 0.03) concentrations were significantly increased after boxing compared to controls. NFL (402±434 ng/L p = 0.004) and GFAP (369±113 ng/L p = 0.001) concentrations remained elevated after the rest period. Conclusion Increased CSF levels of T-tau, NFL, GFAP, and S-100B in >80% of the boxers demonstrate that both the acute and the cumulative effect of head trauma in Olympic boxing may induce CSF biomarker changes that suggest minor central nervous injuries. The lack of normalization of NFL and GFAP after the rest period in a subgroup of boxers may indicate ongoing degeneration. The recurrent head trauma in boxing may be associated with increased risk of chronic traumatic brain injury. PMID:22496755

CSF-biomarkers in Olympic boxing: diagnosis and effects of repetitive head trauma.

PubMed

Neselius, Sanna; Brisby, Helena; Theodorsson, Annette; Blennow, Kaj; Zetterberg, Henrik; Marcusson, Jan

2012-01-01

Sports-related head trauma is common but still there is no established laboratory test used in the diagnostics of minimal or mild traumatic brain injuries. Further the effects of recurrent head trauma on brain injury markers are unknown. The purpose of this study was to investigate the relationship between Olympic (amateur) boxing and cerebrospinal fluid (CSF) brain injury biomarkers. The study was designed as a prospective cohort study. Thirty Olympic boxers with a minimum of 45 bouts and 25 non-boxing matched controls were included in the study. CSF samples were collected by lumbar puncture 1-6 days after a bout and after a rest period for at least 14 days. The controls were tested once. Biomarkers for acute and chronic brain injury were analysed. NFL (mean ± SD, 532±553 vs 135±51 ng/L p = 0.001), GFAP (496±238 vs 247±147 ng/L p<0.001), T-tau (58±26 vs 49±21 ng/L p<0.025) and S-100B (0.76±0.29 vs 0.60±0.23 ng/L p = 0.03) concentrations were significantly increased after boxing compared to controls. NFL (402±434 ng/L p = 0.004) and GFAP (369±113 ng/L p = 0.001) concentrations remained elevated after the rest period. Increased CSF levels of T-tau, NFL, GFAP, and S-100B in >80% of the boxers demonstrate that both the acute and the cumulative effect of head trauma in Olympic boxing may induce CSF biomarker changes that suggest minor central nervous injuries. The lack of normalization of NFL and GFAP after the rest period in a subgroup of boxers may indicate ongoing degeneration. The recurrent head trauma in boxing may be associated with increased risk of chronic traumatic brain injury.

A comparison of early diagnostic utility of Alzheimer disease biomarkers in brain magnetic resonance and cerebrospinal fluid.

PubMed

Monge Argilés, J A; Blanco Cantó, M A; Leiva Salinas, C; Flors, L; Muñoz Ruiz, C; Sánchez Payá, J; Gasparini Berenguer, R; Leiva Santana, C

2014-09-01

The goals of this study were to compare the early diagnostic utility of Alzheimer disease biomarkers in the CSF with those in brain MRI in conditions found in our clinical practice, and to ascertain the diagnostic accuracy of both techniques used together. Between 2008 and 2009, we included 30 patients with mild cognitive impairment (MCI) who were examined using 1.5 Tesla brain MRI and AD biomarker analysis in CSF. MRI studies were evaluated by 2 radiologists according to the Korf́s visual scale. CSF biomarkers were analysed using INNOTEST reagents for Aβ1-42, total-tau and phospho-tau181p. We evaluated clinical changes 2 years after inclusion. By 2 years after inclusion, 15 of the original 30 patients (50%) had developed AD (NINCDS-ADRA criteria). The predictive utility of AD biomarkers in CSF (RR 2.7; 95% CI, 1.1-6.7; P<.01) was greater than that of MRI (RR 1.5; 95% CI 95%, 0.7-3.4; P<.2); using both techniques together yielded a sensitivity and a negative predictive value of 100%. Normal results on both complementary tests ruled out progression to AD (100%) within 2 years of inclusion. Our results show that the diagnostic accuracy of biomarkers in CSF is higher than that of biomarkers in MRI. Combined use of both techniques is highly accurate for either early diagnosis or exclusion of AD in patients with MCI. Copyright © 2013 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

Hybrid Monte Carlo-Diffusion Method For Light Propagation in Tissue With a Low-Scattering Region

NASA Astrophysics Data System (ADS)

Hayashi, Toshiyuki; Kashio, Yoshihiko; Okada, Eiji

2003-06-01

The heterogeneity of the tissues in a head, especially the low-scattering cerebrospinal fluid (CSF) layer surrounding the brain has previously been shown to strongly affect light propagation in the brain. The radiosity-diffusion method, in which the light propagation in the CSF layer is assumed to obey the radiosity theory, has been employed to predict the light propagation in head models. Although the CSF layer is assumed to be a nonscattering region in the radiosity-diffusion method, fine arachnoid trabeculae cause faint scattering in the CSF layer in real heads. A novel approach, the hybrid Monte Carlo-diffusion method, is proposed to calculate the head models, including the low-scattering region in which the light propagation does not obey neither the diffusion approximation nor the radiosity theory. The light propagation in the high-scattering region is calculated by means of the diffusion approximation solved by the finite-element method and that in the low-scattering region is predicted by the Monte Carlo method. The intensity and mean time of flight of the detected light for the head model with a low-scattering CSF layer calculated by the hybrid method agreed well with those by the Monte Carlo method, whereas the results calculated by means of the diffusion approximation included considerable error caused by the effect of the CSF layer. In the hybrid method, the time-consuming Monte Carlo calculation is employed only for the thin CSF layer, and hence, the computation time of the hybrid method is dramatically shorter than that of the Monte Carlo method.

Hybrid Monte Carlo-diffusion method for light propagation in tissue with a low-scattering region.

PubMed

Hayashi, Toshiyuki; Kashio, Yoshihiko; Okada, Eiji

2003-06-01

The heterogeneity of the tissues in a head, especially the low-scattering cerebrospinal fluid (CSF) layer surrounding the brain has previously been shown to strongly affect light propagation in the brain. The radiosity-diffusion method, in which the light propagation in the CSF layer is assumed to obey the radiosity theory, has been employed to predict the light propagation in head models. Although the CSF layer is assumed to be a nonscattering region in the radiosity-diffusion method, fine arachnoid trabeculae cause faint scattering in the CSF layer in real heads. A novel approach, the hybrid Monte Carlo-diffusion method, is proposed to calculate the head models, including the low-scattering region in which the light propagation does not obey neither the diffusion approximation nor the radiosity theory. The light propagation in the high-scattering region is calculated by means of the diffusion approximation solved by the finite-element method and that in the low-scattering region is predicted by the Monte Carlo method. The intensity and mean time of flight of the detected light for the head model with a low-scattering CSF layer calculated by the hybrid method agreed well with those by the Monte Carlo method, whereas the results calculated by means of the diffusion approximation included considerable error caused by the effect of the CSF layer. In the hybrid method, the time-consuming Monte Carlo calculation is employed only for the thin CSF layer, and hence, the computation time of the hybrid method is dramatically shorter than that of the Monte Carlo method.

Organic electronics based pressure sensor towards intracranial pressure monitoring

NASA Astrophysics Data System (ADS)

Rai, Pratyush; Varadan, Vijay K.

2010-04-01

The intra-cranial space, which houses the brain, contains cerebrospinal fluid (CSF) that acts as a fluid suspension medium for the brain. The CSF is always in circulation, is secreted in the cranium and is drained out through ducts called epidural veins. The venous drainage system has inherent resistance to the flow. Pressure is developed inside the cranium, which is similar to a rigid compartment. Normally a pressure of 5-15 mm Hg, in excess of atmospheric pressure, is observed at different locations inside the cranium. Increase in Intra-Cranial Pressure (ICP) can be caused by change in CSF volume caused by cerebral tumors, meningitis, by edema of a head injury or diseases related to cerebral atrophy. Hence, efficient ways of monitoring ICP need to be developed. A sensor system and monitoring scheme has been discussed here. The system architecture consists of a membrane less piezoelectric pressure sensitive element, organic thin film transistor (OTFT) based signal transduction, and signal telemetry. The components were fabricated on flexible substrate and have been assembled using flip-chip packaging technology. Material science and fabrication processes, subjective to the device performance, have been discussed. Capability of the device in detecting pressure variation, within the ICP pressure range, is investigated and applicability of measurement scheme to medical conditions has been argued for. Also, applications of such a sensor-OTFT assembly for logic sensor switching and patient specific-secure monitoring system have been discussed.

Herpes simplex encephalitis presenting as stroke-like symptoms with atypical MRI findings and lacking cerebrospinal fluid pleocytosis.

PubMed

Tsuboguchi, Shintaro; Wakasugi, Takahiro; Umeda, Yoshitaka; Umeda, Maiko; Oyake, Mutsuo; Fujita, Nobuya

2017-07-29

A 73-year-old woman presented with sudden onset of right hemiparesis and was diagnosed as having cerebral infarction on the basis of diffusion-weighted brain MRI, which demonstrated lesions in the left parietal cortex. On the 3rd day, the patient developed right upper limb myoclonus, aphasia, and disturbance of consciousness with high fever. On the 6th day, she was transferred to our hospital with suspected viral encephalitis, and treatment with acyclovir was started. By the 6th day, the lesions detected by MRI had expanded to the gyrus cinguli, insula and thalamus, but not to the temporal lobe. At that time, the CSF cell count was 8/μl, and this later increased to 17/μl by the 13th day. Although herpes simplex virus DNA was detected in the CSF on the 6th day, there was no evidence of CSF pleocytosis or temporal lobe abnormalities demonstrable by brain MRI throughout the whole follow-up period. This was very atypical case of herpes simplex encephalitis characterized by a stroke-like episode, atypical MRI findings, and absence of cerebrospinal fluid pleocytosis. It is important to be mindful that herpes simplex encephalitis (HSE) can have an atypical presentation, and that sufficient acyclovir treatment should be initiated until HSE can be ruled out.

Whole-brain radiation fails to boost intracerebral gefitinib concentration in patients with brain metastatic non-small cell lung cancer: a self-controlled, pilot study.

PubMed

Fang, Luo; Sun, Xiaojiang; Song, Yu; Zhang, Yiwen; Li, Fanzhu; Xu, Yaping; Ma, Shenglin; Lin, Nengming

2015-10-01

Whole-brain radiation therapy (WBRT) is generally considered as an efficient strategy to improve blood-brain barrier (BBB) permeability by damaging BBB structure and is therefore, used as a promising pretreatment of chemotherapy. However, the impact of radiotherapy on leaky BBB is still controversial for the reason that BBB of metastatic brain tumor lesion had been breached by tumor metastasizing. Herein, we conducted a self-controlled study to evaluate the effect of WBRT on the permeability of BBB in non-small cell lung cancer (NSCLC) patients with brain metastases (BM). A prospective self-controlled research was performed. Radiation-naive NSCLC patients with BM were enrolled and treated with gefitinib for 2 weeks, and then concurrently combined with WBRT for 2 weeks. Plasma and cerebrospinal fluid (CSF) before and after WBRT were collected on day 15 and 29 after the initiation of gefitinib treatment. The concentrations of gefitinib in these samples were measured by HPLC. Three patients were enrolled and evaluated. The concentrations of gefitinib in plasma and CSF pre-WBRT were comparable to those of post-WBRT. Consequently, no significant change was noted in the CSF-to-plasma ratios of gefitinib before and after WBRT (2.79 ± 1.47 vs. 2.35 ± 1.74 %, p = 0.123). The WBRT may not affect the BBB permeability by determining the concentration of gefitinib in NSCLC patients with BM.

Cerebral Folate Deficiency

ERIC Educational Resources Information Center

Gordon, Neil

2009-01-01

Cerebral folate deficiency (CFD) is associated with low levels of 5-methyltetrahydrofolate in the cerebrospinal fluid (CSF) with normal folate levels in the plasma and red blood cells. The onset of symptoms caused by the deficiency of folates in the brain is at around 4 to 6 months of age. This is followed by delayed development, with deceleration…

MRimaging findings after ventricular puncture in patients with SAH.

PubMed

Tominaga, J; Shimoda, M; Oda, S; Kumasaka, A; Yamazaki, K; Tsugane, R

2001-11-01

Using magnetic resonance (MR) imaging, we studied brain injury from ventricular puncture performed during craniotomy in the acute stage of subarachnoid hemorrhage (SAH). 80 patients underwent craniotomy for aneurysm obliteration within 48 hr after SAH, ventricular puncture for drainage of cerebrospinal fluid (CSF) was performed to reduce intracranial pressure. MR imaging was performed within 3 days following surgery to measure the size of the lesion, and was repeated on postoperative days 14 and 30. Of the 80 patients with ventricular puncture preceding craniotomy, 65 (81%) showed MR evidence of brain injury from the puncture. Overall, 149 lesions were detected. According to coronal images, cortical injuries (54 cases), penetrating injury to tracts along the ventricular tube (55 cases), caudate injury (25 cases), and corpus callosum injury (15 cases). Brain injuries from ventricular puncture did not correlate significantly to patient outcome. While ventricular puncture and drainage of CSF can readily be performed to decrease brain volume at the time of craniotomy in acute-stage SAH, neurosurgeons should be aware of a surprisingly high incidence of brain injury complicating puncture.

Laser Capture Microdissection Assessment of Virus Compartmentalization in the Central Nervous Systems of Macaques Infected with Neurovirulent Simian Immunodeficiency Virus

PubMed Central

Matsuda, Kenta; Brown, Charles R.; Foley, Brian; Goeken, Robert; Whitted, Sonya; Dang, Que; Wu, Fan; Plishka, Ronald; Buckler-White, Alicia

2013-01-01

Nonhuman primate-simian immunodeficiency virus (SIV) models are powerful tools for studying the pathogenesis of human immunodeficiency virus type 1 (HIV-1) in the brain. Our laboratory recently isolated a neuropathogenic viral swarm, SIVsmH804E, a derivative of SIVsmE543-3, which was the result of sequential intravenous passages of viruses isolated from the brains of rhesus macaques with SIV encephalitis. Animals infected with SIVsmH804E or its precursor (SIVsmH783Br) developed SIV meningitis and/or encephalitis at high frequencies. Since we observed macaques with a combination of meningitis and encephalitis, as well as animals in which meningitis or encephalitis was the dominant component, we hypothesized that distinct mechanisms could be driving the two pathological states. Therefore, we assessed viral populations in the meninges and the brain parenchyma by laser capture microdissection. Viral RNAs were isolated from representative areas of the meninges, brain parenchyma, terminal plasma, and cerebrospinal fluid (CSF) and from the inoculum, and the SIV envelope fragment was amplified by PCR. Phylogenetic analysis of envelope sequences from the conventional progressors revealed compartmentalization of viral populations between the meninges and the parenchyma. In one of these animals, viral populations in meninges were closely related to those from CSF and shared signature truncations in the cytoplasmic domain of gp41, consistent with a common origin. Apart from magnetic resonance imaging (MRI) and positron-emission tomography (PET) imaging, CSF is the most accessible assess to the central nervous system for HIV-1-infected patients. However, our results suggest that the virus in the CSF may not always be representative of viral populations in the brain and that caution should be applied in extrapolating between the properties of viruses in these two compartments. PMID:23720733

Post-Traumatic Hypoxia Is Associated with Prolonged Cerebral Cytokine Production, Higher Serum Biomarker Levels, and Poor Outcome in Patients with Severe Traumatic Brain Injury

PubMed Central

Yan, Edwin B.; Satgunaseelan, Laveniya; Paul, Eldho; Bye, Nicole; Nguyen, Phuong; Agyapomaa, Doreen; Kossmann, Thomas; Rosenfeld, Jeffrey V.

2014-01-01

Abstract Secondary hypoxia is a known contributor to adverse outcomes in patients with traumatic brain injury (TBI). Based on the evidence that hypoxia and TBI in isolation induce neuroinflammation, we investigated whether TBI combined with hypoxia enhances cerebral cytokine production. We also explored whether increased concentrations of injury biomarkers discriminate between hypoxic (Hx) and normoxic (Nx) patients, correlate to worse outcome, and depend on blood–brain barrier (BBB) dysfunction. Forty-two TBI patients with Glasgow Coma Scale ≤8 were recruited. Cerebrospinal fluid (CSF) and serum were collected over 6 days. Patients were divided into Hx (n=22) and Nx (n=20) groups. Eight cytokines were measured in the CSF; albumin, S100, myelin basic protein (MBP) and neuronal specific enolase (NSE) were quantified in serum. CSF/serum albumin quotient was calculated for BBB function. Glasgow Outcome Scale Extended (GOSE) was assessed at 6 months post-TBI. Production of granulocye macrophage-colony stimulating factor (GM-CSF) was higher, and profiles of GM-CSF, interferon (IFN)-γ and, to a lesser extent, tumor necrosis factor (TNF), were prolonged in the CSF of Hx but not Nx patients at 4–5 days post-TBI. Interleukin (IL)-2, IL-4, IL-6, and IL-10 increased similarly in both Hx and Nx groups. S100, MBP, and NSE were significantly higher in Hx patients with unfavorable outcome. Among these three biomarkers, S100 showed the strongest correlations to GOSE after TBI-Hx. Elevated CSF/serum albumin quotients lasted for 5 days post-TBI and displayed similar profiles in Hx and Nx patients. We demonstrate for the first time that post-TBI hypoxia is associated with prolonged neuroinflammation, amplified extravasation of biomarkers, and poor outcome. S100 and MBP could be implemented to track the occurrence of post-TBI hypoxia, and prompt adequate treatment. PMID:24279428

Whole-brain intracranial vessel wall imaging at 3 Tesla using cerebrospinal fluid-attenuated T1-weighted 3D turbo spin echo.

PubMed

Fan, Zhaoyang; Yang, Qi; Deng, Zixin; Li, Yuxia; Bi, Xiaoming; Song, Shlee; Li, Debiao

2017-03-01

Although three-dimensional (3D) turbo spin echo (TSE) with variable flip angles has proven to be useful for intracranial vessel wall imaging, it is associated with inadequate suppression of cerebrospinal fluid (CSF) signals and limited spatial coverage at 3 Tesla (T). This work aimed to modify the sequence and develop a protocol to achieve whole-brain, CSF-attenuated T 1 -weighted vessel wall imaging. Nonselective excitation and a flip-down radiofrequency pulse module were incorporated into a commercial 3D TSE sequence. A protocol based on the sequence was designed to achieve T 1 -weighted vessel wall imaging with whole-brain spatial coverage, enhanced CSF-signal suppression, and isotropic 0.5-mm resolution. Human volunteer and pilot patient studies were performed to qualitatively and quantitatively demonstrate the advantages of the sequence. Compared with the original sequence, the modified sequence significantly improved the T 1 -weighted image contrast score (2.07 ± 0.19 versus 3.00 ± 0.00, P = 0.011), vessel wall-to-CSF contrast ratio (0.14 ± 0.16 versus 0.52 ± 0.30, P = 0.007) and contrast-to-noise ratio (1.69 ± 2.18 versus 4.26 ± 2.30, P = 0.022). Significant improvement in vessel wall outer boundary sharpness was observed in several major arterial segments. The new 3D TSE sequence allows for high-quality T 1 -weighted intracranial vessel wall imaging at 3 T. It may potentially aid in depicting small arteries and revealing T 1 -mediated high-signal wall abnormalities. Magn Reson Med 77:1142-1150, 2017. © 2016 International Society for Magnetic Resonance in Medicine. © 2016 International Society for Magnetic Resonance in Medicine.

Amyloid and tau cerebrospinal fluid biomarkers in HIV infection.

PubMed

Gisslén, Magnus; Krut, Jan; Andreasson, Ulf; Blennow, Kaj; Cinque, Paola; Brew, Bruce J; Spudich, Serena; Hagberg, Lars; Rosengren, Lars; Price, Richard W; Zetterberg, Henrik

2009-12-22

Because of the emerging intersections of HIV infection and Alzheimer's disease, we examined cerebrospinal fluid (CSF) biomarkers related of amyloid and tau metabolism in HIV-infected patients. In this cross-sectional study we measured soluble amyloid precursor proteins alpha and beta (sAPPalpha and sAPPbeta), amyloid beta fragment 1-42 (Abeta1-42), and total and hyperphosphorylated tau (t-tau and p-tau) in CSF of 86 HIV-infected (HIV+) subjects, including 21 with AIDS dementia complex (ADC), 25 with central nervous system (CNS) opportunistic infections and 40 without neurological symptoms and signs. We also measured these CSF biomarkers in 64 uninfected (HIV-) subjects, including 21 with Alzheimer's disease, and both younger and older controls without neurological disease. CSF sAPPalpha and sAPPbeta concentrations were highly correlated and reduced in patients with ADC and opportunistic infections compared to the other groups. The opportunistic infection group but not the ADC patients had lower CSF Abeta1-42 in comparison to the other HIV+ subjects. CSF t-tau levels were high in some ADC patients, but did not differ significantly from the HIV+ neuroasymptomatic group, while CSF p-tau was not increased in any of the HIV+ groups. Together, CSF amyloid and tau markers segregated the ADC patients from both HIV+ and HIV- neuroasymptomatics and from Alzheimer's disease patients, but not from those with opportunistic infections. Parallel reductions of CSF sAPPalpha and sAPPbeta in ADC and CNS opportunistic infections suggest an effect of CNS immune activation or inflammation on neuronal amyloid synthesis or processing. Elevation of CSF t-tau in some ADC and CNS infection patients without concomitant increase in p-tau indicates neural injury without preferential accumulation of hyperphosphorylated tau as found in Alzheimer's disease. These biomarker changes define pathogenetic pathways to brain injury in ADC that differ from those of Alzheimer's disease.

Insulin-like growth factor-1 and growth hormone (GH) levels in canine cerebrospinal fluid are unaffected by GH or GH secretagogue (MK-0677) administration.

PubMed

Prahalada, S; Block, G; Handt, L; DeBurlet, G; Cahill, M; Hoe, C M; van Zwieten, M J

1999-01-01

Elevation in circulating GH levels results in a dose-related increase in serum insulin-like growth factor-1 (IGF-1) levels in dogs. However, it is not known whether elevations in systemic IGF-1 and GH levels contribute to the cerebrospinal fluid (CSF) levels of these hormones. Therefore, a study was designed in dogs to determine if elevated circulating GH levels was a result of a GH secretagogue (MK-0677) or if exogenous GH administration resulted in increased IGF-1 and GH levels in the CSF of dogs. A total of 12 normal, young adult male dogs were randomized to three treatment groups (4 dogs/group) based on body weight. There were 4 vehicle control dogs. A group of 4 dogs were dosed orally with MK-0677 (5 mg/kg/day) dissolved in deionized water. A third group of 4 dogs received subcutaneous injections of porcine GH (pGH) at a dose of 0.1 IU/kg/day. From all dogs, blood and CSF samples were collected prior to the initiation of treatment and on days 7 and 15 of treatment. All samples were assayed using a validated radioimmunoassay. Administration of MK-0677 or pGH resulted in a statistically significant (P < or = 0.05) increased body weight gain and increased serum IGF-1 and GH levels. In contrast, administration of MK-0677 resulted in no significant (P > 0.05) increase in CSF IGF-1 or GH levels on days 7 or 15 of the study. The CSF IGF-1 values ranged from 1.2 to 2.0 ng/ml with minimal variation among three separate samples taken during the course of the study from each dog. Similarly, the CSF GH levels were very low (< 0.98 ng/ml to 2.4 ng/ml) in all dogs irrespective of treatment group. This study has demonstrated that there is no correlation between the circulating levels of IGF-1 or GH and the levels of these hormones in the CSF of normal dogs. An approximately 100-fold difference between serum and CSF IGF-1 levels in vehicle control dogs suggest that there is a blood-brain barrier for the circulating IGF-1. Similarly, failure to see an elevation in CSF GH levels despite increases in serum GH levels shows that there is a blood-brain barrier for GH in normal dogs. These results suggest that the likely source of GH and IGF-1 in the CSF of dogs is from the CNS.

Cerebrospinal Fluid Biomarkers and Reserve Variables as Predictors of Future "Non-Cognitive" Outcomes of Alzheimer's Disease.

PubMed

Ingber, Adam P; Hassenstab, Jason; Fagan, Anne M; Benzinger, Tammie L S; Grant, Elizabeth A; Holtzman, David M; Morris, John C; Roe, Catherine M

2016-01-01

The influence of reserve variables and Alzheimer's disease (AD) biomarkers on cognitive test performance has been fairly well-characterized. However, less is known about the influence of these factors on "non-cognitive" outcomes, including functional abilities and mood. We examined whether cognitive and brain reserve variables mediate how AD biomarker levels in cognitively normal persons predict future changes in function, mood, and neuropsychiatric behavior. Non-cognitive outcomes were examined in 328 individuals 50 years and older enrolled in ongoing studies of aging and dementia at the Knight Alzheimer Disease Research Center (ADRC). All participants were cognitively normal at baseline (Clinical Dementia Rating [CDR] 0), completed cerebrospinal fluid (CSF) and structural neuroimaging studies within one year of baseline, and were followed for an average of 4.6 annual visits. Linear mixed effects models explored how cognitive reserve and brain reserve variables mediate the relationships between AD biomarker levels and changes in function, mood, and neuropsychiatric behavior in cognitively normal participants. Education levels did not have a significant effect on predicting non-cognitive decline. However, participants with smaller brain volumes exhibited the worst outcomes on measures of mood, functional abilities, and behavioral disturbance. This effect was most pronounced in individuals who also had abnormal CSF biomarkers. The findings suggest that brain reserve plays a stronger, or earlier, role than cognitive reserve in protecting against non-cognitive impairment in AD.

Sensitive biomarkers of alcoholism's effect on brain macrostructure: similarities and differences between France and the United States

PubMed Central

Le Berre, Anne-Pascale; Pitel, Anne-Lise; Chanraud, Sandra; Beaunieux, Hélène; Eustache, Francis; Martinot, Jean-Luc; Reynaud, Michel; Martelli, Catherine; Rohlfing, Torsten; Pfefferbaum, Adolf; Sullivan, Edith V.

2015-01-01

Alcohol consumption patterns and recognition of health outcomes related to hazardous drinking vary widely internationally, raising the question whether these national differences are reflected in brain damage observed in alcoholism. This retrospective analysis assessed variability of alcoholism's effects on brain cerebrospinal fluid (CSF) and white matter volumes between France and the United States (U.S.). MRI data from two French sites (Caen and Orsay) and a U.S. laboratory (SRI/Stanford University) were acquired on 1.5T imaging systems in 287 controls, 165 uncomplicated alcoholics (ALC), and 26 alcoholics with Korsakoff's Syndrome (KS). All data were analyzed at the U.S. site using atlas-based parcellation. Results revealed graded CSF volume enlargement from ALC to KS and white matter volume deficits in KS only. In ALC from France but not the U.S., CSF and white matter volumes correlated with lifetime alcohol consumption, alcoholism duration, and length of sobriety. MRI highlighted CSF volume enlargement in both ALC and KS, serving as a basis for an ex vacuo process to explain correlated gray matter shrinkage. By contrast, MRI provided a sensitive in vivo biomarker of white matter volume shrinkage in KS only, suggesting a specific process sensitive to mechanisms contributing to Wernicke's encephalopathy, the precursor of KS. Identified structural brain abnormalities may provide biomarkers underlying alcoholism's heterogeneity in and among nations and suggest a substrate of gray matter tissue shrinkage. Proposed are hypotheses for national differences in interpreting whether the severity of sequelae observe a graded phenomenon or a continuum from uncomplicated alcoholism to alcoholism complicated by KS. PMID:26157376

Detection and quantification of microRNA in cerebral microdialysate.

PubMed

Bache, Søren; Rasmussen, Rune; Rossing, Maria; Hammer, Niels Risør; Juhler, Marianne; Friis-Hansen, Lennart; Nielsen, Finn Cilius; Møller, Kirsten

2015-05-07

Secondary brain injury accounts for a major part of the morbidity and mortality in patients with spontaneous aneurysmal subarachnoid hemorrhage (SAH), but the pathogenesis and pathophysiology remain controversial. MicroRNAs (miRNAs) are important posttranscriptional regulators of complementary mRNA targets and have been implicated in the pathophysiology of other types of acute brain injury. Cerebral microdialysis is a promising tool to investigate these mechanisms. We hypothesized that miRNAs would be present in human cerebral microdialysate. RNA was extracted and miRNA profiles were established using high throughput real-time quantification PCR on the following material: 1) Microdialysate sampled in vitro from A) a solution of total RNA extracted from human brain, B) cerebrospinal fluid (CSF) from a neurologically healthy patient, and C) a patient with SAH; and 2) cerebral microdialysate and CSF sampled in vivo from two patients with SAH. MiRNAs were categorized according to their relative recovery (RR) and a pathway analysis was performed for miRNAs exhibiting a high RR in vivo. Seventy-one of the 160 miRNAs detected in CSF were also found in in vivo microdialysate from SAH patients. Furthermore specific miRNAs consistently exhibited either a high or low RR in both in vitro and in vivo microdialysate. Analysis of repeatability showed lower analytical variation in microdialysate than in CSF. MiRNAs are detectable in cerebral microdialysate; a large group of miRNAs consistently showed a high RR in cerebral microdialysate. Measurement of cerebral interstitial miRNA concentrations may aid in the investigation of secondary brain injury in neurocritical conditions.

Cine phase-contrast MRI measurement of CSF flow in the cervical spine: a pilot study in patients with spinal cord injury

NASA Astrophysics Data System (ADS)

Negahdar, MJ; Shakeri, M.; McDowell, E.; Wells, J.; Vitaz, T.; Harkema, S.; Amini, A.

2011-03-01

MRI velocimetry (also known as phase-contrast MRI) is a powerful tool for quantification of cerebrospinal fluid (CSF) flow in various regions of the brain and craniospinal junction and has been accepted as a diagnostic tool to assist with the diagnosis of certain conditions such as hydrocephalus and chiari malformations. Cerebrospinal fluid is continually produced in the ventricles of the brain, flows through the ventricular system and then out and around the brain and spinal cord and is reabsorbed over the convexity of the brain. Any disease process which either impedes the normal pattern of flow or restricts the area where flow occurs can change the pattern of these waveforms with the direction and velocity of flow being determined by the pressure transmitted from the pulsation of the heart and circulation of blood within the central nervous system. Therefore, we hypothesized that phase-contrast MRI could eventually be used as a diagnostic aid in determining the degree of spinal cord compression following injury to the cervical or thoracic spine. In this study, we examined CSF flow in 3 normal subjects and 2 subjects with non-acute injuries in the cervical spine using Cine phasecontrast MRI. CSF flow analysis was performed using an in-house developed software. The flow waveform was calculated in both normal subjects (n=3) as well as subjects with spinal cord injury in the cervical spine (n=2). The bulk flow at C2 was measured to be 0.30 +/- 0.05 cc, at 5 cm distal to C2, it was 0.19+/- 0.07 cc, and at 10 cm distal to C2, it was 0.17+/- 0.05 cc. These results were in good agreement with previously published results. In patients with spinal cord injury, at the site of injury in the cervical spine, bulk flow was found to be 0.08 +/- 0.12 cc, at 5 cm proximal to the site of injury it was found to be 0.18 +/- 0.07 cc, and at 5 cm distal to the site of injury, it was found to be 0.12 +/- 0.01 cc.

Circulating tight junction proteins mirror blood-brain barrier integrity in leukaemia central nervous system metastasis.

PubMed

Zhu, Jing-Cheng; Si, Meng-Ya; Li, Ya-Zhen; Chen, Huan-Zhu; Fan, Zhi-Cheng; Xie, Qing-Dong; Jiao, Xiao-Yang

2017-09-01

The aim of this study was to evaluate the clinical significance of circulating tight junction (TJ) proteins as biomarkers reflecting of leukaemia central nervous system (CNS) metastasis. TJs [claudin5 (CLDN5), occludin (OCLN) and ZO-1] concentrations were measured in serum and cerebrospinal fluid (CSF) samples obtained from 45 leukaemia patients. Serum ZO-1 was significantly higher (p < 0.05), but CSF ZO-1 levels were not significantly higher in the CNS leukaemia (CNSL) compared to the non-CNSL. The CNSL patients also had a lower CLDN5/ZO1 ratio in both serum and CSF than in non-CNSL patients (p < 0.05). The TJ index was negatively associated with WBC CSF , ALB CSF and BBB values in leukaemia patients. Among all of the parameters studied, CLDN5 CSF had the highest specificity in discriminating between CNSL and non-CNSL patients. Therefore, analysing serum and CSF levels of CLDN5, OCLN and the CLDN5/ZO1 ratio is valuable in evaluating the potential of leukaemia CNS metastasis. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Cilia driven flow networks in the brain

NASA Astrophysics Data System (ADS)

Wang, Yong; Faubel, Regina; Westendorf, Chrsitian; Eichele, Gregor; Bodenschatz, Eberhard

Neurons exchange soluble substances via the cerebrospinal fluid (CSF) that fills the ventricular system. The walls of the ventricular cavities are covered with motile cilia that constantly beat and thereby induce a directional flow. We recently discovered that cilia in the third ventricle generate a complex flow pattern leading to partitioning of the ventricular volume and site-directed transport paths along the walls. Transient and daily recurrent alterations in the cilia beating direction lead to changes in the flow pattern. This has consequences for delivery of CSF components along the near wall flow. The contribution of this cilia-induced flow to overall CSF flow remains to be investigated. The state-of-art lattice Boltzmann method is adapted for studying the CFS flow. The 3D geometry of the third ventricle at high resolution was reconstructed. Simulation of CSF flow without cilia in this geometry confirmed that the previous idea about unidirectional flow does not explain how different components of CSF can be delivered to their various target sites. We study the contribution of the cilia-induced flow pattern to overall CSF flow and identify target areas for site-specific delivery of CSF-constituents with respect to the temporal changes.

Evidence that iron accelerates Alzheimer's pathology: a CSF biomarker study.

PubMed

Ayton, Scott; Diouf, Ibrahima; Bush, Ashley Ian

2018-05-01

To investigate whether cerebrospinal fluid (CSF) ferritin (reporting brain iron) is associated with longitudinal changes in CSF β-amyloid (Aβ) and tau. Mixed-effects models of CSF Aβ 1-42 and tau were constructed using data from 296 participants who had baseline measurement of CSF ferritin and annual measurement of CSF tau and Aβ 1-42 for up to 5 years. In subjects with biomarker-confirmed Alzheimer's pathology, high CSF ferritin (>6.2 ng/mL) was associated with accelerated depreciation of CSF Aβ 1-42 (reporting increased plaque formation; p=0.0001). CSF ferritin was neither associated with changes in CSF tau in the same subjects, nor longitudinal changes in CSF tau or Aβ 1-42 in subjects with low baseline pathology. In simulation modelling of the natural history of Aβ deposition, which we estimated to occur over 31.4 years, we predicted that it would take 12.6 years to reach the pathology threshold value of CSF Aβ from healthy normal levels, and this interval is not affected by CSF ferritin. CSF ferritin influences the fall in CSF Aβ over the next phase, where high CSF ferritin accelerated the transition from threshold preclinical Aβ levels to the average level of Alzheimer's subjects from 18.8 to 10.8 years. Iron might facilitate Aβ deposition in Alzheimer's and accelerate the disease process. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Brain immune interactions and air pollution: macrophage inhibitory factor (MIF), prion cellular protein (PrP(C)), Interleukin-6 (IL-6), interleukin 1 receptor antagonist (IL-1Ra), and interleukin-2 (IL-2) in cerebrospinal fluid and MIF in serum differentiate urban children exposed to severe vs. low air pollution.

PubMed

Calderón-Garcidueñas, Lilian; Cross, Janet V; Franco-Lira, Maricela; Aragón-Flores, Mariana; Kavanaugh, Michael; Torres-Jardón, Ricardo; Chao, Chih-Kai; Thompson, Charles; Chang, Jing; Zhu, Hongtu; D'Angiulli, Amedeo

2013-01-01

Mexico City Metropolitan Area children chronically exposed to high concentrations of air pollutants exhibit an early brain imbalance in genes involved in oxidative stress, inflammation, innate and adaptive immune responses along with accumulation of misfolded proteins observed in the early stages of Alzheimer and Parkinson's diseases. A complex modulation of serum cytokines and chemokines influences children's brain structural and gray/white matter volumetric responses to air pollution. The search for biomarkers associating systemic and CNS inflammation to brain growth and cognitive deficits in the short term and neurodegeneration in the long-term is our principal aim. We explored and compared a profile of cytokines, chemokines (Multiplexing LASER Bead Technology) and Cellular prion protein (PrP(C)) in normal cerebro-spinal-fluid (CSF) of urban children with high vs. low air pollution exposures. PrP(C) and macrophage inhibitory factor (MIF) were also measured in serum. Samples from 139 children ages 11.91 ± 4.2 years were measured. Highly exposed children exhibited significant increases in CSF MIF (p = 0.002), IL6 (p = 0.006), IL1ra (p = 0.014), IL-2 (p = 0.04), and PrP(C) (p = 0.039) vs. controls. MIF serum concentrations were higher in exposed children (p = 0.009). Our results suggest CSF as a MIF, IL6, IL1Ra, IL-2, and PrP(C) compartment that can possibly differentiate air pollution exposures in children. MIF, a key neuro-immune mediator, is a potential biomarker bridge to identify children with CNS inflammation. Fine tuning of immune-to-brain communication is crucial to neural networks appropriate functioning, thus the short and long term effects of systemic inflammation and dysregulated neural immune responses are of deep concern for millions of exposed children. Defining the linkage and the health consequences of the brain / immune system interactions in the developing brain chronically exposed to air pollutants ought to be of pressing importance for public health.

Quantification of the cerebrospinal fluid from a new whole body MRI sequence

NASA Astrophysics Data System (ADS)

Lebret, Alain; Petit, Eric; Durning, Bruno; Hodel, Jérôme; Rahmouni, Alain; Decq, Philippe

2012-03-01

Our work aims to develop a biomechanical model of hydrocephalus both intended to perform clinical research and to assist the neurosurgeon in diagnosis decisions. Recently, we have defined a new MR imaging sequence based on SPACE (Sampling Perfection with Application optimized Contrast using different flip-angle Evolution). On these images, the cerebrospinal fluid (CSF) appears as a homogeneous hypersignal. Therefore such images are suitable for segmentation and for volume assessment of the CSF. In this paper we present a fully automatic 3D segmentation of such SPACE MRI sequences. We choose a topological approach considering that CSF can be modeled as a simply connected object (i.e. a filled sphere). First an initial object which must be strictly included in the CSF and homotopic to a filled sphere, is determined by using a moment-preserving thresholding. Then a priority function based on an Euclidean distance map is computed in order to control the thickening process that adds "simple points" to the initial thresholded object. A point is called simple if its addition or its suppression does not result in change of topology neither for the object, nor for the background. The method is validated by measuring fluid volume of brain phantoms and by comparing our volume assessments on clinical data to those derived from a segmentation controlled by expert physicians. Then we show that a distinction between pathological cases and healthy adult people can be achieved by a linear discriminant analysis on volumes of the ventricular and intracranial subarachnoid spaces.

Effects of Spaceflight on Astronaut Brain Structure as Indicated on MRI.

PubMed

Roberts, Donna R; Albrecht, Moritz H; Collins, Heather R; Asemani, Davud; Chatterjee, A Rano; Spampinato, M Vittoria; Zhu, Xun; Chimowitz, Marc I; Antonucci, Michael U

2017-11-02

There is limited information regarding the effects of spaceflight on the anatomical configuration of the brain and on cerebrospinal fluid (CSF) spaces. We used magnetic resonance imaging (MRI) to compare images of 18 astronauts' brains before and after missions of long duration, involving stays on the International Space Station, and of 16 astronauts' brains before and after missions of short duration, involving participation in the Space Shuttle Program. Images were interpreted by readers who were unaware of the flight duration. We also generated paired preflight and postflight MRI cine clips derived from high-resolution, three-dimensional imaging of 12 astronauts after long-duration flights and from 6 astronauts after short-duration flights in order to assess the extent of narrowing of CSF spaces and the displacement of brain structures. We also compared preflight ventricular volumes with postflight ventricular volumes by means of an automated analysis of T 1 -weighted MRIs. The main prespecified analyses focused on the change in the volume of the central sulcus, the change in the volume of CSF spaces at the vertex, and vertical displacement of the brain. Narrowing of the central sulcus occurred in 17 of 18 astronauts after long-duration flights (mean flight time, 164.8 days) and in 3 of 16 astronauts after short-duration flights (mean flight time, 13.6 days) (P<0.001). Cine clips from a subgroup of astronauts showed an upward shift of the brain after all long-duration flights (12 astronauts) but not after short-duration flights (6 astronauts) and narrowing of CSF spaces at the vertex after all long-duration flights (12 astronauts) and in 1 of 6 astronauts after short-duration flights. Three astronauts in the long-duration group had optic-disk edema, and all 3 had narrowing of the central sulcus. A cine clip was available for 1 of these 3 astronauts, and the cine clip showed upward shift of the brain. Narrowing of the central sulcus, upward shift of the brain, and narrowing of CSF spaces at the vertex occurred frequently and predominantly in astronauts after long-duration flights. Further investigation, including repeated postflight imaging conducted after some time on Earth, is required to determine the duration and clinical significance of these changes. (Funded by the National Aeronautics and Space Administration.).

In vivo measurement of apolipoprotein E from the brain interstitial fluid using microdialysis

PubMed Central

2013-01-01

Background The APOE4 allele variant is the strongest known genetic risk factor for developing late-onset Alzheimer’s disease. The link between apolipoprotein E (apoE) and Alzheimer’s disease is likely due in large part to the impact of apoE on the metabolism of amyloid β (Aβ) within the brain. Manipulation of apoE levels and lipidation within the brain has been proposed as a therapeutic target for the treatment of Alzheimer’s disease. However, we know little about the dynamic regulation of apoE levels and lipidation within the central nervous system. We have developed an assay to measure apoE levels in the brain interstitial fluid of awake and freely moving mice using large molecular weight cut-off microdialysis probes. Results We were able to recover apoE using microdialysis from human cerebrospinal fluid (CSF) in vitro and mouse brain parenchyma in vivo. Microdialysis probes were inserted into the hippocampus of wild-type mice and interstitial fluid was collected for 36 hours. Levels of apoE within the microdialysis samples were determined by ELISA. The levels of apoE were found to be relatively stable over 36 hours. No apoE was detected in microdialysis samples from apoE KO mice. Administration of the RXR agonist bexarotene increased ISF apoE levels while ISF Aβ levels were decreased. Extrapolation to zero-flow analysis allowed us to determine the absolute recoverable concentration of apoE3 in the brain ISF of apoE3 KI mice. Furthermore, analysis of microdialysis samples by non-denaturing gel electrophoresis determined lipidated apoE particles in microdialysis samples were consistent in size with apoE particles from CSF. Finally, we found that the concentration of apoE in the brain ISF was dependent upon apoE isoform in human apoE KI mice, following the pattern apoE2>apoE3>apoE4. Conclusions We are able to collect lipidated apoE from the brain of awake and freely moving mice and monitor apoE levels over the course of several hours from a single mouse. Our technique enables assessment of brain apoE dynamics under physiological and pathophysiological conditions and in response to therapeutic interventions designed to affect apoE levels and lipidation within the brain. PMID:23601557

Rectification of pulsatile stress on soft tissues: a mechanism for normal-pressure hydrocephalus

NASA Astrophysics Data System (ADS)

Jalikop, Shreyas; Hilgenfeldt, Sascha

2011-11-01

Hydrocephalus is a pathological condition of the brain that occurs when cerebrospinal fluid (CSF) accumulates excessively in the brain cavities, resulting in compression of the brain parenchyma. Counter-intuitively, normal-pressure hydrocephalus (NPH) does not show elevated pressure differences across the compressed parenchyma. We investigate the effects of nonlinear tissue mechanics and periodic driving in this system. The latter is due to the cardiac cycle, which provides significant intracranial pressure and volume flow rate fluctuations. Nonlinear rectification of the periodic driving within a model of fluid flow in poroelastic material can lead to compression or expansion of the parenchyma, and this effect does not rely on changes in the mean intracranial pressure. The rectification effects can occur gradually over several days, in agreement with clinical studies of NPH.

Near-infrared spectroscopy of the adult head: effect of scattering and absorbing obstructions in the cerebrospinal fluid layer on light distribution in the tissue.

PubMed

Dehghani, H; Delpy, D T

2000-09-01

Previous modeling of near-infrared (NIR) light distribution in models of the adult head incorporating a clear nonscattering cerebrospinal fluid (CSF) layer have shown the latter to have a profound effect on the resulting photon measurement density function (PMDF). In particular, the presence of the CSF limits the PMDF largely to the outer cortical gray matter with little signal contribution from the deeper white matter. In practice, the CSF is not a simple unobstructed clear layer but contains light-scattering membranes and is crossed by various blood vessels. Using a radiosity-diffusion finite-element model, we investigated the effect on the PMDF of introducing intrusions within the clear layer. The results show that the presence of such obstructions does not significantly increase the light penetration into the brain tissue, except immediately adjacent to the obstruction and that its presence also increases the light sampling of the adjacent skull tissues, which would lead to additional contamination of the NIR spectroscopy signal by the surface tissue layers.

Cerebrospinal Fluid Proteome of Patients with Acute Lyme Disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Angel, Thomas E.; Jacobs, Jon M.; Smith, Robert P.

2012-10-05

Acute Lyme disease results from transmission of and infection by the bacterium Borrelia burgdorferi following a tick bite. During acute infection, bacteria can disseminate to the central nervous system (CNS) leading to the development of Lyme meningitis. Here we have analyzed pooled cerebrospinal fluid (CSF) allowing for a deep view into the proteome for a cohort of patients with early-disseminated Lyme disease and CSF inflammation leading to the identification of proteins that reflect host responses, which are distinct for subjects with acute Lyme disease. Additionally, we analyzed individual patient samples and quantified changes in protein abundance employing label-free quantitative massmore » spectrometry based methods. The measured changes in protein abundances reflect the impact of acute Lyme disease on the CNS as presented in CSF. We have identified 89 proteins that differ significantly in abundance in patients with acute Lyme disease. A number of the differentially abundant proteins have been found to be localized to brain synapse and thus constitute important leads for better understanding of the neurological consequence of disseminated Lyme disease.« less

[Met-enkephalin in the cerebrospinal fluid as an indicator of central nervous system injury in meningitis and encephalitis].

PubMed

Cieśla, Andrzej; Pierzchała-Koziec, Krystyna; Mach, Tomasz; Garlicki, Aleksander; Bociaga-Jasik, Monika

2005-05-01

Assessment of met-enkephalin level in the cerebrospinal fluid (CSF) of patients with inflammatory process of the central nervous system (CNS) was performed to estimate the role of opioid system in viral and bacterial meningitis, and encephalitis. The met-enkephalin level, protein concentration and pleocytosis were analysed in the CSF of 53 patients with viral or bacterial meningitis, encephalitis, and in the control group of patients without inflammatory disease of the CNS. The biggest differences have been observed between the groups of patients with bacterial meningitis and those without inflammatory disease of the CNS, but they were statistically insignificant. There was a lack of correlation between met-enkephalin level and some factors of inflammatory process in CSF, such as pleocytosis and protein concentration. We have not revealed any correlation between etiological agent of CNS infection and opioid system of the brain. Despite the fact that, we observed in the study statistically insignificant changes, we suggest to continue investigations, including additional parameters which are characteristic for the CNS diseases.

Measurement of soluble CD59 in CSF in demyelinating disease: Evidence for an intrathecal source of soluble CD59.

PubMed

Zelek, Wioleta M; Watkins, Lewis M; Howell, Owain W; Evans, Rhian; Loveless, Sam; Robertson, Neil P; Beenes, Marijke; Willems, Loek; Brandwijk, Ricardo; Morgan, B Paul

2018-02-01

CD59, a broadly expressed glycosylphosphatidylinositol-anchored protein, is the principal cell inhibitor of complement membrane attack on cells. In the demyelinating disorders, multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), elevated complement protein levels, including soluble CD59 (sCD59), were reported in cerebrospinal fluid (CSF). We compared sCD59 levels in CSF and matched plasma in controls and patients with MS, NMOSD and clinically isolated syndrome (CIS) and investigated the source of CSF sCD59 and whether it was microparticle associated. sCD59 was quantified using enzyme-linked immunosorbent assay (ELISA; Hycult; HK374-02). Patient and control CSF was subjected to western blotting to characterise anti-CD59-reactive materials. CD59 was localised by immunostaining and in situ hybridisation. CSF sCD59 levels were double those in plasma (CSF, 30.2 ng/mL; plasma, 16.3 ng/mL). Plasma but not CSF sCD59 levels differentiated MS from NMOSD, MS from CIS and NMOSD/CIS from controls. Elimination of microparticles confirmed that CSF sCD59 was not membrane anchored. CSF levels of sCD59 are not a biomarker of demyelinating diseases. High levels of sCD59 in CSF relative to plasma suggest an intrathecal source; CD59 expression in brain parenchyma was low, but expression was strong on choroid plexus (CP) epithelium, immediately adjacent the CSF, suggesting that this is the likely source.

Dynamic of CSF and serum biomarkers in HIV-1 subtype C encephalitis with CNS genetic compartmentalization-case study.

PubMed

de Almeida, Sergio M; Rotta, Indianara; Ribeiro, Clea E; Oliveira, Michelli F; Chaillon, Antoine; de Pereira, Ana Paula; Cunha, Ana Paula; Zonta, Marise; Bents, Joao França; Raboni, Sonia M; Smith, Davey; Letendre, Scott; Ellis, Ronald J

2017-06-01

Despite the effective suppression of viremia with antiretroviral therapy, HIV can still replicate in the central nervous system (CNS). This was a longitudinal study of the cerebrospinal fluid (CSF) and serum dynamics of several biomarkers related to inflammation, the blood-brain barrier, neuronal injury, and IgG intrathecal synthesis in serial samples of CSF and serum from a patient infected with HIV-1 subtype C with CNS compartmentalization.The phylogenetic analyses of plasma and CSF samples in an acute phase using next-generation sequencing and F-statistics analysis of C2-V3 haplotypes revealed distinct compartmentalized CSF viruses in paired CSF and peripheral blood mononuclear cell samples. The CSF biomarker analysis in this patient showed that symptomatic CSF escape is accompanied by CNS inflammation, high levels of cell and humoral immune biomarkers, CNS barrier dysfunction, and an increase in neuronal injury biomarkers with demyelization. Independent and isolated HIV replication can occur in the CNS, even in HIV-1 subtype C, leading to compartmentalization and development of quasispecies distinct from the peripheral plasma. These immunological aspects of the HIV CNS escape have not been described previously. To our knowledge, this is the first report of CNS HIV escape and compartmentalization in HIV-1 subtype C.

Decompressive craniectomy and CSF disorders in children.

PubMed

Manfiotto, Marie; Mottolese, Carmine; Szathmari, Alexandru; Beuriat, Pierre-Aurelien; Klein, Olivier; Vinchon, Matthieu; Gimbert, Edouard; Roujeau, Thomas; Scavarda, Didier; Zerah, Michel; Di Rocco, Federico

2017-10-01

Decompressive craniectomy (DC) is a lifesaving procedure but is associated to several post-operative complications, namely cerebrospinal fluid (CSF) dynamics impairment. The aim of this multicentric study was to evaluate the incidence of such CSF alterations after DC and review their impact on the overall outcome. We performed a retrospective multicentric study to analyze the CSF disorders occurring in children aged from 0 to 17 years who had undergone a DC for traumatic brain injury (TBI) in the major Departments of Pediatric Neurosurgery of France between January 2006 and August 2016. Out of 150 children, ranging in age between 7 months and 17 years, mean 10.75 years, who underwent a DC for TBI in 10 French pediatric neurosurgical centers. Sixteen (6 males, 10 females) (10.67%) developed CSF disorders following the surgical procedure and required an extrathecal CSF shunting. External ventricular drainage increased the risk of further complications, especially cranioplasty infection (p = 0.008). CSF disorders affect a minority of children after DC for TBI. They may develop early after the DC but they may develop several months after the cranioplasty (8 months), consequently indicating the necessity of clinical and radiological close follow-up after discharge from the neurosurgical unit. External ventricular drainage and permanent CSF shunt placement increase significantly the risk of cranioplasty infection.

Heavily T2-weighted MR myelography in patients with spontaneous intracranial hypotension: a case-control study.

PubMed

Tsai, P-H; Fuh, J-L; Lirng, J-F; Wang, S-J

2007-08-01

We performed whole-spine heavily T2-weighted magnetic resonance (MR) myelography using a single-shot fast spin-echo pulse sequence in 17 patients (8 M/9 F) with spontaneous intracranial hypotension (SIH) to detect abnormal cerebrospinal fluid (CSF) collections. In addition, a group of age- and sex-matched controls were recruited. Follow-up MR myelography was also done at 3 weeks. MR myelography showed three kinds of abnormal CSF collections in 15 patients with SIH (88%): epidural fluid collection (n = 15, 88%), C1-2 extraspinal collections (n = 6, 35%) and CSF collections along nerve roots in the lower cervical or upper thoracic spines (n = 6, 35%). One patient (6%) showed a meningeal diverticulum. In contrast, none of the controls showed these findings. Overall, MR myelography results helped in early diagnosis of SIH in four (24%) patients whose initial brain MRIs failed to show typical SIH findings. Follow-up MR myelography results were compatible with the clinical changes with kappa statistics of 0.52 and an agreement rate of 76%. Our study showed heavily T2-weighted MR myelography provided a rapid, non-invasive and high yield method to diagnose and follow-up patients with SIH. Whether the CSF collections along the nerve roots represent the ongoing leakage sites warrants further study.

Factors Influencing Norvancomycin Concentration in Plasma and Cerebrospinal Fluid in Patients After Craniotomy and Dosing Guideline: A Population Approach.

PubMed

Li, Xingang; Wu, Yuanxing; Sun, Shusen; Wang, Qiang; Zhao, Zhigang

2018-01-01

Antibacterial spectrum and activity of norvancomycin are comparable with vancomycin, and it has been widely used in China. Norvancomycin can penetrate into the cerebrospinal fluid (CSF) through the damaged blood-brain barrier in patients after craniotomy. Because higher inter-individual variability was observed, we aimed to identify factors related to drug concentration to guide clinicians with norvancomycin dosing. After craniotomy, patients with an indwelling catheter in the operational area/ventricle were intravenously administered norvancomycin. Venous blood and CSF specimens were collected at a scheduled time for measuring drug concentrations. Blood and CSF data were fitted simultaneously with the use of the nonlinear fixed-effects modeling method to develop the population pharmacokinetic model. Covariate analysis was applied to select candidate factors associated with pharmacokinetic parameters. A model-based simulation was performed to find optimized regimens for different subgroups of patients. A 3-compartmental model (central, peripheral, and CSF compartments) with 2 elimination pathways (drug elimination from the kidney and CSF outflow) was developed to characterize the in vivo process of norvancomycin. The covariate analysis identified that weight and drainage amount were strongly associated with the central volume and the drug clearance from CSF, respectively. Goodness-of-fit and model validation suggested that the proposed model was acceptable. A dosage regimen table was created for specific patient populations with different weights and drainage amounts to facilitate clinical application. We identified 2 clinical markers associated with plasma and CSF concentrations. The proposed simulation may be useful to clinicians for norvancomycin dosing in this specific population with normal kidney function. Copyright © 2018. Published by Elsevier Inc.

Cerebrospinal fluid metabolomics reveals altered waste clearance and accelerated aging in HIV patients with neurocognitive impairment

PubMed Central

Cassol, Edana; Misra, Vikas; Dutta, Anupriya; Morgello, Susan; Gabuzda, Dana

2014-01-01

Objective(s): HIV-associated neurocognitive disorders (HAND) remain prevalent in HIV-infected patients on antiretroviral therapy (ART), but the underlying mechanisms are unclear. Some features of HAND resemble those of age-associated cognitive decline in the absence of HIV, suggesting that overlapping mechanisms may contribute to neurocognitive impairment. Design: Cross-sectional analysis of cerebrospinal fluid (CSF) from 100 individuals (46 HIV-positive patients and 54 HIV-negative controls). Methods: Untargeted CSF metabolite profiling was performed using liquid/gas chromatography followed by mass spectrometry. Cytokine profiling was performed by Bioplex. Bioinformatic analyses were performed in Metaboanalyst and R. Results: Alterations in the CSF metabolome of HIV patients on ART mapped to pathways associated with neurotransmitter production, mitochondrial function, oxidative stress, and metabolic waste. Many CSF metabolites altered in HIV overlapped with those altered with advanced age in HIV-negative controls, suggesting a pattern indicative of accelerated aging. Machine learning models identified neurotransmitters (glutamate, N-acetylaspartate), markers of glial activation (myo-inositol), and ketone bodies (beta-hydroxybutyric acid, 1,2-propanediol) as top-ranked classifiers of HAND. These CSF metabolites correlated with worse neurocognitive test scores, plasma inflammatory biomarkers [interferon (IFN)-α, IFN-γ, interleukin (IL)-8, IL-1β, IL-6, IL-2Ra], and intrathecal IFN responses (IFN-γ and kynurenine : tryptophan ratio), suggesting inter-relationships between systemic and intrathecal inflammation and metabolic alterations in CSF. Conclusions: Alterations in the CSF metabolome of HIV patients on ART suggest that persistent inflammation, glial responses, glutamate neurotoxicity, and altered brain waste disposal systems contribute to mechanisms involved in HAND that may be augmented with aging. PMID:24752083

Histological changes in the rat brain and spinal cord following prolonged intracerebroventricular infusion of cerebrospinal fluid from amyotrophic lateral sclerosis patients are similar to those caused by the disease.

PubMed

Gómez-Pinedo, U; Galán, L; Yañez, M; Matias-Guiu, J; Valencia, C; Guerrero-Sola, A; Lopez-Sosa, F; Brin, J R; Benito-Martin, M S; Leon-Espinosa, G; Vela-Souto, A; Lendinez, C; Guillamon-Vivancos, T; Matias-Guiu, J A; Arranz-Tagarro, J A; Barcia, J A; Garcia, A G

2018-05-01

Cerebrospinal fluid (CSF) from amyotrophic lateral sclerosis (ALS) patients induces cytotoxic effects in in vitro cultured motor neurons. We selected CSF with previously reported cytotoxic effects from 32 ALS patients. Twenty-eight adult male rats were intracerebroventricularly implanted with osmotic mini-pumps and divided into 3 groups: 9 rats injected with CSF from non-ALS patients, 15 rats injected with cytotoxic ALS-CSF, and 4 rats injected with a physiological saline solution. CSF was intracerebroventricularly and continuously infused for periods of 20 or 43days after implantation. We conducted clinical assessments and electromyographic examinations, and histological analyses were conducted in rats euthanised 20, 45, and 82days after surgery. Immunohistochemical studies revealed tissue damage with similar characteristics to those found in the sporadic forms of ALS, such as overexpression of cystatinC, transferrin, and TDP-43 protein in the cytoplasm. The earliest changes observed seemed to play a protective role due to the overexpression of peripherin, AKTpan, AKTphospho, and metallothioneins; this expression had diminished by the time we analysed rats euthanised on day 82, when an increase in apoptosis was observed. The first cellular changes identified were activated microglia followed by astrogliosis and overexpression of GFAP and S100B proteins. Our data suggest that ALS could spread through CSF and that intracerebroventricular administration of cytotoxic ALS-CSF provokes changes similar to those found in sporadic forms of the disease. Copyright © 2016 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

The use of droplet digital PCR in liquid biopsies: A highly sensitive technique for MYD88 p.(L265P) detection in cerebrospinal fluid.

PubMed

Hiemcke-Jiwa, Laura S; Minnema, Monique C; Radersma-van Loon, Joyce H; Jiwa, N Mehdi; de Boer, Mirthe; Leguit, Roos J; de Weger, Roel A; Huibers, Manon M H

2018-04-01

The gold standard for diagnosis of central nervous system lymphomas still regards a stereotactic brain biopsy, with the risk of major complications for the patient. As tumor cells can be detected in cerebrospinal fluid (CSF), CSF analysis can be used as an alternative. In this respect, mutation analysis in CSF can be of added value to other diagnostic parameters such a cytomorphology and clonality analysis. A well-known example of targeted mutation analysis entails MYD88 p.(L265P) detection, which is present in the majority of Bing Neel syndrome and primary central nervous system lymphoma (PCNSL) patients. Unfortunately, tumor yield in CSF can be very low. Therefore, use of the highly sensitive droplet digital PCR (ddPCR) might be a suitable analysis strategy for targeted mutation detection. We analyzed 26 formalin fixed paraffin embedded (FFPE) samples (8 positive and 18 negative for MYD88 p.(L265P) mutation) by ddPCR, of which the results were compared with next generation sequencing (NGS). Subsequently, 32 CSF samples were analyzed by ddPCR. ddPCR and NGS results on FFPE material showed 100% concordance. Among the 32 CSF samples, 9 belonged to patients with lymphoplasmacytic lymphoma (LPL) and clinical suspicion of Bing Neel syndrome, and 3 belonged to patients with PCNSL. Nine of these samples tested positive for MYD88 p.(L265P) (8 LPL and 1 PCNSL). This study shows that sensitive MYD88 mutation analysis by ddPCR in CSF is highly reliable and can be applied even when DNA input is low. Therefore, ddPCR is of added value to current diagnostic parameters, especially when the available amount of DNA is limited. Copyright © 2017 John Wiley & Sons, Ltd.

Cerebrospinal fluid and serum levels of interleukin-8 in patients with multiple sclerosis and its correlation with Q-albumin.

PubMed

Matejčíková, Z; Mareš, J; Sládková, V; Svrčinová, T; Vysloužilová, J; Zapletalová, J; Kaňovský, P

2017-05-01

Multiple sclerosis (MS) is an inflammatory-demyelinating disease of the central nervous system (CNS). Autoimmune inflammation is common in the early stages of MS and is followed by neurodegenerative processes. The result of these changes is axon and myelin breakdown. The paraclinical examination methods are an important part of the diagnostic process. Magnetic resonance imaging of the brain and the cervical spinal cord and an examination of cerebrospinal fluid (CSF) are common paraclinical examinations. An increasing number of studies deal with CSF and serum levels of biomarkers and their role in MS. We hypothesized that the level of interleukin-8 (IL-8) could be different in MS patients than in controls. These differences may be related to damage of the blood-brain barrier (BBB). BBB damage is quantified by the quotient of albumin (Q-alb). CSF and serum levels of IL-8 were assessed in 102 patients with newly diagnosed MS meeting McDonald's revised diagnostic criteria and in 102 subjects as a control group. We then correlated these results with Q-alb. Levels of IL-8 in CSF were significantly higher in MS patients than in controls (Mann-Whitney U test, p<0.0001). Serum levels of IL-8 were significantly lower in MS patients than in controls (Mann-Whitney U test, p=0.018). Spearman's correlation analysis proved a significant correlation between levels of IL-8 and Q-alb. As the etiology of MS is only partially known, research dealing with biomarkers in MS should continue. Better knowledge of etiology can provide a new perspective, especially for treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

Cerebrospinal fluid leakage in intracranial hypotension syndrome: usefulness of indirect findings in radionuclide cisternography for detection and treatment monitoring.

PubMed

Morioka, Tomoaki; Aoki, Takatoshi; Tomoda, Yoshinori; Takahashi, Hiroyuki; Kakeda, Shingo; Takeshita, Iwao; Ohno, Masato; Korogi, Yukunori

2008-03-01

To evaluate indirect findings of cerebrospinal fluid (CSF) leakage on radionuclide cisternography and their changes after treatment. This study was approved by the hospital's institutional review board and informed consent was obtained before each examination. A total of 67 patients who were clinically suspected of spontaneous intracranial hypotension (SIH) syndrome underwent radionuclide cisternography, and 27 patients who had direct findings of CSF leakage on radionuclide cisternography were selected for this evaluation. They were 16 males and 11 females, aged between 26 and 58 years. Sequential images of radionuclide cisternography were acquired at 1, 3, 5, and 24 hours after injection. We assessed the presence or absence of 4 indirect findings; early visualization of bladder activity, no visualization of activity over the brain convexities, rapid disappearance of spinal activity, and abnormal visualization of the root sleeves. Changes of the direct and indirect findings after treatment were also evaluated in 14 patients who underwent epidural blood patch treatment. Early visualization of bladder activity was found in all 27 patients. Seven of 27 (25.9%) patients showed no activity over the brain convexities. Rapid disappearance of spinal activity and abnormal root sleeve visualization were present in 2 (7.4%) and 5 (18.5%) patients, respectively. After epidural blood patch, both direct CSF leakage findings and indirect findings of early visualization of bladder activity had disappeared or improved in 12 of 14 patients (85.7%). The other indirect findings also disappeared after treatment in all cases. Indirect findings of radionuclide cisternography, especially early visualization of bladder activity, may be useful in the diagnosis and posttreatment follow-up of CSF leakage.

Opportunistic Neurologic Infections in Patients with Acquired Immunodeficiency Syndrome (AIDS).

PubMed

Albarillo, Fritzie; O'Keefe, Paul

2016-01-01

Infections of the central nervous system (CNS) in individuals with human immunodeficiency virus (HIV) remain a substantial cause of morbidity and mortality despite the introduction of highly active antiretroviral therapy (HAART) especially in the resource-limited regions of the world. Diagnosis of these infections may be challenging because findings on cerebrospinal fluid (CSF) analysis and brain imaging are nonspecific. While brain biopsy provides a definitive diagnosis, it is an invasive procedure associated with a relatively low mortality rate, thus less invasive modalities have been studied in recent years. Diagnosis, therefore, can be established based on a combination of a compatible clinical syndrome, radiologic and CSF findings, and understanding of the role of HIV in these infections. The most common CNS opportunistic infections are AIDS-defining conditions; thus, treatment of these infections in combination with HAART has greatly improved survival.

Comparative pharmacokinetics of two prodrugs of zidovudine in rabbits: enhanced levels of zidovudine in brain tissue.

PubMed

Lupia, R H; Ferencz, N; Lertora, J J; Aggarwal, S K; George, W J; Agrawal, K C

1993-04-01

The pharmacokinetics of two prodrugs of zidovudine (AZT), 1,4-dihydro-1-methyl-3-[(pyridylcarbonyl)oxy] ester and isoleucinyl ester (DPAZT and IAZT, respectively), were investigated in a rabbit model to determine their potential utility as drugs against human immunodeficiency virus. Drugs were administered by intravenous infusion over 5 min at doses equal to 10 mg of AZT per kg of body weight. The levels of the prodrugs and of released AZT in plasma, cerebrospinal fluid (CSF), and brain were determined by high-performance liquid chromatography analysis. DPAZT disappeared rapidly from plasma, whereas IAZT maintained a sustained level in plasma for up to 4 h. The levels in plasma of AZT released from DPAZT were consistently lower than the levels of AZT released from IAZT or AZT itself. At 75 min after infusion of AZT, DPAZT, and IAZT, the CSF plasma AZT ratios were 0.23, 0.30, and 0.25, while the brain/CSF AZT ratios were 0.32, 0.63, and 0.64, respectively. These results indicate that the administration of each of the prodrugs produced a higher concentration of AZT in the brain than did the direct administration of AZT. Both prodrugs therefore may be superior to AZT itself with respect to achieving anti-human immunodeficiency virus concentrations within the central nervous system.

Comparative pharmacokinetics of two prodrugs of zidovudine in rabbits: enhanced levels of zidovudine in brain tissue.

PubMed Central

Lupia, R H; Ferencz, N; Lertora, J J; Aggarwal, S K; George, W J; Agrawal, K C

1993-01-01

The pharmacokinetics of two prodrugs of zidovudine (AZT), 1,4-dihydro-1-methyl-3-[(pyridylcarbonyl)oxy] ester and isoleucinyl ester (DPAZT and IAZT, respectively), were investigated in a rabbit model to determine their potential utility as drugs against human immunodeficiency virus. Drugs were administered by intravenous infusion over 5 min at doses equal to 10 mg of AZT per kg of body weight. The levels of the prodrugs and of released AZT in plasma, cerebrospinal fluid (CSF), and brain were determined by high-performance liquid chromatography analysis. DPAZT disappeared rapidly from plasma, whereas IAZT maintained a sustained level in plasma for up to 4 h. The levels in plasma of AZT released from DPAZT were consistently lower than the levels of AZT released from IAZT or AZT itself. At 75 min after infusion of AZT, DPAZT, and IAZT, the CSF plasma AZT ratios were 0.23, 0.30, and 0.25, while the brain/CSF AZT ratios were 0.32, 0.63, and 0.64, respectively. These results indicate that the administration of each of the prodrugs produced a higher concentration of AZT in the brain than did the direct administration of AZT. Both prodrugs therefore may be superior to AZT itself with respect to achieving anti-human immunodeficiency virus concentrations within the central nervous system. PMID:8494380

Proteomic analysis of cerebrospinal fluid from children with central nervous system tumors identifies candidate proteins relating to tumor metastatic spread.

PubMed

Spreafico, Filippo; Bongarzone, Italia; Pizzamiglio, Sara; Magni, Ruben; Taverna, Elena; De Bortoli, Maida; Ciniselli, Chiara M; Barzanò, Elena; Biassoni, Veronica; Luchini, Alessandra; Liotta, Lance A; Zhou, Weidong; Signore, Michele; Verderio, Paolo; Massimino, Maura

2017-07-11

Central nervous system (CNS) tumors are the most common solid tumors in childhood. Since the sensitivity of combined cerebrospinal fluid (CSF) cytology and radiological neuroimaging in detecting meningeal metastases remains relatively low, we sought to characterize the CSF proteome of patients with CSF tumors to identify biomarkers predictive of metastatic spread. CSF samples from 27 children with brain tumors and 13 controls (extra-CNS non-Hodgkin lymphoma) were processed using core-shell hydrogel nanoparticles, and analyzed with reverse-phase liquid chromatography/electrospray tandem mass spectrometry (LC-MS/MS). Candidate proteins were identified with Fisher's exact test and/or a univariate logistic regression model. Reverse phase protein array (RPPA), Western blot (WB), and ELISA were used in the training set and in an independent set of CFS samples (60 cases, 14 controls) to validate our discovery findings. Among the 558 non-redundant proteins identified by LC-MS/MS, 147 were missing from the CSF database at http://www.biosino.org. Fourteen of the 26 final top-candidate proteins were chosen for validation with WB, RPPA and ELISA methods. Six proteins (type 1 collagen, insulin-like growth factor binding protein 4, procollagen C-endopeptidase enhancer 1, glial cell-line derived neurotrophic factor receptor α2, inter-alpha-trypsin inhibitor heavy chain 4, neural proliferation and differentiation control protein-1) revealed the ability to discriminate metastatic cases from controls. Combining a unique dataset of CSFs from pediatric CNS tumors with a novel enabling nanotechnology led us to identify CSF proteins potentially related to metastatic status.

Peroxiredoxin VI Oxidation in Cerebrospinal Fluid Correlates with TBI Outcome

PubMed Central

Manevich, Y.; Hutchens, S.; Halushka, P.V.; Tew, K.D.; Townsend, D. M.; Jauch, E.C.; Borg, K.

2014-01-01

Traumatic brain injury (TBI) patients would benefit from the identification of reliable biomarkers to predict outcomes and treatment strategies. In our study, cerebrospinal fluid (CSF) from patients with severe TBI was evaluated for oxidant stress-mediated damage progression after hospital admission and subsequent ventriculostomy placement. Interestingly, substantial levels of peroxiredoxin VI (Prdx6), a major antioxidant enzyme normally found in astrocytes, were detected in CSF from control and TBI patients, and were not associated with blood contamination. Functionally, Prdx6 and its associated binding partner glutathione S-transferase pi (GSTP1-1, also detected in CSF) act in tandem to detoxify lipid peroxidation damage to membranes. We found Prdx6 was fully active in CSF of control patients but becomes significantly inactivated (oxidized) under TBI. Furthermore, significant and progressive oxidation of “buried” protein thiol in CSF of TBI patients (as compared to that of non-trauma control) were detected over a 24h period following hospital admission, with increased oxidation correlating with severity of trauma. Conversely, recovery of Prdx6 activity after 24h indicated more favorable patient outcome. Not only is this the first report of an extracellular form of Prdx6 but also the first report of its detection at a substantial level in CSF. Taken together, our data suggest a meaningful correlation between TBI-initiated oxidation of Prdx6, its specific phospholipid hydroperoxide peroxidase activity, and severity of trauma outcome. Consequently, we propose that Prdx6 redox status detection has the potential to be a biomarker for TBI outcome and a future indicator of therapeutic efficacy. PMID:24726861

On the importance of albumin binding for the flux of 7α-hydroxy-3-oxo-4-cholestenoic acid in the brain.

PubMed

Saeed, Ahmed A; Edström, Erik; Pikuleva, Irina; Eggertsen, Gösta; Björkhem, Ingemar

2017-02-01

We confirmed previous findings by a Japanese group that there is an accumulation of 7α-hydroxy-3-oxo-4-cholestenoic acid (7-Hoca) in human subdural hematomas. The accumulation correlated with the time from the bleeding to the sample collection. We present evidence that these accumulations are likely to be caused by the strong affinity of 7-Hoca to albumin and the marked difference between plasma and brain with respect to levels of albumin. In the circulation, 80-90% of 7-Hoca is bound to albumin with a ratio between the steroid acid and albumin of ∼1.4 ng/mg. In cerebrospinal fluid (CSF), the ratio between 7-Hoca and albumin is ∼30 ng/mg. When albumin or hemolyzed blood in a dialysis bag was exposed to CSF, there was a flux of 7-Hoca from CSF to the albumin. We suggest that the major explanation for accumulation of 7-Hoca in subdural hematoma is a flux from the brain into the hematoma due to the high affinity to albumin and the high capacity of 7-Hoca to pass biomembranes. We discuss the possibility that the markedly different ratios between 7-Hoca and albumin in circulation and brain can explain the flux of 7-Hoca from the brain into circulation against a concentration gradient. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

No neurochemical evidence of brain injury after blast overpressure by repeated explosions or firing heavy weapons.

PubMed

Blennow, K; Jonsson, M; Andreasen, N; Rosengren, L; Wallin, A; Hellström, P A; Zetterberg, H

2011-04-01

Psychiatric and neurological symptoms are common among soldiers exposed to blast without suffering a direct head injury. It is not known whether such symptoms are direct consequences of blast overpressure. To examine if repeated detonating explosions or firing if of heavy weapons is associated with neurochemical evidence of brain damage. Three controlled experimental studies. In the first, army officers were exposed to repeated firing of a FH77B howitzer or a bazooka. Cerebrospinal fluid (CSF) was taken post-exposure to measure biomarkers for brain damage. In the second, officers were exposed for up to 150 blasts by firing a bazooka, and in the third to 100 charges of detonating explosives of 180 dB. Serial serum samples were taken after exposure. Results were compared with a control group consisting of 19 unexposed age-matched healthy volunteers. The CSF biomarkers for neuronal/axonal damage (tau and neurofilament protein), glial cell injury (GFAP and S-100b), blood-brain barrier damage (CSF/serum albumin ratio) and hemorrhages (hemoglobin and bilirubin) and the serum GFAP and S-100b showed normal and stable levels in all exposed officers. Repeated exposure to high-impact blast does not result in any neurochemical evidence of brain damage. These findings are of importance for soldiers regularly exposed to high-impact blast when firing artillery shells or other types of heavy weapons. © 2010 John Wiley & Sons A/S.

Multiple roles for the Na,K-ATPase subunits, Atp1a1 and Fxyd1, during brain ventricle development

PubMed Central

Chang, Jessica T.; Lowery, Laura Anne; Sive, Hazel

2012-01-01

Formation of the vertebrate brain ventricles requires both production of cerebrospinal fluid (CSF), and its retention in the ventricles. The Na,K-ATPase is required for brain ventricle development, and we show here that this protein complex impacts three associated processes. The first requires both the alpha subunit (Atp1a1) and the regulatory subunit, Fxyd1, and leads to formation of a cohesive neuroepithelium, with continuous apical junctions. The second process leads to modulation of neuroepithelial permeability, and requires Atp1a1, which increases permeability with partial loss of function and decreases it with overexpression. In contrast, fxyd1 overexpression does not alter neuroepithelial permeability, suggesting that its activity is limited to neuroepithelium formation. RhoA regulates both neuroepithelium formation and permeability, downstream of the Na,K-ATPase. A third process, likely to be CSF production, is RhoA-independent, requiring Atp1a1, but not Fxyd1. Consistent with a role for Na,K-ATPase pump function, the inhibitor ouabain prevents neuroepithelium formation, while intracellular Na+ increases after Atp1a1 and Fxyd1 loss of function. These data include the first reported role for Fxyd1 in the developing brain, and indicate that the Na,K-ATPase regulates three aspects of brain ventricle development essential for normal function - formation of a cohesive neuroepithelium, restriction of neuroepithelial permeability, and production of CSF. PMID:22683378

Effects of parturition and feed restriction on concentrations and distribution of the insulin-like growth factor-binding proteins in plasma and cerebrospinal fluid of dairy cows.

PubMed

Laeger, T; Wirthgen, E; Piechotta, M; Metzger, F; Metges, C C; Kuhla, B; Hoeflich, A

2014-05-01

Hormones and metabolites act as satiety signals in the brain and play an important role in the control of feed intake (FI). These signals can reach the hypothalamus and brainstem, 2 major centers of FI regulation, via the blood stream or the cerebrospinal fluid (CSF). During the early lactation period of high-yielding dairy cows, the increase of FI is often insufficient. Recently, it has been demonstrated that insulin-like growth factors (IGF) may control FI. Thus, we asked in the present study if IGF-binding proteins (IGFBP) are regulated during the periparturient period and in response to feed restriction and therefore might affect FI as well. In addition, we specifically addressed conditional distribution of IGFBP in plasma and CSF. In one experiment, 10 multiparous German Holstein dairy cows were fed ad libitum and samples of CSF and plasma were obtained before morning feeding on d -20, -10, +1, +10, +20, and +40 relative to calving. In a second experiment, 7 cows in second mid-lactation were sampled for CSF and plasma after ad libitum feeding and again after feeding 50% of the previous ad libitum intake for 4 d. Intact IGFBP-2, IGFBP-3, and IGFBP-4 were detected in plasma by quantitative Western ligand blot analysis. In CSF, we were able to predominantly identify intact IGFBP-2 and a specific IGFBP-2 fragment containing detectable binding affinities for biotinylated IGF-II. Whereas plasma concentrations of IGFBP-2 and IGFBP-4 increased during the periparturient period, IGFBP-3 was unaffected over time. In CSF, concentrations of IGFBP-2, both intact and fragmented, were not affected during the periparturient period. Plasma IGF-I continuously decreased until calving but remained at a lower concentration in early lactation than in late pregnancy. Food restriction did not affect concentrations of IGF components present in plasma or CSF. We could show that the IGFBP profiles in plasma and CSF are clearly distinct and that changes in IGFBP in plasma do not simply correspond in the brain. We thus assume independent control of IGFBP distribution between plasma and CSF. Due to the known anorexic effect of IGF-I, elevated plasma concentrations of IGFBP-2 and IGFBP-4 during the postpartum period in conjunction with reduced plasma IGF-I concentrations may be interpreted as an endocrine response against negative energy balance in early lactation in dairy cows. Copyright © 2014 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Improvement effect on the depth-dose distribution by CSF drainage and air infusion of a tumour-removed cavity in boron neutron capture therapy for malignant brain tumours

NASA Astrophysics Data System (ADS)

Sakurai, Yoshinori; Ono, Koji; Miyatake, Shin-ichi; Maruhashi, Akira

2006-03-01

Boron neutron capture therapy (BNCT) without craniotomy for malignant brain tumours was started using an epi-thermal neutron beam at the Kyoto University Reactor in June 2002. We have tried some techniques to overcome the treatable-depth limit in BNCT. One of the effective techniques is void formation utilizing a tumour-removed cavity. The tumorous part is removed by craniotomy about 1 week before a BNCT treatment in our protocol. Just before the BNCT irradiation, the cerebro-spinal fluid (CSF) in the tumour-removed cavity is drained out, air is infused to the cavity and then the void is made. This void improves the neutron penetration, and the thermal neutron flux at depth increases. The phantom experiments and survey simulations modelling the CSF drainage and air infusion of the tumour-removed cavity were performed for the size and shape of the void. The advantage of the CSF drainage and air infusion is confirmed for the improvement in the depth-dose distribution. From the parametric surveys, it was confirmed that the cavity volume had good correlation with the improvement effect, and the larger effect was expected as the cavity volume was larger.

Improvement effect on the depth-dose distribution by CSF drainage and air infusion of a tumour-removed cavity in boron neutron capture therapy for malignant brain tumours.

PubMed

Sakurai, Yoshinori; Ono, Koji; Miyatake, Shin-Ichi; Maruhashi, Akira

2006-03-07

Boron neutron capture therapy (BNCT) without craniotomy for malignant brain tumours was started using an epi-thermal neutron beam at the Kyoto University Reactor in June 2002. We have tried some techniques to overcome the treatable-depth limit in BNCT. One of the effective techniques is void formation utilizing a tumour-removed cavity. The tumorous part is removed by craniotomy about 1 week before a BNCT treatment in our protocol. Just before the BNCT irradiation, the cerebro-spinal fluid (CSF) in the tumour-removed cavity is drained out, air is infused to the cavity and then the void is made. This void improves the neutron penetration, and the thermal neutron flux at depth increases. The phantom experiments and survey simulations modelling the CSF drainage and air infusion of the tumour-removed cavity were performed for the size and shape of the void. The advantage of the CSF drainage and air infusion is confirmed for the improvement in the depth-dose distribution. From the parametric surveys, it was confirmed that the cavity volume had good correlation with the improvement effect, and the larger effect was expected as the cavity volume was larger.

Herpes Simplex Encephalitis (HSE) and its outcome in the Patients who were Admitted to a Tertiary Care Hospital in Mashhad, Iran, over a 10-year Period.

PubMed

Sheybani, F; Arabikhan, H R; Naderi, H R

2013-08-01

The effective cure rate of acyclovir emphasizes the importance of an early diagnosis and treatment in reducing the considerable mortality and the morbidity in patients with Herpes Simplex Encephalitis (HSE). The demographic as well as clinical features, the lab data and the neuroimaging findings of the patients with HSE, which were confirmed by Cerebrospinal Fluid (CSF) PCR and/or brain MRI, were reviewed and analyzed statistically over a 10-year period. Over a 10-year period, the characteristics of 45 patients with HSE were reviewed. 34 (76%) out of the 45 patients showed positive CSF HSV-1 PCR results. 8 (18%) had a normal CSF analysis and a CSF/blood glucose ratio of less than 0.5 was observed in 13 (29%) patients, while 14% had PMN-dominant pleocytosis. 68% of the patients for whom brain MRI was performed, had temporal lobe involvement. While 37 (83%) patients recovered completely, 6 (13%) survived with sequelae, and 2 (4%) died. Because of the increasing number of atypical forms of HSE and the great impact of an early diagnosis and treatment on a favourable outcome, the acyclovir therapy should be administrated for any type of febrile encephalopathy of unknown aetiology, until HSE can be excluded.

Blood-brain-barrier disruption in chronic canine hypothyroidism.

PubMed

Pancotto, Theresa; Rossmeisl, John H; Panciera, David L; Zimmerman, Kurt L

2010-12-01

Central nervous system (CNS) manifestations of hypothyroidism have been associated with cerebrovascular complications. Reports of cerebrospinal fluid (CSF) abnormalities are rare in hypothyroid dogs. The aim of this study was to determine if chronic hypothyroidism causes blood-brain-barrier (BBB) abnormalities that are detectable using indirect CSF biomarkers. The study included 18 normal, euthyroid, female mixed-breed dogs. Hypothyroidism was induced by (131) iodine administration in 9 dogs; 9 served as untreated controls. Evaluations included physical and neurologic examination, complete CSF analysis, serum and CSF protein electrophoresis, measurement of plasma vascular endothelial growth factor (VEGF) and serum S-100B concentrations, and calculation of CSF albumin quota (AQ) and were conducted at baseline and 6, 12, and 18 months after induction of hypothyroidism. Data were analyzed using repeated measures ANOVA. At baseline, differences between groups were not detected for any variable. Throughout the study, controls dogs remained free of neurologic disease and had test variables that remained within reference intervals. Two hypothyroid dogs developed CNS signs during the study, and evidence of cerebrovascular disease was found at necropsy. At 12 and 18 months, the CSF total protein, VEGF, S-100B, and fractional albumin concentrations, and AQ were significantly higher (P<.04) in hypothyroid dogs than controls. Among test variables assayed in serum or plasma, the only significant difference was a higher S-100B concentration in hypothyroid dogs (P=.003) at 18 months. BBB integrity is disrupted in chronic hypothyroidism. Significant increases in CSF concentrations of VEGF and S100-B in hypothyroid dogs indicate dysfunction in both endothelial and glial elements of the BBB. ©2010 American Society for Veterinary Clinical Pathology.

HIV-associated progressive multifocal leukoencephalopathy: longitudinal study of JC virus non-coding control region rearrangements and host immunity.

PubMed

Iannetta, Marco; Bellizzi, Anna; Lo Menzo, Sara; Anzivino, Elena; D'Abramo, Alessandra; Oliva, Alessandra; D'Agostino, Claudia; d'Ettorre, Gabriella; Pietropaolo, Valeria; Vullo, Vincenzo; Ciardi, Maria Rosa

2013-06-01

John Cunningham virus (JCV), the etiological agent of progressive multifocal leukoencephalopathy (PML), contains a hyper-variable non-coding control region usually detected in urine of healthy individuals as archetype form and in the brain and cerebrospinal fluid (CSF) of PML patients as rearranged form. We report a case of HIV-related PML with clinical, immunological and virological data longitudinally collected. On admission (t0), after 8-week treatment with a rescue highly active antiretroviral therapy (HAART), the patient showed a CSF-JCV load of 16,732 gEq/ml, undetectable HIV-RNA and an increase of CD4+ cell count. Brain magnetic resonance imaging (MRI) showed PML-compatible lesions without contrast enhancement. We considered PML-immune reconstitution inflammatory syndrome as plausible because of the sudden onset of neurological symptoms after the effective HAART. An experimental JCV treatment with mefloquine and mirtazapine was added to steroid boli. Two weeks later (t1), motor function worsened and MRI showed expanded lesions with cytotoxic oedema. CSF JCV-DNA increased (26,263 gEq/ml) and JCV viremia was detected. After 4 weeks (t2), JCV was detected only in CSF (37,719 gEq/ml), and 8 weeks after admission (t3), JC viral load decreased in CSF and JCV viremia reappeared. The patient showed high level of immune activation both in peripheral blood and CSF. He died 4 weeks later. Considering disease progression, combined therapy failure and immune hyper-activation, we finally classified the case as classical PML. The archetype variant found in CSF at t0/t3 and a rearranged sequence detected at t1/t2 suggest that PML can develop from an archetype virus and that the appearance of rearranged genotypes contribute to faster disease progression.

The effects of blood and blood products on the arachnoid cell.

PubMed

Hansen, Eric A; Romanova, Liudmila; Janson, Christopher; Lam, Cornelius H

2017-06-01

After traumatic brain injury (TBI), large amounts of red blood cells and hemolytic products are deposited intracranially creating debris in the cerebrospinal fluid (CSF). This debris, which includes heme and bilirubin, is cleared via the arachnoid granulations and lymphatic systems. However, the mechanisms by which erythrocytes and their breakdown products interfere with normal CSF dynamics remain poorly defined. The purpose of this study was to model in vitro how blood breakdown products affect arachnoid cells at the CSF-blood barrier, and the extent to which the resorption of CSF into the venous drainage system is mechanically impaired following TBI. Arachnoid cells were grown to confluency on permeable membranes. Rates of growth and apoptosis were measured in the presence of blood and lysed blood, changes in transepithelial electrical resistance (TEER) was measured in the presence of blood and hemoglobin, and small molecule permeability was determined in the presence of blood, lysed blood, bilirubin, and biliverdin. These results were directly compared with an established rat brain endothelial cell line (RBEC4) co-cultured with rat brain astrocytes. We found that arachnoid cells grown in the presence of whole or lysed erythrocytes had significantly slower growth rates than controls. Bilirubin and biliverdin, despite their low solubilities, altered the paracellular transport of arachnoid cells more than the acute blood breakdown components of whole and lysed blood. Mannitol permeability was up to four times higher in biliverdin treatments than controls, and arachnoid membranes demonstrated significantly decreased small molecule permeabilities in the presence of whole and lysed blood. We conclude that short-term (<24 h) arachnoid cell transport and long-term (>5 days) arachnoid cell viability are affected by blood and blood breakdown products, with important consequences for CSF flow and blood clearance after TBI.

Quantitation of specific binding ratio in 123I-FP-CIT SPECT: accurate processing strategy for cerebral ventricular enlargement with use of 3D-striatal digital brain phantom.

PubMed

Furuta, Akihiro; Onishi, Hideo; Amijima, Hizuru

2018-06-01

This study aimed to evaluate the effect of ventricular enlargement on the specific binding ratio (SBR) and to validate the cerebrospinal fluid (CSF)-Mask algorithm for quantitative SBR assessment of 123 I-FP-CIT single-photon emission computed tomography (SPECT) images with the use of a 3D-striatum digital brain (SDB) phantom. Ventricular enlargement was simulated by three-dimensional extensions in a 3D-SDB phantom comprising segments representing the striatum, ventricle, brain parenchyma, and skull bone. The Evans Index (EI) was measured in 3D-SDB phantom images of an enlarged ventricle. Projection data sets were generated from the 3D-SDB phantoms with blurring, scatter, and attenuation. Images were reconstructed using the ordered subset expectation maximization (OSEM) algorithm and corrected for attenuation, scatter, and resolution recovery. We bundled DaTView (Southampton method) with the CSF-Mask processing software for SBR. We assessed SBR with the use of various coefficients (f factor) of the CSF-Mask. Specific binding ratios of 1, 2, 3, 4, and 5 corresponded to SDB phantom simulations with true values. Measured SBRs > 50% that were underestimated with EI increased compared with the true SBR and this trend was outstanding at low SBR. The CSF-Mask improved 20% underestimates and brought the measured SBR closer to the true values at an f factor of 1.0 despite an increase in EI. We connected the linear regression function (y = - 3.53x + 1.95; r = 0.95) with the EI and f factor using root-mean-square error. Processing with CSF-Mask generates accurate quantitative SBR from dopamine transporter SPECT images of patients with ventricular enlargement.

Prolonged effect of stress at weaning on the brain serotonin metabolism and sexuality of female rats.

PubMed

Tekes, K; Hantos, M; Gyenge, M; Karabélyos, Cs; Csaba, G

2006-12-01

Weanling female rats were stressed (by water and food deprivation for two days) and three months later the following indexes were studied: 5-HT and 5-HIAA levels in five brain regions, blood plasma and cerebrospinal fluid (CSF), sexual activity and nocistatin level of the plasma and CSF. The 5-HIAA content of hypothalamus and brainstem was significantly decreased (in the brainstem with one third) and in the striatum significantly increased. Plasma nocistatin level was significantly increased. Meyerson index and lordosis quotient were similar to control, but the estrus frequency almost doubled in the stressed animals. Much more defense reactions were observed in the stressed females during trials of mating. The results demonstrate that, 1) the perinatal period is not only sensitive to the remote-effects of stress but later could also be stress-sensitive critical periods, and 2) the continuously differentiating (e.g. bone marrow) cells are sensitive to late imprinting by stress, as well as to the brain and the sexual system.

A 29-year-old pregnant woman with worsening left hemiparesis, encephalopathy, and hemodynamic instability: a case report of subacute sclerosing panencephalitis.

PubMed

Reis, Gerald F; Ritter, Jana M; Bellini, William J; Rota, Paul A; Bollen, Andrew W

2015-01-01

A 29-year-old pregnant woman developed progressively worsening encephalopathy, left hemiparesis, and hemodynamic instability over a 6-week period. Initial brain MRI and work-up for infectious and autoimmune causes were normal, although elevated IgG and oligoclonal bands were seen on analysis of the cerebrospinal fluid (CSF). After uncomplicated spontaneous delivery of a preterm healthy infant, her condition worsened. Repeat brain MRI demonstrated generalized volume loss and evidence of corticospinal tract degeneration. She underwent a brain biopsy, which showed characteristic viral inclusions of the type seen in subacute sclerosing panencephalitis (SSPE). The diagnosis was confirmed by immunohistochemistry and electron microscopy, and additional CSF analysis also showed markedly elevated IgG titer for measles. Sequence analysis of the nucleoprotein gene N-450 demonstrated a close relationship to the sequences of viruses in genotype D7. This case documents an ~ 6-month progression to death of SSPE in a pregnant woman.

Ex vivo 18O-labeling mass spectrometry identifies a peripheral amyloid β clearance pathway.

PubMed

Portelius, Erik; Mattsson, Niklas; Pannee, Josef; Zetterberg, Henrik; Gisslén, Magnus; Vanderstichele, Hugo; Gkanatsiou, Eleni; Crespi, Gabriela A N; Parker, Michael W; Miles, Luke A; Gobom, Johan; Blennow, Kaj

2017-02-20

Proteolytic degradation of amyloid β (Aβ) peptides has been intensely studied due to the central role of Aβ in Alzheimer's disease (AD) pathogenesis. While several enzymes have been shown to degrade Aβ peptides, the main pathway of Aβ degradation in vivo is unknown. Cerebrospinal fluid (CSF) Aβ42 is reduced in AD, reflecting aggregation and deposition in the brain, but low CSF Aβ42 is, for unknown reasons, also found in some inflammatory brain disorders such as bacterial meningitis. Using 18 O-labeling mass spectrometry and immune-affinity purification, we examined endogenous proteolytic processing of Aβ in human CSF. The Aβ peptide profile was stable in CSF samples from healthy controls but in CSF samples from patients with bacterial meningitis, showing increased leukocyte cell count, 18 O-labeling mass spectrometry identified proteolytic activities degrading Aβ into several short fragments, including abundant Aβ1-19 and 1-20. After antibiotic treatment, no degradation of Aβ was detected. In vitro experiments located the source of the proteolytic activity to blood components, including leukocytes and erythrocytes, with insulin-degrading enzyme as the likely protease. A recombinant version of the mid-domain anti-Aβ antibody solanezumab was found to inhibit insulin-degrading enzyme-mediated Aβ degradation. 18 O labeling-mass spectrometry can be used to detect endogenous proteolytic activity in human CSF. Using this technique, we found an enzymatic activity that was identified as insulin-degrading enzyme that cleaves Aβ in the mid-domain of the peptide, and could be inhibited by a recombinant version of the mid-domain anti-Aβ antibody solanezumab.

Biomarker Exposure-Response Analysis in Mild-To-Moderate Alzheimer's Disease Trials of Bapineuzumab.

PubMed

Russu, Alberto; Samtani, Mahesh N; Xu, Steven; Adedokun, Omoniyi J; Lu, Ming; Ito, Kaori; Corrigan, Brian; Raje, Sangeeta; Liu, Enchi; Brashear, H Robert; Styren, Scot; Hu, Chuanpu

2016-05-03

Bapineuzumab, an anti-amyloid monoclonal antibody, was evaluated as a candidate for immunotherapy in mild-to-moderate Alzheimer's disease (AD) patients. To assess the treatment effect of bapineuzumab therapy on disease-relevant biomarkers in patients with mild-to-moderate AD, using exposure-response modeling. Biomarker data from two Phase III studies were combined to model the impact of bapineuzumab exposure on week-71 change from baseline in brain amyloid burden by 11C-labeled Pittsburgh compound B (PiB) PET imaging (global cortical average of the Standardized Uptake Value ratio values), cerebrospinal fluid (CSF) phosphorylated (p)-tau concentrations, and brain volumetrics (brain boundary shift integral) by magnetic resonance imaging. Bapineuzumab or placebo was administered as a 1-hour intravenous infusion every 13 weeks for 78 weeks. Pharmacokinetic/pharmacodynamic modeling helped determine the most appropriate exposure-response model and estimate the impact of disease-relevant covariates (baseline biomarker value, APOE*E4 allele copy number, and baseline disease status as measured by Mini-Mental State Examination score) on the three biomarkers. Linear exposure-response relationships with negative and significant slope terms were observed for PiB PET and CSF p-tau concentration. Baseline biomarker value and APOE*E4 carrier status were significant covariates for both biomarkers. No exposure-response relationship on brain boundary shift integral was detected. Bapineuzumab treatment induced exposure-dependent reductions in brain amyloid burden. Effects on CSF p-tau concentrations were significant only in APOE*E4 carriers. No apparent influence of bapineuzumab exposure on brain volume could be demonstrated.

MRBrainS Challenge: Online Evaluation Framework for Brain Image Segmentation in 3T MRI Scans.

PubMed

Mendrik, Adriënne M; Vincken, Koen L; Kuijf, Hugo J; Breeuwer, Marcel; Bouvy, Willem H; de Bresser, Jeroen; Alansary, Amir; de Bruijne, Marleen; Carass, Aaron; El-Baz, Ayman; Jog, Amod; Katyal, Ranveer; Khan, Ali R; van der Lijn, Fedde; Mahmood, Qaiser; Mukherjee, Ryan; van Opbroek, Annegreet; Paneri, Sahil; Pereira, Sérgio; Persson, Mikael; Rajchl, Martin; Sarikaya, Duygu; Smedby, Örjan; Silva, Carlos A; Vrooman, Henri A; Vyas, Saurabh; Wang, Chunliang; Zhao, Liang; Biessels, Geert Jan; Viergever, Max A

2015-01-01

Many methods have been proposed for tissue segmentation in brain MRI scans. The multitude of methods proposed complicates the choice of one method above others. We have therefore established the MRBrainS online evaluation framework for evaluating (semi)automatic algorithms that segment gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) on 3T brain MRI scans of elderly subjects (65-80 y). Participants apply their algorithms to the provided data, after which their results are evaluated and ranked. Full manual segmentations of GM, WM, and CSF are available for all scans and used as the reference standard. Five datasets are provided for training and fifteen for testing. The evaluated methods are ranked based on their overall performance to segment GM, WM, and CSF and evaluated using three evaluation metrics (Dice, H95, and AVD) and the results are published on the MRBrainS13 website. We present the results of eleven segmentation algorithms that participated in the MRBrainS13 challenge workshop at MICCAI, where the framework was launched, and three commonly used freeware packages: FreeSurfer, FSL, and SPM. The MRBrainS evaluation framework provides an objective and direct comparison of all evaluated algorithms and can aid in selecting the best performing method for the segmentation goal at hand.

MRBrainS Challenge: Online Evaluation Framework for Brain Image Segmentation in 3T MRI Scans

PubMed Central

Mendrik, Adriënne M.; Vincken, Koen L.; Kuijf, Hugo J.; Breeuwer, Marcel; Bouvy, Willem H.; de Bresser, Jeroen; Alansary, Amir; de Bruijne, Marleen; Carass, Aaron; El-Baz, Ayman; Jog, Amod; Katyal, Ranveer; Khan, Ali R.; van der Lijn, Fedde; Mahmood, Qaiser; Mukherjee, Ryan; van Opbroek, Annegreet; Paneri, Sahil; Pereira, Sérgio; Rajchl, Martin; Sarikaya, Duygu; Smedby, Örjan; Silva, Carlos A.; Vrooman, Henri A.; Vyas, Saurabh; Wang, Chunliang; Zhao, Liang; Biessels, Geert Jan; Viergever, Max A.

2015-01-01

Many methods have been proposed for tissue segmentation in brain MRI scans. The multitude of methods proposed complicates the choice of one method above others. We have therefore established the MRBrainS online evaluation framework for evaluating (semi)automatic algorithms that segment gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) on 3T brain MRI scans of elderly subjects (65–80 y). Participants apply their algorithms to the provided data, after which their results are evaluated and ranked. Full manual segmentations of GM, WM, and CSF are available for all scans and used as the reference standard. Five datasets are provided for training and fifteen for testing. The evaluated methods are ranked based on their overall performance to segment GM, WM, and CSF and evaluated using three evaluation metrics (Dice, H95, and AVD) and the results are published on the MRBrainS13 website. We present the results of eleven segmentation algorithms that participated in the MRBrainS13 challenge workshop at MICCAI, where the framework was launched, and three commonly used freeware packages: FreeSurfer, FSL, and SPM. The MRBrainS evaluation framework provides an objective and direct comparison of all evaluated algorithms and can aid in selecting the best performing method for the segmentation goal at hand. PMID:26759553

Effects of trauma-related audiovisual stimulation on cerebrospinal fluid norepinephrine and corticotropin-releasing hormone concentrations in post-traumatic stress disorder.

PubMed

Geracioti, Thomas D; Baker, Dewleen G; Kasckow, John W; Strawn, Jeffrey R; Jeffrey Mulchahey, J; Dashevsky, Boris A; Horn, Paul S; Ekhator, Nosakhare N

2008-05-01

Although elevated concentrations of both corticotropin-releasing hormone (CRH) and norepinephrine are present in the cerebrospinal fluid (CSF) of patients with post-traumatic stress disorder (PTSD), the effects of exposure to traumatic stimuli on these stress-related hormones in CSF are unknown. A randomized, within-subject, controlled, cross-over design was used, in which patients with war-related PTSD underwent 6-h continuous lumbar CSF withdrawal on two occasions per patient (6-9 weeks apart). During one session the patients watched a 1-h film containing combat footage (traumatic film) and in the other a 1-h film on how to oil paint (neutral film). At 10-min intervals, we quantified CRH and norepinephrine in CSF, and ACTH and cortisol in plasma, before, during, and after symptom provocation. Subjective anxiety and mood were monitored using 100-mm visual analog scales. Blood pressure and heart rate were obtained every 10min from a left leg monitor. Eight of 10 patients completed two CSF withdrawal procedures each. A major drop in mood and increases in anxiety and blood pressure occurred during the traumatic relative to the neutral videotape. CSF norepinephrine rose during the traumatic film relative to the neutral videotape; this rise directly correlated with magnitude of mood drop. In contrast, CSF CRH concentrations declined during the trauma-related audiovisual stimulus, both absolutely and relative to the neutral stimulus; the magnitude of CRH decline correlated with degree of subjective worsening of anxiety level and mood. Plasma cortisol concentrations were lower and ACTH levels similar during the stress compared with the neutral videotape. CSF concentrations of the stress hormones norepinephrine and CRH differentially change after exposure to 1h of trauma-related audiovisual stimulation in chronic, combat-related PTSD. While the CSF norepinephrine increase was postulated, the decline in CSF CRH levels is surprising and could be due to audiovisual stress-induced increased uptake of CSF CRH into brain tissue, increased CRH utilization, increased CRH degradation, or to an acute stress-related inhibition or suppression of CRH secretion.

Mefloquine improved progressive multifocal leukoencephalopathy in a patient with systemic lupus erythematosus.

PubMed

Beppu, Minako; Kawamoto, Michi; Nukuzuma, Souichi; Kohara, Nobuo

2012-01-01

We describe a case of a 67-year-old man with systemic lupus erythematosus who presented with progressive left hemiplegia. Although the cerebral spinal fluid (CSF) polymerase chain reaction (PCR) for the JC virus was negative, a brain biopsy confirmed the diagnosis of progressive multifocal leukoencephalopathy (PML). The tapering of prednisone and the use of cidofovir could not arrest the disease progression. Administration of mefloquine stopped the extension of the lesion, and resulted in obvious clinical improvement. The CSF nested PCR for the JC virus also became negative. This widely used drug should be tried for the treatment of non-HIV PML.

Learning-based 3T brain MRI segmentation with guidance from 7T MRI labeling.

PubMed

Deng, Minghui; Yu, Renping; Wang, Li; Shi, Feng; Yap, Pew-Thian; Shen, Dinggang

2016-12-01

Segmentation of brain magnetic resonance (MR) images into white matter (WM), gray matter (GM), and cerebrospinal fluid (CSF) is crucial for brain structural measurement and disease diagnosis. Learning-based segmentation methods depend largely on the availability of good training ground truth. However, the commonly used 3T MR images are of insufficient image quality and often exhibit poor intensity contrast between WM, GM, and CSF. Therefore, they are not ideal for providing good ground truth label data for training learning-based methods. Recent advances in ultrahigh field 7T imaging make it possible to acquire images with excellent intensity contrast and signal-to-noise ratio. In this paper, the authors propose an algorithm based on random forest for segmenting 3T MR images by training a series of classifiers based on reliable labels obtained semiautomatically from 7T MR images. The proposed algorithm iteratively refines the probability maps of WM, GM, and CSF via a cascade of random forest classifiers for improved tissue segmentation. The proposed method was validated on two datasets, i.e., 10 subjects collected at their institution and 797 3T MR images from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. Specifically, for the mean Dice ratio of all 10 subjects, the proposed method achieved 94.52% ± 0.9%, 89.49% ± 1.83%, and 79.97% ± 4.32% for WM, GM, and CSF, respectively, which are significantly better than the state-of-the-art methods (p-values < 0.021). For the ADNI dataset, the group difference comparisons indicate that the proposed algorithm outperforms state-of-the-art segmentation methods. The authors have developed and validated a novel fully automated method for 3T brain MR image segmentation. © 2016 American Association of Physicists in Medicine.

Learning-based 3T brain MRI segmentation with guidance from 7T MRI labeling.

PubMed

Deng, Minghui; Yu, Renping; Wang, Li; Shi, Feng; Yap, Pew-Thian; Shen, Dinggang

2016-12-01

Segmentation of brain magnetic resonance (MR) images into white matter (WM), gray matter (GM), and cerebrospinal fluid (CSF) is crucial for brain structural measurement and disease diagnosis. Learning-based segmentation methods depend largely on the availability of good training ground truth. However, the commonly used 3T MR images are of insufficient image quality and often exhibit poor intensity contrast between WM, GM, and CSF. Therefore, they are not ideal for providing good ground truth label data for training learning-based methods. Recent advances in ultrahigh field 7T imaging make it possible to acquire images with excellent intensity contrast and signal-to-noise ratio. In this paper, the authors propose an algorithm based on random forest for segmenting 3T MR images by training a series of classifiers based on reliable labels obtained semiautomatically from 7T MR images. The proposed algorithm iteratively refines the probability maps of WM, GM, and CSF via a cascade of random forest classifiers for improved tissue segmentation. The proposed method was validated on two datasets, i.e., 10 subjects collected at their institution and 797 3T MR images from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. Specifically, for the mean Dice ratio of all 10 subjects, the proposed method achieved 94.52% ± 0.9%, 89.49% ± 1.83%, and 79.97% ± 4.32% for WM, GM, and CSF, respectively, which are significantly better than the state-of-the-art methods (p-values < 0.021). For the ADNI dataset, the group difference comparisons indicate that the proposed algorithm outperforms state-of-the-art segmentation methods. The authors have developed and validated a novel fully automated method for 3T brain MR image segmentation.

Tau protein (MAPT) as a possible biochemical marker of traumatic brain injury in postmortem examination.

PubMed

Olczak, Mieszko; Niderla-Bielińska, Justyna; Kwiatkowska, Magdalena; Samojłowicz, Dorota; Tarka, Sylwia; Wierzba-Bobrowicz, Teresa

2017-11-01

MAPT is a neuronal protein that plays an important role in axonal stabilization, neuronal development, and neuronal polarity. MAPT release into the CSF and blood has been interpreted as indicative of axonal injury as its elevated levels were observed in olympic boxers even after a mild head trauma suggesting minor CNS injuries. In our study we wanted to check the potential relevance of MAPT examination for forensic purposes. The study was carried out using cases of head injury group and cases of sudden death (cardiopulmonary failure, no injuries of the head - control group) provided by forensic pathologists at the Department of Forensic Medicine, Medical University of Warsaw. CSF and blood were collected within 24h after death using suboccipital puncture and femoral vein puncture. Serum and cerebrospinal fluid Tau protein concentrations were compared using an enzyme-linked immunosorbent assay (elisa). Brain specimens (frontal cortex) were collected during forensic autopsies. Sections were stained histologically (hematoxylin-eosin) and immunohistochemically with anti human Tau antibody, anti glial fibrillary acid protein (GFAP), anti human macrosialin (CD68) or anti human endothelial cells (CD34). In our study we documented that elevated levels of serum and CSF MAPT may also be considered a marker for mild traumatic brain injury and traumatic brain injury (mTBI and TBI). An increase in CSF and serum levels of MAPT in the absence of visible macroscopic traumatic CNS changes indicates that even minor head injuries may result in changes at the neuronal level that could remain undiagnosed during regular forensic autopsy and routine histopathological examination. Copyright © 2017 Elsevier B.V. All rights reserved.

A phase II study of icotinib and whole-brain radiotherapy in Chinese patients with brain metastases from non-small cell lung cancer.

PubMed

Fan, Yun; Huang, Zhiyu; Fang, Luo; Miao, Lulu; Gong, Lei; Yu, Haifeng; Yang, Haiyan; Lei, Tao; Mao, Weimin

2015-09-01

Icotinib is a new first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. A phase II study was conducted to evaluate the efficacy and safety of icotinib in combination with whole-brain radiotherapy (WBRT) in Chinese NSCLC patients with brain metastases (BMs); the cerebrospinal fluid (CSF)/plasma concentrations of icotinib were also investigated. Eligible patients had BMs from NSCLC, regardless of the EGFR status. Icotinib was administered at 125 mg orally 3 times/day until tumor progression or unacceptable toxicity, concurrently with WBRT (3.0 Gy per day, 5 days per week, to 30 Gy). CSF and plasma samples were collected simultaneously from 10 patients. Icotinib concentrations in the CSF and plasma were measured by high-performance liquid chromatography coupled with tandem mass spectrometry. Twenty patients were enrolled. The median follow-up time was 20.0 months. The overall response rate was 80.0%. The median progression-free survival time was 7.0 months (95% CI 1.2-13.2 months), and the median survival time (MST) was 14.6 months (95% CI 12.5-16.7 months). Of the 18 patients with known EGFR status, the MST was 22.0 months for those with an EGFR mutation and was 7.5 months for those with wild-type EGFR (P = 0.0001). The CSF concentration and penetration rate of icotinib were 11.6 ± 9.1 ng/mL and 1.4 ± 1.1%, respectively. No patient experienced ≥grade 4 toxicity. Icotinib was well tolerated in combination with WBRT and showed efficacy in patients with BMs from NSCLC. This clinical benefit was related to the presence of activating EGFR mutations.

Glioblastoma-synthesized G-CSF and GM-CSF contribute to growth and immunosuppression: Potential therapeutic benefit from dapsone, fenofibrate, and ribavirin.

PubMed

Kast, Richard E; Hill, Quentin A; Wion, Didier; Mellstedt, Håkan; Focosi, Daniele; Karpel-Massler, Georg; Heiland, Tim; Halatsch, Marc-Eric

2017-05-01

Increased ratio of circulating neutrophils to lymphocytes is a common finding in glioblastoma and other cancers. Data reviewed establish that any damage to brain tissue tends to cause an increase in G-CSF and/or GM-CSF (G(M)-CSF) synthesized by the brain. Glioblastoma cells themselves also synthesize G(M)-CSF. G(M)-CSF synthesized by brain due to damage by a growing tumor and by the tumor itself stimulates bone marrow to shift hematopoiesis toward granulocytic lineages away from lymphocytic lineages. This shift is immunosuppressive and generates the relative lymphopenia characteristic of glioblastoma. Any trauma to brain-be it blunt, sharp, ischemic, infectious, cytotoxic, tumor encroachment, or radiation-increases brain synthesis of G(M)-CSF. G(M)-CSF are growth and motility enhancing factors for glioblastomas. High levels of G(M)-CSF contribute to the characteristic neutrophilia and lymphopenia of glioblastoma. Hematopoietic bone marrow becomes entrained with, directed by, and contributes to glioblastoma pathology. The antibiotic dapsone, the lipid-lowering agent fenofibrate, and the antiviral drug ribavirin are Food and Drug Administration- and European Medicines Agency-approved medicines that have potential to lower synthesis or effects of G(M)-CSF and thus deprive a glioblastoma of some of the growth promoting contributions of bone marrow and G(M)-CSF.

A Mechanics-Based Framework Leading to Improved Diagnosis and Treatment of Hydrocephalus

NASA Astrophysics Data System (ADS)

Cohen, Benjamin; Soren, Vedels; Wagshul, Mark; Egnor, Michael; Voorhees, Abram; Wei, Timothy

2007-11-01

Hydrocephalus is defined as an accumulation of cerebrospinal fluid (CSF) in the cranium, at the expense of brain tissue. The result is a disruption of the normal pressure and/or flow dynamics of the intracranial blood and CSF. We seek to introduce integral control volume analysis to the study of hydrocephalus. The goal is to provide a first principles framework to integrate a broad spectrum of sometimes disparate investigations into a highly complex, multidisciplinary problem. The general technique for the implementation of control volumes to hydrocephalus will be presented. This includes factors faced in choosing control volumes and making the required measurements to evaluate mass and momentum conservation. In addition, the use of our Digital Particle Image Velocimetry (DPIV) processing program has been extended to measure the displacement of the ventricles' walls from Magnetic Resonance (MR) images. This is done to determine the volume change of the intracranial fluid spaces.

Nanowire array chips for molecular typing of rare trafficking leukocytes with application to neurodegenerative pathology

NASA Astrophysics Data System (ADS)

Kwak, Minsuk; Kim, Dong-Joo; Lee, Mi-Ri; Wu, Yu; Han, Lin; Lee, Sang-Kwon; Fan, Rong

2014-05-01

Despite the presence of the blood-brain barrier (BBB) that restricts the entry of immune cells and mediators into the central nervous system (CNS), a small number of peripheral leukocytes can traverse the BBB and infiltrate into the CNS. The cerebrospinal fluid (CSF) is one of the major routes through which trafficking leukocytes migrate into the CNS. Therefore, the number of leukocytes and their phenotypic compositions in the CSF may represent important sources to investigate immune-to-brain interactions or diagnose and monitor neurodegenerative diseases. Due to the paucity of trafficking leucocytes in the CSF, a technology capable of efficient isolation, enumeration, and molecular typing of these cells in the clinical settings has not been achieved. In this study, we report on a biofunctionalized silicon nanowire array chip for highly efficient capture and multiplexed phenotyping of rare trafficking leukocytes in small quantities (50 microliters) of clinical CSF specimens collected from neurodegenerative disease patients. The antibody coated 3D nanostructured materials exhibited vastly improved rare cell capture efficiency due to high-affinity binding and enhanced cell-substrate interactions. Moreover, our platform creates multiple cell capture interfaces, each of which can selectively isolate specific leukocyte phenotypes. A comparison with the traditional immunophenotyping using flow cytometry demonstrated that our novel silicon nanowire-based rare cell analysis platform can perform rapid detection and simultaneous molecular characterization of heterogeneous immune cells. Multiplexed molecular typing of rare leukocytes in CSF samples collected from Alzheimer's disease patients revealed the elevation of white blood cell counts and significant alterations in the distribution of major leukocyte phenotypes. Our technology represents a practical tool for potentially diagnosing and monitoring the pathogenesis of neurodegenerative diseases by allowing an effective hematological analysis of the CSF from patients.Despite the presence of the blood-brain barrier (BBB) that restricts the entry of immune cells and mediators into the central nervous system (CNS), a small number of peripheral leukocytes can traverse the BBB and infiltrate into the CNS. The cerebrospinal fluid (CSF) is one of the major routes through which trafficking leukocytes migrate into the CNS. Therefore, the number of leukocytes and their phenotypic compositions in the CSF may represent important sources to investigate immune-to-brain interactions or diagnose and monitor neurodegenerative diseases. Due to the paucity of trafficking leucocytes in the CSF, a technology capable of efficient isolation, enumeration, and molecular typing of these cells in the clinical settings has not been achieved. In this study, we report on a biofunctionalized silicon nanowire array chip for highly efficient capture and multiplexed phenotyping of rare trafficking leukocytes in small quantities (50 microliters) of clinical CSF specimens collected from neurodegenerative disease patients. The antibody coated 3D nanostructured materials exhibited vastly improved rare cell capture efficiency due to high-affinity binding and enhanced cell-substrate interactions. Moreover, our platform creates multiple cell capture interfaces, each of which can selectively isolate specific leukocyte phenotypes. A comparison with the traditional immunophenotyping using flow cytometry demonstrated that our novel silicon nanowire-based rare cell analysis platform can perform rapid detection and simultaneous molecular characterization of heterogeneous immune cells. Multiplexed molecular typing of rare leukocytes in CSF samples collected from Alzheimer's disease patients revealed the elevation of white blood cell counts and significant alterations in the distribution of major leukocyte phenotypes. Our technology represents a practical tool for potentially diagnosing and monitoring the pathogenesis of neurodegenerative diseases by allowing an effective hematological analysis of the CSF from patients. Electronic supplementary information (ESI) available: Additional data are available in the supplementary tables and supplementary figures. See DOI: 10.1039/c3nr06465d

Focused Ultrasound-Induced Blood–Brain Barrier Opening to Enhance Temozolomide Delivery for Glioblastoma Treatment: A Preclinical Study

PubMed Central

Wei, Kuo-Chen; Chu, Po-Chun; Wang, Hay-Yan Jack; Huang, Chiung-Yin; Chen, Pin-Yuan; Tsai, Hong-Chieh; Lu, Yu-Jen; Lee, Pei-Yun; Tseng, I-Chou; Feng, Li-Ying; Hsu, Peng-Wei; Yen, Tzu-Chen; Liu, Hao-Li

2013-01-01

The purpose of this study is to assess the preclinical therapeutic efficacy of magnetic resonance imaging (MRI)-monitored focused ultrasound (FUS)-induced blood-brain barrier (BBB) disruption to enhance Temozolomide (TMZ) delivery for improving Glioblastoma Multiforme (GBM) treatment. MRI-monitored FUS with microbubbles was used to transcranially disrupt the BBB in brains of Fisher rats implanted with 9L glioma cells. FUS-BBB opening was spectrophotometrically determined by leakage of dyes into the brain, and TMZ was quantitated in cerebrospinal fluid (CSF) and plasma by LC-MS\\MS. The effects of treatment on tumor progression (by MRI), animal survival and brain tissue histology were investigated. Results demonstrated that FUS-BBB opening increased the local accumulation of dyes in brain parenchyma by 3.8-/2.1-fold in normal/tumor tissues. Compared to TMZ alone, combined FUS treatment increased the TMZ CSF/plasma ratio from 22.7% to 38.6%, reduced the 7-day tumor progression ratio from 24.03 to 5.06, and extended the median survival from 20 to 23 days. In conclusion, this study provided preclinical evidence that FUS BBB-opening increased the local concentration of TMZ to improve the control of tumor progression and animal survival, suggesting its clinical potential for improving current brain tumor treatment. PMID:23527068

Thyroxine (T4) Transfer from Blood to Cerebrospinal Fluid in Sheep Isolated Perfused Choroid Plexus: Role of Multidrug Resistance-Associated Proteins and Organic Anion Transporting Polypeptides

PubMed Central

Zibara, Kazem; Zein, Nabil El; Sabra, Mirna; Hneino, Mohammad; Harati, Hayat; Mohamed, Wael; Kobeissy, Firas H.; Kassem, Nouhad

2017-01-01

Thyroxine (T4) enters the brain either directly across the blood–brain barrier (BBB) or indirectly via the choroid plexus (CP), which forms the blood–cerebrospinal fluid barrier (B-CSF-B). In this study, using isolated perfused CP of the sheep by single-circulation paired tracer and steady-state techniques, T4 transport mechanisms from blood into lateral ventricle CP has been characterized as the first step in the transfer across the B-CSF-B. After removal of sheep brain, the CPs were perfused with 125I-T4 and 14C-mannitol. Unlabeled T4 was applied during single tracer technique to assess the mode of maximum uptake (Umax) and the net uptake (Unet) on the blood side of the CP. On the other hand, in order to characterize T4 protein transporters, steady-state extraction of 125I-T4 was measured in presence of different inhibitors such as probenecid, verapamil, BCH, or indomethacin. Increasing the concentration of unlabeled-T4 resulted in a significant reduction in Umax%, which was reflected by a complete inhibition of T4 uptake into CP. In fact, the obtained Unet% decreased as the concentration of unlabeled-T4 increased. The addition of probenecid caused a significant inhibition of T4 transport, in comparison to control, reflecting the presence of a carrier mediated process at the basolateral side of the CP and the involvement of multidrug resistance-associated proteins (MRPs: MRP1 and MRP4) and organic anion transporting polypeptides (Oatp1, Oatp2, and Oatp14). Moreover, verapamil, the P-glycoprotein (P-gp) substrate, resulted in ~34% decrease in the net extraction of T4, indicating that MDR1 contributes to T4 entry into CSF. Finally, inhibition in the net extraction of T4 caused by BCH or indomethacin suggests, respectively, a role for amino acid “L” system and MRP1/Oatp1 in mediating T4 transfer. The presence of a carrier-mediated transport mechanism for cellular uptake on the basolateral membrane of the CP, mainly P-gp and Oatp2, would account for the efficient T4 transport from blood to CSF. The current study highlights a carrier-mediated transport mechanism for T4 movement from blood to brain at the basolateral side of B-CSF-B/CP, as an alternative route to BBB. PMID:28588548

Theoretical and experimental investigation of near-infrared light propagation in a model of the adult head.

PubMed

Okada, E; Firbank, M; Schweiger, M; Arridge, S R; Cope, M; Delpy, D T

1997-01-01

Near-infrared light propagation in various models of the adult head is analyzed by both time-of-flight measurements and mathematical prediction. The models consist of three- or four-layered slabs, the latter incorporating a clear cerebrospinal fluid (CSF) layer. The most sophisticated model also incorporates slots that imitate sulci on the brain surface. For each model, the experimentally measured mean optical path length as a function of source-detector spacing agrees well with predictions from either a Monte Carlo model or a finite-element method based on diffusion theory or a hybrid radiosity-diffusion theory. Light propagation in the adult head is shown to be highly affected by the presence of the clear CSF layer, and both the optical path length and the spatial sensitivity profile of the models with a CSF layer are quite different from those without the CSF layer. However, the geometry of the sulci and the boundary between the gray and the white matter have little effect on the detected light distribution.

Kynurenine 3-monooxygenase polymorphisms: relevance for kynurenic acid synthesis in patients with schizophrenia and healthy controls

PubMed Central

Holtze, Maria; Saetre, Peter; Engberg, Göran; Schwieler, Lilly; Werge, Thomas; Andreassen, Ole A.; Hall, Håkan; Terenius, Lars; Agartz, Ingrid; Jönsson, Erik G.; Schalling, Martin; Erhardt, Sophie

2012-01-01

Background Patients with schizophrenia show increased brain and cerebrospinal fluid (CSF) concentrations of the endogenous N-methyl-d-aspartate receptor antagonist kynurenic acid (KYNA). This compound is an end-metabolite of the kynurenine pathway, and its formation indirectly depends on the activity of kynurenine 3-monooxygenase (KMO), the enzyme converting kynurenine to 3-hydroxykynurenine. Methods We analyzed the association between KMO gene polymorphisms and CSF concentrations of KYNA in patients with schizophrenia and healthy controls. Fifteen single nucleotide polymorphisms (SNPs) were selected covering KMO and were analyzed in UNPHASED. Results We included 17 patients with schizophrenia and 33 controls in our study. We found an association between a KMO SNP (rs1053230), encoding an amino acid change of potential importance for substrate interaction, and CSF concentrations of KYNA. Limitations Given the limited sample size, the results are tentative until replication. Conclusion Our results suggest that the nonsynonymous KMO SNP rs1053230 influences CSF concentrations of KYNA. PMID:21693093

CSF/serum albumin ratio in dementias: a cross-sectional study on 1861 patients.

PubMed

Skillbäck, Tobias; Delsing, Louise; Synnergren, Jane; Mattsson, Niklas; Janelidze, Shorena; Nägga, Katarina; Kilander, Lena; Hicks, Ryan; Wimo, Anders; Winblad, Bengt; Hansson, Oskar; Blennow, Kaj; Eriksdotter, Maria; Zetterberg, Henrik

2017-11-01

A connection between dementias and blood-brain barrier (BBB) dysfunction has been suggested, but previous studies have yielded conflicting results. We examined cerebrospinal fluid (CSF)/serum albumin ratio in a large cohort of patients diagnosed with Alzheimer's disease (AD, early onset [EAD, n = 130], late onset AD [LAD, n = 666]), vascular dementia (VaD, n = 255), mixed AD and VaD (MIX, n = 362), Lewy body dementia (DLB, n = 50), frontotemporal dementia (FTD, n = 56), Parkinson's disease dementia (PDD, n = 23), other dementias (other, n = 48), and dementia not otherwise specified (NOS, n = 271). We compared CSF/serum albumin ratio to 2 healthy control groups (n = 292, n = 20), between dementia diagnoses, and tested biomarker associations. Patients in DLB, LAD, VaD, MIX, other, and NOS groups had higher CSF/serum albumin ratio than controls. CSF/serum albumin ratio correlated with CSF neurofilament light in LAD, MIX, VaD, and other groups but not with AD biomarkers. Our data show that BBB leakage is common in dementias. The lack of association between CSF/serum albumin ratio and AD biomarkers suggests that BBB dysfunction is not inherent to AD but might represent concomitant cerebrovascular pathology. Copyright © 2017 Elsevier Inc. All rights reserved.

Cerebrospinal Fluid Biomarkers and Reserve Variables as Predictors of Future “Non-Cognitive” Outcomes of Alzheimer’s Disease

PubMed Central

Ingber, Adam P.; Hassenstab, Jason; Fagan, Anne M.; Benzinger, Tammie L.S.; Grant, Elizabeth A.; Holtzman, David M.; Morris, John C.; Roe, Catherine M.

2016-01-01

Background The influence of reserve variables and Alzheimer’s disease (AD) biomarkers on cognitive test performance has been fairly well-characterized. However, less is known about the influence of these factors on “non-cognitive” outcomes, including functional abilities and mood. Objective We examined whether cognitive and brain reserve variables mediate how AD biomarker levels in cognitively normal persons predict future changes in function, mood, and neuropsychiatric behavior. Methods Non-cognitive outcomes were examined in 328 individuals 50 years and older enrolled in ongoing studies of aging and dementia at the Knight Alzheimer Disease Research Center (ADRC). All participants were cognitively normal at baseline (Clinical Dementia Rating [CDR] 0), completed cerebrospinal fluid (CSF) and structural neuroimaging studies within one year of baseline, and were followed for an average of 4.6 annual visits. Linear mixed effects models explored how cognitive reserve and brain reserve variables mediate the relationships between AD biomarker levels and changes in function, mood, and neuropsychiatric behavior in cognitively normal participants. Results Education levels did not have a significant effect on predicting non-cognitive decline. However, participants with smaller brain volumes exhibited the worst outcomes on measures of mood, functional abilities, and behavioral disturbance. This effect was most pronounced in individuals who also had abnormal CSF biomarkers. Conclusions The findings suggest that brain reserve plays a stronger, or earlier, role than cognitive reserve in protecting against non-cognitive impairment in AD. PMID:27104893

Evaluating Cancer of the Central Nervous System Through Next-Generation Sequencing of Cerebrospinal Fluid

PubMed Central

Pentsova, Elena I.; Shah, Ronak H.; Tang, Jiabin; Boire, Adrienne; You, Daoqi; Briggs, Samuel; Omuro, Antonio; Lin, Xuling; Fleisher, Martin; Grommes, Christian; Panageas, Katherine S.; Meng, Fanli; Selcuklu, S. Duygu; Ogilvie, Shahiba; Distefano, Natalie; Shagabayeva, Larisa; Rosenblum, Marc; DeAngelis, Lisa M.; Viale, Agnes; Berger, Michael F.

2016-01-01

Purpose Cancer spread to the central nervous system (CNS) often is diagnosed late and is unresponsive to therapy. Mechanisms of tumor dissemination and evolution within the CNS are largely unknown because of limited access to tumor tissue. Materials and Methods We sequenced 341 cancer-associated genes in cell-free DNA from cerebrospinal fluid (CSF) obtained through routine lumbar puncture in 53 patients with suspected or known CNS involvement by cancer. Results We detected high-confidence somatic alterations in 63% (20 of 32) of patients with CNS metastases of solid tumors, 50% (six of 12) of patients with primary brain tumors, and 0% (zero of nine) of patients without CNS involvement by cancer. Several patients with tumor progression in the CNS during therapy with inhibitors of oncogenic kinases harbored mutations in the kinase target or kinase bypass pathways. In patients with glioma, the most common malignant primary brain tumor in adults, examination of cell-free DNA uncovered patterns of tumor evolution, including temozolomide-associated mutations. Conclusion The study shows that CSF harbors clinically relevant genomic alterations in patients with CNS cancers and should be considered for liquid biopsies to monitor tumor evolution in the CNS. PMID:27161972

Diagnosis and Treatment of Central Nervous System Infections in the Emergency Department

PubMed Central

Dorsett, Maia

2016-01-01

Central nervous system (CNS) infections, including meningitis, encephalitis, and brain abscess, are rare but time-sensitive emergency department (ED) diagnoses. Patients with CNS infection can present to the ED with a host of non-specific signs and symptoms, including headache, fever, altered mental status, and behavioral changes. In meningitis, the classic triad of fever, neck stiffness, and altered mental status occurs in only a minority of patients. Classic physical examination maneuvers, such Kernig’s and Brudzinski’s signs, are relatively insensitive although specific for predicting cerebrospinal fluid (CSF) pleocytosis. Patients with parenchymal involvement, as occurs with encephalitis and brain abscess, may also have focal neurologic deficits or seizures. Neuroimaging and CSF fluid analysis can appear benign early in the course of meningitis and encephalitis, and clinicians should not be falsely reassured. Delaying antibiotic and antiviral therapies negatively impacts outcomes, particularly with bacterial meningitis and herpes simplex virus encephalitis. As with other rare, life-threatening diagnoses encountered in emergency medicine, the diagnosis and treatment of CNS infections requires vigilance and a high index of suspicion based on the history and physical examination which must be confirmed with appropriate imaging and laboratory evaluation. PMID:27741995

Brain metabolic correlates of CSF Tau protein in a large cohort of Alzheimer's disease patients: A CSF and FDG PET study.

PubMed

Chiaravalloti, Agostino; Barbagallo, Gaetano; Ricci, Maria; Martorana, Alessandro; Ursini, Francesco; Sannino, Pasqualina; Karalis, Georgios; Schillaci, Orazio

2018-01-01

Physiopathological mechanisms of Alzheimer's disease (AD) are still matter of debate. Especially the role of amyloid β and tau pathology in the development of the disease are still matter of debate. Changes in tau and amyloid β peptide concentration in cerebrospinal fluid (CSF) and hypometabolic patterns at fluorine-18 fluorodeoxyglucose ( 18 F-FDG) PET scanning are considered as biomarkers of AD. The present study was aimed to evaluate the relationships between the concentrations of CSF total Tau (t-Tau), phosphorilated Tau (p-Tau) and Aβ 1-42 amyloid peptide with 18 F-FDG brain distribution in a group of patients with AD. We examined 131 newly diagnosed AD patients according to the NINCDS-ADRDA criteria and 20 healthy controls. The mean (±SD) age of the patients was 70 (±7) years; 57 were male and 74 were female. All patients and controls underwent a complete clinical investigation, including medical history, neurological examination, mini-mental state examination (MMSE), a complete blood screening (including routine exams, thyroid hormones and a complete neuropsychological evaluation). Structural MRI was performed not earlier than 1 month before the 18 F-FDG PET/CT. The following patients were excluded: those with isolated deficits and/or unmodified MMSE (=25/30) on revisit (period of follow-up: 6, 12 and 18 months); patients who had had a clinically manifest acute stroke in the last 6 months with a Hachinsky score greater than 4; and patients with radiological evidence of subcortical lesions. All AD patients were taken off cholinesterase inhibitor treatment throughout the study. We performed lumbar puncture and CSF sampling for diagnostic purposes 2 weeks (±2 days) before the PET/CT scan. The relationship between brain F-FDG uptake and CSF biomarkers was analysed using statistical parametric mapping (SPM8; Wellcome Department of Cognitive Neurology, London, UK) implemented in Matlab R2012b using the MMSE score, sex and age, and other CSF biomarkers as covariates. t-Tau, p-Tau and Aβ(1-42) in CSF resulted 774 ± 345 pg/ml, 98 ± 64 pg/ml and 348.8 ± 111 pg/ml respectively. SPM analysis showed a significant negative correlation between CSF t-Tau and 18 F FDG uptake in right temporal, parietal and frontal lobe (Brodmann areas, BA, 20, 40 and 8; P fdr and few corr < 0.001, ke 19534). We did not find any significant relationships with other CSF biomarkers. t-Tau deposition in brain is related to temporal, parietal and frontal hypometabolism in AD. Copyright © 2017 Elsevier B.V. All rights reserved.

African trypanosomes and brain infection - the unsolved question.

PubMed

Mogk, Stefan; Boßelmann, Christian M; Mudogo, Celestin N; Stein, Jasmin; Wolburg, Hartwig; Duszenko, Michael

2017-08-01

African trypanosomes induce sleeping sickness. The parasites are transmitted during the blood meal of a tsetse fly and appear primarily in blood and lymph vessels, before they enter the central nervous system. During the latter stage, trypanosomes induce a deregulation of sleep-wake cycles and some additional neurological disorders. Historically, it was assumed that trypanosomes cross the blood-brain barrier and settle somewhere between the brain cells. The brain, however, is a strictly controlled and immune-privileged area that is completely surrounded by a dense barrier that covers the blood vessels: this is the blood-brain barrier. It is known that some immune cells are able to cross this barrier, but this requires a sophisticated mechanism and highly specific cell-cell interactions that have not been observed for trypanosomes within the mammalian host. Interestingly, trypanosomes injected directly into the brain parenchyma did not induce an infection. Likewise, after an intraperitoneal infection of rats, Trypanosoma brucei brucei was not observed within the brain, but appeared readily within the cerebrospinal fluid (CSF) and the meninges. Therefore, the parasite did not cross the blood-brain barrier, but the blood-CSF barrier, which is formed by the choroid plexus, i.e. the part of the ventricles where CSF is produced from blood. While there is no question that trypanosomes are able to invade the brain to induce a deadly encephalopathy, controversy exists about the pathway involved. This review lists experimental results that support crossing of the blood-brain barrier and of the blood-CSF barrier and discuss the implications that either pathway would have on infection progress and on the survival strategy of the parasite. For reasons discussed below, we prefer the latter pathway and suggest the existence of an additional distinct meningeal stage, from which trypanosomes could invade the brain via the Virchow-Robin space thereby bypassing the blood-brain barrier. We also consider healthy carriers, i.e. people living symptomless with the disease for up to several decades, and discuss implications the proposed meningeal stage would have for new anti-trypanosomal drug development. Considering the re-infection of blood, a process called relapse, we discuss the likely involvement of the newly described glymphatic connection between the meningeal space and the lymphatic system, that seems also be important for other infectious diseases. © 2016 Cambridge Philosophical Society.

Absence of Colony Stimulation Factor-1 Receptor Results in Loss of Microglia, Disrupted Brain Development and Olfactory Deficits

PubMed Central

Etgen, Anne M.; Dobrenis, Kostantin; Pollard, Jeffrey W.

2011-01-01

The brain contains numerous mononuclear phagocytes called microglia. These cells express the transmembrane tyrosine kinase receptor for the macrophage growth factor colony stimulating factor-1 (CSF-1R). Using a CSF-1R-GFP reporter mouse strain combined with lineage defining antibody staining we show in the postnatal mouse brain that CSF-1R is expressed only in microglia and not neurons, astrocytes or glial cells. To study CSF-1R function we used mice homozygous for a null mutation in the Csflr gene. In these mice microglia are >99% depleted at embryonic day 16 and day 1 post-partum brain. At three weeks of age this microglial depletion continues in most regions of the brain although some contain clusters of rounded microglia. Despite the loss of microglia, embryonic brain development appears normal but during the post-natal period the brain architecture becomes perturbed with enlarged ventricles and regionally compressed parenchyma, phenotypes most prominent in the olfactory bulb and cortex. In the cortex there is increased neuronal density, elevated numbers of astrocytes but reduced numbers of oligodendrocytes. Csf1r nulls rarely survive to adulthood and therefore to study the role of CSF-1R in olfaction we used the viable null mutants in the Csf1 (Csf1op) gene that encodes one of the two known CSF-1R ligands. Food-finding experiments indicate that olfactory capacity is significantly impaired in the absence of CSF-1. CSF-1R is therefore required for the development of microglia, for a fully functional olfactory system and the maintenance of normal brain structure. PMID:22046273

Blood-Brain Barrier Function and Biomarkers of Central Nervous System Injury in Rickettsial Versus Other Neurological Infections in Laos.

PubMed

Dittrich, Sabine; Sunyakumthorn, Piyanate; Rattanavong, Sayaphet; Phetsouvanh, Rattanaphone; Panyanivong, Phonepasith; Sengduangphachanh, Amphonsavanh; Phouminh, Phonelavanh; Anantatat, Tippawan; Chanthongthip, Anisone; Lee, Sue J; Dubot-Pérès, Audrey; Day, Nicholas P J; Paris, Daniel H; Newton, Paul N; Turner, Gareth D H

2015-08-01

Blood-brain barrier (BBB) function and cerebrospinal fluid (CSF) biomarkers were measured in patients admitted to hospital with severe neurological infections in the Lao People's Democratic Republic (N = 66), including bacterial meningitis (BM; N = 9) or tuberculosis meningitis (TBM; N = 11), Japanese encephalitis virus (JEV; N = 25), and rickettsial infections (N = 21) including murine and scrub typhus patients. The albumin index (AI) and glial fibrillary acidic protein (GFAP) levels were significantly higher in BM and TBM than other diseases but were also raised in individual rickettsial patients. Total tau protein was significantly raised in the CSF of JEV patients. No differences were found between clinical or neurological symptoms, AI, or biomarker levels that allowed distinction between severe neurological involvement by Orientia tsutsugamushi compared with Rickettsia species. © The American Society of Tropical Medicine and Hygiene.

Subacute sclerosing panencephalitis and chronic viral encephalitis.

PubMed

Anlar, Banu

2013-01-01

Subacute sclerosing panencephalitis (SSPE) is a chronic infection of the central nervous system associated with the presence of mutant measles virus in the brain. It presents as a progressive, usually fatal disease. The diagnosis is based on clinical criteria and an elevated titer of measles antibodies in the cerebrospinal fluid (CSF). Electroencephalography and imaging studies provide supportive laboratory data. A brain biopsy is indicated only when CSF serology is negative or equivocal in a suspected case to assess the presence of inclusion bodies, measles virus antigens, or viral RNA. Among many drugs and methods tried in the treatment, the highest rate of stabilization or improvement was obtained with intraventricular human lymphoblastoid interferon-α and oral inosiplex. Further research for more available and efficient therapeutic regimens is warranted. Measles and SSPE are preventable by maintenance of high rates of immunization in the population. Copyright © 2013 Elsevier B.V. All rights reserved.

A comprehensive non-clinical evaluation of the CNS penetration potential of antimuscarinic agents for the treatment of overactive bladder

PubMed Central

Callegari, Ernesto; Malhotra, Bimal; Bungay, Peter J; Webster, Rob; Fenner, Katherine S; Kempshall, Sarah; LaPerle, Jennifer L; Michel, Martin C; Kay, Gary G

2011-01-01

AIMS To assess and compare the mechanisms of central nervous system (CNS) penetration of antimuscarinic overactive bladder (OAB) agents. METHODS Physical properties were computed or compiled from the literature. Rats were administered 5-hydroxymethyl tolterodine (HMT), darifenacin, oxybutynin, solifenacin, tolterodine or trospium subcutaneously. At 1 h postdose, plasma, brain and cerebrospinal fluid (CSF) concentrations were determined using LC-MS/MS assays. Brain and plasma protein binding were determined in vitro. Permeability in the presence and absence of the efflux transporter P-glycoprotein (P-gp) was assessed in RRCK and MDCK-MDR1 transwell assays. RESULTS Oxybutynin displayed extensive CNS penetration, with brain : plasma ratios (B : P), unbound brain : unbound plasma ratios (Kp,free) and CSF : free plasma ratios each >1. Tolterodine (B : P = 2.95, Kp,free = 0.23 and CSF : free plasma = 0.16) and solifenacin (B : P = 3.04, Kp,free = 0.28 and CSF : free plasma = 1.41) showed significant CNS penetration but with some restriction from CNS as indicated by Kp,free values significantly <1. 5-HMT, darifenacin and trospium displayed much lower B : P (0.03–0.16), Kp,free (0.01–0.04) and CSF : free plasma (0.004–0.06), consistent with poor CNS penetration. Permeability in RRCK cells was low for trospium (0.63 × 10−6 cm s−1), moderate for 5-HMT (11.7 × 10−6 cm s−1) and high for darifenacin, solifenacin, tolterodine and oxybutynin (21.5–38.2 × 10−6 cm s−1). In MDCK-MDR1 cells 5-HMT, darifenacin and trospium, were P-gp substrates, whereas oxybutynin, solifenacin and tolterodine were not P-gp substrates. CONCLUSIONS Brain penetration was low for antimuscarinics that are P-gp substrates (5-HMT, darifenacin and trospium), and significant for those that are not P-gp substrates (oxybutynin, solifenacin and tolterodine). CNS adverse events reported in randomized controlled clinical trials show general alignment with the preclinical data described in this study. PMID:21392072

Numerical Study of the Cerebro-Spinal Fluid (CSF) Dynamics Under Quasistatic Condition During a Cardiac Cycle

DTIC Science & Technology

2001-10-25

THE CEREBRO -SPINAL FLUID (CSF) DYNAMICS UNDER QUASI- STATIC CONDITION DURING A CARDIAC CYCLE Loïc FIN, Reinhard GREBE, Olivier BALÉDENT, Ilana...from... to) - Title and Subtitle Numerical Study of the Cerebro -Spinal Fluid (CSF) Dynamics Under Quasistatic Condition During a Cardiac Cycle

Diagnostic function of the neuroinflammatory biomarker YKL-40 in Alzheimer's disease and other neurodegenerative diseases.

PubMed

Baldacci, Filippo; Lista, Simone; Cavedo, Enrica; Bonuccelli, Ubaldo; Hampel, Harald

2017-04-01

Neuroinflammation is a crucial mechanism in the pathophysiology of neurodegenerative diseases pathophysiology. Cerebrospinal fluid (CSF) YKL-40 - an indicator of microglial activation - has recently been identified by proteomic studies as a candidate biomarker for Alzheimer's disease (AD). Areas covered: We review the impact of CSF YKL-40 as a pathophysiological biomarker for AD and other neurodegenerative diseases. CSF YKL-40 concentrations have been shown to predict progression from prodromal mild cognitive impairment to AD dementia. Moreover, a positive association between CSF YKL-40 and other biomarkers of neurodegeneration - particularly total tau protein - has been reported during the asymptomatic preclinical stage of AD and other neurodegenerative diseases. Albeit preliminary, current data do not support an association between APOE-ε4 status and CSF YKL-40 concentrations. When interpreting the diagnostic/prognostic significance of CSF YKL-40 concentrations in neurodegenerative diseases, potential confounders - including age, metabolic and cardiovascular risk factors, diagnostic criteria for selecting cases/controls - need to be considered. Expert opinion/commentary: CSF YKL-40 represents a pathophysiological biomarker reflecting immune/inflammatory mechanisms in neurodegenerative diseases, associated with tau protein pathology. Besides being associated with tau pathology, CSF YKL-40 adds to the growing array of biomarkers reflecting distinct molecular brain mechanisms potentially useful for stratifying individuals for biomarker-guided, targeted anti-inflammatory therapies emerging from precision medicine.

Cerebrospinal Fluid Markers of Macrophage and Lymphocyte Activation after Traumatic Brain Injury in Children

PubMed Central

Newell, Elizabeth; Shellington, David K.; Simon, Dennis W.; Bell, Michael J.; Kochanek, Patrick M.; Feldman, Keri; Bayır, Hülya; Aneja, Rajesh K.; Carcillo, Joseph A.; Clark, Robert S. B.

2015-01-01

Objective The magnitude and role of the cellular immune response following pediatric traumatic brain injury (TBI) remains unknown. We tested the hypothesis that macrophage/microglia and T-cell activation occurs following pediatric TBI by measuring cerebrospinal fluid (CSF) levels of sCD163 and ferritin, and sIL-2Rα, respectively, and determined whether these biomarkers were associated with relevant clinical variables and outcome. Design Retrospective analysis of samples from an established, single-center CSF bank. Setting Pediatric Intensive Care Unit (PICU) in a tertiary Children’s Hospital Patients Sixty-six pediatric patients after severe TBI (Glasgow coma scale score [GCS]<8) age 1 mo-16 y and 17 control patients age 1 mo-14 y. Measurements and Main Results CSF levels of sCD163, ferritin, and sIL-2Rα were determined by ELISA at 2 time points (t1=17±10, t2=72±15 h) for each TBI patient. CSF sCD163, ferritin, and sIL2Rα levels after TBI were compared with controls and analyzed for associations with age, patient sex, initial GCS, diagnosis of abusive head trauma (AHT), the presence of hemorrhage on computerized tomography scan, and Glasgow outcome scale score (GOS). CSF sCD163 was increased in TBI patients at t2 vs. t1 and controls (95.4[21.8–134.0] vs. 31.0[5.7–77.7] and 27.8[19.1–43.1] ng/ml, respectively; median[IQ]; P<0.05). CSF ferritin was increased in TBI patients at t2 and t1 vs. controls (8.3[7.5–19.8] and 8.9[7.5–26.7] vs. [7.5[0.0–0.0] ng/ml, respectively; P<0.05). CSF sIL-2Rα in TBI patients at t2 and t1 were not different vs. controls. Multivariate regression revealed associations between high ferritin and age ≤ 4 y, lower GCS, AHT, and unfavorable GOS. Conclusions Children with TBI demonstrate evidence for macrophage activation after TBI, and in terms of CSF ferritin, this appears more prominent with young age, initial injury severity, AHT, and unfavorable outcome. Further study is needed to determine whether biomarkers of macrophage activation may be used to discriminate between aberrant and adaptive immune responses, and whether inflammation represents a therapeutic target after TBI. PMID:25850867

The iodide space in rabbit brain

PubMed Central

Ahmed, Nawal; Van Harreveld, A.

1969-01-01

1. The iodide space in rabbit brain varies greatly depending on the conditions under which it is determined. 2. When 131I- only is used the iodide space 4 hr after administration of the marker is of the order of 2%. The iodide content of the cerebrospinal fluid (c.s.f.) is about 1% of that of the serum. 3. Depression of the active iodide transport by perchlorate increases the space to 8·2% and the iodide content of the c.s.f. to 26% of that of the serum. 4. The active iodide transport can also be depressed by saturation with unlabelled iodide. Up to a serum iodide concentration of 5 mM the space determined after 5 hr remained constant at 2·7%. The iodide space grew when the serum iodide content was enhanced from 5 to 20 mM, to become constant at a value of 10·6% on further increase of the serum iodide (up to 50 mM). The iodide content of the c.s.f. increased in a similar manner as the space with the iodide concentration of the serum to about 1/3 of the serum concentration. The iodide space of the muscle was independent of the plasma iodide content. 5. From 4 to 8 hr after administration of 131I- alone or with unlabelled iodide (to a serum concentration of 15 mM) the iodide space remained relatively constant. 6. When 131I- was administered in the fluid with which the ventricles were perfused an iodide space of about 7% was attained after about 5 hr. 7. In experiments in which 131I- was administered intravenously and the sink action of the c.s.f. was eliminated by perfusion of the ventricles with a perfusate containing as much 131I- as the plasma, the iodide space was 10·2%. When in addition active iodide transport was depressed by perchlorate the space increased to 16·8%. 8. Intravenous administration of labelled and unlabelled iodide (to a serum concentration of 20-40 mM) and ventricle perfusion with the same concentration of 131I- and unlabelled iodide as in the plasma yielded an iodide space of 20·8%. In similar experiments the iodide concentration of the perfusate was so adjusted that after 5 hr perfusion its iodide content hardly changed during the passage through the ventricles. Under these conditions the iodide concentration of the extracellular and perfusion fluids can be considered to be near equal. The iodide space computed on the basis of the iodide content of the outflowing fluid was 22·5%. 9. The large iodide space could be equated with the extracellular space if the iodide remained extracellular. This seems to be the case in the muscle where the iodide space is similar to the inulin space. 10. The large effects on the iodide space of perchlorate and saturation with unlabelled iodide in experiments in which the marker was administered intravenously and in the perfusate (7 and 8) suggests the presence of an active iodide transport from the brain extracellular fluid into the blood over the blood—brain barrier. PMID:4310942

Overton's Rule Helps To Estimate the Penetration of Anti-Infectives into Patients' Cerebrospinal Fluid

PubMed Central

Djukic, Marija; Munz, Martin; Sörgel, Fritz; Holzgrabe, Ulrike; Eiffert, Helmut

2012-01-01

In 1900, Ernst Overton found that the entry of anilin dyes through the cell membranes of living cells depended on the lipophilicity of the dyes. The brain is surrounded by barriers consisting of lipid layers that possess several inward and outward active transport systems. In the absence of meningeal inflammation, the cerebrospinal fluid (CSF) penetration of anti-infectives in humans estimated by the ratio of the area under the concentration-time curve (AUC) in CSF (AUCCSF) to that in serum (AUCCSF/AUCS) correlated positively with the lipid-water partition coefficient at pH 7.0 (log D) (Spearman's rank correlation coefficient rS = 0.40; P = 0.01) and negatively with the molecular mass (MM) (rS = −0.33; P = 0.04). The ratio of AUCCSF to the AUC of the fraction in serum that was not bound (AUCCSF/AUCS,free) strongly correlated with log D (rS = 0.67; P < 0.0001). In the presence of meningeal inflammation, AUCCSF/AUCS also correlated positively with log D (rS = 0.46; P = 0.002) and negatively with the MM (rS = −0.37; P = 0.01). The correlation of AUCCSF/AUCS,free with log D (rS = 0.66; P < 0.0001) was as strong as in the absence of meningeal inflammation. Despite these clear correlations, Overton's rule was able to explain only part of the differences in CSF penetration of the individual compounds. The site of CSF withdrawal (lumbar versus ventricular CSF), age of the patients, underlying diseases, active transport, and alterations in the pharmacokinetics by comedications also appeared to strongly influence the CSF penetration of the drugs studied. PMID:22106225

Cerebrospinal fluid Plasmodium falciparum histidine-rich protein-2 in pediatric cerebral malaria.

PubMed

Thakur, Kiran T; Vareta, Jimmy; Carson, Kathryn A; Kampondeni, Samuel; Potchen, Michael J; Birbeck, Gretchen L; MacCormick, Ian; Taylor, Terrie; Sullivan, David J; Seydel, Karl B

2018-03-23

Cerebral malaria (CM) causes a rapidly developing coma, and remains a major contributor to morbidity and mortality in malaria-endemic regions. This study sought to determine the relationship between cerebrospinal fluid (CSF) Plasmodium falciparum histidine rich protein-2 (PfHRP-2) and clinical, laboratory and radiographic features in a cohort of children with retinopathy-positive CM. Patients included in the study were admitted (2009-2013) to the Pediatric Research Ward (Queen Elizabeth Central Hospital, Blantyre, Malawi) meeting World Health Organization criteria for CM with findings of malarial retinopathy. Enzyme-linked immunosorbent assay was used to determine plasma and CSF PfHRP-2 levels. Wilcoxon rank-sum tests and multivariable logistic regression analysis assessed the association of clinical and radiographic characteristics with the primary outcome of death during hospitalization. In this cohort of 94 patients, median age was 44 (interquartile range 29-62) months, 53 (56.4%) patients were male, 6 (7%) were HIV-infected, and 10 (11%) died during hospitalization. Elevated concentrations of plasma lactate (p = 0.005) and CSF PfHRP-2 (p = 0.04) were significantly associated with death. On multivariable analysis, higher PfHRP-2 in the CSF was associated with death (odds ratio 9.00, 95% confidence interval 1.44-56.42) while plasma PfHRP-2 was not (odds ratio 2.05, 95% confidence interval 0.45-9.35). Elevation of CSF, but not plasma PfHRP-2, is associated with death in this paediatric CM cohort. PfHRP-2 egress into the CSF may represent alteration of blood brain barrier permeability related to the sequestration of parasitized erythrocytes in the cerebral microvasculature.

Regulated Extracellular Choline Acetyltransferase Activity— The Plausible Missing Link of the Distant Action of Acetylcholine in the Cholinergic Anti-Inflammatory Pathway

PubMed Central

Aeinehband, Shahin; Behbahani, Homira; Grandien, Alf; Nilsson, Bo; Ekdahl, Kristina N.; Lindblom, Rickard P. F.; Piehl, Fredrik; Darreh-Shori, Taher

2013-01-01

Acetylcholine (ACh), the classical neurotransmitter, also affects a variety of nonexcitable cells, such as endothelia, microglia, astrocytes and lymphocytes in both the nervous system and secondary lymphoid organs. Most of these cells are very distant from cholinergic synapses. The action of ACh on these distant cells is unlikely to occur through diffusion, given that ACh is very short-lived in the presence of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), two extremely efficient ACh-degrading enzymes abundantly present in extracellular fluids. In this study, we show compelling evidence for presence of a high concentration and activity of the ACh-synthesizing enzyme, choline-acetyltransferase (ChAT) in human cerebrospinal fluid (CSF) and plasma. We show that ChAT levels are physiologically balanced to the levels of its counteracting enzymes, AChE and BuChE in the human plasma and CSF. Equilibrium analyses show that soluble ChAT maintains a steady-state ACh level in the presence of physiological levels of fully active ACh-degrading enzymes. We show that ChAT is secreted by cultured human-brain astrocytes, and that activated spleen lymphocytes release ChAT itself rather than ACh. We further report differential CSF levels of ChAT in relation to Alzheimer’s disease risk genotypes, as well as in patients with multiple sclerosis, a chronic neuroinflammatory disease, compared to controls. Interestingly, soluble CSF ChAT levels show strong correlation with soluble complement factor levels, supporting a role in inflammatory regulation. This study provides a plausible explanation for the long-distance action of ACh through continuous renewal of ACh in extracellular fluids by the soluble ChAT and thereby maintenance of steady-state equilibrium between hydrolysis and synthesis of this ubiquitous cholinergic signal substance in the brain and peripheral compartments. These findings may have important implications for the role of cholinergic signaling in states of inflammation in general and in neurodegenerative disease, such as Alzheimer’s disease and multiple sclerosis in particular. PMID:23840379

Serratia marcescens meningitis: epidemiology, prognostic factors and treatment outcomes.

PubMed

Wu, Yen-Mu; Hsu, Po-Chang; Yang, Chien-Chang; Chang, Hong-Jyun; Ye, Jung-Jr; Huang, Ching-Tai; Lee, Ming-Hsun

2013-08-01

Serratia marcescens is a rare pathogen of central nervous system infections. This study was to investigate the epidemiology, prognostic factors, and treatment outcomes of S. marcescens meningitis. This retrospective analysis included 33 patients with culture-proven S. marcescens meningitis hospitalized between January 2000 and June 2011. Of the 33 patients enrolled, only one did not receive neurosurgery before the onset of S. marcescens meningitis. Patients with S. marcescens meningitis had higher ratios of brain solid tumors (54.5%) and neurosurgery (97.0%) with a mortality rate of 15.2%. The mean interval between the first neurosurgical procedure and the diagnosis of meningitis was 17.1 days (range, 4-51 days). Only one third-generation cephalosporin-resistant S. marcescens isolate was recovered from the patients' cerebrospinal fluid (CSF) specimens. Compared with the favorable outcome group (n = 20), the unfavorable outcome group (n = 13) had a higher percentage of brain solid tumors, more intensive care unit stays, and higher Sequential Organ Failure Assessment score, CSF lactate and serum C-reactive protein concentrations at diagnosis of meningitis. Under the multiple regression analysis, CSF lactate concentration ≥2-fold the upper limit of normal (ULN) was independently associated with unfavorable outcomes (odds ratio, 7.20; 95% confidence interval, 1.08-47.96; p = 0.041). S. marcescens meningitis is highly associated with neurosurgical procedures for brain solid tumors. CSF lactate concentration ≥2x ULN may predict an unfavorable outcome. Its mortality is not high and empiric treatment with parenteral third-generation cephalosporins may have a satisfactory clinical response. Copyright © 2012. Published by Elsevier B.V.

Clinical and cognitive implications of cerebrospinal fluid oligoclonal bands in multiple sclerosis patients.

PubMed

Anagnostouli, Maria; Christidi, Foteini; Zalonis, Ioannis; Nikolaou, Chryssoula; Lyrakos, Dimitrios; Triantafyllou, Nikolaos; Evdokimidis, Ioannis; Kilidireas, Constantinos

2015-11-01

The presence of cerebrospinal fluid oligoclonal bands (CSF-OCB) in Caucasian patients with multiple sclerosis (MS) is supportive of diagnosis, though the relation with patients' clinical and specifically cognitive features has never been established or thoroughly examined. Thus, we investigated the clinical and for the first time the cognitive profile of MS patients in relation to CSF-OCB. We studied 108 patients with and without OCB and recorded demographic characteristics and detailed clinical data. A comprehensive neuropsychological battery covering different cognitive domains (attention/processing speed, memory, perception/constructions, reasoning, executive functions) was administered to MS patients and 142 demographically related healthy controls (HC). We did not find any significant differences between patients with and without OCB on demographic and clinical parameters (p > 0.05), including subtype and brain neuroimaging findings. Results revealed significantly higher cognitive scores in HC compared to both OCB subgroups, with more widespread cognitive changes in patients with OCB. Analysis between OCB subgroups showed significantly worse performance in patients with OCB on visual memory (Rey's complex figure test-recall; p = 0.006). Concluding, the presence of CSF-OCB in our MS patients tends to be related to more widespread cognitive changes, specifically worse visual memory. Future longitudinal studies in different populations are warranted to better clarify the clinical and cognitive characteristics related to CSF-OCB which could serve as early biomarker in disease monitoring.

Effective scattering coefficient of the cerebral spinal fluid in adult head models for diffuse optical imaging

NASA Astrophysics Data System (ADS)

Custo, Anna; Wells, William M., III; Barnett, Alex H.; Hillman, Elizabeth M. C.; Boas, David A.

2006-07-01

An efficient computation of the time-dependent forward solution for photon transport in a head model is a key capability for performing accurate inversion for functional diffuse optical imaging of the brain. The diffusion approximation to photon transport is much faster to simulate than the physically correct radiative transport equation (RTE); however, it is commonly assumed that scattering lengths must be much smaller than all system dimensions and all absorption lengths for the approximation to be accurate. Neither of these conditions is satisfied in the cerebrospinal fluid (CSF). Since line-of-sight distances in the CSF are small, of the order of a few millimeters, we explore the idea that the CSF scattering coefficient may be modeled by any value from zero up to the order of the typical inverse line-of-sight distance, or approximately 0.3 mm-1, without significantly altering the calculated detector signals or the partial path lengths relevant for functional measurements. We demonstrate this in detail by using a Monte Carlo simulation of the RTE in a three-dimensional head model based on clinical magnetic resonance imaging data, with realistic optode geometries. Our findings lead us to expect that the diffusion approximation will be valid even in the presence of the CSF, with consequences for faster solution of the inverse problem.

Tau proteins in the cerebrospinal fluid of patients with subacute sclerosing panencephalitis.

PubMed

Yuksel, Deniz; Yilmaz, Deniz; Uyar, Neval Y; Senbil, Nesrin; Gurer, Yavuz; Anlar, Banu

2010-06-01

Neurodegenerative diseases characterized by cytoskeletal deformation and neurofibrillary tangles are associated with altered levels of tau and related proteins in cerebrospinal fluid (CSF). Neuronal or glial fibrillary tangles have been shown in 20% of subacute sclerosing panencephalitis (SSPE) patients. We therefore investigated CSF samples from 60 newly diagnosed SSPE and 31 neurological control patients for total tau (t-tau), phosphorylated tau (p-tau), and S100-B levels by ELISA. There was no difference between patient and control groups in t-tau and S100-B levels. p-Tau was lower in the SSPE group (p=0.009). Past history of measles infection, measles immunization status, latent period between measles and onset of SSPE, duration of symptoms, frequency of myoclonia, neurological deficit index, stage and progression rate of the disease, CSF glucose levels and cell counts, CSF and serum measles IgG titer, distribution of lesions on brain magnetic resonance imaging were not related to t-tau, p-tau and S100-B levels. Mental status and age were negatively correlated with t-tau, and male gender and EEG abnormalities were associated with higher t-tau levels. The levels of tau proteins in our patients suggest there is no, or only scarce and immature, neurofibrillary tangle formation in SSPE. Autopsy studies showing neurofibrillary tangles might have examined older patients with longer disease and more parenchymal involvement. Copyright (c) 2009 Elsevier B.V. All rights reserved.

[Antibiotic diffusion to central nervous system].

PubMed

Cabrera-Maqueda, J M; Fuentes Rumí, L; Valero López, G; Baidez Guerrero, A E; García Molina, E; Díaz Pérez, J; García-Vázquez, E

2018-02-01

Central nervous system (CNS) infections caused by pathogens with a reduced sensitivity to drugs are a therapeutic challenge. Transport of fluid and solutes is tightly controlled within CNS, where vasculature exhibits a blood-brain barrier (BBB).The entry of drugs, including antibiotics, into the cerebro-spinal fluid (CSF) is governed by molecular size, lipophilicity, plasma protein binding and their affinity to transport systems at the BBB. The ratio of the AUCCSF (Area under the curve in CSF)/AUCS (Area under the curve in serum) is the most accurate parameter to characterize drug penetration into the CSF. Linezolid, some fluoroquinolones and metronidazole get high CSF concentrations and are useful for treating susceptible pathogens. Some highly active antibiotic compounds with low BBB permeability can be directly administered into the ventricles together with concomitant intravenous therapy. The ideal antibiotic to treat CNS infections should be that with a small moderately lipophilic molecule, low plasma protein binding and low affinity to efflux pumps at BBB. Knowledge of the pharmacokinetics and pharmacodynamics of antibiotics at the BBB will assist to optimize antibiotic treatment in CNS infections. This article reviews the physicochemical properties of the main groups of antibiotics to assess which compounds are most promising for the treatment of CNS infections and how to use them in the daily clinical practice. © The Author 2018. Published by Sociedad Española de Quimioterapia.

Dexamethasone increases production of C-type natriuretic peptide in the sheep brain.

PubMed

Wilson, Michele O; McNeill, Bryony A; Barrell, Graham K; Prickett, Timothy C R; Espiner, Eric A

2017-10-01

Although C-type natriuretic peptide (CNP) has high abundance in brain tissues and cerebrospinal fluid (CSF), the source and possible factors regulating its secretion within the central nervous system (CNS) are unknown. Here we report the dynamic effects of a single IV bolus of dexamethasone or saline solution on plasma, CSF, CNS and pituitary tissue content of CNP products in adult sheep, along with changes in CNP gene expression in selected tissues. Both CNP and NTproCNP (the amino-terminal product of proCNP) in plasma and CSF showed dose-responsive increases lasting 12-16 h after dexamethasone, whereas other natriuretic peptides were unaffected. CNS tissue concentrations of CNP and NTproCNP were increased by dexamethasone in all of the 12 regions examined. Abundance was highest in limbic tissues, pons and medulla oblongata. Relative to controls, CNP gene expression ( NPPC ) was upregulated by dexamethasone in 5 of 7 brain tissues examined. Patterns of responses differed in pituitary tissue. Whereas the abundance of CNP in both lobes of the pituitary gland greatly exceeded that of brain tissues, neither CNP nor NTproCNP concentration was affected by dexamethasone, despite an increase in NPPC expression. This is the first report of enhanced production and secretion of CNP in brain tissues in response to a corticosteroid. Activation of CNP secretion within CNS tissues by dexamethasone, not exhibited by other natriuretic peptides, suggests an important role for CNP in settings of acute stress. Differential findings in pituitary tissues likely relate to altered processing of proCNP storage and secretion. © 2017 Society for Endocrinology.

Microstructural white matter alterations in preclinical Alzheimer’s disease detected using free water elimination diffusion tensor imaging

PubMed Central

Ly, Martina; Carlsson, Cynthia M.; Okonkwo, Ozioma C.; Zetterberg, Henrik; Blennow, Kaj; Sager, Mark A.; Asthana, Sanjay; Johnson, Sterling C.; Alexander, Andrew L.; Bendlin, Barbara B.

2017-01-01

Brain changes associated with Alzheimer’s disease (AD) begin decades before disease diagnosis. While β-amyloid plaques and neurofibrillary tangles are defining features of AD, neuronal loss and synaptic pathology are closely related to the cognitive dysfunction. Brain imaging methods that are tuned to assess degeneration of myelinated nerve fibers in the brain (collectively called white matter) include diffusion tensor imaging (DTI) and related techniques, and are expected to shed light on disease-related loss of structural connectivity. Participants (N = 70, ages 47–76 years) from the Wisconsin Registry for Alzheimer’s Prevention study underwent DTI and hybrid diffusion imaging to determine a free-water elimination (FWE-DTI) model. The study assessed the extent to which preclinical AD pathology affects brain white matter. Preclinical AD pathology was determined using cerebrospinal fluid (CSF) biomarkers. The sample was enriched for AD risk (APOE ε4 and parental history of AD). AD pathology assessed by CSF analyses was significantly associated with altered microstructure on both DTI and FWE-DTI. Affected regions included frontal, parietal, and especially temporal white matter. The f-value derived from the FWE-DTI model appeared to be the most sensitive to the relationship between the CSF AD biomarkers and microstructural alterations in white matter. These findings suggest that white matter degeneration is an early pathological feature of AD that may have utility both for early disease detection and as outcome measures for clinical trials. More complex models of microstructural diffusion properties including FWE-DTI may provide increased sensitivity to early brain changes associated with AD over standard DTI. PMID:28291839

A case of acyclovir neurotoxicity presenting with atypical cerebrospinal fluid findings.

PubMed

Thind, Guramrinder Singh; Roach, Richard

2017-05-22

An 82-year-old man with a history of end-stage renal disease presented with progressively worsening confusion and somnolence for the past 4-5 days. The patient was diagnosed with herpes zoster by his primary care physician 5 days ago and was started on a course of valacyclovir 1 g three times a day (dose not adjusted for renal impairment).A lumbar puncture was performed and cerebrospinal fluid (CSF) studies revealed 37 white blood cells (WBCs)/hpf (100% monocytes), protein 64 mg/dL and glucose 52 mg/dL. He was started on ceftriaxone, ampicillin and acyclovir. MRI of the brain was done and was unremarkable. Acyclovir-induced encephalopathy was high on differential, but his CSF findings were concerning for viral encephalitis. Nonetheless, all antimicrobials were discontinued and he was scheduled for a 5-hour dialysis session. The very next day, he showed immense improvement and eventually recovered completely. CSF PCR tests for both herpes simplex virus and varicella zoster virus came back negative. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

A new LC-MS based method to quantitate exogenous recombinant transferrin in cerebrospinal fluid: a potential approach for pharmacokinetic studies of transferrin-based therapeutics in the central nervous system

PubMed Central

Wang, Shunhai; Bobst, Cedric E.; Kaltashov, Igor A.

2018-01-01

Transferrin (Tf) is an 80 kDa iron-binding protein which is viewed as a promising drug carrier to target the central nervous system due to its ability to penetrate the blood-brain barrier (BBB). Among the many challenges during the development of Tf-based therapeutics, sensitive and accurate quantitation of the administered Tf in cerebrospinal fluid (CSF) remains particularly difficult due to the presence of abundant endogenous Tf. Herein, we describe the development of a new LC-MS based method for sensitive and accurate quantitation of exogenous recombinant human Tf in rat CSF. By taking advantage of a His-tag present in recombinant Tf and applying Ni affinity purification, the exogenous hTf can be greatly enriched from rat CSF, despite the presence of the abundant endogenous protein. Additionally, we applied a newly developed O18-labeling technique that can generate internal standards at the protein level, which greatly improved the accuracy and robustness of quantitation. The developed method was investigated for linearity, accuracy, precision and lower limit of quantitation, all of which met the commonly accepted criteria for bioanalytical method validation. PMID:26307718

An update on the use of cerebrospinal fluid analysis as a diagnostic tool in multiple sclerosis.

PubMed

Gastaldi, Matteo; Zardini, Elisabetta; Franciotta, Diego

2017-01-01

Intrathecal B-lymphocyte activation is a hallmark of multiple sclerosis (MS), a multi-factorial inflammatory-demyelinating disease of the central nervous system. Such activation has a counterpart in the cerebrospinal fluid (CSF) oligoclonal IgG bands (OCB), whose diagnostic role in MS has been downgraded within the current McDonald's criteria. With a theoretico-practical approach, the authors review the physiopathological basis of the CSF dynamics, and the state-of-the-art of routine CSF analysis and CSF biomarkers in MS. Areas covered: The authors discuss pros and cons of CSF analysis, including critical evaluations of both well-established, and promising diagnostic and prognostic laboratory tools. New acquisitions on the CSF and cerebral interstitial fluid dynamics are also presented. The authors searched the PubMed database for English-language articles reported between January 2010 and June 2016, using the key words 'multiple sclerosis', 'cerebrospinal fluid', 'oligoclonal bands'. Reference lists of relevant articles were scanned for additional studies. Expert commentary: The availability of performing high-quality, routine CSF tests in specialized laboratories, the emerging potential of novel CSF biomarkers, and the trend for early treatments should induce a reappraisal of CSF analysis for diagnostic and prognostic purposes in MS. Further procedural and methodological improvements seem to be necessary in both research and translational diagnostic CSF settings.

Cerebrospinal fluid culture

MedlinePlus

... Alternative Names Culture - CSF; Spinal fluid culture; CSF culture Images Pneumococci organism References Karcher DS, McPherson RA. Cerebrospinal, synovial, serous body fluids, and alternative specimens. In: McPherson RA, Pincus ...

Mechanisms that determine the internal environment of the developing brain: a transcriptomic, functional and ultrastructural approach.

PubMed

Liddelow, Shane A; Dziegielewska, Katarzyna M; Ek, C Joakim; Habgood, Mark D; Bauer, Hannelore; Bauer, Hans-Christian; Lindsay, Helen; Wakefield, Matthew J; Strazielle, Nathalie; Kratzer, Ingrid; Møllgård, Kjeld; Ghersi-Egea, Jean-François; Saunders, Norman R

2013-01-01

We provide comprehensive identification of embryonic (E15) and adult rat lateral ventricular choroid plexus transcriptome, with focus on junction-associated proteins, ionic influx transporters and channels. Additionally, these data are related to new structural and previously published permeability studies. Results reveal that most genes associated with intercellular junctions are expressed at similar levels at both ages. In total, 32 molecules known to be associated with brain barrier interfaces were identified. Nine claudins showed unaltered expression, while two claudins (6 and 8) were expressed at higher levels in the embryo. Expression levels for most cytoplasmic/regulatory adaptors (10 of 12) were similar at the two ages. A few junctional genes displayed lower expression in embryos, including 5 claudins, occludin and one junctional adhesion molecule. Three gap junction genes were enriched in the embryo. The functional effectiveness of these junctions was assessed using blood-delivered water-soluble tracers at both the light and electron microscopic level: embryo and adult junctions halted movement of both 286Da and 3kDa molecules into the cerebrospinal fluid (CSF). The molecular identities of many ion channel and transporter genes previously reported as important for CSF formation and secretion in the adult were demonstrated in the embryonic choroid plexus (and validated with immunohistochemistry of protein products), but with some major age-related differences in expression. In addition, a large number of previously unidentified ion channel and transporter genes were identified for the first time in plexus epithelium. These results, in addition to data obtained from electron microscopical and physiological permeability experiments in immature brains, indicate that exchange between blood and CSF is mainly transcellular, as well-formed tight junctions restrict movement of small water-soluble molecules from early in development. These data strongly indicate the brain develops within a well-protected internal environment and the exchange between the blood, brain and CSF is transcellular and not through incomplete barriers.

Prevention of intraoperative cerebrospinal fluid leaks by lumbar cerebrospinal fluid drainage during surgery for pituitary macroadenomas.

PubMed

Mehta, Gautam U; Oldfield, Edward H

2012-06-01

Cerebrospinal fluid leakage is a major complication of transsphenoidal surgery. An intraoperative CSF leak, which occurs in up to 50% of pituitary tumor cases, is the only modifiable risk factor for postoperative leaks. Although several techniques have been described for surgical repair when an intraoperative leak is noted, none has been proposed to prevent an intraoperative CSF leak. The authors postulated that intraoperative CSF drainage would diminish tension on the arachnoid, decrease the rate of intraoperative CSF leakage during surgery for larger tumors, and reduce the need for surgical repair of CSF leaks. The results of 114 transsphenoidal operations for pituitary macroadenoma performed without intraoperative CSF drainage were compared with the findings from 44 cases in which a lumbar subarachnoid catheter was placed before surgery to drain CSF at the time of dural exposure and tumor removal. Cerebrospinal fluid drainage reduced the rate of intraoperative CSF leakage from 41% to 5% (p < 0.001). This reduction occurred in macroadenomas with (from 57% to 5%, p < 0.001) and those without suprasellar extension (from 29% to 0%, p = 0.31). The rate of postoperative CSF leakage was similar (5% vs 5%), despite the fact that intraoperative CSF drainage reduced the need for operative repair (from 32% to 5%, p < 0.001). There were no significant catheter-related complications. Cerebrospinal fluid drainage during transsphenoidal surgery for macroadenomas reduces the rate of intraoperative CSF leaks. This preventative measure obviated the need for surgical repair of intraoperative CSF leaks using autologous fat graft placement, other operative techniques, postoperative lumbar drainage, and/or reoperation in most patients and is associated with minimal risks.

Sex-Specific Life Course Changes in the Neuro-Metabolic Phenotype of Glut3 Null Heterozygous Mice: Ketogenic Diet Ameliorates Electroencephalographic Seizures and Improves Sociability.

PubMed

Dai, Yun; Zhao, Yuanzi; Tomi, Masatoshi; Shin, Bo-Chul; Thamotharan, Shanthie; Mazarati, Andrey; Sankar, Raman; Wang, Elizabeth A; Cepeda, Carlos; Levine, Michael S; Zhang, Jingjing; Frew, Andrew; Alger, Jeffry R; Clark, Peter M; Sondhi, Monica; Kositamongkol, Sudatip; Leibovitch, Leah; Devaskar, Sherin U

2017-04-01

We tested the hypothesis that exposure of glut3+/- mice to a ketogenic diet ameliorates autism-like features, which include aberrant behavior and electrographic seizures. We first investigated the life course sex-specific changes in basal plasma-cerebrospinal fluid (CSF)-brain metabolic profile, brain glucose transport/uptake, glucose and monocarboxylate transporter proteins, and adenosine triphosphate (ATP) in the presence or absence of systemic insulin administration. Glut3+/- male but not female mice (5 months of age) displayed reduced CSF glucose/lactate concentrations with no change in brain Glut1, Mct2, glucose uptake or ATP. Exogenous insulin-induced hypoglycemia increased brain glucose uptake in glut3+/- males alone. Higher plasma-CSF ketones (β-hydroxybutyrate) and lower brain Glut3 in females vs males proved protective in the former while enhancing vulnerability in the latter. As a consequence, increased synaptic proteins (neuroligin4 and SAPAP1) with spontaneous excitatory postsynaptic activity subsequently reduced hippocampal glucose content and increased brain amyloid β1-40 deposition in an age-dependent manner in glut3+/- males but not females (4 to 24 months of age). We then explored the protective effect of a ketogenic diet on ultrasonic vocalization, sociability, spatial learning and memory, and electroencephalogram seizures in male mice (7 days to 6 to 8 months of age) alone. A ketogenic diet partially restored sociability without affecting perturbed vocalization, spatial learning and memory, and reduced seizure events. We conclude that (1) sex-specific and age-dependent perturbations underlie the phenotype of glut3+/- mice, and (2) a ketogenic diet ameliorates seizures caused by increased cortical excitation and improves sociability, but fails to rescue vocalization and cognitive deficits in glut3+/- male mice. Copyright © 2017 Endocrine Society.

Sex-Specific Life Course Changes in the Neuro-Metabolic Phenotype of Glut3 Null Heterozygous Mice: Ketogenic Diet Ameliorates Electroencephalographic Seizures and Improves Sociability

PubMed Central

Dai, Yun; Zhao, Yuanzi; Tomi, Masatoshi; Shin, Bo-Chul; Thamotharan, Shanthie; Mazarati, Andrey; Sankar, Raman; Wang, Elizabeth A.; Cepeda, Carlos; Levine, Michael S.; Zhang, Jingjing; Frew, Andrew; Alger, Jeffry R.; Clark, Peter M.; Sondhi, Monica; Kositamongkol, Sudatip; Leibovitch, Leah

2017-01-01

We tested the hypothesis that exposure of glut3+/− mice to a ketogenic diet ameliorates autism-like features, which include aberrant behavior and electrographic seizures. We first investigated the life course sex-specific changes in basal plasma–cerebrospinal fluid (CSF)–brain metabolic profile, brain glucose transport/uptake, glucose and monocarboxylate transporter proteins, and adenosine triphosphate (ATP) in the presence or absence of systemic insulin administration. Glut3+/− male but not female mice (5 months of age) displayed reduced CSF glucose/lactate concentrations with no change in brain Glut1, Mct2, glucose uptake or ATP. Exogenous insulin-induced hypoglycemia increased brain glucose uptake in glut3+/− males alone. Higher plasma-CSF ketones (β-hydroxybutyrate) and lower brain Glut3 in females vs males proved protective in the former while enhancing vulnerability in the latter. As a consequence, increased synaptic proteins (neuroligin4 and SAPAP1) with spontaneous excitatory postsynaptic activity subsequently reduced hippocampal glucose content and increased brain amyloid β1-40 deposition in an age-dependent manner in glut3+/− males but not females (4 to 24 months of age). We then explored the protective effect of a ketogenic diet on ultrasonic vocalization, sociability, spatial learning and memory, and electroencephalogram seizures in male mice (7 days to 6 to 8 months of age) alone. A ketogenic diet partially restored sociability without affecting perturbed vocalization, spatial learning and memory, and reduced seizure events. We conclude that (1) sex-specific and age-dependent perturbations underlie the phenotype of glut3+/− mice, and (2) a ketogenic diet ameliorates seizures caused by increased cortical excitation and improves sociability, but fails to rescue vocalization and cognitive deficits in glut3+/− male mice. PMID:28324109

Prenatal cocaine effects on brain structure in early infancy.

PubMed

Grewen, Karen; Burchinal, Margaret; Vachet, Clement; Gouttard, Sylvain; Gilmore, John H; Lin, Weili; Johns, Josephine; Elam, Mala; Gerig, Guido

2014-11-01

Prenatal cocaine exposure (PCE) is related to subtle deficits in cognitive and behavioral function in infancy, childhood and adolescence. Very little is known about the effects of in utero PCE on early brain development that may contribute to these impairments. The purpose of this study was to examine brain structural differences in infants with and without PCE. We conducted MRI scans of newborns (mean age = 5 weeks) to determine cocaine's impact on early brain structural development. Subjects were three groups of infants: 33 with PCE co-morbid with other drugs, 46 drug-free controls and 40 with prenatal exposure to other drugs (nicotine, alcohol, marijuana, opiates, SSRIs) but without cocaine. Infants with PCE exhibited lesser total gray matter (GM) volume and greater total cerebral spinal fluid (CSF) volume compared with controls and infants with non-cocaine drug exposure. Analysis of regional volumes revealed that whole brain GM differences were driven primarily by lesser GM in prefrontal and frontal brain regions in infants with PCE, while more posterior regions (parietal, occipital) did not differ across groups. Greater CSF volumes in PCE infants were present in prefrontal, frontal and parietal but not occipital regions. Greatest differences (GM reduction, CSF enlargement) in PCE infants were observed in dorsal prefrontal cortex. Results suggest that PCE is associated with structural deficits in neonatal cortical gray matter, specifically in prefrontal and frontal regions involved in executive function and inhibitory control. Longitudinal study is required to determine whether these early differences persist and contribute to deficits in cognitive functions and enhanced risk for drug abuse seen at school age and in later life. Copyright © 2014 Elsevier Inc. All rights reserved.

Air pollution and children: neural and tight junction antibodies and combustion metals, the role of barrier breakdown and brain immunity in neurodegeneration.

PubMed

Calderón-Garcidueñas, Lilian; Vojdani, Aristo; Blaurock-Busch, Eleonore; Busch, Yvette; Friedle, Albrecht; Franco-Lira, Maricela; Sarathi-Mukherjee, Partha; Martínez-Aguirre, Xavier; Park, Su-Bin; Torres-Jardón, Ricardo; D'Angiulli, Amedeo

2015-01-01

Millions of children are exposed to concentrations of air pollutants, including fine particulate matter (PM2.5), above safety standards. In the Mexico City Metropolitan Area (MCMA) megacity, children show an early brain imbalance in oxidative stress, inflammation, innate and adaptive immune response-associated genes, and blood-brain barrier breakdown. We investigated serum and cerebrospinal fluid (CSF) antibodies to neural and tight junction proteins and environmental pollutants in 139 children ages 11.91 ± 4.2 y with high versus low air pollution exposures. We also measured metals in serum and CSF. MCMA children showed significantly higher serum actin IgG, occludin/zonulin 1 IgA, IgG, myelin oligodendrocyte glycoprotein IgG and IgM (p < 0.01), myelin basic protein IgA and IgG, S-100 IgG and IgM, and cerebellar IgG (p < 0.001). Serum IgG antibodies to formaldehyde, benzene, and bisphenol A, and concentrations of Ni and Cd were significantly higher in exposed children (p < 0.001). CSF MBP antibodies and nickel concentrations were higher in MCMA children (p = 0.03). Air pollution exposure damages epithelial and endothelial barriers and is a robust trigger of tight junction and neural antibodies. Cryptic 'self' tight junction antigens can trigger an autoimmune response potentially contributing to the neuroinflammatory and Alzheimer and Parkinson's pathology hallmarks present in megacity children. The major factor determining the impact of neural antibodies is the integrity of the blood-brain barrier. Defining the air pollution linkage of the brain/immune system interactions and damage to physical and immunological barriers with short and long term neural detrimental effects to children's brains ought to be of pressing importance for public health.

Cytokine profiling in the prefrontal cortex of Parkinson's Disease and Multiple System Atrophy patients.

PubMed

Rydbirk, Rasmus; Elfving, Betina; Andersen, Mille Dahl; Langbøl, Mia Aggergaard; Folke, Jonas; Winge, Kristian; Pakkenberg, Bente; Brudek, Tomasz; Aznar, Susana

2017-10-01

Parkinson's Disease (PD) and Multiple System Atrophy (MSA) are neurodegenerative diseases characterized neuropathologically by alpha-synuclein accumulation in brain cells. This accumulation is hypothesized to contribute to constitutive neuroinflammation, and to participate in the neurodegeneration. Cytokines, which are the main inflammatory signalling molecules, have been identified in blood and cerebrospinal fluid of PD patients, but studies investigating the human brain levels are scarce. It is documented that neurotrophins, necessary for survival of brain cells and known to interact with cytokines, are altered in the basal ganglia of PD patients. In regards to MSA, no major study has investigated brain cytokine or neurotrophin protein expression. Here, we measured protein levels of 18 cytokines (IL-2, 4-8, 10, 12, 13, 17, G-CSF, GM-CSF, IFN-γ, MCP-1, MIP-1α and 1β, TNF-α) and 5 neurotrophins (BDNF, GDNF, bFGF, PDGF-BB, VEGF) in the dorsomedial prefrontal cortex in brains of MSA and PD patients and control subjects. We found altered expression of IL-2, IL-13, and G-CSF, but no differences in neurotrophin levels. Further, in MSA patients we identified increased mRNA levels of GSK3β that is involved in neuroinflammatory pathways. Lastly, we identified increased expression of the neurodegenerative marker S100B, but not CRP, in PD and MSA patients, indicating local rather than systemic inflammation. Supporting this, in both diseases we observed increased MHC class II + and CD45 + positive cells, and low numbers of infiltrating CD3 + cells. In conclusion, we identified neuroinflammatory responses in PD and MSA which seems more widespread in the brain than neurotrophic changes. Copyright © 2017 Elsevier Inc. All rights reserved.

Unsupervised segmentation of brain regions with similar microstructural properties: application to alcoholism.

PubMed

Cosa, Alejandro; Canals, Santiago; Valles-Lluch, Ana; Moratal, David

2013-01-01

In this work, a novel brain MRI segmentation approach evaluates microstructural differences between groups. Going further from the traditional segmentation of brain tissues (white matter -WM-, gray matter -GM- and cerebrospinal fluid -CSF- or a mixture of them), a new way to classify brain areas is proposed using their microstructural MR properties. Eight rats were studied using the proposed methodology identifying regions which present microstructural differences as a consequence on one month of hard alcohol consumption. Differences in relaxation times of the tissues have been found in different brain regions (p<0.05). Furthermore, these changes allowed the automatic classification of the animals based on their drinking history (hit rate of 93.75 % of the cases).

Zymographic patterns of MMP-2 and MMP-9 in the CSF and cerebellum of dogs with subacute distemper leukoencephalitis.

PubMed

Machado, Gisele F; Melo, Guilherme D; Souza, Milena S; Machado, Andressa A; Migliolo, Daniela S; Moraes, Olívia C; Nunes, Cáris M; Ribeiro, Erica S

2013-07-15

Distemper leukoencephalitis is a disease caused by the canine distemper virus (CDV) infection. It is a demyelinating disease affecting mainly the white matter of the cerebellum and areas adjacent to the fourth ventricle; the enzymes of the matrix metalloproteinases (MMPs) group, especially MMP-2 and MMP-9 have a key role in the myelin basic protein fragmentation and in demyelination, as well as in leukocyte traffic into the nervous milieu. To evaluate the involvement of MMPs during subacute distemper leukoencephalitis, we measured the levels of MMP-2 and MMP-9 by zymography in the cerebrospinal fluid (CSF) and in the cerebellum of 14 dogs naturally infected with CDV and 10 uninfected dogs. The infected dogs presented high levels of pro-MMP-2 in the CSF and elevated levels of pro-MMP-2 and pro-MMP-9 in the cerebellar tissue. Active MMP-2 was detected in the CSF of some infected dogs. As active MMP-2 and MMP-9 are required for cellular migration across the blood-brain barrier and any interference between MMPs and their inhibitors may result in an amplification of demyelination, this study gives additional support to the involvement of MMPs during subacute distemper leukoencephalitis and suggests that MMP-2 and MMP-9 may take part in the brain inflammatory changes of this disease. Copyright © 2013 Elsevier B.V. All rights reserved.

CSF total protein

MedlinePlus

CSF total protein is a test to determine the amount of protein in your spinal fluid, also called cerebrospinal fluid (CSF). ... The normal protein range varies from lab to lab, but is typically about 15 to 60 milligrams per deciliter (mg/dL) ...

Impact of cysts during radiofrequency lesioning in deep brain structures—a simulation and in vitro study

NASA Astrophysics Data System (ADS)

Johansson, Johannes D.; Loyd, Dan; Wårdell, Karin; Wren, Joakim

2007-06-01

Radiofrequency lesioning of nuclei in the thalamus or the basal ganglia can be used to reduce symptoms caused by e.g. movement disorders such as Parkinson's disease. Enlarged cavities containing cerebrospinal fluid (CSF) are commonly present in the basal ganglia and tend to increase in size and number with age. Since the cavities have different electrical and thermal properties compared with brain tissue, it is likely that they can affect the lesioning process and thereby the treatment outcome. Computer simulations using the finite element method and in vitro experiments have been used to investigate the impact of cysts on lesions' size and shape. Simulations of the electric current and temperature distributions as well as convective movements have been conducted for various sizes, shapes and locations of the cysts as well as different target temperatures. Circulation of the CSF caused by the heating was found to spread heat effectively and the higher electric conductivity of the CSF increased heating of the cyst. These two effects were together able to greatly alter the resulting lesion size and shape when the cyst was in contact with the electrode tip. Similar results were obtained for the experiments.

Gray-white matter and cerebrospinal fluid volume differences in children with Specific Language Impairment and/or Reading Disability.

PubMed

Girbau-Massana, Dolors; Garcia-Marti, Gracian; Marti-Bonmati, Luis; Schwartz, Richard G

2014-04-01

We studied gray-white matter and cerebrospinal fluid (CSF) alterations that may be critical for language, through an optimized voxel-based morphometry evaluation in children with Specific Language Impairment (SLI), compared to Typical Language Development (TLD). Ten children with SLI (8;5-10;9) and 14 children with TLD (8;2-11;8) participated. They received a comprehensive language and reading test battery. We also analyzed a subgroup of six children with SLI+RD (Reading Disability). Brain images from 3-Tesla MRIs were analyzed with intelligence, age, gender, and total intracranial volume as covariates. Children with SLI or SLI+RD exhibited a significant lower overall gray matter volume than children with TLD. Particularly, children with SLI showed a significantly lower volume of gray matter compared to children with TLD in the right postcentral parietal gyrus (BA4), and left and right medial occipital gyri (BA19). The group with SLI also exhibited a significantly greater volume of gray matter in the right superior occipital gyrus (BA19), which may reflect a brain reorganization to compensate for their lower volumes at medial occipital gyri. Children with SLI+RD, compared to children with TLD, showed a significantly lower volume of: (a) gray matter in the right postcentral parietal gyrus; and (b) white matter in the right inferior longitudinal fasciculus (RILF), which interconnects the temporal and occipital lobes. Children with TLD exhibited a significantly lower CSF volume than children with SLI and children with SLI+RD respectively, who had somewhat smaller volumes of gray matter allowing for more CSF volume. The significant lower gray matter volume at the right postcentral parietal gyrus and greater cerebrospinal fluid volume may prove to be unique markers for SLI. We discuss the association of poor knowledge/visual representations and language input to brain development. Our comorbid study showed that a significant lower volume of white matter in the right inferior longitudinal fasciculus may be unique to children with SLI and Reading Disability. It was significantly associated to reading comprehension of sentences and receptive language composite z-score, especially receptive vocabulary and oral comprehension of stories. Copyright © 2014 Elsevier Ltd. All rights reserved.

Regionally specific changes in the hippocampal circuitry accompany progression of cerebrospinal fluid biomarkers in preclinical Alzheimer's disease.

PubMed

Tardif, Christine L; Devenyi, Gabriel A; Amaral, Robert S C; Pelleieux, Sandra; Poirier, Judes; Rosa-Neto, Pedro; Breitner, John; Chakravarty, M Mallar

2018-02-01

Neuropathological and in vivo brain imaging studies agree that the cornu ammonis 1 and subiculum subfields of the hippocampus are most vulnerable to atrophy in the prodromal phases of Alzheimer's disease (AD). However, there has been limited investigation of the structural integrity of the components of the hippocampal circuit, including subfields and extra-hippocampal white matter structure, in relation to the progression of well-accepted cerebrospinal fluid (CSF) biomarkers of AD, amyloid-β 1-42 (Aβ) and total-tau (tau). We investigated these relationships in 88 aging asymptomatic individuals with a parental or multiple-sibling familial history of AD. Apolipoprotein (APOE) ɛ4 risk allele carriers were identified, and all participants underwent cognitive testing, structural magnetic resonance imaging, and lumbar puncture for CSF assays of tau, phosphorylated-tau (p-tau) and Aβ. Individuals with a reduction in CSF Aβ levels (an indicator of amyloid accretion into neuritic plaques) as well as evident tau pathology (believed to be linked to neurodegeneration) exhibited lower subiculum volume, lower fornix microstructural integrity, and a trend towards lower cognitive score than individuals who showed only reduction in CSF Aβ. In contrast, persons with normal levels of tau showed an increase in structural MR markers in relation to declining levels of CSF Aβ. These results suggest that hippocampal subfield volume and extra-hippocampal white matter microstructure demonstrate a complex pattern where an initial volume increase is followed by decline among asymptomatic individuals who, in some instances, may be a decade or more away from onset of cognitive or functional impairment. © 2017 Wiley Periodicals, Inc.

A 51-year-old man with intramedullary spinal cord abscess having a patent foramen ovale

PubMed Central

Higuchi, Kanako; Ishihara, Hiroyuki; Okuda, Shiho; Kanda, Fumio

2011-01-01

The authors report a case of a 51-year-old man with intramedullary spinal cord abscess (ISCA) having a patent foramen ovale (PFO). He developed fever and tetraplegia after a recent dental treatment. MRI showed ISCA with longitudinal swelling from the upper cervical to the lumbar spinal cord. Cerebrospinal fluid (CSF) analysis indicated bacterial meningitis, and the culture of CSF revealed Streptococcus viridans. Transoesophageal echocardiography revealed the existence of a PFO. We suspected another possibility other than systemic bacteraemia, that paradoxical bacteric embolisation through PFO after the dental treatment caused ISCA. While several reports of brain abscess with PFO are available, this is the first report of ISCA with PFO. PMID:22696715

Cross-Sectional and Longitudinal Cognitive Correlates of FDDNP PET and CSF Amyloid-β and Tau in Parkinson's Disease1.

PubMed

Buongiorno, Mariateresa; Antonelli, Francesca; Compta, Yaroslau; Fernandez, Yolanda; Pavia, Javier; Lomeña, Francisco; Ríos, José; Ramírez, Isabel; García, José Ramón; Soler, Marina; Cámara, Ana; Fernández, Manel; Basora, Misericòrdia; Salazar, Fàtima; Sanchez-Etayo, Gerard; Valldeoriola, Francesc; Barrio, Jorge Raúl; Marti, Maria Jose

2017-01-01

Tau and amyloid-β (Aβ) aggregates have been suggested to play a role in the development of dementia in Parkinson's disease (PD). Positron emission tomography (PET) with [18F]FDDNP and the determination of cerebrospinal fluid (CSF) levels of these proteins constitute a means to visualize in vivo Aβ and tau brain accumulation. Information about longitudinal changes of these CSF and PET biomarkers in PD with regard to progression to dementia is lacking. We assessed the cross-sectional and longitudinal associations of CSF and PET biomarkers of tau and Aβ with PD-related cognitive dysfunction in 6 healthy-controls (HC), 16 patients with PD without dementia (PDND), and 8 PD with dementia (PDD). All subjects underwent comprehensive neuropsychological testing, [18F]FDDNP PET, and CSF Aβ-tau determination. After 18 months, the PDND group was re-assessed clinically and by neuropsychological, PET, and CSF determinations. Cross-sectionally, PDD had higher [18F]FDDNP binding in lateral temporal regions and lower levels of CSF Aβ levels compared to PDND, with a congruent correlation between the [18F]FDDNP binding and CSF Aβ levels. Longitudinally, higher baseline lateral temporal [18F]FDDNP binding was associated to longitudinal worsening in cognitive performances and progression to dementia among subjects classified as PDND at baseline, who additionally disclosed at follow-up an increase in lateral-temporal FDDNP binding, as well as a reduction in CSF Aβ and an increase in CSF tau levels. These results confirm the relevance of these CSF and PET biomarkers to PDD, being specifically the first to show [18F]FDDNP PET as a dementia risk biomarker in PD, along with longitudinal CSF and PET changes over time.

CSF neurofilament concentration reflects disease severity in frontotemporal degeneration

PubMed Central

Scherling, Carole S.; Hall, Tracey; Berisha, Flora; Klepac, Kristen; Karydas, Anna; Coppola, Giovanni; Kramer, Joel H.; Rabinovici, Gil; Ahlijanian, Michael; Miller, Bruce L.; Seeley, William; Grinberg, Lea T.; Rosen, Howard; Meredith, Jere; Boxer, Adam L.

2014-01-01

Objective Cerebrospinal fluid (CSF) neurofilament light chain (NfL) concentration is elevated in neurological disorders including frontotemporal degeneration (FTD). We investigated the clinical correlates of elevated CSF NfL levels in FTD. Methods CSF NfL, amyloid-β42 (Aβ42), tau and phosphorylated tau (ptau) concentrations were compared in 47 normal controls (NC), 8 asymptomatic gene carriers (NC2) of FTD-causing mutations, 79 FTD (45 behavioral variant frontotemporal dementia [bvFTD], 18 progressive nonfluent aphasia [PNFA], 16 semantic dementia [SD]), 22 progressive supranuclear palsy, 50 Alzheimer’s disease, 6 Parkinson’s disease and 17 corticobasal syndrome patients. Correlations between CSF analyte levels were performed with neuropsychological measures and the Clinical Dementia Rating scale sum of boxes (CDRsb). Voxel-based morphometry of structural MR images determined the relationship between brain volume and CSF NfL. Results Mean CSF NfL concentrations were higher in bvFTD, SD and PNFA than other groups. NfL in NC2 was similar to NC. CSF NfL, but not other CSF measures, correlated with CDRsb and neuropsychological measures in FTD, and not in other diagnostic groups. Analyses in two independent FTD cohorts and a group of autopsy verified or biomarker enriched cases confirmed the larger group analysis. In FTD, gray and white matter volume negatively correlated with CSF NfL concentration, such that individuals with highest NfL levels exhibited the most atrophy. Interpretation CSF NfL is elevated in symptomatic FTD and correlates with disease severity. This measurement may be a useful surrogate endpoint of disease severity in FTD clinical trials. Longitudinal studies of CSF NfL in FTD are warranted. PMID:24242746

The β-amyloid peptide compromises Reelin signaling in Alzheimer’s disease

PubMed Central

Cuchillo-Ibañez, Inmaculada; Mata-Balaguer, Trinidad; Balmaceda, Valeria; Arranz, Juan José; Nimpf, Johannes; Sáez-Valero, Javier

2016-01-01

Reelin is a signaling protein that plays a crucial role in synaptic function, which expression is influenced by β-amyloid (Aβ). We show that Reelin and Aβ oligomers co-immunoprecipitated in human brain extracts and were present in the same size-exclusion chromatography fractions. Aβ treatment of cells led to increase expression of Reelin, but secreted Reelin results trapped together with Aβ aggregates. In frontal cortex extracts an increase in Reelin mRNA, and in soluble and insoluble (guanidine-extractable) Reelin protein, was associated with late Braak stages of Alzheimer’s disease (AD), while expression of its receptor, ApoER2, did not change. However, Reelin-dependent induction of Dab1 phosphorylation appeared reduced in AD. In cells, Aβ reduced the capacity of Reelin to induce internalization of biotinylated ApoER2 and ApoER2 processing. Soluble proteolytic fragments of ApoER2 generated after Reelin binding can be detected in cerebrospinal fluid (CSF). Quantification of these soluble fragments in CSF could be a tool to evaluate the efficiency of Reelin signaling in the brain. These CSF-ApoER2 fragments correlated with Reelin levels only in control subjects, not in AD, where these fragments diminished. We conclude that while Reelin expression is enhanced in the Alzheimer’s brain, the interaction of Reelin with Aβ hinders its biological activity. PMID:27531658

CTP (Cochlin-tomoprotein) detection in the profuse fluid leakage (gusher) from cochleostomy.

PubMed

Ikezono, Tetsuo; Sugizaki, Kazuki; Shindo, Susumu; Sekiguchi, Satomi; Pawankar, Ruby; Baba, Shunkichi; Yagi, Toshiaki

2010-08-01

By testing 125 samples, we confirmed that Cochlin-tomoprotein (CTP) is present in the perilymph, not in cerebrospinal fluid (CSF). Perilymph and CSF exist in two distinct compartments, even in the case of a malformed inner ear with a bony defect in the lamina cribrosa, as described here. Cochleostomy might have suddenly decreased the perilymph pressure, allowing the influx of CSF into the inner ear resulting in profuse fluid leakage, first perilymph then CSF. The first purpose of this study was to further confirm the specificity of the perilymph-specific protein CTP that we reported recently. Secondly, we assessed the nature of the fluid leakage from the cochleostomy using the CTP detection test. A standardized CTP detection test was performed on 65 perilymph and 60 CSF samples. Samples of profuse fluid leakage collected from cochleostomy during cochlear implantation surgery of one patient with branchio-oto-renal (BOR) syndrome were also tested by the CTP detection test. CTP was detected in 60 of 65 perilymph samples but not in any of the CSF samples. The leaked fluid was shown to contain CTP, i.e. perilymph, at the outset, and then the CTP detection signals gradually disappeared as time elapsed.

Investigation of Tear Biomarkers as an Indicator of Human Health

NASA Technical Reports Server (NTRS)

Morton, Stephen; Tucker, Bethany; Crucian, Brian; Steinberg, Susan; Hagan, Suzanne

2017-01-01

Scientific literature suggests that tear biomarkers can be used as a guide towards clinical diagnosis of human health (Hagan et al., 2016). This study will investigate whether tear biomarkers represents a research and clinical opportunity to assess human health prior to, during, and after exposure to the spaceflight environment. The focus of this study is to compare biomarkers previously identified as potentially relevant to both ocular and brain health against unique physiological outcomes of exposure to the space flight environment. Study subjects suffering from terrestrial conditions thought to be similar to Spaceflight Associated Neuro-ocular Syndrome (SANS: formerly VIIP), e.g. patients with idiopathic intracranial hypertension (IIH) and optic neuritis may be relevant to conditions associated with spaceflight. This study will review methodologies, tear biomarkers related to state of ocular and brain health, the strengths and weakness of using tear fluid biomarkers versus other body fluid samples, and will survey current tear fluid biomarker knowledge in research and clinical practice. A strength of using tear biomarkers is that sampling is non-invasive and used as a guide in understanding pathologies, including ocular and systemic inflammatory conditions (Cocho et al., 2016)., Salvisberg et al., 2014). Moreover, tear biomarkers may reflect diseases affecting the central nervous system (CNS) (Salvisberg et al., 2014). For example, in multiple sclerosis (MS), the concordance rate between tear biomarkers versus cerebrospinal fluid (CSF) is approximately 83%, indicating that, in the majority of cases, tears are at least as effective as CSF in potentially identifying novel MS biomarkers (Devos et al., 2001).

Cerebrospinal fluid biomarkers of infantile congenital hydrocephalus

PubMed Central

Limbrick, David D.; Baksh, Brandon; Morgan, Clinton D.; Habiyaremye, Gakwaya; McAllister, James P.; Inder, Terrie E.; Mercer, Deanna; Holtzman, David M.; Strahle, Jennifer; Wallendorf, Michael J.; Morales, Diego M.

2017-01-01

Introduction Hydrocephalus is a complex neurological disorder with a pervasive impact on the central nervous system. Previous work has demonstrated derangements in the biochemical profile of cerebrospinal fluid (CSF) in hydrocephalus, particularly in infants and children, in whom neurodevelopment is progressing in parallel with concomitant neurological injury. The objective of this study was to examine the CSF of children with congenital hydrocephalus (CHC) to gain insight into the pathophysiology of hydrocephalus and identify candidate biomarkers of CHC with potential diagnostic and therapeutic value. Methods CSF levels of amyloid precursor protein (APP) and derivative isoforms (sAPPα, sAPPβ, Aβ42), tau, phosphorylated tau (pTau), L1CAM, NCAM-1, aquaporin 4 (AQP4), and total protein (TP) were measured by ELISA in 20 children with CHC. Two comparative groups were included: age-matched controls and children with other neurological diseases. Demographic parameters, ventricular frontal-occipital horn ratio, associated brain malformations, genetic alterations, and surgical treatments were recorded. Logistic regression analysis and receiver operating characteristic curves were used to examine the association of each CSF protein with CHC. Results CSF levels of APP, sAPPα, sAPPβ, Aβ42, tau, pTau, L1CAM, and NCAM-1 but not AQP4 or TP were increased in untreated CHC. CSF TP and normalized L1CAM levels were associated with FOR in CHC subjects, while normalized CSF tau levels were associated with FOR in control subjects. Predictive ability for CHC was strongest for sAPPα, especially in subjects ≤12 months of age (p<0.0001 and AUC = 0.99), followed by normalized sAPPβ (p = 0.0001, AUC = 0.95), tau, APP, and L1CAM. Among subjects ≤12 months, a normalized CSF sAPPα cut-point of 0.41 provided the best prediction of CHC (odds ratio = 528, sensitivity = 0.94, specificity = 0.97); these infants were 32 times more likely to have CHC. Conclusions CSF proteins such as sAPPα and related proteins hold promise as biomarkers of CHC in infants and young children, and provide insight into the pathophysiology of CHC during this critical period in neurodevelopment. PMID:28212403

IL-8 is a key mediator of neuroinflammation in severe traumatic brain injuries.

PubMed

Kushi, H; Saito, T; Makino, K; Hayashi, N

2003-01-01

The subjects were 22 patients with severe head injury. The average age was 45 +/- 18.3 years. There were 13 survivors and 9 fatalities. Samples of peripheral blood and cerebrospinal fluid (CSF) were taken four times, at the time of admission and at 24, 72, and 168 hours later. IL-6: For the survivor group, peripheral blood levels were 181, 105, 37, and 26 pg/ml, respectively (median values). CSF levels were 5376, 3565, 328, and 764 pg/ml, respectively. For the fatality group, peripheral blood levels were 102, 176, 873, and 3059 pg/ml, respectively, whereas CSF levels were 15241, 97384, 548225, and 366500 pg/ml, respectively. IL-8: For the survivor group, peripheral blood levels were 36, 15, 15, and 15 pg/ml, respectively, whereas CSF levels were 23736, 4074, 355, and 1509 pg/ml, respectively. For the fatality group, peripheral blood levels were 21, 28, 43, and 77 pg/mL, respectively, whereas CSF levels were 29003, 8906, 5852, and 8220 pg/ml, respectively. IL-6 and IL-8 levels were significantly higher after 72 hours in the fatality group. The fact that CSF IL-8 was 1000 times that in the peripheral blood at the time of admission, and decreased thereafter, indicates that IL-8 is a key mediator of neuroinflammation.

Mechanism of West Nile Virus Neuroinvasion: A Critical Appraisal

PubMed Central

Suen, Willy W.; Prow, Natalie A.; Hall, Roy A.; Bielefeldt-Ohmann, Helle

2014-01-01

West Nile virus (WNV) is an important emerging neurotropic virus, responsible for increasingly severe encephalitis outbreaks in humans and horses worldwide. However, the mechanism by which the virus gains entry to the brain (neuroinvasion) remains poorly understood. Hypotheses of hematogenous and transneural entry have been proposed for WNV neuroinvasion, which revolve mainly around the concepts of blood-brain barrier (BBB) disruption and retrograde axonal transport, respectively. However, an over‑representation of in vitro studies without adequate in vivo validation continues to obscure our understanding of the mechanism(s). Furthermore, WNV infection in the current rodent models does not generate a similar viremia and character of CNS infection, as seen in the common target hosts, humans and horses. These differences ultimately question the applicability of rodent models for pathogenesis investigations. Finally, the role of several barriers against CNS insults, such as the blood-cerebrospinal fluid (CSF), the CSF-brain and the blood-spinal cord barriers, remain largely unexplored, highlighting the infancy of this field. In this review, a systematic and critical appraisal of the current evidence relevant to the possible mechanism(s) of WNV neuroinvasion is conducted. PMID:25046180

Detecting occlusion inside a ventricular catheter using photoacoustic imaging through skull

NASA Astrophysics Data System (ADS)

Tavakoli, Behnoosh; Guo, Xiaoyu; Taylor, Russell H.; Kang, Jin U.; Boctor, Emad M.

2014-03-01

Ventricular catheters are used to treat hydrocephalus by diverting the excess of the cerebrospinal fluid (CSF) to the reabsorption site so as to regulate the intracranial pressure. The failure rate of these shunts is extremely high due to the ingrown tissue that blocks the CSF flow. We have studied a method to image the occlusion inside the shunt through the skull. In this approach the pulsed laser light coupled to the optical fiber illuminate the occluding tissue inside the catheter and an external ultrasound transducer is applied to detect the generated photoacoustic signal. The feasibility of this method is investigated using a phantom made of ovis aries brain tissue and adult human skull. We were able to image the target inside the shunt located 20mm deep inside the brain through about 4mm thick skull bone. This study could lead to the development of a simple, safe and non-invasive device for percutaneous restoration of patency to occluded shunts. This will eliminate the need of the surgical replacement of the occluded catheters which expose the patients to risks including hemorrhage and brain injury.

Human papillomavirus infection is associated with decreased levels of GM-CSF in cervico-vaginal fluid of infected women.

PubMed

Comar, Manola; Monasta, Lorenzo; Zanotta, Nunzia; Vecchi Brumatti, Liza; Ricci, Giuseppe; Zauli, Giorgio

2013-10-01

Although human papillomavirus (HPV) is the most common sexually transmitted infection, there are very scant data about the influence of this virus on the in vitro fertilization outcome. To assess the presence of HPV in the cervico-vaginal fluid in relationship to the in vitro fertilization (IVF) outcome and to the concentration of selected cytokines, known to affect embryo implantation and gestation: granulocyte-macrophage colony stimulating factor (GM-CSF) and granulocyte colony stimulating factor (G-CSF). Cervico-vaginal samples were collected on the day of oocyte pick-up from 82 women. Vaginas were flushed with 50 mL of sterile water and 3 mL of fluid was collected. Twelve women (15%) were positive for HPV. Interestingly, among HPV(+) women live birth rate was about half of the rate in HPV(-) women, although the differences were not statistically significant due to the low number of cases. Cervico-vaginal samples of a sub-group of 29 (8 HPV(+) and 21 HPV(-)) women were analyzed for GM-CSF and G-CSF by ELISA. GM-CSF but not G-CSF was significantly lower in the cervico-vaginal fluid of HPV(+) than in HPV(-) women. Since GM-CSF plays an important role during pregnancy, the reduced levels of GM-CSF in the cervico-vaginal fluid of HPV(+) women might contribute to explain the reduced live birth rate observed in HPV(+) women. Copyright © 2013 Elsevier B.V. All rights reserved.

Neospora caninum and Ehrlichia canis co-infection in a dog with meningoencephalitis.

PubMed

Aroch, Itamar; Baneth, Gad; Salant, Harold; Nachum-Biala, Yaarit; Berkowitz, Asaf; Shamir, Merav; Chai, Orit

2018-06-01

An 8-year-old mixed-breed dog was presented for acute, progressive weakness and ataxia, inappetence, and weight loss. The patient was mentally normal, but nonambulatory, with a right head tilt, right positional ventral strabismus, and slight head tremors. A neurologic lesion was localized to the cerebellum and right brainstem. Cerebrospinal fluid (CSF) analysis showed a markedly increased protein concentration and mixed pleocytosis, with eosinophil predominance (44%), intracytoplasmic inclusions within eosinophils, consistent with Ehrlichia canis (E canis) morulae, and Toxoplasma gondii (T gondii) or Neospora caninum (N caninum) tachyzoites within eosinophils and monocytes. A serum indirect immunofluorescent antibody test was positive for N caninum (titer 1:12 800) and negative for T gondii. Both blood and CSF PCR results were N caninum- and E canis-positive and T gondii- and Anaplasma phagocytophilum-negative, and blood PCR, but not CSF PCR, was Hepatozoon canis-positive. The dog was treated for 30 days with clindamycin, sulfamethoxazole-trimethoprim, doxycycline, prednisone, and cephalosporin, but did not improve neurologically, and was euthanized. Brain histopathology showed moderate multifocal, subacute meningoencephalitis with necrosis and gliosis. The neurologic disease was mostly attributed to central nervous system (CNS) neosporosis, with the possible contribution of ehrlichiosis, which was likely a manifestation of blood-brain barrier disruption. Hepatozoonosis was probably a result or cause of underlying immunosuppression. To our knowledge, this is the first report of CNSN caninum and E canis co-infection detected by both CSF PCR and cytology and E canis morulae identified within CSF eosinophils. © 2018 American Society for Veterinary Clinical Pathology.

Myeloid microvesicles are a marker and therapeutic target for neuroinflammation.

PubMed

Verderio, Claudia; Muzio, Luca; Turola, Elena; Bergami, Alessandra; Novellino, Luisa; Ruffini, Francesca; Riganti, Loredana; Corradini, Irene; Francolini, Maura; Garzetti, Livia; Maiorino, Chiara; Servida, Federica; Vercelli, Alessandro; Rocca, Mara; Dalla Libera, Dacia; Martinelli, Vittorio; Comi, Giancarlo; Martino, Gianvito; Matteoli, Michela; Furlan, Roberto

2012-10-01

Microvesicles (MVs) have been indicated as important mediators of intercellular communication and are emerging as new biomarkers of tissue damage. Our previous data indicate that reactive microglia/macrophages release MVs in vitro. The aim of the study was to evaluate whether MVs are released by microglia/macrophages in vivo and whether their number varies in brain inflammatory conditions, such as multiple sclerosis (MS). Electron and fluorescence microscopy and flow cytometry were used to detect myeloid MVs in the cerebrospinal fluid (CSF) of healthy controls, MS patients, and rodents affected by experimental autoimmune encephalomyelitis (EAE), the animal model of MS. Myeloid MVs were detected in CSF of healthy controls. In relapsing and remitting EAE mice, the concentration of myeloid MVs in the CSF was significantly increased and closely associated with disease course. Analysis of MVs in the CSF of 28 relapsing patients and 28 patients with clinical isolated syndrome from 2 independent cohorts revealed higher levels of myeloid MVs than in 13 age-matched controls, indicating a clinical value of MVs as a companion tool to capture disease activity. Myeloid MVs were found to spread inflammatory signals both in vitro and in vivo at the site of administration; mice impaired in MV shedding were protected from EAE, suggesting a pathogenic role for MVs in the disease. Finally, FTY720, the first approved oral MS drug, significantly reduced the amount of MVs in the CSF of EAE-treated mice. These findings identify myeloid MVs as a marker and therapeutic target of brain inflammation. Copyright © 2012 American Neurological Association.

The influence of body position on cerebrospinal fluid pressure gradient and movement in cats with normal and impaired craniospinal communication.

PubMed

Klarica, Marijan; Radoš, Milan; Erceg, Gorislav; Petošić, Antonio; Jurjević, Ivana; Orešković, Darko

2014-01-01

Intracranial hypertension is a severe therapeutic problem, as there is insufficient knowledge about the physiology of cerebrospinal fluid (CSF) pressure. In this paper a new CSF pressure regulation hypothesis is proposed. According to this hypothesis, the CSF pressure depends on the laws of fluid mechanics and on the anatomical characteristics inside the cranial and spinal space, and not, as is today generally believed, on CSF secretion, circulation and absorption. The volume and pressure changes in the newly developed CSF model, which by its anatomical dimensions and basic biophysical features imitates the craniospinal system in cats, are compared to those obtained on cats with and without the blockade of craniospinal communication in different body positions. During verticalization, a long-lasting occurrence of negative CSF pressure inside the cranium in animals with normal cranio-spinal communication was observed. CSF pressure gradients change depending on the body position, but those gradients do not enable unidirectional CSF circulation from the hypothetical site of secretion to the site of absorption in any of them. Thus, our results indicate the existence of new physiological/pathophysiological correlations between intracranial fluids, which opens up the possibility of new therapeutic approaches to intracranial hypertension.

Quantitative Gd-DOTA uptake from cerebrospinal fluid into rat brain using 3D VFA-SPGR at 9.4T.

PubMed

Lee, Hedok; Mortensen, Kristian; Sanggaard, Simon; Koch, Palle; Brunner, Hans; Quistorff, Bjørn; Nedergaard, Maiken; Benveniste, Helene

2018-03-01

We propose a quantitative technique to assess solute uptake into the brain parenchyma based on dynamic contrast-enhanced MRI (DCE-MRI). With this approach, a small molecular weight paramagnetic contrast agent (Gd-DOTA) is infused in the cerebral spinal fluid (CSF) and whole brain gadolinium concentration maps are derived. We implemented a 3D variable flip angle spoiled gradient echo (VFA-SPGR) longitudinal relaxation time (T1) technique, the accuracy of which was cross-validated by way of inversion recovery rapid acquisition with relaxation enhancement (IR-RARE) using phantoms. Normal Wistar rats underwent Gd-DOTA infusion into CSF via the cisterna magna and continuous MRI for approximately 130 min using T1-weighted imaging. Dynamic Gd-DOTA concentration maps were calculated and parenchymal uptake was estimated. In the phantom study, T1 discrepancies between the VFA-SPGR and IR-RARE sequences were approximately 6% with a transmit coil inhomogeneity correction. In the in vivo study, contrast transport profiles indicated maximal parenchymal retention of approximately 19% relative to the total amount delivered into the cisterna magna. Imaging strategies for accurate 3D contrast concentration mapping at 9.4T were developed and whole brain dynamic concentration maps were derived to study solute transport via the glymphatic system. The newly developed approach will enable future quantitative studies of the glymphatic system in health and disease states. Magn Reson Med 79:1568-1578, 2018. © 2017 International Society for Magnetic Resonance in Medicine. © 2017 International Society for Magnetic Resonance in Medicine.

ZO-1 expression is suppressed by GM-CSF via miR-96/ERG in brain microvascular endothelial cells.

PubMed

Zhang, Hu; Zhang, Shuhong; Zhang, Jilin; Liu, Dongxin; Wei, Jiayi; Fang, Wengang; Zhao, Weidong; Chen, Yuhua; Shang, Deshu

2018-05-01

The level of granulocyte-macrophage colony-stimulating factor (GM-CSF) increases in some disorders such as vascular dementia, Alzheimer's disease, and multiple sclerosis. We previously reported that in Alzheimer's disease patients, a high level of GM-CSF in the brain parenchyma downregulated expression of ZO-1, a blood-brain barrier tight junction protein, and facilitated the infiltration of peripheral monocytes across the blood-brain barrier. However, the molecular mechanism underlying regulation of ZO-1 expression by GM-CSF is unclear. Herein, we found that the erythroblast transformation-specific (ETS) transcription factor ERG cooperated with the proto-oncogene protein c-MYC in regulation of ZO-1 transcription in brain microvascular endothelial cells (BMECs). The ERG expression was suppressed by miR-96 which was increased by GM-CSF through the phosphoinositide-3 kinase (PI3K)/Akt pathway. Inhibition of miR-96 prevented ZO-1 down-regulation induced by GM-CSF both in vitro and in vivo. Our results revealed the mechanism of ZO-1 expression reduced by GM-CSF, and provided a potential target, miR-96, which could block ZO-1 down-regulation caused by GM-CSF in BMECs.

Phenotype of postural instability/gait difficulty in Parkinson disease: relevance to cognitive impairment and mechanism relating pathological proteins and neurotransmitters

PubMed Central

Zuo, Li-Jun; Piao, Ying-Shan; Li, Li-Xia; Yu, Shu-Yang; Guo, Peng; Hu, Yang; Lian, Teng-Hong; Wang, Rui-Dan; Yu, Qiu-Jin; Jin, Zhao; Wang, Ya-Jie; Wang, Xiao-Min; Chan, Piu; Chen, Sheng-Di; Wang, Yong-Jun; Zhang, Wei

2017-01-01

Parkinson disease (PD) is identified as tremor-dominant (TD) and postural instability and gait difficulty (PIGD) phenotypes. The relationships between motor phenotypes and cognitive impairment and the underlying mechanisms relating pathological proteins and neurotransmitters in cerebrospinal fluid (CSF) are unknown. We evaluated the motor symptoms and cognitive function by scales, and detected the levels of pathological proteins and neurotransmitters in CSF. TD group and PIGD group had significantly higher levels of total tau, tau phosphorylated at the position of threonine 181(P-tau181t), threonine 231, serine 396, serine 199 and lower β amyloid (Aβ)1–42 level in CSF than those in control group; PIGD group had significantly higher P-tau181t level and lower Aβ1–42 level than those in TD group. In PD group, PIGD severity was negatively correlated with MoCA score and Aβ1–42 level in CSF, and positively correlated with Hoehn-Yahr stage and P-tau181t level in CSF. In PIGD group, PIGD severity was negatively correlated with homovanillic acid (HVA) level in CSF, and HVA level was positively correlated with Aβ1–42 level in CSF. PIGD was significantly correlated with cognitive impairment, which underlying mechanism might be involved in Aβ1–42 aggregation in brain and relevant neurochemical disturbance featured by the depletion of HVA in CSF. PMID:28332604

Central-Variant Posterior Reversible Encephalopathy Syndrome with Albuminocytologic Dissociation.

PubMed

Lee, Sang-Woo; Lee, Seung-Jae

2018-01-01

Posterior reversible encephalopathy syndrome (PRES) is a disorder of reversible vasogenic brain edema which mainly involves the parieto-occipital lobes in various clinical settings. The main mechanism is known to be cerebral autoregulation failure and endothelial dysfunction leading to the disruption of the blood-brain barrier. We report the case of a 47-year-old woman with PRES which involved the brain stem and thalami, sparing the cerebral hemispheres. She was admitted to the emergency room because of acute-onset confusion. Her initial blood pressure was 270/220 mm Hg. Routine blood lab tests showed pleocytosis, hyperglycemia, and azotemia. Brain magnetic resonance imaging (MRI) showed a lesion of vasogenic edema involving nearly the whole area of pons, the left side of the midbrain, and the bilateral medial thalami. Cerebrospinal fluid (CSF) examination revealed an increased level of protein with normal white blood cell count. With conservative care, the patient markedly recovered 3 days after symptom onset, and a follow-up MRI confirmed complete resolution of the vasogenic edema. This case suggests that PRES can rarely involve the "central zone" only, sparing the cerebral hemispheres, which may be confused with other neurological diseases. Besides, the CSF albuminocytologic dissociation may suggest the disruption of the blood-brain barrier in patients with PRES.

Hollow mandrin facilitates external ventricular drainage placement.

PubMed

Heese, O; Regelsberger, J; Kehler, U; Westphal, M

2005-07-01

Placement of ventricular catheters is a routine procedure in neurosurgery. Ventricle puncture is done using a flexible ventricular catheter stabilised by a solid steel mandrin in order to improve stability during brain penetration. A correct catheter placement is confirmed after removing the solid steel mandrin by observation of cerebrospinal fluid (CSF) flow out of the flexible catheter. Incorrect placement makes further punctures necessary. The newly developed device allows CSF flow observation during the puncture procedure and in addition precise intracranial pressure (ICP) measurement. The developed mandrin is hollow with a blunt tip. On one side 4-5 small holes with a diameter of 0.8 mm are drilled corresponding exactly with the holes in the ventricular catheter, allowing CSF to pass into the hollow mandrin as soon as the ventricle is reached. By connecting a small translucent tube at the distal portion of the hollow mandrin ICP can be measured without loss of CSF. The system has been used in 15 patients with subarachnoid haemorrhage (SAH) or intraventricular haemeorrhage (IVH) and subsequent hydrocephalus. The new system improved the external ventricular drainage implantation procedure. In all 15 patients catheter placement was correct. ICP measurement was easy to perform immediately at ventricle puncture. In 4 patients at puncture no spontaneous CSF flow was observed, therefore by connecting a syringe and gentle aspiration of CSF correct placement was confirmed in this unexpected low pressure hydrocephalus. Otherwise by using the conventional technique further punctures would have been necessary. Advantages of the new technique are less puncture procedures with a lower risk of damage to neural structures and reduced risk of intracranial haemorrhages. Implantation of the ventricular catheter to far into the brain can be monitored and this complication can be overcome. Using the connected pressure monitoring tube an exact measurement of the opening intracranial pressure can be obtained performed without losing CSF.

Measurement of peak CSF flow velocity at cerebral aqueduct, before and after lumbar CSF drainage, by use of phase-contrast MRI: utility in the management of idiopathic normal pressure hydrocephalus.

PubMed

Sharma, Ashwani Kumar; Gaikwad, Shailesh; Gupta, Vipul; Garg, Ajay; Mishra, Nalini K

2008-04-01

Since it was first described, normal pressure hydrocephalus (NPH) and its treatment by means of cerebrospinal fluid (CSF) shunting have been the focus of much investigation. Whatever be the cause of NPH, it has been hypothesized that in this disease there occurs decreased arterial expansion and an increased brain expansion leading to increased transmantle pressure. We cannot measure the latter, but fortunately the effect of these changes (increased peak flow velocity through the aqueduct) can be quantified with cine phase-contrast magnetic resonance imaging (MRI). This investigation was thus undertaken to characterize and measure CSF peak flow velocity at the level of the aqueduct, before and after lumbar CSF drainage, by means of a phase-contrast cine MRI and determine its role in selecting cases for shunt surgery. 37 patients with clinically suspected NPH were included in the study. Changes in the hyperdynamic peak CSF flow velocity with 50 ml lumbar CSF drainage (mimicking shunt) were evaluated in them for considering shunt surgery. 14 out of 15 patients who were recommended for shunt surgery, based on changes peak flow velocity after lumbar CSF drainage, improved after shunt surgery. None of the cases which were not recommended for shunt surgery, based on changes in CSF peak flow velocity after lumbar CSF drainage, improved after shunt surgery (2 out of 22 cases). The study concluded that the phase-contrast MR imaging, done before and after CSF drainage, is a sensitive method to support the clinical diagnosis of normal pressure hydrocephalus, selecting patients of NPH who are likely to benefit from shunt surgery, and to select patients of NPH who are not likely to benefit from shunt surgery.

Imaging Signs in Spontaneous Intracranial Hypotension: Prevalence and Relationship to CSF Pressure.

PubMed

Kranz, P G; Tanpitukpongse, T P; Choudhury, K R; Amrhein, T J; Gray, L

2016-07-01

Patients with spontaneous intracranial hypotension often exhibit low CSF pressure and changes on brain MR imaging and/or evidence of CSF leak on myelography. We investigated whether individual imaging signs of spontaneous intracranial hypotension correlate with measured CSF pressure and how frequently these 2 markers of spontaneous intracranial hypotension were concordant. We performed a retrospective, cross-sectional study of 99 subjects with spontaneous intracranial hypotension. Prevalence of brain and myelographic imaging signs of spontaneous intracranial hypotension was recorded. CSF pressure among subjects with or without individual imaging signs was compared by using a 2-tailed t test and ANOVA. Concordance between low CSF pressure (≤6 cm H2O) and imaging was defined as the presence of the sign in a subject with low CSF pressure or absence of the sign when pressure was not low. Dural enhancement, brain sagging, and venous distension sign were present in 83%, 61%, and 75% of subjects, respectively, and myelographic evidence of CSF leak was seen in 55%. Marginal correlations between CSF pressure and brain sagging (P = .046) and the venous distension sign (P = .047) were found. Dural enhancement and myelographic evidence of leak were not significantly correlated with CSF pressure. Rates of concordance between imaging signs and low CSF pressure were generally low, ranging from 39% to 55%. Brain and myelographic signs of spontaneous intracranial hypotension correlate poorly with CSF pressure. These findings reinforce the need to base the diagnosis of spontaneous intracranial hypotension on multiple diagnostic criteria and suggest the presence of patient-specific variables that influence CSF pressure in these individuals. © 2016 by American Journal of Neuroradiology.

The Glymphatic Pathway.

PubMed

Benveniste, Helene; Lee, Hedok; Volkow, Nora D

2017-01-01

The overall premise of this review is that cerebrospinal fluid (CSF) is transported within a dedicated peri-vascular network facilitating metabolic waste clearance from the central nervous system while we sleep. The anatomical profile of the network is complex and has been defined as a peri-arterial CSF influx pathway and peri-venous clearance routes, which are functionally coupled by interstitial bulk flow supported by astrocytic aquaporin 4 water channels. The role of the newly discovered system in the brain is equivalent to the lymphatic system present in other body organs and has been termed the "glymphatic pathway" or "(g)lymphatics" because of its dependence on glial cells. We will discuss and review the general anatomy and physiology of CSF from the perspective of the glymphatic pathway, a discovery which has greatly improved our understanding of key factors that control removal of metabolic waste products from the central nervous system in health and disease and identifies an additional purpose for sleep. A brief historical and factual description of CSF production and transport will precede the ensuing discussion of the glymphatic system along with a discussion of its clinical implications.

Periodic oscillation of intracranial pressure in ventricular dilation: a preliminary report.

PubMed

Kuchiwaki, H; Misu, N; Kageyama, N; Ishiguri, H; Takada, S

1987-12-01

Artificial pressure waves (PWs) were generated by manual inflation of a balloon in the trigonum of the lateral ventricle in seven adult mongrel dogs with normal cerebrospinal fluid (CSF) circulation. In 14 of 16 series of continuous appearances of artificial PWs, local shifts of the brain were successfully monitored using small strain-gauge sensors at the periventricular structures in these animals. Of the 14 series, 13 showed displacements of the periventricular structures, suggesting ventricular dilation. These results did not always correlate with macroscopic findings. They are thought to be due largely to periventricular oedemas and, in part, non-uniform dilations of the ventricles during PWs. We conclude that a water hammer formed by reflection of an increased pulse pressure of PWs at the site of CSF absorption causes a shift of CSF from the ventricle to the periventricular structures through the wall of the ventricle. This phenomenon appears amplified in patients with impaired CSF absorption. Thus, PWs have a pathological role in the progress of ventricular dilation in patients with normal pressure hydrocephalus.

Validation of serum markers for blood-brain barrier disruption in traumatic brain injury.

PubMed

Blyth, Brian J; Farhavar, Arash; Gee, Christopher; Hawthorn, Brendan; He, Hua; Nayak, Akshata; Stöcklein, Veit; Bazarian, Jeffrey J

2009-09-01

The blood-brain barrier (BBB), which prevents the entry into the central nervous system (CNS) of most water-soluble molecules over 500 Da, is often disrupted after trauma. Post-traumatic BBB disruption may have important implications for prognosis and therapy. Assessment of BBB status is not routine in clinical practice because available techniques are invasive. The gold-standard measure, the cerebrospinal fluide (CSF)-serum albumin quotient (Q(A)), requires the measurement of albumin in CSF and serum collected contemporaneously. Accurate, less invasive techniques are necessary. The objective of this study was to evaluate the relationship between Q(A) and serum concentrations of monomeric transthyretin (TTR) or S100B. Nine subjects with severe traumatic brain injury (TBI; Glasgow Coma Scale [GCS] score < or =8) and 11 subjects with non-traumatic headache who had CSF collected by ventriculostomy or lumbar puncture (LP) were enrolled. Serum and CSF were collected at the time of LP for headache subjects and at 12, 24, and 48 h after ventriculostomy for TBI subjects. The Q(A) was calculated for all time points at which paired CSF and serum samples were available. Serum S100B and TTR levels were also measured. Pearson's correlation coefficient and area under the receiver operating characteristic (ROC) curve were used to determine the relationship between the serum proteins and QA. Seven TBI subjects had abnormal Q(A)'s indicating BBB dysfunction. The remaining TBI and control subjects had normal BBB function. No significant relationship between TTR and QA was found. A statistically significant linear correlation between serum S100B and Q(A) was present (r = 0.432, p = 0.02). ROC analysis demonstrated a significant relationship between Q(A) and serum S100B concentrations at 12 h after TBI (AUC = 0.800; SE 0.147, 95% CI 0.511-1.089). Using an S100B concentration cutoff of 0.027 ng=ml, specificity for abnormal Q(A) was 90% or higher at each time point. We conclude that serum S100B concentrations accurately indicate BBB dysfunction at 12 h after TBI.

Cerebrospinal fluid monocyte chemoattractant protein-1 in alcoholics: support for a neuroinflammatory model of chronic alcoholism.

PubMed

Umhau, John C; Schwandt, Melanie; Solomon, Matthew G; Yuan, Peixiong; Nugent, Allison; Zarate, Carlos A; Drevets, Wayne C; Hall, Samuel D; George, David T; Heilig, Markus

2014-05-01

Liver inflammation in alcoholism has been hypothesized to influence the development of a neuroinflammatory process in the brain characterized by neurodegeneration and altered cognitive function. Monocyte chemoattractant protein-1/chemokine (C-C motif) ligand 2 (MCP-1/CCL2) elevations have been noted in the alcoholic brain at autopsy and may have a role in this process. We studied cerebrospinal fluid (CSF) levels of MCP-1 as well as interleukin-1β and tumor necrosis factor-α in 13 healthy volunteers and 28 alcoholics during weeks 1 and 4 following detoxification. Serum liver enzymes were obtained as markers of alcohol-related liver inflammation. Compared to healthy volunteers, MCP-1 levels were significantly higher in alcoholics both on day 4 and day 25 (p < 0.0001). Using multiple regression analysis, we found that MCP-1 concentrations were positively associated with the liver enzymes gamma glutamyltransferase (GGT; p = 0.03) and aspartate aminotransferase/glutamic oxaloacetic transaminase (AST/GOT; p = 0.004). These preliminary findings are consistent with the hypothesis that neuroinflammation as indexed by CSF MCP-1 is associated with alcohol-induced liver inflammation, as defined by peripheral concentrations of GGT and AST/GOT. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

Cerebrospinal Fluid Cortisol Mediates Brain-Derived Neurotrophic Factor Relationships to Mortality after Severe TBI: A Prospective Cohort Study

PubMed Central

Munoz, Miranda J.; Kumar, Raj G.; Oh, Byung-Mo; Conley, Yvette P.; Wang, Zhensheng; Failla, Michelle D.; Wagner, Amy K.

2017-01-01

Distinct regulatory signaling mechanisms exist between cortisol and brain derived neurotrophic factor (BDNF) that may influence secondary injury cascades associated with traumatic brain injury (TBI) and predict outcome. We investigated concurrent CSF BDNF and cortisol relationships in 117 patients sampled days 0–6 after severe TBI while accounting for BDNF genetics and age. We also determined associations between CSF BDNF and cortisol with 6-month mortality. BDNF variants, rs6265 and rs7124442, were used to create a gene risk score (GRS) in reference to previously published hypothesized risk for mortality in “younger patients” (<48 years) and hypothesized BDNF production/secretion capacity with these variants. Group based trajectory analysis (TRAJ) was used to create two cortisol groups (high and low trajectories). A Bayesian estimation approach informed the mediation models. Results show CSF BDNF predicted patient cortisol TRAJ group (P = 0.001). Also, GRS moderated BDNF associations with cortisol TRAJ group. Additionally, cortisol TRAJ predicted 6-month mortality (P = 0.001). In a mediation analysis, BDNF predicted mortality, with cortisol acting as the mediator (P = 0.011), yielding a mediation percentage of 29.92%. Mediation effects increased to 45.45% among younger patients. A BDNF*GRS interaction predicted mortality in younger patients (P = 0.004). Thus, we conclude 6-month mortality after severe TBI can be predicted through a mediation model with CSF cortisol and BDNF, suggesting a regulatory role for cortisol with BDNF's contribution to TBI pathophysiology and mortality, particularly among younger individuals with severe TBI. Based on the literature, cortisol modulated BDNF effects on mortality after TBI may be related to known hormone and neurotrophin relationships to neurological injury severity and autonomic nervous system imbalance. PMID:28337122

Sodium-dependent transport of sugars and iodide from the cerebral venticles of the rabbit.

PubMed

Bradbury, M W; Brondsted, H E

1973-10-01

1. The objective was to discover whether the extraction of sugars and iodide from the perfused cerebral ventricles is Na(+)-dependent.2. In the ventriculo-aqueductal and ventriculo-cisternal perfusion systems in the rabbit the extraction of (14)C-labelled D-hexoses (glucose, 3-O-methyl-glucose, alpha-methyl-glucoside and galactose), (131)I(-) and (24)Na was inhibited when 82% of the Na(+) in the perfusion fluid was replaced by choline. The extraction returned to control levels when the Na(+) concentration in the perfusion fluid was returned to normal.3. Ouabain, 5 x 10(-5)M in the perfusion fluid inhibited the extraction of the above (14)C sugars and (131)I(-), but hardly affected that of [(3)H]2-deoxy-D-glucose. It enhanced the extraction of (24)Na. C.s.f. production was usually totally inhibited.4. The extraction of [(14)C]urea remained unchanged during perfusion with low Na(+) fluid or ouabain.5. Recovery from brain of [(14)C]3-O-methyl-glucose, [(3)H]2-deoxy-glucose and (131)I(-) was low while recovery of [(14)C]alpha-methyl-glucoside and (24)Na was high. On an equal weight basis recovery of [(14)C]3-O-methyl-glucose was about twelve times higher from the choroid plexus than from the brain.6. Part of the movement of (14)C sugars may be explained on basis of a Na(+)-gradient hypothesis with involvement of the Na(+) pump at the blood-c.s.f. or blood-brain barriers.7. The rate of c.s.f. production from the first three ventricles comprised about 40% of the rate from all four ventricles. The extraction of sugars, urea and cations was similar in both perfusion systems while the extraction of (131)I(-) was higher in the ventriculo-cisternal system than in the ventriculo-aqueductal system.

[Endoscopic endonasal detection of cerebrospinal fluid leakage with topical fluorescein].

PubMed

Sato, Taku; Kishida, Yugo; Watanabe, Tadashi; Tani, Akiko; Tada, Yasuhiro; Tamura, Takamitsu; Ichikawa, Masahiro; Sakuma, Jun; Omori, Koichi; Saito, Kiyoshi

2013-08-01

We evaluated the effectiveness of intraoperative topical application of fluorescein to detect the leakage point of cerebrospinal fluid(CSF)rhinorrhea. Three patients with CSF rhinorrhea were treated with an endoscopic endonasal technique. Ten percent fluorescein was topically used for intraoperative localization of the leak site. A change of the fluorescein color from brown to green due to dilation of CSF were recognized as evidence of CSF rhinorrhea. We repeated the procedure to detect any small defects. All CSF rhinorrheas were successfully repaired by this endoscopic endonasal approach. Topical application of fluorescein is simple and sensitive for identifying intraoperative CSF rhinorrhea.

Understanding the functions and relationships of the glymphatic system and meningeal lymphatics.

PubMed

Louveau, Antoine; Plog, Benjamin A; Antila, Salli; Alitalo, Kari; Nedergaard, Maiken; Kipnis, Jonathan

2017-09-01

Recent discoveries of the glymphatic system and of meningeal lymphatic vessels have generated a lot of excitement, along with some degree of skepticism. Here, we summarize the state of the field and point out the gaps of knowledge that should be filled through further research. We discuss the glymphatic system as a system that allows CNS perfusion by the cerebrospinal fluid (CSF) and interstitial fluid (ISF). We also describe the recently characterized meningeal lymphatic vessels and their role in drainage of the brain ISF, CSF, CNS-derived molecules, and immune cells from the CNS and meninges to the peripheral (CNS-draining) lymph nodes. We speculate on the relationship between the two systems and their malfunction that may underlie some neurological diseases. Although much remains to be investigated, these new discoveries have changed our understanding of mechanisms underlying CNS immune privilege and CNS drainage. Future studies should explore the communications between the glymphatic system and meningeal lymphatics in CNS disorders and develop new therapeutic modalities targeting these systems.

Orbital cellulitis and brain abscess – rare complications of maxillo-spheno-ethmoidal rhinosinusitis

PubMed Central

Constantin, Farah; Niculescu, Patricia-Alexandra; Petre, Oana; Balasa, Daniel; Tunas, Alexandru; Rusu, Ioana; Lupascu, Mihai; Orodel, Cristiana

2017-01-01

Sinus infections can be complicated by ocular infections and, in late phases, by brain parenchyma infection. The article debates the case of a 12-year-old patient suffering from paucisymptomatic maxillo-spheno-ethmoidal rhinosinusitis, which was later complicated by orbital cellulitis, ending with the development of a brain abscess. The treatment is complex, initially targeting the source of the infection through draining the collection by middle maxillary antrostomy and anterior posterior ethmoidectomy, then the ablation of the brain abscess and postoperatively with prolonged massive antibiotherapy. Abbreviation: URI = upper respiratory infection, CT = computer tomography, MRI = magnetic resonance imaging, BA = brain abscess, VAS = visual scale of pain, ENT = ear, nose, throat, RE VA = right eye visual acuity, RE = right eye, CSF = cerebrospinal fluid PMID:29450387

Direct exposure of guinea pig CNS to human luteinizing hormone increases cerebrospinal fluid and cerebral beta amyloid levels.

PubMed

Wahjoepramono, Eka J; Wijaya, Linda K; Taddei, Kevin; Bates, Kristyn A; Howard, Matthew; Martins, Georgia; deRuyck, Karl; Matthews, Paul M; Verdile, Giuseppe; Martins, Ralph N

2011-01-01

Luteinizing hormone (LH) has been shown to alter the metabolism of beta amyloid (Aβ), a key protein in Alzheimer's disease (AD) pathogenesis. While LH and components required for LH receptor signalling are present in the brain, their role in the CNS remains unclear. In vitro, LH has been shown to facilitate neurosteroid production and alter Aβ metabolism. However, whether LH can directly modulate cerebral Aβ levels in vivo has not previously been studied. In this study, we investigated the effect of chronic administration of LH to the guinea pig CNS on cerebral Aβ levels. Gonadectomised male animals were administered, via cortical placement, either placebo or LH slow-release pellets. At 14 and 28 days after treatment, animals were sacrificed. Brain, plasma and CSF were collected and Aβ levels measured via ELISA. Levels of the Aβ precursor protein (APP) and the neurosteroidogenic enzyme cytochrome P450 side-chain cleavage enzyme (P450scc) were also assayed. An increase in CSF Aβ40 levels was observed 28 days following treatment. These CSF data also reflected changes in Aβ40 levels observed in brain homogenates. No change was observed in plasma Aβ40 levels but APP and its C-terminal fragments (APP-CTF) were significantly increased in response to LH exposure. Protein expression of P450scc was increased after 28 days of LH exposure, suggesting activation of the LH receptor. These data indicate that direct exposure of guinea pig CNS to LH results in altered brain Aβ levels, perhaps due to altered APP expression/metabolism. Copyright © 2011 S. Karger AG, Basel.

First evidence of the conversion of paracetamol to AM404 in human cerebrospinal fluid

PubMed Central

Sharma, Chhaya V; Long, Jamie H; Shah, Seema; Rahman, Junia; Perrett, David; Ayoub, Samir S; Mehta, Vivek

2017-01-01

Paracetamol is arguably the most commonly used analgesic and antipyretic drug worldwide, however its mechanism of action is still not fully established. It has been shown to exert effects through multiple pathways, some actions suggested to be mediated via N-arachidonoylphenolamine (AM404). AM404, formed through conjugation of paracetamol-derived p-aminophenol with arachidonic acid in the brain, is an activator of the capsaicin receptor, TRPV1, and inhibits the reuptake of the endocannabinoid, anandamide, into postsynaptic neurons, as well as inhibiting synthesis of PGE2 by COX-2. However, the presence of AM404 in the central nervous system following administration of paracetamol has not yet been demonstrated in humans. Cerebrospinal fluid (CSF) and blood were collected from 26 adult male patients between 10 and 211 minutes following intravenous administration of 1 g of paracetamol. Paracetamol was measured by high-performance liquid chromatography with UV detection. AM404 was measured by liquid chromatography-tandem mass spectrometry. AM404 was detected in 17 of the 26 evaluable CSF samples at 5–40 nmol⋅L−1. Paracetamol was measurable in CSF within 10 minutes, with a maximum measured concentration of 60 μmol⋅L−1 at 206 minutes. This study is the first to report on the presence of AM404 in human CSF following paracetamol administration. This may represent an important finding in our understanding of paracetamol’s mechanism of action, although measured concentrations were far below the previously documented IC50 for this metabolite. PMID:29238213

The Effect of Body Posture on Brain Glymphatic Transport.

PubMed

Lee, Hedok; Xie, Lulu; Yu, Mei; Kang, Hongyi; Feng, Tian; Deane, Rashid; Logan, Jean; Nedergaard, Maiken; Benveniste, Helene

2015-08-05

The glymphatic pathway expedites clearance of waste, including soluble amyloid β (Aβ) from the brain. Transport through this pathway is controlled by the brain's arousal level because, during sleep or anesthesia, the brain's interstitial space volume expands (compared with wakefulness), resulting in faster waste removal. Humans, as well as animals, exhibit different body postures during sleep, which may also affect waste removal. Therefore, not only the level of consciousness, but also body posture, might affect CSF-interstitial fluid (ISF) exchange efficiency. We used dynamic-contrast-enhanced MRI and kinetic modeling to quantify CSF-ISF exchange rates in anesthetized rodents' brains in supine, prone, or lateral positions. To validate the MRI data and to assess specifically the influence of body posture on clearance of Aβ, we used fluorescence microscopy and radioactive tracers, respectively. The analysis showed that glymphatic transport was most efficient in the lateral position compared with the supine or prone positions. In the prone position, in which the rat's head was in the most upright position (mimicking posture during the awake state), transport was characterized by "retention" of the tracer, slower clearance, and more CSF efflux along larger caliber cervical vessels. The optical imaging and radiotracer studies confirmed that glymphatic transport and Aβ clearance were superior in the lateral and supine positions. We propose that the most popular sleep posture (lateral) has evolved to optimize waste removal during sleep and that posture must be considered in diagnostic imaging procedures developed in the future to assess CSF-ISF transport in humans. The rodent brain removes waste better during sleep or anesthesia compared with the awake state. Animals exhibit different body posture during the awake and sleep states, which might affect the brain's waste removal efficiency. We investigated the influence of body posture on brainwide transport of inert tracers of anesthetized rodents. The major finding of our study was that waste, including Aβ, removal was most efficient in the lateral position (compared with the prone position), which mimics the natural resting/sleeping position of rodents. Although our finding awaits testing in humans, we speculate that the lateral position during sleep has advantage with regard to the removal of waste products including Aβ, because clinical studies have shown that sleep drives Aβ clearance from the brain. Copyright © 2015 the authors 0270-6474/15/3511034-11$15.00/0.

The Influence of Body Position on Cerebrospinal Fluid Pressure Gradient and Movement in Cats with Normal and Impaired Craniospinal Communication

PubMed Central

Radoš, Milan; Erceg, Gorislav; Petošić, Antonio; Jurjević, Ivana

2014-01-01

Intracranial hypertension is a severe therapeutic problem, as there is insufficient knowledge about the physiology of cerebrospinal fluid (CSF) pressure. In this paper a new CSF pressure regulation hypothesis is proposed. According to this hypothesis, the CSF pressure depends on the laws of fluid mechanics and on the anatomical characteristics inside the cranial and spinal space, and not, as is today generally believed, on CSF secretion, circulation and absorption. The volume and pressure changes in the newly developed CSF model, which by its anatomical dimensions and basic biophysical features imitates the craniospinal system in cats, are compared to those obtained on cats with and without the blockade of craniospinal communication in different body positions. During verticalization, a long-lasting occurrence of negative CSF pressure inside the cranium in animals with normal cranio-spinal communication was observed. CSF pressure gradients change depending on the body position, but those gradients do not enable unidirectional CSF circulation from the hypothetical site of secretion to the site of absorption in any of them. Thus, our results indicate the existence of new physiological/pathophysiological correlations between intracranial fluids, which opens up the possibility of new therapeutic approaches to intracranial hypertension. PMID:24748150

The Paravascular Pathway for Brain Waste Clearance: Current Understanding, Significance and Controversy.

PubMed

Bacyinski, Andrew; Xu, Maosheng; Wang, Wei; Hu, Jiani

2017-01-01

The paravascular pathway, also known as the "glymphatic" pathway, is a recently described system for waste clearance in the brain. According to this model, cerebrospinal fluid (CSF) enters the paravascular spaces surrounding penetrating arteries of the brain, mixes with interstitial fluid (ISF) and solutes in the parenchyma, and exits along paravascular spaces of draining veins. Studies have shown that metabolic waste products and solutes, including proteins involved in the pathogenesis of neurodegenerative diseases such as amyloid-beta, may be cleared by this pathway. Consequently, a growing body of research has begun to explore the association between glymphatic dysfunction and various disease states. However, significant controversy exists in the literature regarding both the direction of waste clearance as well as the anatomical space in which the waste-fluid mixture is contained. Some studies have found no evidence of interstitial solute clearance along the paravascular space of veins. Rather, they demonstrate a perivascular pathway in which waste is cleared from the brain along an anatomically distinct perivascular space in a direction opposite to that of paravascular flow. Although possible explanations have been offered, none have been able to fully reconcile the discrepancies in the literature, and many questions remain. Given the therapeutic potential that a comprehensive understanding of brain waste clearance pathways might offer, further research and clarification is highly warranted.

Investigating structural brain changes of dehydration using voxel-based morphometry.

PubMed

Streitbürger, Daniel-Paolo; Möller, Harald E; Tittgemeyer, Marc; Hund-Georgiadis, Margret; Schroeter, Matthias L; Mueller, Karsten

2012-01-01

Dehydration can affect the volume of brain structures, which might imply a confound in volumetric and morphometric studies of normal or diseased brain. Six young, healthy volunteers were repeatedly investigated using three-dimensional T(1)-weighted magnetic resonance imaging during states of normal hydration, hyperhydration, and dehydration to assess volume changes in gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF). The datasets were analyzed using voxel-based morphometry (VBM), a widely used voxel-wise statistical analysis tool, FreeSurfer, a fully automated volumetric segmentation measure, and SIENAr a longitudinal brain-change detection algorithm. A significant decrease of GM and WM volume associated with dehydration was found in various brain regions, most prominently, in temporal and sub-gyral parietal areas, in the left inferior orbito-frontal region, and in the extra-nuclear region. Moreover, we found consistent increases in CSF, that is, an expansion of the ventricular system affecting both lateral ventricles, the third, and the fourth ventricle. Similar degrees of shrinkage in WM volume and increase of the ventricular system have been reported in studies of mild cognitive impairment or Alzheimer's disease during disease progression. Based on these findings, a potential confound in GM and WM or ventricular volume studies due to the subjects' hydration state cannot be excluded and should be appropriately addressed in morphometric studies of the brain.

Investigating Structural Brain Changes of Dehydration Using Voxel-Based Morphometry

PubMed Central

Streitbürger, Daniel-Paolo; Möller, Harald E.; Tittgemeyer, Marc; Hund-Georgiadis, Margret; Schroeter, Matthias L.; Mueller, Karsten

2012-01-01

Dehydration can affect the volume of brain structures, which might imply a confound in volumetric and morphometric studies of normal or diseased brain. Six young, healthy volunteers were repeatedly investigated using three-dimensional T 1-weighted magnetic resonance imaging during states of normal hydration, hyperhydration, and dehydration to assess volume changes in gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF). The datasets were analyzed using voxel-based morphometry (VBM), a widely used voxel-wise statistical analysis tool, FreeSurfer, a fully automated volumetric segmentation measure, and SIENAr a longitudinal brain-change detection algorithm. A significant decrease of GM and WM volume associated with dehydration was found in various brain regions, most prominently, in temporal and sub-gyral parietal areas, in the left inferior orbito-frontal region, and in the extra-nuclear region. Moreover, we found consistent increases in CSF, that is, an expansion of the ventricular system affecting both lateral ventricles, the third, and the fourth ventricle. Similar degrees of shrinkage in WM volume and increase of the ventricular system have been reported in studies of mild cognitive impairment or Alzheime s disease during disease progression. Based on these findings, a potential confound in GM and WM or ventricular volume studies due to the subjects’ hydration state cannot be excluded and should be appropriately addressed in morphometric studies of the brain. PMID:22952926

Cerebrospinal Fluid Mechanics and Its Coupling to Cerebrovascular Dynamics

NASA Astrophysics Data System (ADS)

Linninger, Andreas A.; Tangen, Kevin; Hsu, Chih-Yang; Frim, David

2016-01-01

Cerebrospinal fluid (CSF) is not stagnant but displays fascinating oscillatory flow patterns inside the ventricular system and reversing fluid exchange between the cranial vault and spinal compartment. This review provides an overview of the current knowledge of pulsatile CSF motion. Observations contradicting classical views about its bulk production and clearance are highlighted. A clinical account of diseases of abnormal CSF flow dynamics, including hydrocephalus, syringomyelia, Chiari malformation type 1, and pseudotumor cerebri, is also given. We survey medical imaging modalities used to observe intracranial dynamics in vivo. Additionally, we assess the state of the art in predictive models of CSF dynamics. The discussion addresses open questions regarding CSF dynamics as they relate to the understanding and management of diseases.

Platelet-derived growth factor predicts prolonged relapse-free period in multiple sclerosis.

PubMed

Stampanoni Bassi, Mario; Iezzi, Ennio; Marfia, Girolama A; Simonelli, Ilaria; Musella, Alessandra; Mandolesi, Georgia; Fresegna, Diego; Pasqualetti, Patrizio; Furlan, Roberto; Finardi, Annamaria; Mataluni, Giorgia; Landi, Doriana; Gilio, Luana; Centonze, Diego; Buttari, Fabio

2018-04-14

In the early phases of relapsing-remitting multiple sclerosis (RR-MS), a clear correlation between brain lesion load and clinical disability is often lacking, originating the so-called clinico-radiological paradox. Different factors may contribute to such discrepancy. In particular, synaptic plasticity may reduce the clinical expression of brain damage producing enduring enhancement of synaptic strength largely dependent on neurotrophin-induced protein synthesis. Cytokines released by the immune cells during acute inflammation can alter synaptic transmission and plasticity possibly influencing the clinical course of MS. In addition, immune cells may promote brain repair during the post-acute phases, by secreting different growth factors involved in neuronal and oligodendroglial cell survival. Platelet-derived growth factor (PDGF) is a neurotrophic factor that could be particularly involved in clinical recovery. Indeed, PDGF promotes long-term potentiation of synaptic activity in vitro and in MS and could therefore represent a key factor improving the clinical compensation of new brain lesions. The aim of the present study is to explore whether cerebrospinal fluid (CSF) PDGF concentrations at the time of diagnosis may influence the clinical course of RR-MS. At the time of diagnosis, we measured in 100 consecutive early MS patients the CSF concentrations of PDGF, of the main pro- and anti-inflammatory cytokines, and of reliable markers of neuronal damage. Clinical and radiological parameters of disease activity were prospectively collected during follow-up. CSF PDGF levels were positively correlated with prolonged relapse-free survival. Radiological markers of disease activity, biochemical markers of neuronal damage, and clinical parameters of disease progression were instead not influenced by PDGF concentrations. Higher CSF PDGF levels were associated with an anti-inflammatory milieu within the central nervous system. Our results suggest that PDGF could promote a more prolonged relapse-free period during the course of RR-MS, without influencing inflammation reactivation and inflammation-driven neuronal damage and likely enhancing adaptive plasticity.

Two-dimensional finite element modelling of the neonatal head.

PubMed

Gibson, A; Bayford, R H; Holder, D S

2000-02-01

Electrical impedance tomography (EIT) could allow the early diagnosis of infant brain injury following birth asphyxia. The purpose of this work was to determine the effect of variations in skull, scalp or cerebrospinal fluid (CSF) resistivity, as these vary in clinical conditions and could degrade image quality. These factors were investigated using finite element models of the adult and neonatal head. The results suggest that there is a wide range over which the resistivity of the neonatal skull has little effect on the sensitivity to a central impedance change. The scalp and CSF appear to shunt current away from the brain; when their resistivity was decreased from normal values, this shunting effect increased and caused a decrease in sensitivity to a central resistance change. The resistivity of neonatal skull has not, to our knowledge, been directly measured and will anyway vary within and between individuals; this work suggests that EIT will be relatively insensitive to variations in neonatal skull impedance.

Antiretroviral Therapy and Central Nervous System HIV-1 Infection

PubMed Central

Price, Richard W.; Spudich, Serena

2008-01-01

Central nervous system (CNS) HIV-1 infection begins during primary viremia and continues throughout the course of untreated systemic infection. While frequently accompanied by local inflammatory reactions detectable in cerebrospinal fluid (CSF), CNS HIV-1 infection is not usually clinically apparent. In a minority of patients, CNS HIV-1 infection evolves late in the course of systemic infection into encephalitis, which compromises brain function and presents clinically as AIDS dementia complex (ADC). Combination highly active antiretroviral therapy (HAART) has had a major impact on all aspects of HIV-1 CNS infection and disease. In those with asymptomatic infection, HAART usually effectively suppresses CSF HIV-1 and markedly reduces the incidence of symptomatic ADC. In those presenting with ADC, HAART characteristically prevents neurological progression and leads to variable, and at times substantial, recovery. Treatment has similarly reduced CNS opportunistic infections. With better control of these severe disorders, attention has turned to the possible consequences of chronic silent infection, and the issue of whether indolent, low-grade brain injury might require earlier treatment intervention. PMID:18447615

Quantitative analysis of multiple sclerosis: a feasibility study

NASA Astrophysics Data System (ADS)

Li, Lihong; Li, Xiang; Wei, Xinzhou; Sturm, Deborah; Lu, Hongbing; Liang, Zhengrong

2006-03-01

Multiple Sclerosis (MS) is an inflammatory and demyelinating disorder of the central nervous system with a presumed immune-mediated etiology. For treatment of MS, the measurements of white matter (WM), gray matter (GM), and cerebral spinal fluid (CSF) are often used in conjunction with clinical evaluation to provide a more objective measure of MS burden. In this paper, we apply a new unifying automatic mixture-based algorithm for segmentation of brain tissues to quantitatively analyze MS. The method takes into account the following effects that commonly appear in MR imaging: 1) The MR data is modeled as a stochastic process with an inherent inhomogeneity effect of smoothly varying intensity; 2) A new partial volume (PV) model is built in establishing the maximum a posterior (MAP) segmentation scheme; 3) Noise artifacts are minimized by a priori Markov random field (MRF) penalty indicating neighborhood correlation from tissue mixture. The volumes of brain tissues (WM, GM) and CSF are extracted from the mixture-based segmentation. Experimental results of feasibility studies on quantitative analysis of MS are presented.

Purulent meningoventriculitis caused by Streptococcus equi subspecies zooepidemicus in a snow leopard (Panthera uncia).

PubMed

Yamaguchi, R; Nakamura, S; Hori, H; Kato, Y; Une, Y

2012-01-01

Streptococcus equi subspecies zooepidemicus (SEZ) is a zoonotic pathogen that causes respiratory tract infections in man and animals. SEZ infections are very rare in felids. This report describes purulent meningoventriculitis caused by SEZ in an approximately 16-year-old male snow leopard (Panthera uncia). The animal exhibited neurological signs and died 1 month after their onset. On necropsy examination, the surface blood vessels of the brain were swollen and there was an increased volume and turbidity of cerebrospinal fluid (CSF). Microscopically, suppurative inflammation accompanied by gram-positive cocci was observed in the meninges and near the ventricles. SEZ was isolated from the brain tissue and CSF. This is the first report of infection with SEZ in a felid other than a domestic cat. This animal had not had direct contact with horses, but it had been fed horse flesh that may have been the source of infection. Copyright © 2012 Elsevier Ltd. All rights reserved.

Trans-nasal-trans-sphenoidal brain injury by a fencing foil: an unusual case report and brief literature review.

PubMed

Özay, Rafet; Balkan, Mehmet S; Tönge, Çağhan; Şekerci, Zeki

2017-11-01

In this report, the authors present an unusual case of a 10-year-old child who suffered a severe headache and rhinorrhea that occurred as a result of fencing foil sports injury via trans-nasal-trans-sphenoidal (TNTS) pathway. Following trauma, the child had shown neurological symptoms such a pupil dilatation, change in consciousness and mild hemiparesia. Imaging demonstrated destruction of bone structures including posterior wall of sphenoid sinus and antero-superior part of sella turcica, and also a contusion at right thalamic region. For treatment of rhinorrhea lumbar drainage system (LDS) had planted in order to relieve cerebrospinal fluid (CSF) leakage. After the treatment, the patient had fully recovered without any need of further surgical intervention. CSF leakage had prevented and neurological symptoms were completely treated. This case represents the first report of brain injury via TNTS pathway in a sports practice. Diagnosis, clinic follow-up and treatment options of this rare accidental sports injury are discussed.

Increased cerebrospinal fluid complement C5 levels in major depressive disorder and schizophrenia.

PubMed

Ishii, Takashi; Hattori, Kotaro; Miyakawa, Tomoko; Watanabe, Kentaro; Hidese, Shinsuke; Sasayama, Daimei; Ota, Miho; Teraishi, Toshiya; Hori, Hiroaki; Yoshida, Sumiko; Nunomura, Akihiko; Nakagome, Kazuyuki; Kunugi, Hiroshi

2018-03-04

Inflammation has been implicated in a variety of psychiatric disorders. We aimed to determine whether levels of complement C5 protein in the cerebrospinal fluid (CSF), which may reflect activation of the complement system in the brain, are altered in patients with major psychiatric disorders. Additionally, we examined possible associations of CSF C5 levels with clinical variables. Subjects comprised 89 patients with major depressive disorder (MDD), 66 patients with bipolar disorder (BPD), 96 patients with schizophrenia, and 117 healthy controls, matched for age, sex, and ethnicity (Japanese). Diagnosis was made according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, criteria. CSF C5 levels were measured by enzyme-linked immunosorbent assay. CSF C5 levels were significantly increased in the patients with MDD (p < 0.001) and in the patients with schizophrenia (p = 0.001), compared with the healthy controls. The rate of individuals with an "abnormally high C5 level" (i.e., above the 95th percentile value of the control subjects) was significantly increased in all psychiatric groups, relative to the control group (all p < 0.01). Older age, male sex, and greater body mass index tended to associate with higher C5 levels. There was a significantly positive correlation between C5 levels and chlorpromazine-equivalent dose in the patients with schizophrenia. Thus, we found, for the first time, elevated C5 levels in the CSF of patients with major psychiatric disorders. Our results suggest that the activated complement system may contribute to neurological pathogenesis in a portion of patients with major psychiatric disorders. Copyright © 2018 Elsevier Inc. All rights reserved.

Cerebrospinal Fluid Levels of Monoamine Metabolites in the Epileptic Baboon

PubMed Central

Szabó, C. Ákos; Patel, Mayuri; Uteshev, Victor V.

2016-01-01

The baboon represents a natural model for genetic generalized epilepsy and sudden unexpected death in epilepsy (SUDEP). In this retrospective study, cerebrospinal fluid (CSF) monoamine metabolites and scalp electroencephalography (EEG) were evaluated in 263 baboons of a pedigreed colony. CSF monoamine abnormalities have been linked to reduced seizure thresholds, behavioral abnormalities and SUDEP in various animal models of epilepsy. The levels of 3-hydroxy-4-methoxyphenylglycol, 5-hydroxyindolacetic acid and homovanillic acid in CSF samples drawn from the cisterna magna were analyzed using high-performance liquid chromatography. These levels were compared between baboons with seizures (SZ), craniofacial trauma (CFT) and asymptomatic, control (CTL) baboons, between baboons with abnormal and normal EEG studies. We hypothesized that the CSF levels of major monoaminergic metabolites (i.e., dopamine, serotonin and norepinephrine) associate with the baboons’ electroclinical status and thus can be used as clinical biomarkers applicable to seizures/epilepsy. However, despite apparent differences in metabolite levels between the groups, usually lower in SZ and CFT baboons and in baboons with abnormal EEG studies, we did not find any statistically significant differences using a logistic regression analysis. Significant correlations between the metabolite levels, especially between 5-HIAA and HVA, were preserved in all electroclinical groups. While we were not able to demonstrate significant differences in monoamine metabolites in relation to seizures or EEG markers of epilepsy, we cannot exclude the monoaminergic system as a potential source of pathogenesis in epilepsy and SUDEP. A prospective study evaluating serial CSF monoamine levels in baboons with recently witnessed seizures, and evaluation of abnormal expression and function of monoaminergic receptors and transporters within epilepsy-related brain regions, may impact the electroclinical status. PMID:26924854

Cerebrospinal fluid inflammatory markers in patients with multiple sclerosis: a pilot study.

PubMed

Matejčíková, Z; Mareš, J; Přikrylová Vranová, H; Klosová, J; Sládková, V; Doláková, J; Zapletalová, J; Kaňovský, P

2015-02-01

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Autoimmune inflammation is common in the early stages of MS. This stage is followed by the neurodegenerative process. The result of these changes is axon and myelin breakdown. Although MS is according to McDonald's revised diagnostic criteria primarily a clinical diagnosis, paraclinical investigation methods are an important part in the diagnosis of MS. In common practice, magnetic resonance imaging of the brain and spinal cord, examination of cerebrospinal fluid (CSF) and examination of visual evoked potentials are used. There are an increasing number of studies dealing with biomarkers in CSF and their role in the diagnosis and treatment of MS. We hypothesized that the levels of some markers could be changed in MS in comparison with controls. We studied five inflammatory markers [interleukin-6 (IL-6), interleukin-8, interleukin-10 (IL-10), beta-2-microglobulin, orosomucoid]. CSF and serum levels of inflammatory markers were assessed in 38 patients with newly diagnosed MS meeting McDonald's revised diagnostic criteria and in 28 subjects as a control group (CG). Levels of beta-2-microglobulin and interleukin-8 in CSF were found to be significantly higher in MS patients in comparison to CG (p < 0.001 resp. p = 0.007). No differences in other CSF markers (IL-6, IL-10 and orosomucoid) and serum levels of all markers between both groups were found. The levels of two studied inflammatory markers were found to be increased at the time of first clinical symptoms of MS. Research on the role of inflammatory and neurodegenerative markers in MS should continue.

Oligoclonal bands in the cerebrospinal fluid of amyotrophic lateral sclerosis patients with disease-associated mutations.

PubMed

Ticozzi, Nicola; Tiloca, Cinzia; Mencacci, Niccolò E; Morelli, Claudia; Doretti, Alberto; Rusconi, Daniela; Colombrita, Claudia; Sangalli, Davide; Verde, Federico; Finelli, Palma; Messina, Stefano; Ratti, Antonia; Silani, Vincenzo

2013-01-01

In amyotrophic lateral sclerosis (ALS) cerebrospinal fluid (CSF) analysis is usually performed to exclude inflammatory processes of the central nervous system. Although in a small subset of patients an intrathecal synthesis of IgG is detectable, usually there is no clear explanation for this evidence. This study investigates the occurrence of oligoclonal bands (OCBs) in the CSF of a large series of ALS patients, attempting a correlation with genotype data. CSF was collected from 259 ALS patients. CSF parameters were measured according to standard procedures, and detection of OCBs performed by isoelectric focusing. The patients were screened for mutations in SOD1, FUS, TARDBP, ANG, OPTN, and C9ORF72. We observed the presence of OCBs in the CSF of 9/259 ALS patients (3.5 %), and of disease-associated mutations in 12 cases. OCBs were significantly more frequent in mutation carriers compared to the remaining cohort (3/12 vs 6/247; p < 0.01). Among patients with OCBs, two patients had the TARDBP p.A382T mutation (one of which in homozygous state), and one the ANG p.P-4S variant. Both patients carrying the p.A382T mutation had an atypical phenotype, one of them manifesting signs suggestive of a cerebellar involvement, and the other presenting neuroradiological findings suggestive of an inflammatory disorder of the central nervous system. Our results suggest that ALS patients with OCBs may harbor mutations in disease-causing genes. We speculate that mutations in both TARDBP and ANG genes may disrupt the blood-brain barrier (BBB), promoting local immune responses and neuroinflammation. The role of mutant TARDBP and ANG genes on BBB integrity of ALS patients warrants further investigation.

Ptau-Aβ42 ratio as a continuous trait for biomarker discovery for early stage Alzheimer’s disease in multiplex immunoassay panels of Cerebrospinal fluid

PubMed Central

Harari, Oscar; Cruchaga, Carlos; Kauwe, John S.K.; Ainscough, Benjamin J.; Bales, Kelly; Pickering, Eve H.; Bertelsen, Sarah; Fagan, Anne M.; Holtzman, David M.; Morris, John C.; Goate, Alison M.

2014-01-01

Background Identification of the physiological changes that occur during the early stages of Alzheimer’s disease (AD) may provide critical insights for the diagnosis, prognosis and treatment of disease. Cerebrospinal fluid (CSF) biomarkers are a rich source of information that reflect the brain proteome. Methods We applied a novel approach to screen a panel of ~190 CSF analytes quantified by multiplex immunoassay and detected common associations in the Knight- Alzheimer’s Disease Research Center (ADRC;N=311) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI;N=293) cohorts. CSF ptau181-Aβ42 ratio was used as a continuous trait, rather than case control status in these analyses. Results We demonstrate the ptau181-Aβ42 ratio has more statistical power than traditional modeling approaches and that the levels of CSF Fatty Acid Binding Protein (H-FABP) and 12 other correlated analytes increase as the disease progresses. These results were validated using the traditional case control status model. Stratification of our dataset demonstrated that increases in these analytes occur very early in the disease course and were apparent even in non-demented individuals with AD pathology (low ptau181, low Aβ42) compared to pathology-negative elderly control subjects (low ptau181, high Aβ42). FABP-Aβ42 ratio demonstrates a similar hazard ratio for disease conversion to ptau181-Aβ42 even though the overlap in classification is incomplete suggesting that FABP contributes independent information as a predictor Conclusions Our results clearly indicate that the approach presented here can be employed to correctly identify novel biomarkers for AD, and that CSF H-FABP levels start to increase at very early stages of the disease. PMID:24548642

Age-Related Decrease in Heat Shock 70-kDa Protein 8 in Cerebrospinal Fluid Is Associated with Increased Oxidative Stress.

PubMed

Loeffler, David A; Klaver, Andrea C; Coffey, Mary P; Aasly, Jan O; LeWitt, Peter A

2016-01-01

Age-associated declines in protein homeostasis mechanisms ("proteostasis") are thought to contribute to age-related neurodegenerative disorders. The increased oxidative stress which occurs with aging can activate a key proteostatic process, chaperone-mediated autophagy. This study investigated age-related alteration in cerebrospinal fluid (CSF) concentrations of heat shock 70-kDa protein 8 (HSPA8), a molecular chaperone involved in proteostatic mechanisms including chaperone-mediated autophagy, and its associations with indicators of oxidative stress (8-hydroxy-2'-deoxyguanosine [8-OHdG] and 8-isoprostane) and total anti-oxidant capacity. We examined correlations between age, HSPA8, 8-OHdG, 8-isoprostane, and total antioxidant capacity (TAC) in CSF samples from 34 healthy subjects ranging from 20 to 75 years of age. Age was negatively associated with HSPA8 (ρ = -0.47; p = 0.005). An age-related increase in oxidative stress was indicated by a positive association between age and 8-OHdG (ρ = 0.61; p = 0.0001). HSPA8 was moderately negatively associated with 8-OHdG (ρ = -0.58; p = 0.0004). Age and HSPA8 were weakly associated with 8-isoprostane and TAC (range of ρ values: -0.15 to 0.16). Our findings in this exploratory study suggest that during healthy aging, CSF HSPA8 may decrease, perhaps due in part to an increase in oxidative stress. Our results also suggest that 8-OHdG may be more sensitive than 8-isoprostane for measuring oxidative stress in CSF. Further studies are indicated to determine if our findings can be replicated with a larger cohort, and if the age-related decrease in HSPA8 in CSF is reflected by a similar change in the brain.

Age-Related Decrease in Heat Shock 70-kDa Protein 8 in Cerebrospinal Fluid Is Associated with Increased Oxidative Stress

PubMed Central

Loeffler, David A.; Klaver, Andrea C.; Coffey, Mary P.; Aasly, Jan O.; LeWitt, Peter A.

2016-01-01

Age-associated declines in protein homeostasis mechanisms (“proteostasis”) are thought to contribute to age-related neurodegenerative disorders. The increased oxidative stress which occurs with aging can activate a key proteostatic process, chaperone-mediated autophagy. This study investigated age-related alteration in cerebrospinal fluid (CSF) concentrations of heat shock 70-kDa protein 8 (HSPA8), a molecular chaperone involved in proteostatic mechanisms including chaperone-mediated autophagy, and its associations with indicators of oxidative stress (8-hydroxy-2′-deoxyguanosine [8-OHdG] and 8-isoprostane) and total anti-oxidant capacity. We examined correlations between age, HSPA8, 8-OHdG, 8-isoprostane, and total antioxidant capacity (TAC) in CSF samples from 34 healthy subjects ranging from 20 to 75 years of age. Age was negatively associated with HSPA8 (ρ = –0.47; p = 0.005). An age-related increase in oxidative stress was indicated by a positive association between age and 8-OHdG (ρ = 0.61; p = 0.0001). HSPA8 was moderately negatively associated with 8-OHdG (ρ = –0.58; p = 0.0004). Age and HSPA8 were weakly associated with 8-isoprostane and TAC (range of ρ values: –0.15 to 0.16). Our findings in this exploratory study suggest that during healthy aging, CSF HSPA8 may decrease, perhaps due in part to an increase in oxidative stress. Our results also suggest that 8-OHdG may be more sensitive than 8-isoprostane for measuring oxidative stress in CSF. Further studies are indicated to determine if our findings can be replicated with a larger cohort, and if the age-related decrease in HSPA8 in CSF is reflected by a similar change in the brain. PMID:27507943

Selective increase of cerebrospinal fluid IL-6 during experimental systemic inflammation in humans: association with depressive symptoms.

PubMed

Engler, H; Brendt, P; Wischermann, J; Wegner, A; Röhling, R; Schoemberg, T; Meyer, U; Gold, R; Peters, J; Benson, S; Schedlowski, M

2017-10-01

Systemic inflammation is accompanied by profound behavioral and mood changes that resemble symptoms of depression. Findings in animals suggest that pro-inflammatory cytokines released by activated immune cells in the periphery evoke these behavioral symptoms by driving inflammatory changes in the brain. However, experimental data in humans are lacking. Here we demonstrate in healthy male volunteers (10 endotoxin treated, 8 placebo treated) that intravenous administration of low-dose endotoxin (0.8 ng/kg body weight), a prototypical pathogen-associated molecular pattern that activates the innate immune system, not only induces a significant increase in peripheral blood cytokine concentrations (that is, tumor necrosis factor-α, interleukin (IL)-6, IL-10) but also results, with some latency, in a robust and selective increase of IL-6 in the cerebrospinal fluid (CSF). Moreover, we found a strong association between the endotoxin-induced increase of IL-6 in the CSF and the severity of mood impairment, with larger increases in CSF IL-6 concentration followed by a greater deterioration in mood. Taken together, these findings suggest that the appearance of depressive symptoms in inflammatory conditions might be primarily linked to an increase in central IL-6 concentration, identifying IL-6 as a potential therapeutic target in mood disorders.

A new liquid chromatography-mass spectrometry-based method to quantitate exogenous recombinant transferrin in cerebrospinal fluid: a potential approach for pharmacokinetic studies of transferrin-based therapeutics in the central nervous systems.

PubMed

Wang, Shunhai; Bobst, Cedric E; Kaltashov, Igor A

2015-01-01

Transferrin (Tf) is an 80 kDa iron-binding protein that is viewed as a promising drug carrier to target the central nervous system as a result of its ability to penetrate the blood-brain barrier. Among the many challenges during the development of Tf-based therapeutics, the sensitive and accurate quantitation of the administered Tf in cerebrospinal fluid (CSF) remains particularly difficult because of the presence of abundant endogenous Tf. Herein, we describe the development of a new liquid chromatography-mass spectrometry-based method for the sensitive and accurate quantitation of exogenous recombinant human Tf in rat CSF. By taking advantage of a His-tag present in recombinant Tf and applying Ni affinity purification, the exogenous human serum Tf can be greatly enriched from rat CSF, despite the presence of the abundant endogenous protein. Additionally, we applied a newly developed (18)O-labeling technique that can generate internal standards at the protein level, which greatly improved the accuracy and robustness of quantitation. The developed method was investigated for linearity, accuracy, precision, and lower limit of quantitation, all of which met the commonly accepted criteria for bioanalytical method validation.

Dihydroxyphenylglycol as a Biomarker of Norepinephrine Transporter Inhibition by Atomoxetine: Human Model to Assess Central and Peripheral Effects of Dosing.

PubMed

Bieck, Peter R; Leibowitz, Mark; Lachno, D Richard; Ledent, Edouard; Padich, Robert; Jhee, Stan

2016-12-01

To assess the primary metabolite of norepinephrine, 3,4-dihydroxyphenylglycol (DHPG), as a sensitive biomarker for norepinephrine transporter (NET) function and the relationship of DHPG measured peripherally and centrally, NET was antagonized with 80 mg/d atomoxetine for 18 days. Twelve healthy subjects were treated with atomoxetine in an open-label, multiple-dose exploratory study. Plasma atomoxetine reached steady state by day 6, and the pharmacokinetic results demonstrated availability of atomoxetine to the central nervous system. The cerebrospinal fluid (CSF)/plasma ratios of atomoxetine based on area under concentration-time curve from 0 to 12 hours postdose (AUC0-12), maximum concentration (Cmax), and predose were 0.3%, 0.2%, and 11%, respectively. Plasma from atomoxetine-treated subjects (ex vivo) significantly inhibited radioligand binding to human NET (P < 0.001) only 1 hour after dosing. Plasma DHPG and DHPG/norepinephrine (ratio) during repeated posture tests were reduced significantly (P < 0.001) on day 5 and stayed significantly reduced up to 1 day after treatment. In CSF, both DHPG and the ratio were significantly reduced (P < 0.001) on day 18. Urine results showed significant decreases for both DHPG and the ratio (P = 0.010 to P < 0.001). Brain-derived neurotrophic factor in CSF was lesser than the limits of detection. The findings suggest that NET blockade can be assessed with DHPG concentration or with the ratio in plasma, CSF, and urine. The data suggest that DHPG is a useful biomarker to proactively assess the pharmacological activity of compounds intended to inhibit NET activity within the brain. The study shows that CSF is a medium for early identification and quantification of biomarkers useful in assessing novel neuroscience targets.

Impact of APOE4-CSF Aβ interaction on hippocampal volume loss over 1 year in MCI

PubMed Central

Chiang, G.C.; Insel, P.S.; Tosun, D.; Schuff, N.; Truran-Sacrey, D.; Raptentsetsang, S.T.; Thompson, P.M.; Reiman, E.M.; Jack, C.R.; Fox, N.C.; Jagust, W.J.; Harvey, D.J.; Beckett, L.A.; Gamst, A.; Aisen, P.S.; Petersen, R.C.; Weiner, M.W.

2011-01-01

Background The majority of studies relating amyloid pathology with brain volumes have been cross-sectional. Apolipoprotein E4 (APOE4), a genetic risk factor for Alzheimer’s disease (AD), is also associated with hippocampal volume loss. No studies have considered the effects of amyloid pathology and APOE4 together on longitudinal volume loss. Methods We evaluated whether an abnormal level of cerebrospinal fluid beta-amyloid (CSF Aβ) and APOE4 carrier status were independently associated with greater hippocampal volume loss over 1 year. We then assessed whether APOE4 status and CSF Aβ acted synergistically, testing the significance of an interaction term in the regression analysis. We included 297 participants: 77 cognitively normal (NC), 144 with mild cognitive impairment (MCI), and 76 with AD. Results An abnormal CSF Aβ level was found to be associated with greater hippocampal volume loss over 1 year in each group. APOE4 was associated with hippocampal volume loss only in the NC and MCI groups. APOE4 carriers with abnormal CSF Aβ in the MCI group acted synergistically to produce disproportionately greater volume loss than noncarriers. Conclusion Baseline CSF Aβ predicts progression of hippocampal volume loss. APOE4 carrier status amplifies the degree of neurodegeneration in MCI. Understanding the effect of interactions between genetic risk and amyloid pathology will be important in clinical trials and our understanding of the disease process. PMID:21889115

Mapping correlations between ventricular expansion and CSF amyloid and tau biomarkers in 240 subjects with Alzheimer’s disease, mild cognitive impairment and elderly controls

PubMed Central

Chou, Yi-Yu; Leporé, Natasha; Avedissian, Christina; Madsen, Sarah K.; Parikshak, Neelroop; Hua, Xue; Shaw, Leslie M.; Trojanowski, John Q.; Weiner, Michael W.; Toga, Arthur W.; Thompson, Paul M.

2009-01-01

Automated ventricular mapping with multi-atlas fluid image alignment reveals genetic effects in Alzheimer’s disease, NeuroImage 40(2): 615–630); with this method, we calculated minimal numbers of subjects needed to detect correlations between clinical scores and ventricular maps. We also assessed correlations between emerging CSF biomarkers of Alzheimer’s disease pathology and localizable deficits in the brain, in 80 AD, 80 mild cognitive impairment (MCI), and 80 healthy controls from the Alzheimer’s Disease Neuroimaging Initiative. Six expertly segmented images and their embedded parametric mesh surfaces were fluidly registered to each brain; segmentations were averaged within subjects to reduce errors. Surface-based statistical maps revealed powerful correlations between surface morphology and 4 variables: (1) diagnosis, (2) depression severity, (3) cognitive function at baseline, and (4) future cognitive decline over the following year. Cognitive function was assessed using the mini-mental state exam (MMSE), global and sum-of-boxes clinical dementia rating (CDR) scores, at baseline and 1-year follow-up. Lower CSF Aβ1–42 protein levels, a biomarker of AD pathology assessed in 138 of the 240 subjects, were correlated with lateral ventricular expansion. Using false discovery rate (FDR) methods, 40 and 120 subjects, respectively, were needed to discriminate AD and MCI from normal groups. 120 subjects were required to detect correlations between ventricular enlargement and MMSE, global CDR, sum-of-boxes CDR and clinical depression scores. Ventricular expansion maps correlate with pathological and cognitive measures in AD, and may be useful in future imaging-based clinical trials. PMID:19236926

Molecular Characterisation of Transport Mechanisms at the Developing Mouse Blood–CSF Interface: A Transcriptome Approach

PubMed Central

Liddelow, Shane A.; Temple, Sally; Møllgård, Kjeld; Gehwolf, Renate; Wagner, Andrea; Bauer, Hannelore; Bauer, Hans-Christian; Phoenix, Timothy N.; Dziegielewska, Katarzyna M.; Saunders, Norman R.

2012-01-01

Exchange mechanisms across the blood–cerebrospinal fluid (CSF) barrier in the choroid plexuses within the cerebral ventricles control access of molecules to the central nervous system, especially in early development when the brain is poorly vascularised. However, little is known about their molecular or developmental characteristics. We examined the transcriptome of lateral ventricular choroid plexus in embryonic day 15 (E15) and adult mice. Numerous genes identified in the adult were expressed at similar levels at E15, indicating substantial plexus maturity early in development. Some genes coding for key functions (intercellular/tight junctions, influx/efflux transporters) changed expression during development and their expression patterns are discussed in the context of available physiological/permeability results in the developing brain. Three genes: Secreted protein acidic and rich in cysteine (Sparc), Glycophorin A (Gypa) and C (Gypc), were identified as those whose gene products are candidates to target plasma proteins to choroid plexus cells. These were investigated using quantitative- and single-cell-PCR on plexus epithelial cells that were albumin- or total plasma protein-immunopositive. Results showed a significant degree of concordance between plasma protein/albumin immunoreactivity and expression of the putative transporters. Immunohistochemistry identified SPARC and GYPA in choroid plexus epithelial cells in the embryo with a subcellular distribution that was consistent with transport of albumin from blood to cerebrospinal fluid. In adult plexus this pattern of immunostaining was absent. We propose a model of the cellular mechanism in which SPARC and GYPA, together with identified vesicle-associated membrane proteins (VAMPs) may act as receptors/transporters in developmentally regulated transfer of plasma proteins at the blood–CSF interface. PMID:22457777

A single dose of the γ-secretase inhibitor semagacestat alters the cerebrospinal fluid peptidome in humans.

PubMed

Hölttä, Mikko; Dean, Robert A; Siemers, Eric; Mawuenyega, Kwasi G; Sigurdson, Wendy; May, Patrick C; Holtzman, David M; Portelius, Erik; Zetterberg, Henrik; Bateman, Randall J; Blennow, Kaj; Gobom, Johan

2016-03-07

In Alzheimer's disease, beta-amyloid peptides in the brain aggregate into toxic oligomers and plaques, a process which is associated with neuronal degeneration, memory loss, and cognitive decline. One therapeutic strategy is to decrease the production of potentially toxic beta-amyloid species by the use of inhibitors or modulators of the enzymes that produce beta-amyloid from amyloid precursor protein (APP). The failures of several such drug candidates by lack of effect or undesired side-effects underscore the importance to monitor the drug effects in the brain on a molecular level. Here we evaluate if peptidomic analysis in cerebrospinal fluid (CSF) can be used for this purpose. Fifteen human healthy volunteers, divided into three groups, received a single dose of placebo or either 140 mg or 280 mg of the γ-secretase inhibitor semagacestat (LY450139). Endogenous peptides in CSF, sampled prior to administration of the drug and at six subsequent time points, were analyzed by liquid chromatography coupled to mass spectrometry, using isobaric labeling based on the tandem mass tag approach for relative quantification. Out of 302 reproducibly detected peptides, 11 were affected by the treatment. Among these, one was derived from APP and one from amyloid precursor-like protein 1. Nine peptides were derived from proteins that may not be γ-secretase substrates per se, but that are regulated in a γ-secretase-dependent manner. These results indicate that a CSF peptidomic approach may be a valuable tool both to verify target engagement and to identify other pharmacodynamic effects of the drug. Data are available via ProteomeXchange with identifier PXD003075. NCT00765115 , registered 30/09/2008.

Effects of inhibitors on chloride outflux from CSF

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nishimura, M.; Johnson, D.C.; Pappagianopoulos, P.

1986-03-05

The regulation of the CSF (Cl/sup -/) plays a key role in CNS acid-base homeostasis. The authors have shown in previous studies that chloride influx from blood to CSF is largely dependent upon sodium-coupled carrier mediated movement. Therefore, the mechanism of chloride outflux from CSF to brain was evaluated in anesthetized dogs using ventricular-cisternal perfusion (VCP) with the short-lived isotope /sup 38/Cl/sup -/ and dextran. The outflux of /sup 38/Cl/sup -/ from CSF was determined from the different movements between /sup 38/Cl/sup -/ and dextran using a one compartment model. VCP was performed at a rate of 1.4 ml/min formore » 14 min, and then slowed to 0.28 ml/min. The /sup 38/Cl/sup -/ activity decreased to a steady state level about 12% lower than that of dextran within 40-50 minutes. Under control conditions (19 runs in 7 dogs), the rate of chloride outflux was 0.059 +/- 0.004 min/sup -1/ (mean +/- SE). It was not significantly changed after the inclusion of bumetanide (10/sup -5/ molar) in the VCP fluid (n=6), which inhibits sodium-coupled Cl/sup -/ transport, or with acetazolamide 4.5 x 10/sup -3/ molar (n=4) which inhibits carbonic anhydrase. The authors conclude that chloride outflux from CSF is not dependent upon sodium-coupled carrier mediated movement, which is in contrast with chloride influx from blood to CSF, nor is it dependent upon carbonic anhydrase activity.« less

Association between Plasma Homocysteine Levels and Neuronal Injury in HIV Infection

PubMed Central

Ahlgren, Erika; Hagberg, Lars; Fuchs, Dietmar; Andersson, Lars-Magnus; Nilsson, Staffan; Zetterberg, Henrik; Gisslén, Magnus

2016-01-01

Objective To investigate the role of homocysteine in neuronal injury in HIV infection. Methods Using a cross-sectional design and archived samples, we compared concentrations of plasma homocysteine and cerebrospinal fluid (CSF) neurofilament light protein (NFL), a sensitive marker of neuronal injury, in 83 HIV-1-infected subjects without antiretroviral treatment. We also analyzed plasma vitamin B12, serum folate, CSF, and plasma HIV RNA, the immune activation marker neopterin in CSF and serum, and albumin ratio as a marker of blood-brain barrier integrity. Twenty-two subjects provided a second sample median of 12.5 months after antiretroviral treatment initiation. Results A significant correlation was found between plasma homocysteine and CSF NFL concentrations in untreated individuals (r = 0.52, p < 0.0001). As expected, there was a significant inverse correlation between homocysteine and B12 (r = –0.41, p < 0.001) and folate (r = –0.40, p = < 0.001) levels. In a multiple linear regression analysis homocysteine stood out as an independent predictor of CSF NFL in HIV-1-infected individuals. The correlation of plasma homocysteine and CSF NFL was also present in the group receiving antiretroviral therapy (r = 0.51, p = 0.016). Conclusion A correlation between plasma homocysteine and axonal injury, as measured by CSF NFL, was found in both untreated and treated HIV. While this study is not able to prove a causal link, homocysteine and functional B12/folate deficiency appear to play a role in neural injury in HIV-infected individuals. PMID:27441551

Association between Plasma Homocysteine Levels and Neuronal Injury in HIV Infection.

PubMed

Ahlgren, Erika; Hagberg, Lars; Fuchs, Dietmar; Andersson, Lars-Magnus; Nilsson, Staffan; Zetterberg, Henrik; Gisslén, Magnus

2016-01-01

To investigate the role of homocysteine in neuronal injury in HIV infection. Using a cross-sectional design and archived samples, we compared concentrations of plasma homocysteine and cerebrospinal fluid (CSF) neurofilament light protein (NFL), a sensitive marker of neuronal injury, in 83 HIV-1-infected subjects without antiretroviral treatment. We also analyzed plasma vitamin B12, serum folate, CSF, and plasma HIV RNA, the immune activation marker neopterin in CSF and serum, and albumin ratio as a marker of blood-brain barrier integrity. Twenty-two subjects provided a second sample median of 12.5 months after antiretroviral treatment initiation. A significant correlation was found between plasma homocysteine and CSF NFL concentrations in untreated individuals (r = 0.52, p < 0.0001). As expected, there was a significant inverse correlation between homocysteine and B12 (r = -0.41, p < 0.001) and folate (r = -0.40, p = < 0.001) levels. In a multiple linear regression analysis homocysteine stood out as an independent predictor of CSF NFL in HIV-1-infected individuals. The correlation of plasma homocysteine and CSF NFL was also present in the group receiving antiretroviral therapy (r = 0.51, p = 0.016). A correlation between plasma homocysteine and axonal injury, as measured by CSF NFL, was found in both untreated and treated HIV. While this study is not able to prove a causal link, homocysteine and functional B12/folate deficiency appear to play a role in neural injury in HIV-infected individuals.

CSF inflammation and axonal damage are increased and correlate in progressive multiple sclerosis.

PubMed

Romme Christensen, Jeppe; Börnsen, Lars; Khademi, Mohsen; Olsson, Tomas; Jensen, Poul Erik; Sørensen, Per Soelberg; Sellebjerg, Finn

2013-06-01

The mechanism underlying disease progression in progressive multiple sclerosis (MS) is uncertain. Pathological studies found widespread inflammation in progressive MS brains correlating with disease progression and axonal damage. To study cerebrospinal fluid (CSF) biomarkers and clarify whether inflammation and axonal damage are associated in progressive MS. Using enzyme-linked immunosorbent assay (ELISA), we analysed CSF from 40 secondary progressive (SPMS), 21 primary progressive (PPMS), and 36 relapsing-remitting (RRMS) and 20 non-inflammatory neurological disease (NIND) patients. Twenty-two of the SPMS patients participated in an MBP8298 peptide clinical trial and had CSF follow-up after one year. Compared to NIND patients, inflammatory biomarkers osteopontin and matrix metalloproteinase-9 (MMP9) were increased in all MS patients while CXCL13 was increased in RRMS and SPMS patients. Biomarkers of axonal damage (NFL) and demyelination (MBP) were increased in all MS patients. In progressive MS patients CSF levels of osteopontin and CXCL13 correlated with NFL while osteopontin and MMP9 correlated with MBP. MBP8298 treatment did not affect the levels of the biomarkers after one year of treatment. All biomarkers were continuously increased after one year of follow-up except MBP, which decreased. CSF biomarkers of inflammation, axonal damage and demyelination are continuously increased in progressive MS patients and correlate. These findings parallel pathology studies, emphasise a relationship between inflammation, axonal damage and demyelination and support the use of CSF biomarkers in progressive MS clinical trials.

CSF protein changes associated with hippocampal sclerosis risk gene variants highlight impact of GRN/PGRN.

PubMed

Fardo, David W; Katsumata, Yuriko; Kauwe, John S K; Deming, Yuetiva; Harari, Oscar; Cruchaga, Carlos; Nelson, Peter T

2017-04-01

Hippocampal sclerosis of aging (HS-Aging) is a common cause of dementia in older adults. We tested the variability in cerebrospinal fluid (CSF) proteins associated with previously identified HS-Aging risk single nucleotide polymorphisms (SNPs). Alzheimer's Disease Neuroimaging Initiative cohort (ADNI; n=237) data, combining both multiplexed proteomics CSF and genotype data, were used to assess the association between CSF analytes and risk SNPs in four genes (SNPs): GRN (rs5848), TMEM106B (rs1990622), ABCC9 (rs704180), and KCNMB2 (rs9637454). For controls, non-HS-Aging SNPs in APOE (rs429358/rs7412) and MAPT (rs8070723) were also analyzed against Aβ1-42 and total tau CSF analytes. The GRN risk SNP (rs5848) status correlated with variation in CSF proteins, with the risk allele (T) associated with increased levels of AXL Receptor Tyrosine Kinase (AXL), TNF-Related Apoptosis-Inducing Ligand Receptor 3 (TRAIL-R3), Vascular Cell Adhesion Molecule-1 (VCAM-1) and clusterin (CLU) (all p<0.05 after Bonferroni correction). The TRAIL-R3 correlation was significant in meta-analysis with an additional dataset (p=5.05×10 -5 ). Further, the rs5848 SNP status was associated with increased CSF tau protein - a marker of neurodegeneration (p=0.015). These data are remarkable since this GRN SNP has been found to be a risk factor for multiple types of dementia-related brain pathologies. Copyright © 2017 Elsevier Inc. All rights reserved.

Novel laser tissue-soldering technique for dural reconstruction.

PubMed

Gil, Ziv; Shaham, Amit; Vasilyev, Tamar; Brosh, Tamar; Forer, Boaz; Katzir, Abraham; Fliss, Dan M

2005-07-01

The goal of this study was to use a modified version of the CO2 laser-soldering system to develop a simple and reliable technique for the repair of dural defects after excision of brain tumors. The authors used a CO2 fiber optic laser system that they had developed for heating, monitoring, and controlling tissue temperature in situ and in real time, thereby reducing damage to the brain parenchyma. They adapted the system for dural closure by using free fascial grafts in a porcine model. Measures for estimation of reconstruction quality included visual assessment under magnification and direct measurements of adhesive strength and cerebrospinal fluid leak (CSF) pressure. Reliable soldering was achieved in 54 of 57 experiments, providing a 95% success rate. The average peak adhesive strength was 82 +/- 3 mN/cm2. The measured leak pressure of the fascia-dura mater bond was 66 +/- 5 mm Hg. Conventional suturing performed using Prolene stitches resulted in immediate CSF leakage from areas between the stitches and from the area of the needle hole itself. Fascia-dura mater soldering using the CO2 laser is feasible and may support CSF pressure up to six times higher than normal intracranial pressure. Findings of this study may provide a basis for the development of new tools for dural reconstruction.

The inner CSF–brain barrier: developmentally controlled access to the brain via intercellular junctions

PubMed Central

Whish, Sophie; Dziegielewska, Katarzyna M.; Møllgård, Kjeld; Noor, Natassya M.; Liddelow, Shane A.; Habgood, Mark D.; Richardson, Samantha J.; Saunders, Norman R.

2015-01-01

In the adult the interface between the cerebrospinal fluid and the brain is lined by the ependymal cells, which are joined by gap junctions. These intercellular connections do not provide a diffusional restrain between the two compartments. However, during development this interface, initially consisting of neuroepithelial cells and later radial glial cells, is characterized by “strap” junctions, which limit the exchange of different sized molecules between cerebrospinal fluid and the brain parenchyma. Here we provide a systematic study of permeability properties of this inner cerebrospinal fluid-brain barrier during mouse development from embryonic day, E17 until adult. Results show that at fetal stages exchange across this barrier is restricted to the smallest molecules (286Da) and the diffusional restraint is progressively removed as the brain develops. By postnatal day P20, molecules the size of plasma proteins (70 kDa) diffuse freely. Transcriptomic analysis of junctional proteins present in the cerebrospinal fluid-brain interface showed expression of adherens junctional proteins, actins, cadherins and catenins changing in a development manner consistent with the observed changes in the permeability studies. Gap junction proteins were only identified in the adult as was claudin-11. Immunohistochemistry was used to localize at the cellular level some of the adherens junctional proteins of genes identified from transcriptomic analysis. N-cadherin, β - and α-catenin immunoreactivity was detected outlining the inner CSF-brain interface from E16; most of these markers were not present in the adult ependyma. Claudin-5 was present in the apical-most part of radial glial cells and in endothelial cells in embryos, but only in endothelial cells including plexus endothelial cells in adults. Claudin-11 was only immunopositive in the adult, consistent with results obtained from transcriptomic analysis. These results provide information about physiological, molecular and morphological-related permeability changes occurring at the inner cerebrospinal fluid-brain barrier during brain development. PMID:25729345

Influence of gravity for optimal head positions in the treatment of head injury patients.

PubMed

Li, Xiaogai; von Holst, Hans; Kleiven, Svein

2011-10-01

Brain edema is a major neurological complication of traumatic brain injury (TBI), commonly including a pathologically increased intracranial pressure (ICP) associated with poor outcome. In this study, gravitational force is suggested to have a significant impact on the pressure of the edema zone in the brain tissue and the objective of the study was to investigate the significance of head position on edema at the posterior part of the brain using a finite element (FE) model. A detailed FE model including the meninges, brain tissue and a fully connected cerebrospinal fluid (CSF) system was used in this study. Brain tissue was modelled as a poroelastic material consisting of an elastic solid skeleton composed of neurons and neuroglia, permeated by interstitial fluid. The effect of head positions (supine and prone position) due to gravity was investigated for a localized brain edema at the posterior part of the brain. The water content increment at the edema zone remained nearly identical for both positions. However, the interstitial fluid pressure (IFP) inside the edema zone decreased around 15% by having the head in a prone position compared with a supine position. The decrease of IFP inside the edema zone by changing patient position from supine to prone has the potential to alleviate the damage to central nervous system nerves. These observations indicate that considering the patient's head position during intensive care and at rehabilitation might be of importance to the treatment of edematous regions in TBI patients.

Early-onset Infectious Complications among Penetrating and Severe Closed Traumatic Brain Injury in Active Duty Deployed during OIF and OEF, 2008-2013

DTIC Science & Technology

2015-02-01

seizures, hydrocephalus, cerebral spinal fluid (CSF) leaks, infections inside the skull, vascular injuries, and cranial nerve injuries. 9-11 The...bacterial infection ). Neurosurgical procedures were based on ICD-9-CM procedure codes used to describe interventions related to severe TBI. 21 The...study of critical care trauma patients, traumatic shock was the only admission characteristic associated with infection , and infection developed

Partial volume correction and image segmentation for accurate measurement of standardized uptake value of grey matter in the brain.

PubMed

Bural, Gonca; Torigian, Drew; Basu, Sandip; Houseni, Mohamed; Zhuge, Ying; Rubello, Domenico; Udupa, Jayaram; Alavi, Abass

2015-12-01

Our aim was to explore a novel quantitative method [based upon an MRI-based image segmentation that allows actual calculation of grey matter, white matter and cerebrospinal fluid (CSF) volumes] for overcoming the difficulties associated with conventional techniques for measuring actual metabolic activity of the grey matter. We included four patients with normal brain MRI and fluorine-18 fluorodeoxyglucose (F-FDG)-PET scans (two women and two men; mean age 46±14 years) in this analysis. The time interval between the two scans was 0-180 days. We calculated the volumes of grey matter, white matter and CSF by using a novel segmentation technique applied to the MRI images. We measured the mean standardized uptake value (SUV) representing the whole metabolic activity of the brain from the F-FDG-PET images. We also calculated the white matter SUV from the upper transaxial slices (centrum semiovale) of the F-FDG-PET images. The whole brain volume was calculated by summing up the volumes of the white matter, grey matter and CSF. The global cerebral metabolic activity was calculated by multiplying the mean SUV with total brain volume. The whole brain white matter metabolic activity was calculated by multiplying the mean SUV for the white matter by the white matter volume. The global cerebral metabolic activity only reflects those of the grey matter and the white matter, whereas that of the CSF is zero. We subtracted the global white matter metabolic activity from that of the whole brain, resulting in the global grey matter metabolism alone. We then divided the grey matter global metabolic activity by grey matter volume to accurately calculate the SUV for the grey matter alone. The brain volumes ranged between 1546 and 1924 ml. The mean SUV for total brain was 4.8-7. Total metabolic burden of the brain ranged from 5565 to 9617. The mean SUV for white matter was 2.8-4.1. On the basis of these measurements we generated the grey matter SUV, which ranged from 8.1 to 11.3. The accurate metabolic activity of the grey matter can be calculated using the novel segmentation technique that we applied to MRI. By combining these quantitative data with those generated from F-FDG-PET images we were able to calculate the accurate metabolic activity of the grey matter. These types of measurements will be of great value in accurate analysis of the data from patients with neuropsychiatric disorders.

Implantable Systems for Continuous Liquorpheresis and CSF Replacement

PubMed Central

2017-01-01

Liquorpheresis (cerebrospinal fluid filtration) comprises a therapeutical approach that has been proposed to treat several neurological conditions where antibodies, inflammatory mediators, or abnormal peptides are the cause or play an important role in the pathogenesis of the disease. Continuous or intermittent cerebrospinal fluid (CSF) replacement may be an alternative approach not explored thus far. Here, we review previous experiences in the use of liquorpheresis in autoimmune and degenerative neurological diseases. Then we describe previous technical reports  and provide some new innovations in order to design bidirectional CSF shunting systems that can be complemented either with a deposit of artificial CSF or with a filter of CSF, allowing CSF replacement or liquorpheresis respectively. Both options would lead to mechanical dilution of the patient’s CSF. PMID:28413734

The pathway of subarachnoid CSF moving into the spinal parenchyma and the role of astrocytic aquaporin-4 in this process.

PubMed

Wei, Fang; Zhang, Cui; Xue, Rong; Shan, Lidong; Gong, Shan; Wang, Guoqing; Tao, Jin; Xu, Guangyin; Zhang, Guoxing; Wang, Linhui

2017-08-01

It has been proved that cerebrospinal fluid (CSF) in the subarachnoid space could reenter the brain parenchyma via the perivascular space. The present study was designed to explore the pathway of subarachnoid CSF flux into the spinal cord and the potential role of aquaporin-4 (AQP4) in this process. Fluorescently tagged cadaverine, for the first time, was used to study CSF movement in mice. Following intracisternal infusion of CSF tracers, the cervical spinal cord was sliced and prepared for fluorescence imaging. Some sections were subject with immunostaining in order to observe tracer distribution and AQP4 expression. Fluorescently tagged cadaverine rapidly entered the spinal cord. Tracer influx into the spinal parenchyma was time dependent. At 10min post-infusion, cadaverine was largely distributed in the superficial tissue adjacent to the pial surface. At 70min post-infusion, cadaverine was distributed in the whole cord and especially concentrated in the gray matter. Furthermore, fluorescent tracer could enter the spinal parenchyma either along the perivascular space or across the pial surface. AQP4 was observed highly expressed in the astrocytic endfeet surrounding blood vessels and the pial surface. Blocking AQP4 by its specific inhibitor TGN-020 strikingly reduced the inflow of CSF tracers into the spinal cord. Subarachnoid CSF could flow into the spinal cord along the perivascular space or across the pial surface, in which AQP4 is involved. Our observation provides a basis for the study on CSF movement in the spinal cord when some neurological diseases occur. Copyright © 2017 Elsevier Inc. All rights reserved.

Bacterial meningoencephalomyelitis in dogs: a retrospective study of 23 cases (1990-1999).

PubMed

Radaelli, Simona T; Platt, Simon R

2002-01-01

The clinical records of 23 dogs (1990-1999) with histopathologically confirmed bacterial meningoencephalomyelitis were evaluated retrospectively. No breed, age, sex, or weight predisposition was found. All the dogs presented with clinical signs of a brain lesion, whereas 5 of 23 had neck pain. Pyrexia was detected in 11 of 23 dogs on admission. CBCs revealed neutrophilic leucocytosis in 7 of 21 dogs and thrombocytopenia in 3 of 21 dogs. The serum chemistry profiles were abnormal in 15 of 21 dogs. The results of cerebrospinal fluid (CSF) analysis were abnormal in 13 of 14 dogs and aerobic CSF culture was positive for bacteria in 1of 8 samples. At postmortem examination, the lesions were localized to the central nervous system. Escherichia coli, Streptococcus, and Klebsiella spp were the most frequently isolated bacteria from cultures collected at postmortem examination. Twelve papers reporting 51 total clinical cases of canine bacterial meningoencephalomyelitis were reviewed. The clinical signs and results of the CBC, serum chemistry, blood culture, and CSF analysis were collated and compared with those of this study. The results of the CSF analysis in this study were similar to those in the literature. CSF cultures documented in the literature were positive for Staphylococcus, Pasteurella. Actinomyces, Nocardia spp, and various anaerobic species including Peptostreptococcus, Eubacterium, and Bacteroides spp.

Assessment of the dynamics of human glymphatic system by near-infrared spectroscopy.

PubMed

Myllylä, Teemu; Harju, Markus; Korhonen, Vesa; Bykov, Alexander; Kiviniemi, Vesa; Meglinski, Igor

2017-08-12

Fluctuations in brain water content has attracted increasing interest, particularly as regards studies of the glymphatic system, which is connected with the complex organization of dural lymphatic vessels, responsible for cleaning tissue. Disturbances of glymphatic circulation are associated with several brain disorders, including dementia. This article introduces an approach to noninvasive measurement of water dynamics in the human brain utilizing near-infrared spectroscopy (NIRS). We demonstrate the possibility to sense dynamic variations of water content between the skull and grey matter, for instance, in the subarachnoid space. Measured fluctuations in water content, especially in the cerebrospinal fluid (CSF), are assumed to be correlated with the dynamics of glymphatic circulation. The sampling volume for the NIRS optode was estimated by Monte Carlo modelling for the wavelengths of 660, 740, 830 and 980 nm. In addition, using combinations of these wavelengths, this article presents the calculation models for quantifying water and haemodynamics. The presented NIRS technique allows long-term functional brain monitoring, including sleeping time. Furthermore, it is used in combination with different magnetic neuroimaging techniques, particularly magnetic resonance encephalography. Using the combined setup, we report the preliminary results on the interaction between CSF and blood oxygen level-dependent fluctuations. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Glycoblotting method allows for rapid and efficient glycome profiling of human Alzheimer's disease brain, serum and cerebrospinal fluid towards potential biomarker discovery.

PubMed

Gizaw, Solomon T; Ohashi, Tetsu; Tanaka, Masakazu; Hinou, Hiroshi; Nishimura, Shin-Ichiro

2016-08-01

Understanding of the significance of posttranslational glycosylation in Alzheimer's disease (AD) is of growing importance for the investigation of the pathogenesis of AD as well as discovery research of the disease-specific serum biomarkers. We designed a standard protocol for the glycoblotting combined with MALDI-TOFMS to perform rapid and quantitative profiling of the glycan parts of glycoproteins (N-glycans) and glycosphingolipids (GSLs) using human AD's post-mortem samples such as brain tissues (dissected cerebral cortices such as frontal, parietal, occipital, and temporal domains), serum and cerebrospinal fluid (CSF). The structural profiles of the major N-glycans released from glycoproteins and the total expression levels of the glycans were found to be mostly similar between the brain tissues of the AD patients and those of the normal control group. In contrast, the expression levels of the serum and CSF protein N-glycans such as bisect-type and multiply branched glycoforms were increased significantly in AD patient group. In addition, the levels of some gangliosides such as GM1, GM2 and GM3 appeared to alter in the AD patient brain and serum samples when compared with the normal control groups. Alteration of the expression levels of major N- and GSL-glycans in human brain tissues, serum and CSF of AD patients can be monitored quantitatively by means of the glycoblotting-based standard protocols. The changes in the expression levels of the glycans derived from the human post-mortem samples uncovered by the standardized glycoblotting method provides potential serum biomarkers in central nervous system disorders and can contribute to the insight into the molecular mechanisms in the pathogenesis of neurodegenerative diseases and future drug discovery. Most importantly, the present preliminary trials using human post-mortem samples of AD patients suggest that large-scale serum glycomics cohort by means of various-types of human AD patients as well as the normal control sera can facilitate the discovery research of highly sensitive and reliable serum biomarkers for an early diagnosis of AD. This article is part of a Special Issue entitled "Glycans in personalised medicine" Guest Editor: Professor Gordan Lauc. Copyright © 2016 Elsevier B.V. All rights reserved.

The concentration of CYFRA 21-1, NSE and CEA in cerebro-spinal fluid can be useful indicators for diagnosis of meningeal carcinomatosis of lung cancer.

PubMed

Wang, Peng; Piao, Yingzhe; Zhang, Xiaohui; Li, Wenliang; Hao, Xishan

2013-01-01

We aimed to investigate the concentration of CYFRA 21-1, NSE and CEA in cerebro-spinal fluid (CSF) and to explore their clinical value in the meningeal carcinomatosis (MC) of lung cancer. So that, sensitive and specificity of CSF examination can be improved in the initial diagnosis of MC. A total of 35 lung cancer patients and 35 patients with benign brain tumor in the same period enrolled in this study. The concentrations of tumor markers CEA, CYFRA 21-1 and NSE in CSF and peripheral blood were examined. The concentrations of three tumor markers of CYFRA 21-1, NSE and CEA in blood serum and CSF were obviously higher than that of benign disease group. In MC patients, the concentrations of three tumor markers of CYFRA 21-1, NSE and CEA in blood serum were significant lower than that in CSF. The maximum of Youden's index was identified as the cutoff value of indicator of MC in three tumor markers in CSF which were CEA > 4.7 μg/L, NSE > 14.6 μg/L and CYFRA21-1 > 5.5 μg/L respectively. Based on the cutoff values, the CEA had the highest sensitivity while the CYFRA21-1 had the highest specificitiy. Three tumor markers in the CSF had higher positive rate than those in blood serum. We combined the levels of CEA, NSE and CYFRA21-1 in CSF to diagnosis of MC. Positive of CEA or CYFRA21-1 had the greatest sensitivity of 100% while the specificity of 91.4%; the positive of both CEA and CYFRA21-1 had the highest specificity of 100% while the sensitivity of 74.3%. Both positive predictive value and negative predictive value were 100% when combination positive were confirmed when the all three markers were positive. The combination of CEA and CYFRA21-1 can be recommended in early screening of meningeal carcinoma. Especially, for the patient who was difficult to be diagnosed by CSF histology and MRI, it will be a useful auxiliary marker in diagnosis of MC. The combination of CEA, NSE and CYFRA21-1 can be an effective clinically confirmation and exclusively diagnose indictor of MC.

Impact of Aromatase Genetic Variation on Hormone Levels and Global Outcome after Severe TBI

PubMed Central

Garringer, Julie A.; Niyonkuru, Christian; McCullough, Emily H.; Loucks, Tammy; Dixon, C. Edward; Conley, Yvette P.; Berga, Sarah

2013-01-01

Abstract Although experimental traumatic brain injury (TBI) studies support estradiol as a neuroprotectant and potent stimulator of neuroplasticity, clinical studies suggest a negative association between endogenous estradiol profiles and mortality/poor outcomes. However, no studies have evaluated associations with cerebral spinal fluid (CSF) hormone profiles and aromatase gene (cytochrome P450 [CYP]19A1) variability on clinical TBI outcomes. We evaluated 110 adults with severe TBI. Average and daily estradiol, testosterone, and estradiol/testosterone ratios (E2:T) were measured using CSF and serum samples and compared to healthy controls. Eighteen tagging and four functional single-nucleotide polymorphisms (SNPs) for CYP19A1 were genotyped and compared to hormones, acute mortality, and Glasgow Outcome Scale (GOS) scores 6 months post-TBI. TBI subjects had lower CSF estradiol over time versus controls. CSF testosterone was initially high, but declined over time. E2/T ratios were initially low, compared to controls, but rose over time. Higher mean E2/T ratio in bivariate analysis was associated with lower mortality (p=0.019) and better GOS-6 scores (p=0.030). rs2470152 influenced CSF E2/T ratio and also serum and CSF testosterone (p≤0.05 all comparisons). Multiple-risk SNPs rs2470152, rs4646, and rs2470144 were associated with worse GOS-6 scores (p≤0.05, all comparisons), and those with>1 risk SNP variant had a higher risk for poor outcome, compared with those with ≤1 risk variant. TBI results in low CSF estradiol and dynamic CSF testosterone and E2/T ratio. In contrast to clinical serum hormone studies, higher CSF E2/T ratio was associated with better outcome. Further, genetic variation in CYP19A1 influences both hormone dynamics and outcome post-TBI. PMID:23540392

Anti-lysophosphatidic acid antibodies improve traumatic brain injury outcomes

PubMed Central

2014-01-01

Background Lysophosphatidic acid (LPA) is a bioactive phospholipid with a potentially causative role in neurotrauma. Blocking LPA signaling with the LPA-directed monoclonal antibody B3/Lpathomab is neuroprotective in the mouse spinal cord following injury. Findings Here we investigated the use of this agent in treatment of secondary brain damage consequent to traumatic brain injury (TBI). LPA was elevated in cerebrospinal fluid (CSF) of patients with TBI compared to controls. LPA levels were also elevated in a mouse controlled cortical impact (CCI) model of TBI and B3 significantly reduced lesion volume by both histological and MRI assessments. Diminished tissue damage coincided with lower brain IL-6 levels and improvement in functional outcomes. Conclusions This study presents a novel therapeutic approach for the treatment of TBI by blocking extracellular LPA signaling to minimize secondary brain damage and neurological dysfunction. PMID:24576351

A Hybrid Hierarchical Approach for Brain Tissue Segmentation by Combining Brain Atlas and Least Square Support Vector Machine

PubMed Central

Kasiri, Keyvan; Kazemi, Kamran; Dehghani, Mohammad Javad; Helfroush, Mohammad Sadegh

2013-01-01

In this paper, we present a new semi-automatic brain tissue segmentation method based on a hybrid hierarchical approach that combines a brain atlas as a priori information and a least-square support vector machine (LS-SVM). The method consists of three steps. In the first two steps, the skull is removed and the cerebrospinal fluid (CSF) is extracted. These two steps are performed using the toolbox FMRIB's automated segmentation tool integrated in the FSL software (FSL-FAST) developed in Oxford Centre for functional MRI of the brain (FMRIB). Then, in the third step, the LS-SVM is used to segment grey matter (GM) and white matter (WM). The training samples for LS-SVM are selected from the registered brain atlas. The voxel intensities and spatial positions are selected as the two feature groups for training and test. SVM as a powerful discriminator is able to handle nonlinear classification problems; however, it cannot provide posterior probability. Thus, we use a sigmoid function to map the SVM output into probabilities. The proposed method is used to segment CSF, GM and WM from the simulated magnetic resonance imaging (MRI) using Brainweb MRI simulator and real data provided by Internet Brain Segmentation Repository. The semi-automatically segmented brain tissues were evaluated by comparing to the corresponding ground truth. The Dice and Jaccard similarity coefficients, sensitivity and specificity were calculated for the quantitative validation of the results. The quantitative results show that the proposed method segments brain tissues accurately with respect to corresponding ground truth. PMID:24696800

Segmentation of tumor and edema along with healthy tissues of brain using wavelets and neural networks.

PubMed

Demirhan, Ayşe; Toru, Mustafa; Guler, Inan

2015-07-01

Robust brain magnetic resonance (MR) segmentation algorithms are critical to analyze tissues and diagnose tumor and edema in a quantitative way. In this study, we present a new tissue segmentation algorithm that segments brain MR images into tumor, edema, white matter (WM), gray matter (GM), and cerebrospinal fluid (CSF). The detection of the healthy tissues is performed simultaneously with the diseased tissues because examining the change caused by the spread of tumor and edema on healthy tissues is very important for treatment planning. We used T1, T2, and FLAIR MR images of 20 subjects suffering from glial tumor. We developed an algorithm for stripping the skull before the segmentation process. The segmentation is performed using self-organizing map (SOM) that is trained with unsupervised learning algorithm and fine-tuned with learning vector quantization (LVQ). Unlike other studies, we developed an algorithm for clustering the SOM instead of using an additional network. Input feature vector is constructed with the features obtained from stationary wavelet transform (SWT) coefficients. The results showed that average dice similarity indexes are 91% for WM, 87% for GM, 96% for CSF, 61% for tumor, and 77% for edema.

Neuropsychiatric lupus and auto-antibodies against ionotropic glutamate receptor (NMDAR)

PubMed Central

Cohen-Solal, J.F.G.; Diamond, B.

2010-01-01

Almost half of lupus patients will experience neuropsychiatric symptoms during the course of their disease. The etiology of the neuronal damages are still uncertain and probably multiple. Auto-antibodies reactive with brain have been postulated to play a role. The observation of pathogenic auto-antibodies binding the NR2A and NR2B subunits of the ionotropic glutamate receptor (NMDAR) illustrates this hypothesis. First studies showed that 40% of lupus patients possess serum titers of anti-NR2A/B antibody, but the presence of these auto-antibodies is not always associated with the occurrence of neuronal damages or neuropsychiatric symptoms. Nevertheless, their presence is observed in the cerebro-spinal fluid (CSF) of one half of the patients suffering from neurolupus. The presence in the serum of these auto-antibodies anti-NR2A/B of the NMDAR is preliminary to their presence in the CSF where their deleterious effect is observable. Their entry into the brain is dependent on a breach of the blood brain barrier (BBB). In conclusion, the serum titer of auto-antibodies against NR2A/B subunits is an indication of the potential for neuro-psychiatric manifestations during the course of the disease. PMID:20605660

Clinical and laboratory features of HTLV-I asymptomatic carriers and patients with HTLV-I-associated myelopathy/tropical spastic paraparesis from the Brazilian Amazon

PubMed Central

Takatani, Massanobu; Crispim, Myuki Esashika; Fraiji, Nelson; Stefani, Mariane Martins Araujo; Kiesslich, Dagmar

2017-01-01

ABSTRACT Clinical and laboratory parameters including blood and cerebrospinal fluid (CSF) neopterin were investigated in human-T-lymphotropic-virus-type-I associated-myelopathy/tropical-spastic-paraparesis-HAM/TSP and in HTLV-I carriers. HAM/TSP (n = 11, 2 males/9 females, median age = 48 years), recently diagnosed HTLV-I carriers (n = 21, 15 females/6 males, median age = 44 years), healthy individuals (n = 20, 10 males/10 females, median age = 34.6 years) from the Brazilian Amazon (Manaus, Amazonas State) were investigated. Neopterin was measured (IBL ELISA Neopterin, Germany) in serum samples of all the participants, in CSF of 9 HAM/TSP patients as well as in 6 carriers. In HAM/TSP patients, CSF cell counts, protein and glucose were measured, the Osame’s motor-disability-score/OMDS was determined, and brain/spinal cord magnetic-resonance-imaging (MRI) was performed. HAM/TSP patients had normal CSF glucose, leukocyte counts; and normal protein levels predominated. Brain-MRI showed white-matter lesions in 7 out of 11 HAM/TSP patients. OMDS varied from 2-8: 9 were able to walk, 2 were wheel-chair-users. The median serum neopterin concentration in HAM/TSP patients was 6.6 nmol/ L; min. 2.8- max. 12.5 nmol/ L); was lower in carriers (4.3 nmol/L; min. 2.7- max. 7.2 nmol/ L) as well as in healthy participants (4.7 nmol/ L; min. 2.7- max. 8.0 nmol/ L) (p < 0.05). CSF neopterin concentrations in HAM/TSP patients were higher than in serum samples, and higher compared to carriers (p < 0.05). Carriers had similar serum-CSF neopterin concentrations compared to healthy participants. Variable clinical and laboratory profiles were seen in HAM/TSP patients, however our results support the neopterin measurement as a potential biomarker of disease activity. PMID:28380116

Cerebrospinal fluid maraviroc concentrations in HIV-1 infected patients.

PubMed

Yilmaz, Aylin; Watson, Victoria; Else, Laura; Gisslèn, Magnus

2009-11-27

In order to assess the penetration of maraviroc to the central nervous system, we measured maraviroc concentrations in cerebrospinal fluid (CSF) and plasma. Concentrations were determined by liquid chromatography tandem mass spectrometry (lower limit of quantitation 1.25 ng/ml) in seven paired CSF and plasma samples. The median plasma maraviroc concentration was 94.9 ng/ml (range 21.4-478.0) and the median CSF concentration was 3.63 ng/ml (range 1.83-12.2). CSF samples exceeded the median EC90 for maraviroc (0.57 ng/ml) by at least three-fold. The CSF levels of maraviroc found in this study likely contribute to viral suppression in the CSF.