High Throughput ELISAs to Measure a Unique Glycan on Transferrin in Cerebrospinal Fluid: A Possible Extension toward Alzheimer's Disease Biomarker Development

PubMed Central

Shirotani, Keiro; Futakawa, Satoshi; Nara, Kiyomitsu; Hoshi, Kyoka; Saito, Toshie; Tohyama, Yuriko; Kitazume, Shinobu; Yuasa, Tatsuhiko; Miyajima, Masakazu; Arai, Hajime; Kuno, Atsushi; Narimatsu, Hisashi; Hashimoto, Yasuhiro

2011-01-01

We have established high-throughput lectin-antibody ELISAs to measure different glycans on transferrin (Tf) in cerebrospinal fluid (CSF) using lectins and an anti-transferrin antibody (TfAb). Lectin blot and precipitation analysis of CSF revealed that PVL (Psathyrella velutina lectin) bound an unique N-acetylglucosamine-terminated N-glycans on “CSF-type” Tf whereas SSA (Sambucus sieboldiana agglutinin) bound α2,6-N-acetylneuraminic acid-terminated N-glycans on “serum-type” Tf. PVL-TfAb ELISA of 0.5 μL CSF samples detected “CSF-type” Tf but not “serum-type” Tf whereas SSA-TfAb ELISA detected “serum-type” Tf but not “CSF-type” Tf, demonstrating the specificity of the lectin-TfAb ELISAs. In idiopathic normal pressure hydrocephalus (iNPH), a senile dementia associated with ventriculomegaly, amounts of the SSA-reactive Tf were significantly higher than in non-iNPH patients, indicating that Tf glycan analysis by the high-throughput lectin-TfAb ELISAs could become practical diagnostic tools for iNPH. The lectin-antibody ELISAs of CSF proteins might be useful for diagnosis of the other neurological diseases. PMID:21876827

High Throughput ELISAs to Measure a Unique Glycan on Transferrin in Cerebrospinal Fluid: A Possible Extension toward Alzheimer's Disease Biomarker Development.

PubMed

Shirotani, Keiro; Futakawa, Satoshi; Nara, Kiyomitsu; Hoshi, Kyoka; Saito, Toshie; Tohyama, Yuriko; Kitazume, Shinobu; Yuasa, Tatsuhiko; Miyajima, Masakazu; Arai, Hajime; Kuno, Atsushi; Narimatsu, Hisashi; Hashimoto, Yasuhiro

2011-01-01

We have established high-throughput lectin-antibody ELISAs to measure different glycans on transferrin (Tf) in cerebrospinal fluid (CSF) using lectins and an anti-transferrin antibody (TfAb). Lectin blot and precipitation analysis of CSF revealed that PVL (Psathyrella velutina lectin) bound an unique N-acetylglucosamine-terminated N-glycans on "CSF-type" Tf whereas SSA (Sambucus sieboldiana agglutinin) bound α2,6-N-acetylneuraminic acid-terminated N-glycans on "serum-type" Tf. PVL-TfAb ELISA of 0.5 μL CSF samples detected "CSF-type" Tf but not "serum-type" Tf whereas SSA-TfAb ELISA detected "serum-type" Tf but not "CSF-type" Tf, demonstrating the specificity of the lectin-TfAb ELISAs. In idiopathic normal pressure hydrocephalus (iNPH), a senile dementia associated with ventriculomegaly, amounts of the SSA-reactive Tf were significantly higher than in non-iNPH patients, indicating that Tf glycan analysis by the high-throughput lectin-TfAb ELISAs could become practical diagnostic tools for iNPH. The lectin-antibody ELISAs of CSF proteins might be useful for diagnosis of the other neurological diseases.

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.

Efficacy of Perioperative Lumbar Drainage following Endonasal Endoscopic Cerebrospinal Fluid Leak Repair.

PubMed

Ahmed, Omar H; Marcus, Sonya; Tauber, Jenna R; Wang, Binhuan; Fang, Yixin; Lebowitz, Richard A

2017-01-01

Objective Perioperative lumbar drain (LD) use in the setting of endoscopic cerebrospinal fluid (CSF) leak repair is a well-established practice. However, recent data suggest that LDs may not provide significant benefit and may thus confer unnecessary risk. To examine this, we conducted a meta-analysis to investigate the effect of LDs on postoperative CSF leak recurrence following endoscopic repair of CSF rhinorrhea. Data Sources A comprehensive search was performed with the following databases: Ovid MEDLINE (1947 to November 2015), EMBASE (1974 to November 2015), Cochrane Review, and PubMed (1990 to November 2015). Review Method A meta-analysis was performed according to PRISMA guidelines. Results A total of 1314 nonduplicate studies were identified in our search. Twelve articles comprising 508 cases met inclusion criteria. Overall, use of LDs was not associated with significantly lower postoperative CSF leak recurrence rates following endoscopic repair of CSF rhinorrhea (odds ratio: 0.89, 95% confidence interval: 0.40-1.95) as compared with cases performed without LDs. Subgroup analysis of only CSF leaks associated with anterior skull base resections (6 studies, 153 cases) also demonstrated that lumbar drainage did not significantly affect rates of successful repair (odds ratio: 2.67, 95% confidence interval: 0.64-11.10). Conclusions There is insufficient evidence to support that adjunctive lumbar drainage significantly reduces postoperative CSF leak recurrence in patients undergoing endoscopic CSF leak repair. Subgroup analysis examining only those patients whose CSF leaks were associated with anterior skull base resections demonstrated similar results. More level 1 and 2 studies are needed to further investigate the efficacy of LDs, particularly in the setting of patients at high risk for CSF leak recurrence.

Nonuniform Moving Boundary Method for Computational Fluid Dynamics Simulation of Intrathecal Cerebrospinal Flow Distribution in a Cynomolgus Monkey.

PubMed

Khani, Mohammadreza; Xing, Tao; Gibbs, Christina; Oshinski, John N; Stewart, Gregory R; Zeller, Jillynne R; Martin, Bryn A

2017-08-01

A detailed quantification and understanding of cerebrospinal fluid (CSF) dynamics may improve detection and treatment of central nervous system (CNS) diseases and help optimize CSF system-based delivery of CNS therapeutics. This study presents a computational fluid dynamics (CFD) model that utilizes a nonuniform moving boundary approach to accurately reproduce the nonuniform distribution of CSF flow along the spinal subarachnoid space (SAS) of a single cynomolgus monkey. A magnetic resonance imaging (MRI) protocol was developed and applied to quantify subject-specific CSF space geometry and flow and define the CFD domain and boundary conditions. An algorithm was implemented to reproduce the axial distribution of unsteady CSF flow by nonuniform deformation of the dura surface. Results showed that maximum difference between the MRI measurements and CFD simulation of CSF flow rates was <3.6%. CSF flow along the entire spine was laminar with a peak Reynolds number of ∼150 and average Womersley number of ∼5.4. Maximum CSF flow rate was present at the C4-C5 vertebral level. Deformation of the dura ranged up to a maximum of 134 μm. Geometric analysis indicated that total spinal CSF space volume was ∼8.7 ml. Average hydraulic diameter, wetted perimeter, and SAS area were 2.9 mm, 37.3 mm and 27.24 mm2, respectively. CSF pulse wave velocity (PWV) along the spine was quantified to be 1.2 m/s.

Gas chromatography-mass spectrometry-based metabolic profiling of cerebrospinal fluid from epileptic dogs.

PubMed

Hasegawa, Tetsuya; Sumita, Maho; Horitani, Yusuke; Tamai, Reo; Tanaka, Katsuhiro; Komori, Masayuki; Takenaka, Shigeo

2014-04-01

Epilepsy is a common neurological disorder with seizures, but diagnostic approaches in veterinary clinics remain limited. Cerebrospinal fluid (CSF) is a body fluid used for diagnosis in veterinary medicine. In this study, we explored canine epilepsy diagnostic biomarkers using gas chromatography-mass spectrometry (GC-MS)-based metabolic profiling of CSF and multivariate data analysis. Profiles for subjects with idiopathic epilepsy differed significantly from those of healthy controls and subjects with symptomatic epilepsy. Among 60 identified metabolites, the levels of 20 differed significantly among the three groups. Glutamic acid was significantly increased in idiopathic epilepsy, and some metabolites including ascorbic acid were changed in both forms of epilepsy. These findings show that metabolic profiles of CSF differ between idiopathic and symptomatic epilepsy and that metabolites including glutamic acid and ascorbic acid in CSF may be useful for diagnosis of canine epilepsy.

Development of a Physiologically-Based Pharmacokinetic Model of the Rat Central Nervous System

PubMed Central

Badhan, Raj K. Singh; Chenel, Marylore; Penny, Jeffrey I.

2014-01-01

Central nervous system (CNS) drug disposition is dictated by a drug’s physicochemical properties and its ability to permeate physiological barriers. The blood–brain barrier (BBB), blood-cerebrospinal fluid barrier and centrally located drug transporter proteins influence drug disposition within the central nervous system. Attainment of adequate brain-to-plasma and cerebrospinal fluid-to-plasma partitioning is important in determining the efficacy of centrally acting therapeutics. We have developed a physiologically-based pharmacokinetic model of the rat CNS which incorporates brain interstitial fluid (ISF), choroidal epithelial and total cerebrospinal fluid (CSF) compartments and accurately predicts CNS pharmacokinetics. The model yielded reasonable predictions of unbound brain-to-plasma partition ratio (Kpuu,brain) and CSF:plasma ratio (CSF:Plasmau) using a series of in vitro permeability and unbound fraction parameters. When using in vitro permeability data obtained from L-mdr1a cells to estimate rat in vivo permeability, the model successfully predicted, to within 4-fold, Kpuu,brain and CSF:Plasmau for 81.5% of compounds simulated. The model presented allows for simultaneous simulation and analysis of both brain biophase and CSF to accurately predict CNS pharmacokinetics from preclinical drug parameters routinely available during discovery and development pathways. PMID:24647103

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

Modifications of haematology analyzers to improve cell counting and leukocyte differentiating in cerebrospinal fluid controls of the Joint German Society for Clinical Chemistry and Laboratory Medicine.

PubMed

Kleine, Tilmann O; Nebe, C Thomas; Löwer, Christa; Lehmitz, Reinhard; Kruse, Rolf; Geilenkeuser, Wolf-Jochen; Dorn-Beineke, Alexandra

2009-08-01

Flow cytometry (FCM) is used with haematology analyzers (HAs) to count cells and differentiate leukocytes in cerebrospinal fluid (CSF). To evaluate the FCM techniques of HAs, 10 external DGKL trials with CSF controls were carried out in 2004 to 2008. Eight single platform HAs with and without CSF equipment were evaluated with living blood leukocytes and erythrocytes in CSF like DGKL controls: Coulter (LH750,755), Abbott CD3200, CD3500, CD3700, CD4000, Sapphire, ADVIA 120(R) CSF assay, and Sysmex XE-2100(R). Results were compared with visual counting of native cells in Fuchs-Rosenthal chamber, unstained, and absolute values of leukocyte differentiation, assayed by dual platform analysis with immune-FCM (FACSCalibur, CD45, CD14) and the chamber counts. Reference values X were compared with HA values Y by statistical evaluation with Passing/Bablock (P/B) linear regression analysis to reveal conformity of both methods. The HAs, studied, produced no valid results with DGKL CSF controls, because P/B regression revealed no conformity with the reference values due to:-blank problems with impedance analysis,-leukocyte loss with preanalytical erythrocyte lysis procedures, especially of monocytes,-inaccurate results with ADVIA cell sphering and cell differentiation with algorithms and enzyme activities (e.g., peroxidase). HA techniques have to be improved, e.g., using no erythrocyte lysis and CSF adequate techniques, to examine CSF samples precise and accurate. Copyright 2009 International Society for Advancement of Cytometry.

Antiretroviral Treatment Effect on Immune Activation Reduces Cerebrospinal Fluid HIV-1 Infection

PubMed Central

Sinclair, Elizabeth; Ronquillo, Rollie; Lollo, Nicole; Deeks, Steven G.; Hunt, Peter; Yiannoutsos, Constantin T.; Spudich, Serena; Price, Richard W.

2012-01-01

Objective To define the effect of antiretroviral therapy (ART) on activation of T cells in cerebrospinal fluid (CSF) and blood, and interactions of this activation with CSF HIV-1 RNA concentrations. Design Cross-sectional analysis of 14 HIV-negative subjects and 123 neuroasymptomatic HIV-1–infected subjects divided into 3 groups: not on ART (termed “offs”), on ART with plasma HIV-1 RNA >500 copies/mL (“failures”), and on ART with plasma HIV-1 RNA ≤500 copies/mL (“successes”). T-cell activation was measured by coexpression of CD38 and human leukocyte antigen DR (HLA-DR). Other measurements included CSF neopterin and white blood cell (WBC) counts. Results CD8 T-cell activation in CSF and blood was highly correlated across all subjects and was highest in the offs, lower in the failures, and lower still in the successes. While CD8 activation was reduced in failures compared to offs across the range of plasma HIV-1, it maintained a coincident relation to CSF HIV-1 in both viremic groups. In addition to correlation with CSF HIV-1 concentrations, CD8 activation in blood and CSF correlated with CSF WBCs and CSF neopterin. Multivariate analysis confirmed the association of blood CD8 T-cell activation, along with plasma HIV-1 RNA and CSF neopterin, with CSF HIV-1 RNA levels. Conclusions The similarity of CD8 T-cell activation in blood and CSF suggests these cells move from blood to CSF with only minor changes in CD38/HLA-DR expression. Differences in the relation of CD8 activation to HIV-1 concentrations in the blood and CSF in the 2 viremic groups suggest that changes in immune activation not only modulate CSF HIV-1 replication but also contribute to CSF treatment effects. The magnitude of systemic HIV-1 infection and intrathecal macrophage activation are also important determinants of CSF HIV-1 RNA levels. PMID:18362693

Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation.

PubMed

Achariyar, Thiyagaragan M; Li, Baoman; Peng, Weiguo; Verghese, Philip B; Shi, Yang; McConnell, Evan; Benraiss, Abdellatif; Kasper, Tristan; Song, Wei; Takano, Takahiro; Holtzman, David M; Nedergaard, Maiken; Deane, Rashid

2016-12-08

Apolipoprotein E (apoE) is a major carrier of cholesterol and essential for synaptic plasticity. In brain, it's expressed by many cells but highly expressed by the choroid plexus and the predominant apolipoprotein in cerebrospinal fluid (CSF). The role of apoE in the CSF is unclear. Recently, the glymphatic system was described as a clearance system whereby CSF and ISF (interstitial fluid) is exchanged via the peri-arterial space and convective flow of ISF clearance is mediated by aquaporin 4 (AQP4), a water channel. We reasoned that this system also serves to distribute essential molecules in CSF into brain. The aim was to establish whether apoE in CSF, secreted by the choroid plexus, is distributed into brain, and whether this distribution pattern was altered by sleep deprivation. We used fluorescently labeled lipidated apoE isoforms, lenti-apoE3 delivered to the choroid plexus, immunohistochemistry to map apoE brain distribution, immunolabeled cells and proteins in brain, Western blot analysis and ELISA to determine apoE levels and radiolabeled molecules to quantify CSF inflow into brain and brain clearance in mice. Data were statistically analyzed using ANOVA or Student's t- test. We show that the glymphatic fluid transporting system contributes to the delivery of choroid plexus/CSF-derived human apoE to neurons. CSF-delivered human apoE entered brain via the perivascular space of penetrating arteries and flows radially around arteries, but not veins, in an isoform specific manner (apoE2 > apoE3 > apoE4). Flow of apoE around arteries was facilitated by AQP4, a characteristic feature of the glymphatic system. ApoE3, delivered by lentivirus to the choroid plexus and ependymal layer but not to the parenchymal cells, was present in the CSF, penetrating arteries and neurons. The inflow of CSF, which contains apoE, into brain and its clearance from the interstitium were severely suppressed by sleep deprivation compared to the sleep state. Thus, choroid plexus/CSF provides an additional source of apoE and the glymphatic fluid transporting system delivers it to brain via the periarterial space. By implication, failure in this essential physiological role of the glymphatic fluid flow and ISF clearance may also contribute to apoE isoform-specific disorders in the long term.

Research into the Physiology of Cerebrospinal Fluid Reaches a New Horizon: Intimate Exchange between Cerebrospinal Fluid and Interstitial Fluid May Contribute to Maintenance of Homeostasis in the Central Nervous System

PubMed Central

MATSUMAE, Mitsunori; SATO, Osamu; HIRAYAMA, Akihiro; HAYASHI, Naokazu; TAKIZAWA, Ken; ATSUMI, Hideki; SORIMACHI, Takatoshi

2016-01-01

Cerebrospinal fluid (CSF) plays an essential role in maintaining the homeostasis of the central nervous system. The functions of CSF include: (1) buoyancy of the brain, spinal cord, and nerves; (2) volume adjustment in the cranial cavity; (3) nutrient transport; (4) protein or peptide transport; (5) brain volume regulation through osmoregulation; (6) buffering effect against external forces; (7) signal transduction; (8) drug transport; (9) immune system control; (10) elimination of metabolites and unnecessary substances; and finally (11) cooling of heat generated by neural activity. For CSF to fully mediate these functions, fluid-like movement in the ventricles and subarachnoid space is necessary. Furthermore, the relationship between the behaviors of CSF and interstitial fluid in the brain and spinal cord is important. In this review, we will present classical studies on CSF circulation from its discovery over 2,000 years ago, and will subsequently introduce functions that were recently discovered such as CSF production and absorption, water molecule movement in the interstitial space, exchange between interstitial fluid and CSF, and drainage of CSF and interstitial fluid into both the venous and the lymphatic systems. Finally, we will summarize future challenges in research. This review includes articles published up to February 2016. PMID:27245177

Pyridoxal 5'-phosphate, pyridoxal, and 4-pyridoxic acid in the paired serum and cerebrospinal fluid of children.

PubMed

Akiyama, Tomoyuki; Hayashi, Yumiko; Hanaoka, Yoshiyuki; Shibata, Takashi; Akiyama, Mari; Tsuchiya, Hiroki; Yamaguchi, Tokito; Kobayashi, Katsuhiro

2017-09-01

We quantified pyridoxal 5'-phosphate (PLP), pyridoxal (PL), and 4-pyridoxic acid (PA) in paired serum and cerebrospinal fluid (CSF) samples from children and investigated the effect of age on the concentrations and CSF-to-serum ratios of these vitamers. Serum and CSF samples prospectively collected from 49 pediatric patients were analyzed. PLP, PL, and PA were measured using high-performance liquid chromatography with fluorescence detection, using pre-column derivatization by semicarbazide. Effects of age on these vitamers, the PLP-to-PL ratio, CSF-to-serum PLP ratio, and CSF-to-serum PL ratio were evaluated using correlation analysis. The PLP, PL, and PA concentrations in the serum and CSF were higher at younger ages, except for CSF PA concentrations that were mostly below the limit of detection (<1.2nmol/l). The PLP-to-PL ratios in the serum and CSF correlated positively with age. The CSF-to-serum PLP ratio and CSF-to-serum PL ratio were independent of age. Age-related changes in PLP, PL, and PA in serum and in CSF from pediatric patients and CSF-to-serum ratios of PLP and PL demonstrated in this study will provide valuable information for evaluating PLP supply to the central nervous system from the peripheral blood. Copyright © 2017 Elsevier B.V. All rights reserved.

Analysis of clinical outcomes in pediatric bacterial meningitis focusing on patients without cerebrospinal fluid pleocytosis.

PubMed

Lin, Wen-Li; Chi, Hsin; Huang, Fu-Yuan; Huang, Daniel Tsung-Ning; Chiu, Nan-Chang

2016-10-01

Cerebrospinal fluid (CSF) cell count and biochemical examinations and cultures form the basis for the diagnosis of bacterial meningitis. However, some patients do not have typical findings and are at a higher risk of being missed or having delayed treatment. To better understand the correlation between CSF results and outcomes, we evaluated CSF data focusing on the patients with atypical findings. This study enrolled CSF culture-proven bacterial meningitis patients aged from 1 month to 18 years in a medical center. The patients were divided into "normal" and "abnormal" groups for each laboratory result and in combination. The correlations between the laboratory results and the outcomes were analyzed. A total of 175 children with confirmed bacterial meningitis were enrolled. In CSF examinations, 16.2% of patients had normal white blood cell counts, 29.5% had normal glucose levels, 24.5% had normal protein levels, 10.2% had normal results in two items, and 8.6% had normal results in all three items. In logistic regression analysis, a normal CSF leukocyte count and increased CSF protein level were related to poor outcomes. Patients with meningitis caused by Streptococcus pneumoniae and hyponatremia were at a higher risk of mortality and the development of sequelae. In children with bacterial meningitis, nontypical CSF findings and, in particular, normal CSF leukocyte count and increased protein level may indicate a worse prognosis. Copyright © 2014. Published by Elsevier B.V.

A new look at cerebrospinal fluid circulation

PubMed Central

2014-01-01

According to the traditional understanding of cerebrospinal fluid (CSF) physiology, the majority of CSF is produced by the choroid plexus, circulates through the ventricles, the cisterns, and the subarachnoid space to be absorbed into the blood by the arachnoid villi. This review surveys key developments leading to the traditional concept. Challenging this concept are novel insights utilizing molecular and cellular biology as well as neuroimaging, which indicate that CSF physiology may be much more complex than previously believed. The CSF circulation comprises not only a directed flow of CSF, but in addition a pulsatile to and fro movement throughout the entire brain with local fluid exchange between blood, interstitial fluid, and CSF. Astrocytes, aquaporins, and other membrane transporters are key elements in brain water and CSF homeostasis. A continuous bidirectional fluid exchange at the blood brain barrier produces flow rates, which exceed the choroidal CSF production rate by far. The CSF circulation around blood vessels penetrating from the subarachnoid space into the Virchow Robin spaces provides both a drainage pathway for the clearance of waste molecules from the brain and a site for the interaction of the systemic immune system with that of the brain. Important physiological functions, for example the regeneration of the brain during sleep, may depend on CSF circulation. PMID:24817998

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.

High-performance liquid chromatographic determination of histamine in biological samples: the cerebrospinal fluid challenge--a review.

PubMed

Wang, Zhaopin; Wu, Juanli; Wu, Shihua; Bao, Aimin

2013-04-24

Histamine, a neurotransmitter crucially involved in a number of basic physiological functions, undergoes changes in neuropsychiatric disorders. Detection of histamine in biological samples such as cerebrospinal fluid (CSF) is thus of clinical importance. The most commonly used method for measuring histamine levels is high performance liquid chromatography (HPLC). However, factors such as very low levels of histamine, the even lower CSF-histamine and CSF-histamine metabolite levels, especially in certain neuropsychiatric diseases, rapid formation of histamine metabolites, and other confounding elements during sample collection, make analysis of CSF-histamine and CSF-histamine metabolites a challenging task. Nonetheless, this challenge can be met, not only with respect to HPLC separation column, derivative reagent, and detector, but also in terms of optimizing the CSF sample collection. This review aims to provide a general insight into the quantitative analyses of histamine in biological samples, with an emphasis on HPLC instruments, methods, and hyphenated techniques, with the aim of promoting the development of an optimal and practical protocol for the determination of CSF-histamine and/or CSF-histamine metabolites. Copyright © 2013 Elsevier B.V. All rights reserved.

Cerebrospinal fluid lactate level as a diagnostic biomarker for bacterial meningitis in children

PubMed Central

2014-01-01

Background Cerebrospinal fluid (CSF) lactate is a potential biomarker for bacterial meningitis in children. To this end, we performed a single-center retrospective cohort study of children from Sao Paulo, Brazil, with CSF pleocytosis to evaluate the ability of CSF lactate to distinguish between children with bacterial and aseptic meningitis. We determined the optimum cutoff point for CSF lactate using receiver-operator curve (ROC) analysis. Findings We identified 451 children of whom 40 (9%) had bacterial meningitis. Children with bacterial meningitis had a higher median CSF lactate level [9.6 mmol/l, interquartile range (IQR) 3.2-38.5 mmol/l bacterial meningitis vs. 2.0 mmol/l, IQR 1.2-2.8 mmol/l aseptic meningitis]. A CSF lactate cutoff point of 3.0 mmol/l had a sensitivity of 95% [95% confidence interval (CI) 83-99%), specificity of 94% (95% CI 90-96%) and negative predictive value of 99.3% (95% CI 97.7-99.9%) for bacterial meningitis. Conclusions In combination with a validated meningitis clinical prediction rule, the CSF lactate level can be used to distinguish between bacterial and aseptic meningitis in children with CSF pleocytosis. PMID:24576334

Cerebrospinal fluid lactate level as a diagnostic biomarker for bacterial meningitis in children.

PubMed

Mekitarian Filho, Eduardo; Horita, Sérgio Massaru; Gilio, Alfredo Elias; Nigrovic, Lise E

2014-02-27

Cerebrospinal fluid (CSF) lactate is a potential biomarker for bacterial meningitis in children. To this end, we performed a single-center retrospective cohort study of children from Sao Paulo, Brazil, with CSF pleocytosis to evaluate the ability of CSF lactate to distinguish between children with bacterial and aseptic meningitis. We determined the optimum cutoff point for CSF lactate using receiver-operator curve (ROC) analysis. We identified 451 children of whom 40 (9%) had bacterial meningitis. Children with bacterial meningitis had a higher median CSF lactate level [9.6 mmol/l, interquartile range (IQR) 3.2-38.5 mmol/l bacterial meningitis vs. 2.0 mmol/l, IQR 1.2-2.8 mmol/l aseptic meningitis]. A CSF lactate cutoff point of 3.0 mmol/l had a sensitivity of 95% [95% confidence interval (CI) 83-99%), specificity of 94% (95% CI 90-96%) and negative predictive value of 99.3% (95% CI 97.7-99.9%) for bacterial meningitis. In combination with a validated meningitis clinical prediction rule, the CSF lactate level can be used to distinguish between bacterial and aseptic meningitis in children with CSF pleocytosis.

Label-free Quantitative Proteomics of Mouse Cerebrospinal Fluid Detects β-Site APP Cleaving Enzyme (BACE1) Protease Substrates In Vivo*

PubMed Central

Dislich, Bastian; Wohlrab, Felix; Bachhuber, Teresa; Müller, Stephan A.; Kuhn, Peer-Hendrik; Hogl, Sebastian; Meyer-Luehmann, Melanie; Lichtenthaler, Stefan F.

2015-01-01

Analysis of murine cerebrospinal fluid (CSF) by quantitative mass spectrometry is challenging because of low CSF volume, low total protein concentration, and the presence of highly abundant proteins such as albumin. We demonstrate that the CSF proteome of individual mice can be analyzed in a quantitative manner to a depth of several hundred proteins in a robust and simple workflow consisting of single ultra HPLC runs on a benchtop mass spectrometer. The workflow is validated by a comparative analysis of BACE1−/− and wild-type mice using label-free quantification. The protease BACE1 cleaves the amyloid precursor protein (APP) as well as several other substrates and is a major drug target in Alzheimer's disease. We identified a total of 715 proteins with at least 2 unique peptides and quantified 522 of those proteins in CSF from BACE1−/− and wild-type mice. Several proteins, including the known BACE1 substrates APP, APLP1, CHL1 and contactin-2 showed lower abundance in the CSF of BACE1−/− mice, demonstrating that BACE1 substrate identification is possible from CSF. Additionally, ectonucleotide pyrophosphatase 5 was identified as a novel BACE1 substrate and validated in cells using immunoblots and by an in vitro BACE1 protease assay. Likewise, receptor-type tyrosine-protein phosphatase N2 and plexin domain-containing 2 were confirmed as BACE1 substrates by in vitro assays. Taken together, our study shows the deepest characterization of the mouse CSF proteome to date and the first quantitative analysis of the CSF proteome of individual mice. The BACE1 substrates identified in CSF may serve as biomarkers to monitor BACE1 activity in Alzheimer patients treated with BACE inhibitors. PMID:26139848

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.

Evaluation of peptide adsorption-controlled liquid chromatography-tandem mass spectrometric (PAC-LC-MS/MS) method for simple and simultaneous quantitation of amyloid β 1-38, 1-40, 1-42 and 1-43 peptides in dog cerebrospinal fluid.

PubMed

Goda, Ryoya; Kobayashi, Nobuhiro

2012-05-01

To evaluate the usefulness of the peptide adsorption-controlled liquid chromatography-tandem mass spectrometry (PAC-LC-MS/MS) for reproducible measurement of peptides in biological fluids, simultaneous quantitation of amyloid β 1-38, 1-40, 1-42 and 1-43 peptides (Aβ38, Aβ40, Aβ42 and Aβ43) in dog cerebrospinal fluid (CSF) was tried. Each stable isotope labeled Aβ was used as the internal standard to minimize the influence of CSF matrix on the reproducible Aβ quantitation. To reduce a loss of Aβ during the pretreatment procedures, the dog CSF diluted by water-acetic acid-methanol (2:6:1, v/v/v) was loaded on PAC-LC-MS/MS directly. Quantification of the Aβ in the diluted dog CSF was carried out using multiple reaction monitoring (MRM) mode. The [M+5H(5+)] and b(5+) ion fragment of each peptide were chosen as the precursor and product ions for MRM transitions of each peptide. The calibration curves were drawn from Aβ standard calibration solutions using PAC-LC-MS/MS. Analysis of dog CSF samples suggests that the basal concentration of Aβ38, Aβ40, Aβ42 and Aβ43 in dog CSF is approximately 300, 900, 200 and 30 pM, respectively. This is the first time Aβ concentrations in dog CSF have been reported. Additionally, the evaluation of intra- and inter-day reproducibility of analysis of Aβ standard solution, the freeze-thaw stability and the room temperature stability of Aβ standard solution suggest that the PAC-LC-MS/MS method enables reproducible Aβ quantitation. Copyright © 2012 Elsevier B.V. All rights reserved.

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.

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.

Multiplicity of cerebrospinal fluid functions: New challenges in health and disease

PubMed Central

Johanson, Conrad E; Duncan, John A; Klinge, Petra M; Brinker, Thomas; Stopa, Edward G; Silverberg, Gerald D

2008-01-01

This review integrates eight aspects of cerebrospinal fluid (CSF) circulatory dynamics: formation rate, pressure, flow, volume, turnover rate, composition, recycling and reabsorption. Novel ways to modulate CSF formation emanate from recent analyses of choroid plexus transcription factors (E2F5), ion transporters (NaHCO3 cotransport), transport enzymes (isoforms of carbonic anhydrase), aquaporin 1 regulation, and plasticity of receptors for fluid-regulating neuropeptides. A greater appreciation of CSF pressure (CSFP) is being generated by fresh insights on peptidergic regulatory servomechanisms, the role of dysfunctional ependyma and circumventricular organs in causing congenital hydrocephalus, and the clinical use of algorithms to delineate CSFP waveforms for diagnostic and prognostic utility. Increasing attention focuses on CSF flow: how it impacts cerebral metabolism and hemodynamics, neural stem cell progression in the subventricular zone, and catabolite/peptide clearance from the CNS. The pathophysiological significance of changes in CSF volume is assessed from the respective viewpoints of hemodynamics (choroid plexus blood flow and pulsatility), hydrodynamics (choroidal hypo- and hypersecretion) and neuroendocrine factors (i.e., coordinated regulation by atrial natriuretic peptide, arginine vasopressin and basic fibroblast growth factor). In aging, normal pressure hydrocephalus and Alzheimer's disease, the expanding CSF space reduces the CSF turnover rate, thus compromising the CSF sink action to clear harmful metabolites (e.g., amyloid) from the CNS. Dwindling CSF dynamics greatly harms the interstitial environment of neurons. Accordingly the altered CSF composition in neurodegenerative diseases and senescence, because of adverse effects on neural processes and cognition, needs more effective clinical management. CSF recycling between subarachnoid space, brain and ventricles promotes interstitial fluid (ISF) convection with both trophic and excretory benefits. Finally, CSF reabsorption via multiple pathways (olfactory and spinal arachnoidal bulk flow) is likely complemented by fluid clearance across capillary walls (aquaporin 4) and arachnoid villi when CSFP and fluid retention are markedly elevated. A model is presented that links CSF and ISF homeostasis to coordinated fluxes of water and solutes at both the blood-CSF and blood-brain transport interfaces. Outline 1 Overview 2 CSF formation 2.1 Transcription factors 2.2 Ion transporters 2.3 Enzymes that modulate transport 2.4 Aquaporins or water channels 2.5 Receptors for neuropeptides 3 CSF pressure 3.1 Servomechanism regulatory hypothesis 3.2 Ontogeny of CSF pressure generation 3.3 Congenital hydrocephalus and periventricular regions 3.4 Brain response to elevated CSF pressure 3.5 Advances in measuring CSF waveforms 4 CSF flow 4.1 CSF flow and brain metabolism 4.2 Flow effects on fetal germinal matrix 4.3 Decreasing CSF flow in aging CNS 4.4 Refinement of non-invasive flow measurements 5 CSF volume 5.1 Hemodynamic factors 5.2 Hydrodynamic factors 5.3 Neuroendocrine factors 6 CSF turnover rate 6.1 Adverse effect of ventriculomegaly 6.2 Attenuated CSF sink action 7 CSF composition 7.1 Kidney-like action of CP-CSF system 7.2 Altered CSF biochemistry in aging and disease 7.3 Importance of clearance transport 7.4 Therapeutic manipulation of composition 8 CSF recycling in relation to ISF dynamics 8.1 CSF exchange with brain interstitium 8.2 Components of ISF movement in brain 8.3 Compromised ISF/CSF dynamics and amyloid retention 9 CSF reabsorption 9.1 Arachnoidal outflow resistance 9.2 Arachnoid villi vs. olfactory drainage routes 9.3 Fluid reabsorption along spinal nerves 9.4 Reabsorption across capillary aquaporin channels 10 Developing translationally effective models for restoring CSF balance 11 Conclusion PMID:18479516

Potential of fluid-attenuated inversion recovery (FLAIR) in identification of temporomandibular joint effusion compared with T2-weighted images.

PubMed

Imoto, Kenichi; Otonari-Yamamoto, Mika; Nishikawa, Keiichi; Sano, Tsukasa; Yamamoto, Aya

2011-08-01

The purpose of this study was to determine the potential of fluid-attenuated inversion recovery (FLAIR) sequence images in the identification of joint effusion (JE) compared with T2-weighted images. A total of 31 joints (28 patients) with JE were investigated by magnetic resonance imaging (MRI). Regions of interest were placed over JE, cerebrospinal fluid (CSF), and gray matter (GM) on T2-weighted and FLAIR images and their signal intensities compared. The signal intensity ratios (SIRs) of JE and CSF were calculated with GM as the reference point. The Pearson product-moment correlation coefficient was used for the statistical analysis. The SIR of JE showed a strong correlation between T2-weighted and FLAIR images. However, no correlation was observed for CSF. The average suppression ratio for JE was lower than that for CSF. MRI using FLAIR sequences revealed that JE was not just water content, but a fluid accumulation containing elements such as protein. Further studies are needed, and FLAIR sequences could be useful for the diagnosis of pain and symptoms of the temporomandibular joint (TMJ). Copyright © 2011 Mosby, Inc. All rights reserved.

Label-Free LC-MS/MS Proteomic Analysis of Cerebrospinal Fluid Identifies Protein/Pathway Alterations and Candidate Biomarkers for Amyotrophic Lateral Sclerosis.

PubMed

Collins, Mahlon A; An, Jiyan; Hood, Brian L; Conrads, Thomas P; Bowser, Robert P

2015-11-06

Analysis of the cerebrospinal fluid (CSF) proteome has proven valuable to the study of neurodegenerative disorders. To identify new protein/pathway alterations and candidate biomarkers for amyotrophic lateral sclerosis (ALS), we performed comparative proteomic profiling of CSF from sporadic ALS (sALS), healthy control (HC), and other neurological disease (OND) subjects using label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS). A total of 1712 CSF proteins were detected and relatively quantified by spectral counting. Levels of several proteins with diverse biological functions were significantly altered in sALS samples. Enrichment analysis was used to link these alterations to biological pathways, which were predominantly related to inflammation, neuronal activity, and extracellular matrix regulation. We then used our CSF proteomic profiles to create a support vector machines classifier capable of discriminating training set ALS from non-ALS (HC and OND) samples. Four classifier proteins, WD repeat-containing protein 63, amyloid-like protein 1, SPARC-like protein 1, and cell adhesion molecule 3, were identified by feature selection and externally validated. The resultant classifier distinguished ALS from non-ALS samples with 83% sensitivity and 100% specificity in an independent test set. Collectively, our results illustrate the utility of CSF proteomic profiling for identifying ALS protein/pathway alterations and candidate disease biomarkers.

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

[Cerebrospinal fluid findings in chronic active Epstein-Barr virus infection with central nervous system involvement].

PubMed

Yoshimori, Mayumi; Imadome, Ken-Ichi; Tomii, Shohei; Yamamoto, Kouhei; Miura, Osamu; Arai, Ayako

2018-01-01

As chronic active Epstein-Barr virus (EBV) infection (CAEBV) progresses, EBV-infected tumor cells invade the central nervous system (CNS). To establish a diagnostic procedure for CNS invasion, we retrospectively analyzed cerebrospinal fluid (CSF) obtained from eight patients. Two patients presented with consciousness disturbance and were diagnosed with CNS invasion based on scan and autopsy results, respectively. The remaining six patients were diagnosed without CNS invasion by clinical findings and scans. In the two patients with CNS invasion, the number of mononuclear cells and the protein concentration were increased, whereas the CSF to serum glucose ratio and the adenosine deaminase concentration were raised. In one of the two patients, however, bacterial meningitis could not be excluded. Cytological examination of CSF demonstrated class 1-3. Notably, the CSF EBV-DNA load was positive in all patients, independent of CNS invasion diagnosis, and the CSF load correlated with that of the peripheral blood. Taken together, this indicates that CSF may lack the specific markers of CNS invasion in CAEBV patients. The CSF EBV-DNA load and the cytological analysis did not reflect CNS invasion; therefore, new biomarkers need to be established.

GM-CSF overexpression after influenza a virus infection prevents mortality and moderates M1-like airway monocyte/macrophage polarization.

PubMed

Halstead, E Scott; Umstead, Todd M; Davies, Michael L; Kawasawa, Yuka Imamura; Silveyra, Patricia; Howyrlak, Judie; Yang, Linlin; Guo, Weichao; Hu, Sanmei; Hewage, Eranda Kurundu; Chroneos, Zissis C

2018-01-05

Influenza A viruses cause life-threatening pneumonia and lung injury in the lower respiratory tract. Application of high GM-CSF levels prior to infection has been shown to reduce morbidity and mortality from pathogenic influenza infection in mice, but the mechanisms of protection and treatment efficacy have not been established. Mice were infected intranasally with influenza A virus (PR8 strain). Supra-physiologic levels of GM-CSF were induced in the airways using the double transgenic GM-CSF (DTGM) or littermate control mice starting on 3 days post-infection (dpi). Assessment of respiratory mechanical parameters was performed using the flexiVent rodent ventilator. RNA sequence analysis was performed on FACS-sorted airway macrophage subsets at 8 dpi. Supra-physiologic levels of GM-CSF conferred a survival benefit, arrested the deterioration of lung mechanics, and reduced the abundance of protein exudates in bronchoalveolar (BAL) fluid to near baseline levels. Transcriptome analysis, and subsequent validation ELISA assays, revealed that excess GM-CSF re-directs macrophages from an "M1-like" to a more "M2-like" activation state as revealed by alterations in the ratios of CXCL9 and CCL17 in BAL fluid, respectively. Ingenuity pathway analysis predicted that GM-CSF surplus during IAV infection elicits expression of anti-inflammatory mediators and moderates M1 macrophage pro-inflammatory signaling by Type II interferon (IFN-γ). Our data indicate that application of high levels of GM-CSF in the lung after influenza A virus infection alters pathogenic "M1-like" macrophage inflammation. These results indicate a possible therapeutic strategy for respiratory virus-associated pneumonia and acute lung injury.

A UPLC-MS/MS method for analysis of vancomycin in human cerebrospinal fluid and comparison with the chemiluminescence immunoassay.

PubMed

Mei, Shenghui; Wang, Jiaqing; Zhu, Leting; Chen, Ruiling; Li, Xingang; Chen, Kai; Chen, Guangqiang; Zhou, Jianxin; Wang, Qiang; Zhao, Zhigang

2017-08-01

Vancomycin (VCM) is clinically used in treating patients with postoperative intracranial infections. The cerebrospinal fluid (CSF) concentration of VCM varies greatly among patients. To guide the dosage regimens, monitoring of VCM in CSF is needed. However a method for analysis of VCM in human CSF is lacking. An ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was developed and validated for analysis of VCM in human CSF, and the agreement of UPLC-MS/MS and chemiluminescence immunoassay (CLIA) in the analysis of CSF VCM was evaluated. The ion transitions were m/z 725.5 > 144.1 for VCM and m/z 455.2 > 308.2 for methotrexate (internal standard). The agreement between UPLC-MS/MS and CLIA was evaluated by Bland-Altman plot in 179 samples. The calibration range of the UPLC-MS/MS method was 1-400 mg/L. The inaccuracy and imprecision were -0.69-10.80% and <4.95%. The internal standard normalized recovery and matrix factor were 86.14-99.31 and 85.84-92.07%, respectively. The measurements of CLIA and UPLC-MS/MS were strongly correlated (r > 0.98). The 95% limit of agreement of the ratio of CLIA to UPLC-MS/MS was 61.66-107.40%. Further studies are warranted to confirm the results. Copyright © 2017 John Wiley & Sons, Ltd.

Cerebrospinal Fluid Glucose and Lactate: Age-Specific Reference Values and Implications for Clinical Practice

PubMed Central

Leen, Wilhelmina G.; Willemsen, Michèl A.; Wevers, Ron A.; Verbeek, Marcel M.

2012-01-01

Cerebrospinal fluid (CSF) analysis is an important tool in the diagnostic work-up of many neurological disorders, but reference ranges for CSF glucose, CSF/plasma glucose ratio and CSF lactate based on studies with large numbers of CSF samples are not available. Our aim was to define age-specific reference values. In 1993 The Nijmegen Observational CSF Study was started. Results of all CSF samples that were analyzed between 1993 and 2008 at our laboratory were systematically collected and stored in our computerized database. After exclusion of CSF samples with an unknown or elevated erythrocyte count, an elevated leucocyte count, elevated concentrations of bilirubin, free hemoglobin, or total protein 9,036 CSF samples were further studied for CSF glucose (n = 8,871), CSF/plasma glucose ratio (n = 4,516) and CSF lactate values (n = 7,614). CSF glucose, CSF/plasma glucose ratio and CSF lactate were age-, but not sex dependent. Age-specific reference ranges were defined as 5–95th percentile ranges. CSF glucose 5th percentile values ranged from 1.8 to 2.9 mmol/L and 95th percentile values from 3.8 to 5.6 mmol/L. CSF/plasma glucose ratio 5th percentile values ranged from 0.41 to 0.53 and 95th percentile values from 0.82 to 1.19. CSF lactate 5th percentile values ranged from 0.88 to 1.41 mmol/L and 95th percentile values from 2.00 to 2.71 mmol/L. Reference ranges for all three parameters were widest in neonates and narrowest in toddlers, with lower and upper limits increasing with age. These reference values allow a reliable interpretation of CSF results in everyday clinical practice. Furthermore, hypoglycemia was associated with an increased CSF/plasma glucose ratio, whereas hyperglycemia did not affect the CSF/plasma glucose ratio. PMID:22880096

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 ...

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.

Cerebrospinal Fluid (CSF) Analysis

MedlinePlus

... Internet]. Allina Health; c2017. Cerebrospinal fluid IgG measurement, quantitative [updated 2016 Mar 29; cited 2017 Oct 22]; [ ... Clinic [Internet]. Mayo Foundation for Medical Education and Research; c1998–2017. Lumbar puncture (spinal tap): Risks; 2014 ...

Crystals seen on CSF microscopy in a case of suspected subarachnoid haemorrhage

PubMed Central

Weiand, Daniel; Hanning, Ian; Mouhamadou, Moussa; Wearmouth, Debbie

2015-01-01

Although crystals are rarely identified on cerebrospinal fluid (CSF) microscopy, their presence can be of significant diagnostic value. We report a case of oxalate crystals seen on CSF microscopy of a 43-year-old woman. The patient presented with headaches, nausea and vomiting. CT of the head showed a small focus of hyper-density, suspicious of haemorrhage, in the right side of the pontine cistern. CSF cell count was within the normal range. Although no organisms were seen on microscopy, copious oxalate crystals were seen. The same crystals were seen on microscopy of CSF collected in a fluoride oxalate container used for glucose analysis. A follow-up contrast-enhanced CT angiogram did not demonstrate any abnormalities. It transpired that excess CSF had been collected into a fluoride oxalate container. This had subsequently been decanted into a plain container for microbiological analysis. Correct specimen collection should be emphasised when teaching lumbar puncture technique. PMID:26139652

Cerebrospinal fluid monocytes in bacterial meningitis, viral meningitis, and neuroborreliosis.

PubMed

Martinot, M; Greigert, V; Souply, L; Rosolen, B; De Briel, D; Mohseni Zadeh, M; Kaiser, J-D

2018-04-05

Cerebrospinal fluid (CSF) leukocytes analysis is commonly used to diagnose meningitis and to differentiate bacterial from viral meningitis. Interpreting CSF monocytes can be difficult for physicians, especially in France where lymphocytes and monocytes results are sometimes pooled. We assessed SF monocytes in patients presenting with microbiologically confirmed meningitis (CSF leukocyte count>10/mm 3 for adults or >30/mm 3 for children<2 months), i.e. bacterial meningitis (BM), viral meningitis (VM), and neuroborreliosis (NB). Two-hundred patients (82 BM, 86 VM, and 32 NB) were included. The proportions of monocytes were higher in VM (median 8%; range 0-57%) than in BM (median 5%; range 0-60%, P=0.03) or NB (median 5%; range 0-53%, P=0.46), with a high value overlap between conditions. CSF monocytes should not be used to discriminate BM from VM and NB because of value overlaps. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Cerebrospinal fluid white cell count: discriminatory or otherwise for enteroviral meningitis in infants and young children?

PubMed

Tan, Natalie Woon Hui; Lee, Elis Yuexian; Khoo, Gloria Mei Chin; Tee, Nancy Wen Sim; Krishnamoorthy, Subramania; Choong, Chew Thye

2016-04-01

Non-polio enteroviruses (EV) are the most common viruses causing aseptic meningitis in children. We aim to evaluate the cerebrospinal fluid (CSF) characteristics of neonates and children with EV meningitis with a view to determine whether it could be discriminatory or otherwise in making a positive diagnosis. We performed a 3-year (July 2008-July 2011) retrospective study of children ≤16 years, treated at a tertiary children's hospital, with positive CSF EV polymerase chain reaction (PCR) and negative blood and CSF bacterial cultures. A total of 206 children were studied. The median CSF white cell count was 79 cells/mm(3) (range 0-4608 cells/mm(3)). CSF pleocytosis was observed in 99/150 (66%) aged ≤90 days, 3/4 (75%) aged 90 days-1 year, and 49/52 (94%) children ≥3 years. There was a huge variability in CSF pleocytosis in infants ≤90 days, where 34% of them had no pleocytosis, while in 66%, a wide range of pleocytosis that might even suggest bacterial meningitis was noted. CSF red cells were low, and protein or sugar values were not discriminatory. CSF pleocytosis in relation to increasing age was found to be statistically significant (p < 0.001). Early lumbar puncture within 48 h of symptoms and absence of CSF pleocytosis was also statistically significant (p = 0.039). CSF pleocytosis in EV meningitis is commoner in older children. As there was a huge variability in CSF pleocytosis in infants ≤90 days particularly, CSF analysis including EV PCR could avoid unnecessary antibiotic therapy.

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) ...

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.

HIV-1 Viral Escape in Cerebrospinal Fluid of Subjects on Suppressive Antiretroviral Treatment

PubMed Central

Edén, Arvid; Fuchs, Dietmar; Hagberg, Lars; Nilsson, Staffan; Spudich, Serena; Svennerholm, Bo; Price, Richard W.; Gisslén, Magnus

2010-01-01

Background. Occasional cases of viral escape in cerebrospinal fluid (CSF) despite suppression of plasma human immunodeficiency virus type 1 (HIV-1) RNA have been reported. We investigated CSF viral escape in subjects treated with commonly used antiretroviral therapy regimens in relation to intrathecal immune activation and central nervous system penetration effectiveness (CPE) rank. Methods. Sixty-nine neurologically asymptomatic subjects treated with antiretroviral therapy >6 months and plasma HIV-1 RNA <50 copies/mL were cross-sectionally included in the analysis. Antiretroviral therapy regimens included efavirenz, lopinavir/ritonavir or atazanavir/ritonavir combined with tenofovir, abacavir, or zidovudine and emtricitabine or lamivudine. HIV-1 RNA was analyzed with real-time polymerase chain reaction assays. Neopterin was analyzed by enzyme-linked immunosorbent assay. Results. Seven (10%) of the 69 subjects had detectable CSF HIV-1 RNA, in median 121 copies/mL (interquartile range, 54–213 copies/mL). Subjects with detectable CSF virus had significantly higher CSF neopterin and longer duration of treatment. Previous treatment interruptions were more common in subjects with CSF escape. Central nervous system penetration effectiveness rank was not a significant predictor of detectable CSF virus or CSF neopterin levels. Conclusions. Viral escape in CSF is more common than previously reported, suggesting that low-grade central nervous system infection may continue in treated patients. Although these findings need extension in longitudinal studies, they suggest the utility of monitoring CSF responses, as new treatment combinations and strategies modify clinical practice. PMID:21050119

HIV-1 viral escape in cerebrospinal fluid of subjects on suppressive antiretroviral treatment.

PubMed

Edén, Arvid; Fuchs, Dietmar; Hagberg, Lars; Nilsson, Staffan; Spudich, Serena; Svennerholm, Bo; Price, Richard W; Gisslén, Magnus

2010-12-15

Occasional cases of viral escape in cerebrospinal fluid (CSF) despite suppression of plasma human immunodeficiency virus type 1 (HIV-1) RNA have been reported. We investigated CSF viral escape in subjects treated with commonly used antiretroviral therapy regimens in relation to intrathecal immune activation and central nervous system penetration effectiveness (CPE) rank. Sixty-nine neurologically asymptomatic subjects treated with antiretroviral therapy >6 months and plasma HIV-1 RNA <50 copies/mL were cross-sectionally included in the analysis. Antiretroviral therapy regimens included efavirenz, lopinavir/ritonavir or atazanavir/ritonavir combined with tenofovir, abacavir, or zidovudine and emtricitabine or lamivudine. HIV-1 RNA was analyzed with real-time polymerase chain reaction assays. Neopterin was analyzed by enzyme-linked immunosorbent assay. Seven (10%) of the 69 subjects had detectable CSF HIV-1 RNA, in median 121 copies/mL (interquartile range, 54-213 copies/mL). Subjects with detectable CSF virus had significantly higher CSF neopterin and longer duration of treatment. Previous treatment interruptions were more common in subjects with CSF escape. Central nervous system penetration effectiveness rank was not a significant predictor of detectable CSF virus or CSF neopterin levels. Viral escape in CSF is more common than previously reported, suggesting that low-grade central nervous system infection may continue in treated patients. Although these findings need extension in longitudinal studies, they suggest the utility of monitoring CSF responses, as new treatment combinations and strategies modify clinical practice.

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.

Analysis of L-serine-O-phosphate in cerebrospinal spinal fluid by derivatization-liquid chromatography/mass spectrometry.

PubMed

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

2014-05-01

L-serine-O-phosphate (L-SOP), the precursor of L-serine, is a potent agonist against the group III metabotropic glutamate receptors (mGluRs) and, thus, is of interest as a potential biomarker for monitoring modulation of neurotransmitter release. So far, no reports are available on the analysis of L-SOP in cerebrospinal fluid (CSF). Here a novel method is presented to determine L-SOP levels in CSF employing precolumn derivatization with (5-N-succinimidoxy-5-oxopentyl)triphenylphosphonium bromide (SPTPP) coupled to liquid chromatography/mass spectrometry (derivatization-LC/MS, d-LC/MS). Copyright © 2014 Elsevier Inc. All rights reserved.

Cerebrospinal fluid protein and glucose examinations and tuberculosis:
Will laboratory safety regulations force a change of practice?

PubMed

Tormey, William P; O'Hagan, Christopher

2015-01-01

Cerebrospinal fluid (CSF) protein and glucose examinations are usually performed in chemical pathology departments on autoanalysers. Tuberculosis (TB) is a group 3 biological agent under Directive 2000/54/EC of the European Parliament but in the biochemistry laboratory, no extra precautions are taken in its analysis in possible TB cases. The issue of laboratory practice and safety in the biochemical analyses of CSF specimens, when tuberculosis infection is in question is addressed in the context of ambiguity in the implementation of current national and international health and safety regulations. Additional protective measures for laboratory staff during the analysis of CSF TB samples should force a change in current laboratory practice and become a regulatory issue under ISO 15189. Annual Mantoux skin test or an interferon-γ release assay for TB should be mandatory for relevant staff. This manuscript addresses the issue of biochemistry laboratory practice and safety in the biochemical analyses of CSF specimens when tuberculosis infection is in question in the context of the ambiguity of statutory health and safety regulations.

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.

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.

CPA melanoma: diagnosis and management.

PubMed

Brackmann, Derald E; Doherty, Joni K

2007-06-01

Melanoma rarely invades the cerebellopontine angle (CPA) and can evade accurate diagnosis, which may alter management decisions. Diagnosis may be facilitated via careful history, magnetic resonance imaging (MRI) findings, and cerebrospinal fluid (CSF) analysis. Retrospective case review. Tertiary referral center. Thirteen internal auditory canal/CPA lesions in eight patients who presented with CPA syndrome and who had a pathological diagnosis consistent with malignant melanoma. There were four bilateral and four unilateral lesions. Six of eight patients had a history of melanoma. One was apparently primary CPA lesion, whereas all others were metastatic. T1- and T2-weighted precontrast and postcontrast gadolinium-enhanced MRI were obtained, including fat suppression and fluid-attenuated inversion recovery sequence images in two patients; lumbar puncture with CSF centrifugation and cytological analysis confirmed the diagnosis in two patients. Translabyrinthine craniotomy was performed for tumor extirpation in five patients. Symptoms at presentation, MRI findings, presence of malignant cells in CSF, tumor progression, intraoperative findings, response to treatment, time interval from initial diagnosis of melanoma elsewhere, and survival. Seven of eight patients had history and/or MRI findings suggestive of malignancy in the internal auditory canal and/or CPA, and diagnosis was confirmed via CSF analysis in two patients. In one patient, diagnosis was made at surgery. Internal auditory canal melanoma portends a grim prognosis, can occur up to 17 years after initial melanoma diagnosis/treatment, and can be detected with appropriate MRI sequences, especially enhanced fluid-attenuated inversion recovery images. In disseminated cases, diagnosis can be confirmed with lumbar puncture demonstrating malignant cells. Management includes tumor resection when melanoma seems to be solitary and malignant cells are not present in CSF. Intrathecal chemotherapy and radiation are recommended for dissemination, although the survival rate is still poor.

MicroRNA Profile in Patients with Alzheimer's Disease: Analysis of miR-9-5p and miR-598 in Raw and Exosome Enriched Cerebrospinal Fluid Samples.

PubMed

Riancho, Javier; Vázquez-Higuera, José Luis; Pozueta, Ana; Lage, Carmen; Kazimierczak, Martha; Bravo, María; Calero, Miguel; Gonalezález, Andrea; Rodríguez, Eloy; Lleó, Alberto; Sánchez-Juan, Pascual

2017-01-01

MicroRNAs have been postulated as potential biomarkers for Alzheimer's disease (AD). Exosomes are nanovesicles which transport microRNAs, proteins, and other cargos. It has been hypothesized that the exosome traffic might be increased in neurodegenerative disorders. i) To assess the cerebrospinal fluid (CSF) microRNA profile in a group of AD patients and control subjects and to validate a group of microRNAs previously reported by other authors. ii) To compare microRNA levels in whole CSF and in the exosome-enriched fraction in AD patients. A panel of 760 microRNAs was analyzed in the CSF of 10 AD patients and 10 healthy subjects. Among microRNAs differently expressed, we selected those that had been previously reported by other authors. Candidates were validated in a larger group by individual qPCR assays. MicroRNA expression was also evaluated in exosome-enriched CSF samples of patients with AD and controls. Fifteen microRNAs were differently expressed in AD. MiR-9-5p, miR-134, and miR-598 were selected as candidates for further analysis. MiR-9-5p and miR-598 were detected in 50 and 75% of control CSF samples, respectively, while they were not detected in any AD CSF samples. We observed an opposite pattern when we evaluated the microRNA expression in the exosome-enriched CSF AD samples. No pattern variations were noted among healthy subjects. These data propose miR-9-5p and miR-598 as potential biomarkers for AD. Further studies in plasma and other body fluids will confirm their potential role as easily accessible biomarkers. In addition, our data suggest that exosome trafficking is different between AD and control subjects raising the need to take this phenomenon into consideration in future studies of AD biomarkers.

Qualitative metabolome analysis of human cerebrospinal fluid by 13C-/12C-isotope dansylation labeling combined with liquid chromatography Fourier transform ion cyclotron resonance mass spectrometry.

PubMed

Guo, Kevin; Bamforth, Fiona; Li, Liang

2011-02-01

Metabolome analysis of human cerebrospinal fluid (CSF) is challenging because of low abundance of metabolites present in a small volume of sample. We describe and apply a sensitive isotope labeling LC-MS technique for qualitative analysis of the CSF metabolome. After a CSF sample is divided into two aliquots, they are labeled by (13)C-dansyl and (12)C-dansyl chloride, respectively. The differentially labeled aliquots are then mixed and subjected to LC-MS using Fourier-transform ion cyclotron resonance mass spectrometry (FTICR MS). Dansylation offers significant improvement in the performance of chromatography separation and detection sensitivity. Moreover, peaks detected in the mass spectra can be readily analyzed for ion pair recognition and database search based on accurate mass and/or retention time information. It is shown that about 14,000 features can be detected in a 25-min LC-FTICR MS run of a dansyl-labeled CSF sample, from which about 500 metabolites can be profiled. Results from four CSF samples are compared to gauge the detectability of metabolites by this method. About 261 metabolites are commonly detected in replicate runs of four samples. In total, 1132 unique metabolite ion pairs are detected and 347 pairs (31%) matched with at least one metabolite in the Human Metabolome Database. We also report a dansylation library of 220 standard compounds and, using this library, about 85 metabolites can be positively identified. Among them, 21 metabolites have never been reported to be associated with CSF. These results illustrate that the dansylation LC-FTICR MS method can be used to analyze the CSF metabolome in a more comprehensive manner. © American Society for Mass Spectrometry, 2011

Qualitative Metabolome Analysis of Human Cerebrospinal Fluid by 13C-/12C-Isotope Dansylation Labeling Combined with Liquid Chromatography Fourier Transform Ion Cyclotron Resonance Mass Spectrometry

NASA Astrophysics Data System (ADS)

Guo, Kevin; Bamforth, Fiona; Li, Liang

2011-02-01

Metabolome analysis of human cerebrospinal fluid (CSF) is challenging because of low abundance of metabolites present in a small volume of sample. We describe and apply a sensitive isotope labeling LC-MS technique for qualitative analysis of the CSF metabolome. After a CSF sample is divided into two aliquots, they are labeled by 13C-dansyl and 12C-dansyl chloride, respectively. The differentially labeled aliquots are then mixed and subjected to LC-MS using Fourier-transform ion cyclotron resonance mass spectrometry (FTICR MS). Dansylation offers significant improvement in the performance of chromatography separation and detection sensitivity. Moreover, peaks detected in the mass spectra can be readily analyzed for ion pair recognition and database search based on accurate mass and/or retention time information. It is shown that about 14,000 features can be detected in a 25-min LC-FTICR MS run of a dansyl-labeled CSF sample, from which about 500 metabolites can be profiled. Results from four CSF samples are compared to gauge the detectability of metabolites by this method. About 261 metabolites are commonly detected in replicate runs of four samples. In total, 1132 unique metabolite ion pairs are detected and 347 pairs (31%) matched with at least one metabolite in the Human Metabolome Database. We also report a dansylation library of 220 standard compounds and, using this library, about 85 metabolites can be positively identified. Among them, 21 metabolites have never been reported to be associated with CSF. These results illustrate that the dansylation LC-FTICR MS method can be used to analyze the CSF metabolome in a more comprehensive manner.

A single center study: Aβ42/p-Tau181 CSF ratio to discriminate AD from FTD in clinical setting.

PubMed

Vergallo, Andrea; Carlesi, Cecilia; Pagni, Cristina; Giorgi, Filippo Sean; Baldacci, Filippo; Petrozzi, Lucia; Ceravolo, Roberto; Tognoni, Gloria; Siciliano, Gabriele; Bonuccelli, Ubaldo

2017-10-01

Abnormal levels of beta amyloid (Aβ42) and tau protein concentrations in the cerebral spinal fluid (CSF) have been largely described in Alzheimer's disease (AD). Thus, CSF analysis of these biomarkers has been incorporated in recent AD diagnostic criteria, and it is increasingly performed for neurodegenerative dementia diagnostic workout in clinical setting. Nevertheless, the precise biomarkers CSF features in neurodegenerative dementia, either AD or Frontotemporal dementia (FTD), are still not fully clear today. This is mainly due to lack of CSF clear cutoff values due to a well-known intersite (but even intrasite) variability of CSF procedures, ranging from collection to analysis. Applying CSF biomarker ratios, rather than their single values could represent a useful tool, especially for the differential diagnosis of different forms of dementia. We explored clinical values of six CSF ratios (by combining Aβ42 and tau) in order to better discriminate between AD and FTD; we identified Aβ42/p-Tau 181 ratio as a potential good candidate for helping differentiating AD from FTD in the clinical practice.

Elevated levels of ferritin in the cerebrospinal fluid of amyotrophic lateral sclerosis patients.

PubMed

Zheng, Y; Gao, L; Wang, D; Zang, D

2017-08-01

The aim of the study was to detect changes in the levels of ferritin heavy chain (FHC), ferritin light chain (FLC), and transferrin in the cerebrospinal fluid (CSF) and serum of amyotrophic lateral sclerosis (ALS) patients and to analyze the correlations between the levels of these proteins and various clinical parameters. Cerebrospinal fluid and serum samples were obtained from 54 ALS patients and 46 non-inflammatory neurological disease control (non-INDC) patients. CSF and serum FHC, FLC, and transferring levels were measured via the enzyme-linked immunosorbent method using a commercial ELISA kit, and the times from onset (durations), ALS functional rating scale-revised (ALSFRS-r) scores, and disease progression rates (DPRs) were analyzed by registered neurologists. Statistical analysis was performed via Prism software. Compared with controls, ALS patients exhibited significantly increased FHC and FLC levels in CSF, which were positively correlated with DPR and negatively correlated with duration. Serum transferrin levels were significantly increased in ALS patients but were not correlated with disease progression. FHC and FLC in CSF rapidly increased as the disease worsened. This study demonstrated that the clinical measurement of FHC and FLC in CSF may be beneficial for disease differentiation and evaluating progression in patients with ALS. Compared with levels in serum, the levels of FHC and FLC in CSF might be more reliable for diagnosing and assessing the progression of ALS. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Thinking outside the shunt-sterile CSF malabsorption in pilocytic astrocytomas: case series and review of the literature.

PubMed

Johnson, J A; O'Halloran, P J; Crimmins, D; Caird, J

2016-11-01

Ventriculoperitoneal (VP) shunt insertion is the most common cerebrospinal fluid (CSF) diversionary procedure used for the treatment of chronic hydrocephalus. Sterile CSF ascites is a rare complication of VP shunt insertion. This can arise from either an overproduction of CSF or inadequate filtration of CSF at the level of the peritoneum. By either mechanism, the development of CSF ascites requires an intact VP shunt. The authors discuss two paediatric cases diagnosed with suprasellar pilocytic astrocytomas treated with platinum-based chemotherapy, who subsequently developed sterile CSF ascites. We review the literature with regard to CSF malabsorption and discuss it as a contributing factor to shunt malfunction. CSF malabsorption with resultant ascites is a rare complication of VP shunting with many etiologies. Two common predisposing factors included the use of platinum-based chemotherapeutic agents, as well as the specific neuropathology. Further analysis of these two entities is needed in order to elucidate their role in contributing to the development of CSF ascites in this patient cohort.

Dementia

MedlinePlus

... Blood ammonia levels Blood chemistry ( chem-20 ) Blood gas analysis Cerebrospinal fluid (CSF) analysis Drug or alcohol ... these drugs may be small Control problems with behavior, such as loss of judgment or confusion Someone ...

Evaluation and comparison of an indirect fluorescent antibody test for detection of antibodies to Sarcocystis neurona, using serum and cerebrospinal fluid of naturally and experimentally infected, and vaccinated horses.

PubMed

Duarte, Paulo C; Daft, Barbara M; Conrad, Patricia A; Packham, Andrea E; Saville, William J; MacKay, Robert J; Barr, Bradd C; Wilson, W David; Ng, Terry; Reed, Stephen M; Gardner, Ian A

2004-04-01

The objectives of this study were to evaluate the accuracy of the indirect fluorescent antibody test (IFAT) using serum and cerebrospinal fluid (CSF) of horses naturally and experimentally infected with Sarcocystis neurona, to assess the correlation between serum and CSF titers, and to determine the effect of S. neurona vaccination on the diagnosis of infection. Using receiver-operating characteristic analysis, the areas under the curve for the IFAT were 0.97 (serum) and 0.99 (CSF). Sensitivity and specificity were 83.3 and 96.9% (serum, cutoff 80) and 100 and 99% (CSF, cutoff 5), respectively. Titer-specific likelihood ratios (LRs) ranged from 0.03 to 187.8 for titers between <10 and 640. Median time to conversion was 22-26 days postinfection (DPI) (serum) and 30 DPI (CSF). The correlation between serum and CSF titers was moderately strong (r = 0.6) at 30 DPI. Percentage of vaccinated antibody-positive horses ranged from 0 to 95% between 0 and 112 days after the second vaccination. Thus, the IFAT was reliable and accurate using serum and CSF. Use of LRs potentially improves clinical decision making. Correlation between serum and CSF titers affects the joint accuracy of the IFAT; therefore, the ratio of serum to CSF titers has potential diagnostic value. The S. neurona vaccine could possibly interfere with equine protozoal myeloencephalitis diagnosis.

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.

Reproducibility of Alzheimer’s Disease Cerebrospinal Fluid-Biomarker Measurements under Clinical Routine Conditions

PubMed Central

Vogelgsang, Jonathan; Wedekind, Dirk; Bouter, Caroline; Klafki, Hans-W.; Wiltfang, Jens

2018-01-01

Analysis of cerebrospinal fluid (CSF) is one of the key tools for the state-of-the-art differential diagnosis of dementias. Dementia due to Alzheimer’s disease (AD) is characterized by elevated CSF levels of total Tau (tTau) and phospho-181-Tau (pTau) and low CSF amyloid-β42 (Aβ42). Discrepancies in the laboratory analysis of human materials are well known and much effort has been put into harmonization procedures. In this study, we measured CSF biomarkers of more than 100 patients obtained under clinical routine conditions in two different clinical laboratories. The CSF biomarker levels obtained from the two different sites were significantly correlated: R2 = 0.7129 (tTau, p < 0.001), 0.7914 (pTau, p < 0.001), 0.5078 (Aβ42, p < 0.001), 0.5739 (Aβ40, p < 0.001), and 0.4308 (Aβ42/40, p < 0.001). However, the diagnostic classifications of the Aβ42, tTau, and pTau levels of identical subjects into normal versus pathological range made by the two different sites showed substantial discrepancies (31.5%, 29.6%, and 25.0% discordant cases, respectively). Applying Aβ42/40, instead of CSF Aβ42 alone, lead to a reduction of the discordant cases to 16.8%. Our findings suggest that CSF Aβ42/40 can outperform Aβ42 as a biomarker for AD neuropathology, not only under well-controlled study conditions but also in real life clinical routine. Thus, we recommend the inclusion of Aβ42/40 as a CSF biomarker in the diagnostic procedure. PMID:29439341

[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.

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

Embryonic blood-cerebrospinal fluid barrier formation and function

PubMed Central

Bueno, David; Parvas, Maryam; Hermelo, Ismaïl; Garcia-Fernàndez, Jordi

2014-01-01

During embryonic development and adult life, brain cavities and ventricles are filled with cerebrospinal fluid (CSF). CSF has attracted interest as an active signaling medium that regulates brain development, homeostasis and disease. CSF is a complex protein-rich fluid containing growth factors and signaling molecules that regulate multiple cell functions in the central nervous system (CNS). The composition and substance concentrations of CSF are tightly controlled. In recent years, it has been demonstrated that embryonic CSF (eCSF) has a key function as a fluid pathway for delivering diffusible signals to the developing brain, thus contributing to the proliferation, differentiation and survival of neural progenitor cells, and to the expansion and patterning of the brain. From fetal stages through to adult life, CSF is primarily produced by the choroid plexus. The development and functional activities of the choroid plexus and other blood–brain barrier (BBB) systems in adults and fetuses have been extensively analyzed. However, eCSF production and control of its homeostasis in embryos, from the closure of the anterior neuropore when the brain cavities become physiologically sealed, to the formation of the functional fetal choroid plexus, has not been studied in as much depth and remains open to debate. This review brings together the existing literature, some of which is based on experiments conducted by our research group, concerning the formation and function of a temporary embryonic blood–CSF barrier in the context of the crucial roles played by the molecules in eCSF. PMID:25389383

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

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.

Automated cell counts on CSF samples: A multicenter performance evaluation of the GloCyte system.

PubMed

Hod, E A; Brugnara, C; Pilichowska, M; Sandhaus, L M; Luu, H S; Forest, S K; Netterwald, J C; Reynafarje, G M; Kratz, A

2018-02-01

Automated cell counters have replaced manual enumeration of cells in blood and most body fluids. However, due to the unreliability of automated methods at very low cell counts, most laboratories continue to perform labor-intensive manual counts on many or all cerebrospinal fluid (CSF) samples. This multicenter clinical trial investigated if the GloCyte System (Advanced Instruments, Norwood, MA), a recently FDA-approved automated cell counter, which concentrates and enumerates red blood cells (RBCs) and total nucleated cells (TNCs), is sufficiently accurate and precise at very low cell counts to replace all manual CSF counts. The GloCyte System concentrates CSF and stains RBCs with fluorochrome-labeled antibodies and TNCs with nucleic acid dyes. RBCs and TNCs are then counted by digital image analysis. Residual adult and pediatric CSF samples obtained for clinical analysis at five different medical centers were used for the study. Cell counts were performed by the manual hemocytometer method and with the GloCyte System following the same protocol at all sites. The limits of the blank, detection, and quantitation, as well as precision and accuracy of the GloCyte, were determined. The GloCyte detected as few as 1 TNC/μL and 1 RBC/μL, and reliably counted as low as 3 TNCs/μL and 2 RBCs/μL. The total coefficient of variation was less than 20%. Comparison with cell counts obtained with a hemocytometer showed good correlation (>97%) between the GloCyte and the hemocytometer, including at very low cell counts. The GloCyte instrument is a precise, accurate, and stable system to obtain red cell and nucleated cell counts in CSF samples. It allows for the automated enumeration of even very low cell numbers, which is crucial for CSF analysis. These results suggest that GloCyte is an acceptable alternative to the manual method for all CSF samples, including those with normal cell counts. © 2017 John Wiley & Sons Ltd.

Penetration and distribution of gadolinium-based contrast agents into the cerebrospinal fluid in healthy rats: a potential pathway of entry into the brain tissue.

PubMed

Jost, Gregor; Frenzel, Thomas; Lohrke, Jessica; Lenhard, Diana Constanze; Naganawa, Shinji; Pietsch, Hubertus

2017-07-01

Signal hyperintensity on unenhanced MRI in certain brain regions has been reported after multiple administrations of some, but not all, gadolinium-based contrast agents (GBCAs). One potential initial pathway of GBCA entry into the brain, infiltration from blood into the cerebrospinal fluid (CSF), was systematically evaluated in this preclinical study. GBCA infiltration and distribution in the CSF were investigated in healthy rats using repeated fluid-attenuated MRI up to 4 h after high-dose (1.8 mmol/kg) administration of six marketed and one experimental GBCA. Additionally, gadolinium measurements in CSF, blood and brain tissue samples (after 24 h) were performed using inductively coupled plasma mass spectrometry. Enhanced MRI signals in the CSF spaces with similar distribution kinetics were observed for all GBCAs. No substantial differences in the gadolinium concentrations among the marketed GBCAs were found in the CSF, blood or brain tissue. After 4.5 h, the concentration in the CSF was clearly higher than in blood but was almost completely cleared and lower than the brain tissue concentration after 24 h. In contrast to the brain signal hyperintensities, no differences in penetration and distribution into the CSF of healthy rats exist among the marketed GBCAs. • Gadolinium-based contrast agents can cross the blood-CSF barrier. • Fluid-attenuated MRI shows GBCA distribution with CSF flow. • GBCA structure and physicochemical properties do not impact CSF penetration and distribution. • GBCA clearance from CSF was almost complete within 24 h in rats. • CSF is a potential pathway of GBCA entry into the brain.

Accuracy of 4D Flow measurement of cerebrospinal fluid dynamics in the cervical spine: An in vitro verification against numerical simulation

PubMed Central

Pahlavian, Soroush Heidari; Bunck, Alexander C.; Thyagaraj, Suraj; Giese, Daniel; Loth, Francis; Hedderich, Dennis M.; Kröger, Jan Robert; Martin, Bryn A.

2016-01-01

Abnormal alterations in cerebrospinal fluid (CSF) flow are thought to play an important role in pathophysiology of various craniospinal disorders such as hydrocephalus and Chiari malformation. Three directional phase contrast MRI (4D Flow) has been proposed as one method for quantification of the CSF dynamics in healthy and disease states, but prior to further implementation of this technique, its accuracy in measuring CSF velocity magnitude and distribution must be evaluated. In this study, an MR-compatible experimental platform was developed based on an anatomically detailed 3D printed model of the cervical subarachnoid space and subject specific flow boundary conditions. Accuracy of 4D Flow measurements was assessed by comparison of CSF velocities obtained within the in vitro model with the numerically predicted velocities calculated from a spatially averaged computational fluid dynamics (CFD) model based on the same geometry and flow boundary conditions. Good agreement was observed between CFD and 4D Flow in terms of spatial distribution and peak magnitude of through-plane velocities with an average difference of 7.5% and 10.6% for peak systolic and diastolic velocities, respectively. Regression analysis showed lower accuracy of 4D Flow measurement at the timeframes corresponding to low CSF flow rate and poor correlation between CFD and 4D Flow in-plane velocities. PMID:27043214

Meta-analysis of Cerebrospinal Fluid Cytokine and Tryptophan Catabolite Alterations in Psychiatric Patients: Comparisons Between Schizophrenia, Bipolar Disorder, and Depression.

PubMed

Wang, Alexandre K; Miller, Brian J

2018-01-13

Schizophrenia, bipolar disorder, and major depressive disorder (MDD) have all been associated with immune system dysfunction, including aberrant cerebrospinal fluid (CSF) levels of cytokines and tryptophan catabolites; however, the pattern of alterations has not been compared across disorders. We performed a meta-analysis of CSF cytokine and tryptophan catabolites in patients with these major psychiatric disorders. Articles were identified by searching Pub Med, PsycInfo, and Web of Science, and the reference lists of these studies. Twenty-eight studies met the inclusion criteria (16 schizophrenia, 4 bipolar disorder, and 9 MDD). CSF levels of IL-1β and kynurenic acid were significantly increased in patients with schizophrenia and bipolar disorder compared to healthy controls (P < .001). CSF levels of IL-6 and IL-8 were significantly increased in patients with schizophrenia and MDD compared to healthy controls (P ≤ .013). There is preliminary evidence for similarities in the pattern of CSF cytokine and tryptophan catabolite alterations across major psychiatric disorders, although findings must be interpreted with caution in light of small numbers of studies/subjects. Many CSF alterations are also concordant with those in the peripheral blood, particularly for schizophrenia. Findings have important implications for our understanding of the pathophysiology and treatment of major psychiatric disorders. © The Author(s) 2017. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Hydrodynamic and Longitudinal Impedance Analysis of Cerebrospinal Fluid Dynamics at the Craniovertebral Junction in Type I Chiari Malformation

PubMed Central

Martin, Bryn A.; Kalata, Wojciech; Shaffer, Nicholas; Fischer, Paul; Luciano, Mark; Loth, Francis

2013-01-01

Elevated or reduced velocity of cerebrospinal fluid (CSF) at the craniovertebral junction (CVJ) has been associated with type I Chiari malformation (CMI). Thus, quantification of hydrodynamic parameters that describe the CSF dynamics could help assess disease severity and surgical outcome. In this study, we describe the methodology to quantify CSF hydrodynamic parameters near the CVJ and upper cervical spine utilizing subject-specific computational fluid dynamics (CFD) simulations based on in vivo MRI measurements of flow and geometry. Hydrodynamic parameters were computed for a healthy subject and two CMI patients both pre- and post-decompression surgery to determine the differences between cases. For the first time, we present the methods to quantify longitudinal impedance (LI) to CSF motion, a subject-specific hydrodynamic parameter that may have value to help quantify the CSF flow blockage severity in CMI. In addition, the following hydrodynamic parameters were quantified for each case: maximum velocity in systole and diastole, Reynolds and Womersley number, and peak pressure drop during the CSF cardiac flow cycle. The following geometric parameters were quantified: cross-sectional area and hydraulic diameter of the spinal subarachnoid space (SAS). The mean values of the geometric parameters increased post-surgically for the CMI models, but remained smaller than the healthy volunteer. All hydrodynamic parameters, except pressure drop, decreased post-surgically for the CMI patients, but remained greater than in the healthy case. Peak pressure drop alterations were mixed. To our knowledge this study represents the first subject-specific CFD simulation of CMI decompression surgery and quantification of LI in the CSF space. Further study in a larger patient and control group is needed to determine if the presented geometric and/or hydrodynamic parameters are helpful for surgical planning. PMID:24130704

Occurrence of occult CSF leaks during standard FESS procedures.

PubMed

Bucher, S; Kugler, A; Probst, E; Epprecht, L; Stadler, R S; Holzmann, D; Soyka, M B

2018-03-18

To determine the incidence of occult cerebrospinal fluid leaks (CSF) after functional endoscopic sinus surgery (FESS) and to evaluate the diagnostic performance of beta2-transferrin in blood-contaminated conditions. Prospective cohort study. An analysis of 57 intraoperative samples using hydrogel 6 beta2-transferrin assay after FESS was undertaken. In case of CSF positive samples and continuing rhinorrhea, reanalysis after more than 1 year was conducted. In-vivo analysis of a primary spontaneous CSF leak sample took place to verify difficulties in detecting beta2-transferrin in blood-contaminated settings. Own titrations were performed to evaluate detection limits of CSF by beta2-transferrin and beta-trace protein assays in these settings. An incidence of 13% for occult CSF leaks after FESS was found. In blood-contaminated conditions, routine beta2-transferrin assays showed low sensitivity. In over 1 year follow-up, all samples were negative for CSF and none of them developed clinical relevant CSF leaks or meningitis. Occult and clinically irrelevant CSF leaks do occur in a significant proportion of patients during and shortly after FESS. Intra- and postoperatively, routine beta2-transferrin assays show low sensitivity. They should not be used in these settings. The clinical course of patients with occult CSF leaks indicated possibility of an uneventful follow-up.

Osmolar relation between cerebrospinal fluid and serum in hyperosmolar hypernatraemic dehydration.

PubMed Central

Habel, A H; Simpson, H

1976-01-01

The relation between cerebrospinal fluid (CSF) and serum osmolality was studied in 16 patients with hyperosmolar hypernatraemic dehydration before treatment. After correcting shock and acidosis, 0-45% saline in 2-5 or 5% dextrose was infused in each patient over a 48- to 72-hour period. During rehydration, serum osmolality, electrolyte concentrations, urea nitrogen, and blood pH were measured sequentially. Five patients developed severe neurological abnormalities within 48 hours of addmission (convulsions 2, convulsions with hemiplegia 2, hemiplegia 1). Of these, 3 had residual defects on follow-up at least one year later. This group was indistinguishable from the 11 without significant neurological abnormality, both on clinical grounds before rehydration, and after analysis of admission and subsequent serum biochemical variables. A significant osmolar gap (greater than 4 mmol/kg H2O) between serum and CSF was found in 13 patients. Severe neurological disturbance only occurred when CSF osmolality exceeded that of serum by 7 or more mmol/kg H2O. Discriminant analysis of the paired osmolar data showed that D = -117+1-74 X(CSF osmolality) -1-41 X (serum osmolality), and that severe neurological abnormality was predicted when D was positive. PMID:11753

Abnormal protein in the cerebrospinal fluid of patients with a submicroscopic X-chromosomal deletion associated with Norrie disease: preliminary report.

PubMed

Joy, J E; Poglod, R; Murphy, D L; Sims, K B; de la Chapelle, A; Sankila, E M; Norio, R; Merril, C R

1991-01-01

Norrie disease is an X-linked recessive disorder characterized by congenital blindness and, in many cases, mental retardation. Some Norrie disease cases have been shown to be associated with a submicroscopic deletion in chromosomal region Xp11.3. Cerebrospinal fluid (CSF) was collected from four male patients with an X-chromosomal deletion associated with Norrie disease. CSF proteins were resolved using two-dimensional gel electrophoresis and then analyzed by computer using the Elsie V program. Our analysis revealed a protein that appears to be altered in patients with Norrie disease deletion.

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

Evaluation of the automated hematology analyzer ADVIA® 120 for cerebrospinal fluid analysis and usage of unique hemolysis reagent.

PubMed

Tanada, H; Ikemoto, T; Masutani, R; Tanaka, H; Takubo, T

2014-02-01

In this study, we evaluated the performance of the ADVIA 120 hematology system for cerebrospinal fluid (CSF) assay. Cell counts and leukocyte differentials in CSF were examined with the ADVIA 120 hematology system, while simultaneously confirming an effective hemolysis agent for automated CSF cell counts. The detection limits of both white blood cell (WBC) counts and red blood cell (RBC) counts on the measurement of CSF cell counts by the ADVIA 120 hematology system were superior at 2 cells/μL (10(-6) L). The WBC count was linear up to 9.850 cells/μL, and the RBC count was linear up to approximately 20 000 cells/μL. The intrarun reproducibility indicated good precision. The leukocyte differential of CSF cells, performed by the ADVIA120 hematology system, showed good correlation with the microscopic procedure. The VersaLyse hemolysis solution efficiently lysed the samples without interfering with cell counts and leukocyte differential, even in a sample that included approximately 50 000/μL RBC. These data show the ADVIA 120 hematology system correctly measured the WBC count and leukocyte differential in CSF. The VersaLyse hemolysis solution is considered to be optimal for hemolysis treatment of CSF when measuring cell counts and differentials by the ADVIA 120 hematology system. © 2013 John Wiley & Sons Ltd.

More than a drainage fluid: the role of CSF in signaling in the brain and other effects on brain tissue.

PubMed

Illes, Sebastian

2017-01-01

Current progress in neuroscience demonstrates that the brain is not an isolated organ and is influenced by the systemic environment and extracerebral processes within the body. In view of this new concept, blood and cerebrospinal fluid (CSF) are important body fluids linking extracerebral and intracerebral processes. For decades, substantial evidence has been accumulated indicating that CSF modulates brain states and influences behavior as well as cognition. This chapter provides an overview of how CSF directly modulates the function of different types of brain cells, such as neurons, neural stem cells, and CSF-contacting cells. Alterations in CSF content occur in most pathologic central nervous system (CNS) conditions. In a classic view, the function of CSF is to drain waste products and detrimental factors derived from diseased brain parenchyma. This chapter presents examples for how intra- and extracerebral pathologic processes lead to alterations in the CSF content. Current knowledge about how pathologically altered CSF influences the functionality of brain cells will be presented. Thereby, it becomes evident that CSF has more than a drainage function and has a causal role for the etiology and pathogenesis of different CNS diseases. Copyright © 2017 Elsevier B.V. All rights reserved.

The cerebrospinal fluid proteome in HIV infection: change associated with disease severity.

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

Angel, Thomas E.; Jacobs, Jon M.; Spudich, Serena S.

2012-03-20

Central nervous system (CNS) infection is a constant feature of systemic HIV infection with a clinical spectrum that ranges from chronic asymptomatic infection to severe cognitive and motor dysfunction. Analysis of cerebrospinal fluid (CSF) has played an important part in defining the character of this evolving infection and response to treatment. To further characterize CNS HIV infection and its effects, we applied advanced high-throughput proteomic methods to CSF to identify novel proteins and their changes with disease progression and treatment. After establishing an accurate mass and time (AMT) tag database containing 23,141 AMT tags for CSF peptides, we analyzed 91more » CSF samples by LC-MS from 12 HIV-uninfected and 14 HIV-infected subjects studied in the context of initiation of antiretroviral and correlated abundances of identified proteins (a) within and between subjects, (b) with all other proteins across the entire sample set, and (c) with 'external' CSF biomarkers of infection (HIV RNA), immune activation (neopterin) and neural injury (neurofilament light chain protein, NFL). We identified a mean of 2,333 +/- 328 (SD) peptides covering 307 +/-16 proteins in the 91 CSF sample set. Protein abundances differed both between and within subjects sampled at different time points and readily separated those with and without HIV infection. Proteins also showed inter-correlations across the sample set that were associated with biologically relevant dynamic processes. One-hundred and fifty proteins showed correlations with the external biomarkers. For example, using a threshold of cross correlation coefficient (Pearson's) {le}0.3 and {ge}0.3 for potentially meaningful relationships, a total of 99 proteins correlated with CSF neopterin (43 negative and 56 positive correlations) and related principally to neuronal plasticity and survival and to innate immunity. Pathway analysis defined several networks connecting the identified proteins, including one with amyloid precursor protein as a central node. Advanced CSF proteomic analysis enabled the identification of an array of novel protein changes across the spectrum of CNS HIV infection and disease. This initial analysis clearly demonstrated the value of contemporary state-of-the-art proteomic CSF analysis as a discovery tool in HIV infection with likely similar application to other neurological inflammatory and degenerative diseases.« less

The cerebrospinal fluid proteome in HIV infection: change associated with disease severity

PubMed Central

2012-01-01

Background Central nervous system (CNS) infection is a nearly universal feature of untreated systemic HIV infection with a clinical spectrum that ranges from chronic asymptomatic infection to severe cognitive and motor dysfunction. Analysis of cerebrospinal fluid (CSF) has played an important part in defining the character of this evolving infection and response to treatment. To further characterize CNS HIV infection and its effects, we applied advanced high-throughput proteomic methods to CSF to identify novel proteins and their changes with disease progression and treatment. Results After establishing an accurate mass and time (AMT) tag database containing 23,141 AMT tags for CSF peptides, we analyzed 91 CSF samples by LC-MS from 12 HIV-uninfected and 14 HIV-infected subjects studied in the context of initiation of antiretroviral therapy and correlated abundances of identified proteins a) within and between subjects, b) with all other proteins across the entire sample set, and c) with "external" CSF biomarkers of infection (HIV RNA), immune activation (neopterin) and neural injury (neurofilament light chain protein, NFL). We identified a mean of 2,333 +/- 328 (SD) peptides covering 307 +/-16 proteins in the 91 CSF sample set. Protein abundances differed both between and within subjects sampled at different time points and readily separated those with and without HIV infection. Proteins also showed inter-correlations across the sample set that were associated with biologically relevant dynamic processes. One-hundred and fifty proteins showed correlations with the external biomarkers. For example, using a threshold of cross correlation coefficient (Pearson's) ≤ -0.3 and ≥0.3 for potentially meaningful relationships, a total of 99 proteins correlated with CSF neopterin (43 negative and 56 positive correlations) and related principally to neuronal plasticity and survival and to innate immunity. Pathway analysis defined several networks connecting the identified proteins, including one with amyloid precursor protein as a central node. Conclusions Advanced CSF proteomic analysis enabled the identification of an array of novel protein changes across the spectrum of CNS HIV infection and disease. This initial analysis clearly demonstrated the value of contemporary state-of-the-art proteomic CSF analysis as a discovery tool in HIV infection with likely similar application to other neurological inflammatory and degenerative diseases. PMID:22433316

Cost Analysis of Cerebrospinal Fluid Leaks and Cerebrospinal Fluid Leak Prevention in Patients Undergoing Cerebellopontine Angle Surgery.

PubMed

Chern, Alexander; Hunter, Jacob B; Bennett, Marc L

2017-01-01

To determine if cranioplasty techniques following translabyrinthine approaches to the cerebellopontine angle are cost-effective. Retrospective case series. One hundred eighty patients with available financial data who underwent translabyrinthine approaches at a single academic referral center between 2005 and 2015. Cranioplasty with a dural substitute, layered fat graft, and a resorbable mesh plate secured with screws Main Outcome Measures: billing data was obtained for each patient's hospital course for translabyrinthine approaches and postoperative cerebrospinal fluid (CSF) leaks. One hundred nineteen patients underwent translabyrinthine approaches with an abdominal fat graft closure, with a median cost of $25759.89 (range, $15885.65-$136433.07). Sixty-one patients underwent translabyrinthine approaches with a dural substitute, abdominal fat graft, and a resorbable mesh for closure, with a median cost of $29314.97 (range, $17674.28-$111404.55). The median cost of a CSF leak was $50401.25 (range, $0-$384761.71). The additional cost of a CSF leak when shared by all patients who underwent translabyrinthine approaches is $6048.15. The addition of a dural substitute and a resorbable mesh plate after translabyrinthine approaches reduced the CSF leak from 12 to 1.9%, an 84.2% reduction, and a median savings per patient of $2932.23. Applying our cohort's billing data to previously published cranioplasty techniques, costs, and leak rate improvements after translabyrinthine approaches, all techniques were found to be cost-effective. Resorbable mesh cranioplasty is cost-effective at reducing CSF leaks after translabyrinthine approaches. Per our billing data and achieving the same CSF leak rate, cranioplasty costs exceeding $5090.53 are not cost-effective.

STAT3 activation is associated with cerebrospinal fluid interleukin-10 (IL-10) in primary central nervous system diffuse large B cell lymphoma.

PubMed

Mizowaki, Takashi; Sasayama, Takashi; Tanaka, Kazuhiro; Mizukawa, Katsu; Takata, Kumi; Nakamizo, Satoshi; Tanaka, Hirotomo; Nagashima, Hiroaki; Nishihara, Masamitsu; Hirose, Takanori; Itoh, Tomoo; Kohmura, Eiji

2015-09-01

Signal transducers and activators of transcription 3 (STAT3) are activated by various cytokines and oncogenes; however, the activity and pathogenesis of STAT3 in diffuse large B cell lymphoma of the central nervous system have not been thoroughly elucidated. We investigated the phosphorylation levels of STAT3 in 40 specimens of primary central nervous system diffuse large B-cell lymphoma (PCNS DLBCL) and analyzed the association between phsopho-STAT3 (pSTAT3) expression and cerebrospinal fluid (CSF) concentration of interleukin-10 (IL-10) or IL-6. Immunohistochemistry and Western blot analysis revealed that most of the specimens in PCNS DLBCL expressed pSTST3 protein, and a strong phosphorylation levels of STAT3 was statistically associated with high CSF IL-10 levels, but not with CSF IL-6 levels. Next, we demonstrated that recombinant IL-10 and CSF containing IL-10 induced the phosphorylation of STAT3 in PCNS DLBCL cells. Furthermore, molecular subtype classified by Hans' algorithm was correlated with pSTAT3 expression levels and CSF IL-10 levels. These results suggest that the STAT3 activity is correlated with CSF IL-10 level, which is a useful marker for STAT3 activity in PCNS DLBCLs.

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).

Cerebrospinal fluid rhinorrhea following trans-sphenoidal pituitary macroadenoma surgery: experience from 592 patients.

PubMed

Han, Zong-Li; He, Dong-Sheng; Mao, Zhi-Gang; Wang, Hai-Jun

2008-06-01

To determine the incidence, risk factors, diagnostic procedures, and management of cerebrospinal fluid (CSF) leaks following trans-sphenoidal pituitary macroadenoma surgery. Retrospective analysis of 592 patients. Intra- and post-operative CSF leaks occurred in 14.2 and 4.4% of patients, respectively. Surgical revision, tumor consistency, and tumor margins were independently associated with intra-operative leaks, while the tumor size, consistency, and margins were risk factors of post-operative leaks. The intra-operative leak rate of ACTH adenomas was greater than all other types combined; the incidence of post-operative CSF leaks was highest for FSH adenomas. There were no significant differences among various techniques and we achieved an initial repair success rates of 83.3 and 92.9% for intra- and post-operative CSF leaks, respectively. Of the 26 patients with post-operative CSF leaks, five were complicated by meningitis and four by post-infectious hydrocephalus which required ventriculoperitoneal shunts. CSF leaks have a propensity to occur in cases with fibrous tumors or tumors with indistinct margin and may have some relationship with the tumor type. Endoscopic and microscopic repairs were shown to be effective techniques in managing these types of leaks. Post-infectious hydrocephalus may influence the outcome of the repair and ventriculoperitoneal shunts were necessary in some cases.

The effect of autologous fibrin tissue adhesive on postoperative cerebrospinal fluid leak in spinal cord surgery: a randomized controlled trial.

PubMed

Nakamura, Hiroshi; Matsuyama, Yukihiro; Yoshihara, Hisatake; Sakai, Yoshihito; Katayama, Yoshito; Nakashima, Shojiro; Takamatsu, Jyunki; Ishiguro, Naoki

2005-07-01

A prospective randomized study evaluating the efficacy of autologous fibrin tissue adhesive for decreasing postoperative cerebrospinal fluid (CSF) leak in spinal cord surgery. To compare postoperative CSF leak in 3 groups (i.e., autologous fibrin tissue adhesive used, commercial fibrin glue used, and no fibrin tissue adhesive used) of patients undergoing spinal surgery who needed dural incision. Spinal cord operations, particularly when dural incision is inevitable, sometimes involve postoperative CSF leak. Because CSF leak is a serious complication, countermeasure is necessary to prevent it after dural suture. Commercial fibrin tissue adhesive was formerly used. Because the possibility of prion infection was widely noticed, commercial fibrin tissue adhesive containing animal components has been used less often. In 13 of 39 cases in which dural incision would be made, 400 mL whole blood was drawn, and autologous fibrin tissue adhesive was made of plasma. Cases were divided into 3 groups: (1) dural closure alone, (2) use of autologous fibrin tissue adhesive after dural closure, and (3) use of commercial fibrin tissue adhesive after dural closure. The primary outcome measure was determined as postoperative (3 days) volume of drainage fluid, and results were analyzed using the analysis of variance. The secondary outcome measure was general blood test, coagulation assay, and plasma fibrinogen, and these were analyzed also using the analysis of variance. There was a significant difference in the primary outcome between the autologous and control groups. No complications such as infection or continuous CSF leak were observed in any case. The mean volume of drainage fluid was 586.2 mL in the group with autologous fibrin tissue adhesive and 1026.1 mL in the group without fibrin tissue adhesive. The volume of drainage fluid was significantly lower in the former group than that in the latter group. There was no statistical difference between the volumes of the group with autologous adhesive and with commercial adhesive (639.2 mL). We used autologous fibrin tissue adhesive as a new sealant after dural closure instead of commercial fibrin tissue adhesive. No definitive CSF leak was observed, and the volume of drainage fluid was significantly lower in the group with autologous fibrin tissue adhesive than that in the group without fibrin tissue adhesive. The use of autologous fibrin tissue adhesive was superior to that of commercial fibrin tissue adhesive in cost.

Cerebrospinal fluid asparagine depletion during pegylated asparaginase therapy in children with acute lymphoblastic leukaemia.

PubMed

Henriksen, Louise T; Nersting, Jacob; Raja, Raheel A; Frandsen, Thomas L; Rosthøj, Steen; Schrøder, Henrik; Albertsen, Birgitte K

2014-07-01

L-asparaginase is an important drug in the treatment of childhood acute lymphoblastic leukaemia (ALL). Cerebrospinal fluid (CSF) asparagine depletion is considered a marker of asparaginase effect in the central nervous system (CNS) and may play a role in CNS-directed anti-leukaemia therapy. The objective of this study was to describe CSF asparagine depletion during 30 weeks of pegylated asparaginase therapy, 1000 iu/m(2) i.m. every second week, and to correlate CSF asparagine concentration with serum L-asparaginase enzyme activity. Danish children (1-17 years) with ALL, treated according to the Nordic Society of Paediatric Haematology and Oncology ALL2008 protocol, standard and intermediate risk, were included. CSF samples were obtained throughout L-asparaginase treatment at every scheduled lumbar puncture. A total of 128 samples from 31 patients were available for analysis. Median CSF asparagine concentration decreased from a pre-treatment level of 5·3 μmol/l to median levels ≤1·5 μmol/l. However, only 4/31 patients (five samples) had CSF asparagine concentrations below the limit of detection (0·1 μmol/l). In 11 patients, 24 paired same day serum and CSF samples were obtained. A decrease in CSF asparagine corresponded to serum enzyme activities above 50 iu/l. Higher serum enzyme activities were not followed by more extensive depletion. In conclusion, pegylated asparaginase 1000 iu/m(2) i.m. every second week effectively reduced CSF asparagine levels. © 2014 John Wiley & Sons Ltd.

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

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.

Stable isotope dilution ultra-high performance liquid chromatography-tandem mass spectrometry quantitative profiling of tryptophan-related neuroactive substances in human serum and cerebrospinal fluid.

PubMed

Hényková, Eva; Vránová, Hana Přikrylová; Amakorová, Petra; Pospíšil, Tomáš; Žukauskaitė, Asta; Vlčková, Magdaléna; Urbánek, Lubor; Novák, Ondřej; Mareš, Jan; Kaňovský, Petr; Strnad, Miroslav

2016-03-11

Many compounds related to L-tryptophan (L-TRP) have interesting biological or pharmacological activity, and their abnormal neurotransmission seems to be linked to a wide range of neurodegenerative and psychiatric diseases. A high-throughput method based on ultra-high performance liquid chromatography connected to electrospray tandem mass spectrometry (UHPLC-ESI-MS/MS) was developed for the quantitative analysis of L-TRP and 16 of its metabolites in human serum and cerebrospinal fluid (CSF), representing both major and minor routes of L-TRP catabolism. The combination of a fast LC gradient with selective tandem mass spectrometry enabled accurate analysis of almost 100 samples in 24h. The standard isotope dilution method was used for quantitative determination. The method's lower limits of quantification for serum and cerebrospinal fluid ranged from 0.05 to 15nmol/L and 0.3 to 45nmol/L, respectively. Analytical recoveries ranged from 10.4 to 218.1% for serum and 22.1 to 370.0% for CSF. The method's accuracy ranged from 82.4 to 128.5% for serum matrix and 90.7 to 127.7% for CSF matrix. All intra- and inter-day coefficients of variation were below 15%. These results demonstrate that the new method is capable of quantifying endogenous serum and CSF levels of a heterogeneous group of compounds spanning a wide range of concentrations. The method was used to determine the physiological levels of target analytes in serum and CSF samples from 18 individuals, demonstrating its reliability and potential usefulness in large-scale epidemiological studies. Copyright © 2016 Elsevier B.V. All rights reserved.

Clonal expansion and somatic hypermutation of V(H) genes of B cells from cerebrospinal fluid in multiple sclerosis.

PubMed Central

Qin, Y; Duquette, P; Zhang, Y; Talbot, P; Poole, R; Antel, J

1998-01-01

The cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients is characterized by increased concentrations of immunoglobulin (Ig), which on electrophoretic analysis shows restricted heterogeneity (oligoclonal bands). CSF Ig is composed of both serum and intrathecally produced components. To examine the properties of intrathecal antibody-producing B cells, we analyzed Ig heavy-chain variable (V(H)) region genes of B cells recovered from the CSF of 12 MS patients and 15 patients with other neurological diseases (OND). Using a PCR technique, we could detect rearrangements of Ig V(H) genes in all samples. Sequence analysis of complementarity-determining region 3 (CDR3) of rearranged VDJ genes revealed expansion of a dominant clone or clones in 10 of the 12 MS patients. B cell clonal expansion was identified in 3 of 15 OND. The nucleotide sequences of V(H) genes from clonally expanded CSF B cells in MS patients demonstrated the preferential usage of the V(H) IV family. There were numerous somatic mutations, mainly in the CDRs, with a high replacement-to-silent ratio; the mutations were distributed in a way suggesting that these B cells had been positively selected through their antigen receptor. Our results demonstrate that in MS CSF, there is a high frequency of clonally expanded B cells that have properties of postgerminal center memory or antibody-forming lymphocytes. PMID:9727074

Seed-competent HMW tau species accumulates in the cerebrospinal fluid of Alzheimer's disease mouse model and human patients

PubMed Central

Takeda, Shuko; Commins, Caitlin; DeVos, Sarah L.; Nobuhara, Chloe K.; Wegmann, Susanne; Roe, Allyson D.; Costantino, Isabel; Fan, Zhanyun; Nicholls, Samantha B.; Sherman, Alexis E.; Trisini Lipsanopoulos, Ana T.; Scherzer, Clemens R.; Carlson, George A.; Pitstick, Rose; Peskind, Elaine R.; Raskind, Murray A.; Li, Ge; Montine, Thomas J.; Frosch, Matthew P.; Hyman, Bradley T.

2016-01-01

Objective Cerebrospinal fluid (CSF) tau is an excellent surrogate marker for assessing neuropathological changes that occur in Alzheimer's disease (AD) patients. However, whether the elevated tau in AD CSF is just a marker of neurodegeneration or in fact a part of the disease process is uncertain. Moreover, it is unknown how CSF tau relates to the recently described soluble high-molecular-weight (HMW) species that is found in postmortem AD brain and can be taken up by neurons and seed aggregates. Methods We have examined seeding and uptake properties of brain extracellular tau from various sources including: interstitial fluid (ISF) and CSF from an AD transgenic mouse model, and postmortem ventricular and antemortem lumbar CSF from AD patients. Results We found that brain ISF and CSF tau from the AD mouse model can be taken up by cells and induce intracellular aggregates. Ventricular CSF from AD patients contained a rare HMW tau species that exerted a higher seeding activity. Notably, the HMW tau species was also detected in lumbar CSF from AD patients and its levels were significantly elevated compared with control subjects. HMW tau derived from CSF of AD patients was seed-competent in vitro. Interpretation These findings suggest that CSF from an AD brain contains potentially bioactive HMW tau species giving new insights into the role of CSF tau and biomarker development for AD. PMID:27351289

Human herpesvirus infections of the central nervous system: laboratory diagnosis based on DNA detection by nested PCR in plasma and cerebrospinal fluid samples.

PubMed

Rimério, Carla Aparecida Tavares; De Oliveira, Renato Souza; de Almeida Bonatelli, Murilo Queiroz; Nucci, Anamarli; Costa, Sandra Cecília Botelho; Bonon, Sandra Helena Alves

2015-04-01

Infections of the central nervous systems (CNS) present a diagnostic problem for which an accurate laboratory diagnosis is essential. Invasive practices, such as cerebral biopsy, have been replaced by obtaining a polymerase chain reaction (PCR) diagnosis using cerebral spinal fluid (CSF) as a reference method. Tests on DNA extracted from plasma are noninvasive, thus avoiding all of the collateral effects and patient risks associated with CSF collection. This study aimed to determine whether plasma can replace CSF in nested PCR analysis for the detection of CNS human herpesvirus (HHV) diseases by analysing the proportion of patients whose CSF nested PCR results were positive for CNS HHV who also had the same organism identified by plasma nested PCR. In this study, CSF DNA was used as the "gold standard," and nested PCR was performed on both types of samples. Fifty-two patients with symptoms of nervous system infection were submitted to CSF and blood collection. For the eight HHV, one positive DNA result-in plasma and/or CSF nested PCR-was considered an active HHV infection, whereas the occurrence of two or more HHVs in the same sample was considered a coinfection. HHV infections were positively detected in 27/52 (51.9%) of the CSF and in 32/52 (61.5%) of the plasma, difference not significant, thus nested PCR can be performed on plasma instead of CSF. In conclusion, this findings suggest that plasma as a useful material for the diagnosis of cases where there is any difficulty to perform a CSF puncture. © 2015 Wiley Periodicals, Inc.

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.

The role of brain barriers in fluid movement in the CNS: is there a 'glymphatic' system?

PubMed

Abbott, N Joan; Pizzo, Michelle E; Preston, Jane E; Janigro, Damir; Thorne, Robert G

2018-03-01

Brain fluids are rigidly regulated to provide stable environments for neuronal function, e.g., low K + , Ca 2+ , and protein to optimise signalling and minimise neurotoxicity. At the same time, neuronal and astroglial waste must be promptly removed. The interstitial fluid (ISF) of the brain tissue and the cerebrospinal fluid (CSF) bathing the CNS are integral to this homeostasis and the idea of a glia-lymph or 'glymphatic' system for waste clearance from brain has developed over the last 5 years. This links bulk (convective) flow of CSF into brain along the outside of penetrating arteries, glia-mediated convective transport of fluid and solutes through the brain extracellular space (ECS) involving the aquaporin-4 (AQP4) water channel, and finally delivery of fluid to venules for clearance along peri-venous spaces. However, recent evidence favours important amendments to the 'glymphatic' hypothesis, particularly concerning the role of glia and transfer of solutes within the ECS. This review discusses studies which question the role of AQP4 in ISF flow and the lack of evidence for its ability to transport solutes; summarizes attributes of brain ECS that strongly favour the diffusion of small and large molecules without ISF flow; discusses work on hydraulic conductivity and the nature of the extracellular matrix which may impede fluid movement; and reconsiders the roles of the perivascular space (PVS) in CSF-ISF exchange and drainage. We also consider the extent to which CSF-ISF exchange is possible and desirable, the impact of neuropathology on fluid drainage, and why using CSF as a proxy measure of brain components or drug delivery is problematic. We propose that new work and key historical studies both support the concept of a perivascular fluid system, whereby CSF enters the brain via PVS convective flow or dispersion along larger caliber arteries/arterioles, diffusion predominantly regulates CSF/ISF exchange at the level of the neurovascular unit associated with CNS microvessels, and, finally, a mixture of CSF/ISF/waste products is normally cleared along the PVS of venules/veins as well as other pathways; such a system may or may not constitute a true 'circulation', but, at the least, suggests a comprehensive re-evaluation of the previously proposed 'glymphatic' concepts in favour of a new system better taking into account basic cerebrovascular physiology and fluid transport considerations.

Cerebrospinal Fluid Cytokine Expression Profile in Multiple Sclerosis and Chronic Inflammatory Demyelinating Polyneuropathy.

PubMed

Bonin, Serena; Zanotta, Nunzia; Sartori, Arianna; Bratina, Alessio; Manganotti, Paolo; Trevisan, Giusto; Comar, Manola

2018-02-01

Cerebrospinal fluid (CSF) analysis in patients with particular neurologic disorders is a powerful tool to evaluate specific central nervous system inflammatory markers for diagnostic needs, because CSF represents the specific immune micro-environment to the central nervous system. CSF samples from 49 patients with multiple sclerosis (MS), chronic inflammatory demyelinating polyneuropathy (CIDP), and non-inflammatory neurologic disorders (NIND) as controls were submitted to protein expression profiles of 47 inflammatory biomarkers by multiplex Luminex bead assay to investigate possible differences in the inflammatory process for MS and CIDP. Our results showed differences in CSF cytokine levels in MS and CIDP; in particular, IL12 (p40) was significantly highly expressed in MS in comparison with CIDP and NIND, while SDF-1α and SCGF-β were significantly highly expressed in CIDP cohort when compared to MS and NIND. IL-9, IL-13, and IL-17 had higher expression levels in NIND if compared with the other groups. Our study showed that, despite some common pathogenic mechanisms, central and peripheral nervous system demyelinating diseases, such as MS and CIDP, differ in some specific inflammatory soluble proteins in CSF, underlining differences in the immune response involved in those autoimmune diseases.

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.

[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.

Blood-cerebrospinal fluid barrier permeability in Alzheimer's disease.

PubMed

Chalbot, Sonia; Zetterberg, Henrik; Blennow, Kaj; Fladby, Tormod; Andreasen, Niels; Grundke-Iqbal, Inge; Iqbal, Khalid

2011-01-01

The role of blood-cerebrospinal fluid barrier (BCB) dysfunction in Alzheimer's disease (AD) has been addressed but not yet established. We evaluated the BCB integrity in 179 samples of cerebrospinal fluid (CSF) retrospectively collected from AD patients and control cases using both CSF/serum albumin ratio (QAlb) and CSF secretory Ca2+-dependent phospholipase A2 (sPLA2) activity. These analyses were supplemented with the measurement of total tau, amyloid-β1-42 (Aβ1-42), and ubiquitin CSF levels. We found that due to its higher sensitivity, CSF sPLA2 activity could 1) discriminate AD from healthy controls and 2) showed BCB impairment in neurological control cases while QAlb could not. Moreover, the CSF sPLA2 activity measurement showed that around half of the AD patients were characterized by a BCB impairment. The BCB dysfunction observed in AD was independent from Mini-Mental State Examination score as well as CSF levels of total tau, Aβ1-42, and ubiquitin. Finally, the BCB dysfunction was not limited to any of the CSF biomarkers-based previously identified subgroups of AD. These results suggest that the BCB damage occurs independent of and probably precedes both Aβ and tau pathologies in a restricted subgroup of AD patients.

Predicting Fluid Flow in Stressed Fractures: A Quantitative Evaluation of Methods

NASA Astrophysics Data System (ADS)

Weihmann, S. A.; Healy, D.

2015-12-01

Reliable estimation of fracture stability in the subsurface is crucial to the success of exploration and production in the petroleum industry, and also for wider applications to earthquake mechanics, hydrogeology and waste disposal. Previous work suggests that fracture stability is related to fluid flow in crystalline basement rocks through shear or tensile instabilities of fractures. Our preliminary scoping analysis compares the fracture stability of 60 partly open (apertures 1.5-3 cm) and electrically conductive (low acoustic amplitudes relative to matrix) fractures from a 16 m section of a producing zone in a basement well in Bayoot field, Yemen, to a non-producing zone in the same well (also 16 m). We determine the Critically Stressed Fractures (CSF; Barton et al., 1995) and dilatation tendency (Td; Ferrill et al., 1999). We find that: 1. CSF (Fig. 1) is a poor predictor of high fluid flow in the inflow zone; 88% of the fractures are predicted to be NOT critically stressed and yet they all occur within a zone of high fluid flow rate 2. Td (Fig. 2) is also a poor predictor of high fluid flow in the inflow zone; 67% of the fractures have a LOW Td(< 0.6) 3. For the non-producing zone CSF is a very reliable predictor (100% are not critically stressed) whereas the values of Tdare consistent with their location in non-producing interval (81% are < 0.6) (Fig. 3 & 4). In summary, neither method correlates well with the observed abundance of hydraulically conductive fractures within the producing zone. Within the non-producing zone CSF and Td make reasonably accurate predictions. Fractures may be filled or partially filled with drilling mud or a lower density and electrically conductive fill such as clay in the producing zone and therefore appear (partly) open. In situ stress, fluid pressure, rock properties (friction, strength) and fracture orientation data used as inputs for the CSF and Td calculations are all subject to uncertainty. Our results suggest that scope exists to systematically quantify and explore the impacts of these uncertainties for better predictions of geomechanical stability and fluid conductivity in the subsurface.

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.

Differential melatonin alterations in cerebrospinal fluid and serum of patients with major depressive disorder and bipolar disorder.

PubMed

Bumb, J M; Enning, F; Mueller, J K; van der List, Till; Rohleder, C; Findeisen, P; Noelte, I; Schwarz, E; Leweke, F M

2016-07-01

Melatonin, which plays an important role for regulation of circadian rhythms and the sleep/wake cycle has been linked to the pathophysiology of major depressive and bipolar disorder. Here we investigated melatonin levels in cerebrospinal fluid (CSF) and serum of depression and bipolar patients to elucidate potential differences and commonalities in melatonin alterations across the two disorders. Using enzyme-linked immunosorbent assays, CSF and serum melatonin levels were measured in 108 subjects (27 healthy volunteers, 44 depressed and 37 bipolar patients). Covariate adjusted multiple regression analysis was used to investigate group differences in melatonin levels. In CSF, melatonin levels were significantly decreased in bipolar (P<0.001), but not major depressive disorder. In serum, we observed a significant melatonin decrease in major depressive (P=0.003), but not bipolar disorder. No associations were found between serum and CSF melatonin levels or between melatonin and measures of symptom severity or sleep disruptions in either condition. This study suggests the presence of differential, body fluid specific alterations of melatonin levels in bipolar and major depressive disorder. Further, longitudinal studies are required to explore the disease phase dependency of melatonin alterations and to mechanistically explore the causes and consequences of site-specific alterations. Copyright © 2016 Elsevier Inc. All rights reserved.

Baclofen Solution for Low-Volume Therapeutic Delivery.

PubMed

Meythaler, Jay M; Peduzzi, Jean D

2017-06-01

Baclofen is a zwitterion molecule where increased ions in the excipient increase the solubility. We developed baclofen in a stable solution similar to cerebrospinal fluid (CSF) without bicarbonate and proteins to improve the solubility of the baclofen and to reduce the potential toxicity to the central nervous system (CNS) and subarachnoid space. The objective is to develop a solution of baclofen wherein baclofen is solubilized in a multivalent physiological ion solution such as artificial cerebrospinal fluid (aCSF) at a concentration from 2 mg/cc to 10 mg/cc. First, to determine the solubility of Baclofen in aCSF, solubility was determined at six different pH levels at 37°C, by the addition of aCSF to a known amount of Baclofen. The final concentrations were confirmed by high performance liquid chromatography (HPLC) analysis. Second, the stability of Baclofen at 4 mg/cc investigated in a test manufacturing batch utilizing standard methods of production of 1500 20 cc vials inverted for 18 months at 25°C at 60% humidity. The stability and purity of the baclofen was verified at 18 months by HPLC analysis. Baclofen was initially soluble between pH of 6-8 above 7 mg/cc but fell back to 6.3-5.8 mg/cc level with time. Baclofen produced in vials with inversion were noted to be stable at 4 mg/cc at 18 months with less than 2% breakdown of the baclofen in solution. Baclofen is much more soluble in artificial CSF than normal saline. The artificial CSF may also be less toxic to the subarachnoid space than saline. © 2016 International Neuromodulation Society.

Sarcocystis neurona-specific immunoglobulin G in the serum and cerebrospinal fluid of horses administered S neurona vaccine.

PubMed

Witonsky, Sharon; Morrow, Jennifer K; Leger, Clare; Dascanio, John; Buechner-Maxwell, Virginia; Palmer, Wally; Kline, Kristen; Cook, Anne

2004-01-01

A vaccine against Sarcocystis neurona, which induces equine protozoal myeloencephalitis (EPM), has received conditional licensure in the United States. A major concern is whether the immunoglobulin G (IgG) response elicited by the vaccine will compromise the use of Western blotting (WB) as a diagnostic tool in vaccinated horses with neurologic disease. Our goals were to determine if vaccination (1) causes seroconversion: (2) causes at least a transient increase in S neurona-specific IgG in the cerebrospinal fluid (CSF); and (3) induces an IgG response that can be differentiated from that induced by natural exposure. Horses included in the study (n = 29) were older than 6 months with no evidence of neurologic disease. The presence or absence of anti-S neurona antibodies in the serum of each horse was determined by WB analysis. Seropositive horses had CSF collected and submitted for cytology, CSF index, and WB analysis. The vaccine was administered to all the horses and boostered 3-4 weeks later. On day 14 after the 2nd administration, serum and CSF were collected and analyzed. Eighty-nine percent (8 of 9) of the initial seronegative horses seroconverted after vaccination, of which 57% (4 of 7) had anti-S neurona IgG in their CSE Eighty percent (16 of 20) of the seropositive horses had an increase in serum S neurona IgG after vaccination. Of the 6 of 20 horses that were initially seropositive/CSF negative, 2 were borderline positive for anti-S neurona IgG in the CSF, 2 tested positive, and 2 were excluded because the CSF sample had been contaminated by blood. There were no WB banding patterns that distinguished samples from horses that seroconverted due to vaccination versus natural exposure. Caution must be used in interpreting WB analysis from neurologic horses that have been recently vaccinated for EPM.

Cerebrospinal fluid cytotoxicity does not affect survival in amyotrophic lateral sclerosis.

PubMed

Galán, L; Matías-Guiu, J; Matias-Guiu, J A; Yáñez, M; Pytel, V; Guerrero-Sola, A; Vela-Souto, A; Arranz-Tagarro, J A; Gómez-Pinedo, U; García, A G

2017-09-01

Cerebrospinal fluid (CSF) from some patients with amyotrophic lateral sclerosis (ALS) has been demonstrated to significantly reduce the neuronal viability of primary cell cultures of motor neurons. We aimed to study the potential clinical consequences associated with the cytotoxicity of CSF in a cohort of patients with ALS. We collected CSF from thirty-one patients with ALS. We analysed cytotoxicity by incubating it into the primary cultures of motor cortex neurons. Neural viability was quantified after 24 hours using the colorimetric MTT reduction assay. All patients were followed up from the moment of diagnosis to death, and a complete evaluation during disease progression and survival was performed, including gastrostomy and respiratory assistance. Twenty-one patients (67.7%) presented a cytotoxic CSF. There were no significant differences between patients with and without cytotoxicity regarding mean time from symptom onset to the diagnosis, from the diagnosis to death, from the diagnosis to respiratory assistance with BIPAP, from diagnosis to gastrostomy and from the onset of symptoms to death. In Cox regression analysis, bulbar onset, but not cytotoxicity, gender or age at onset, was associated with a lower risk of survival. Cerebrospinal fluid cytotoxicity was not associated with differential survival rates. This suggests that the presence of cytotoxicity in CSF, measured through neuronal viability in primary cultures of motor cortex neurons, could reflect different mechanisms of the disease, but it does not predict disease outcome. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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.

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.

Does more favourable handling of the cerebrospinal fluid increase the diagnostic sensitivity of Borrelia burgdorferi sensu lato-specific PCR in Lyme neuroborreliosis?

PubMed

Forselv, Kristine J N; Lorentzen, Åslaug R; Ljøstad, Unn; Mygland, Åse; Eikeland, Randi; Kjelland, Vivian; Noraas, Sølvi; Quarsten, Hanne

2018-04-01

Tests for direct detection of Borrelia burgdorferi sensu lato (Bb) in Lyme neuroborreliosis (LNB) are needed. Detection of Bb DNA using PCR is promising, but clinical utility is hampered by low diagnostic sensitivity. We aimed to examine whether diagnostic sensitivity can be improved by the use of larger cerebrospinal fluid (CSF) volumes and faster handling of samples. Patients who underwent CSF examination for LNB were included. We collected two millilitres of CSF for PCR analysis, extracted DNA from the pellets within 24 h and analysed the eluate by two real-time PCR protocols (16S rRNA and OspA). Patients who fulfilled diagnostic criteria for LNB were classified as LNB cases and the rest as controls. Bb DNA in CSF was detected by PCR in seven of 28 adults with LNB. Two were Bb antibody negative. No Bb DNA was detected in CSF from 137 controls. Diagnostic sensitivity was 25% and specificity 100%. There was a non-significant trend towards larger CSF sample volume, faster handling of the sample, shorter duration of symptoms, and higher CSF cell count in the PCR-positive cases. We did not find that optimized handling of CSF increased diagnostic sensitivity of PCR in adults with LNB. However, our case series is small and we hypothesize that the importance of these factors will be clarified in further studies with larger case series and altered study design. PCR for diagnosis of LNB may be useful in cases without Bb antibodies due to short duration of symptoms.

Determination of aluminum in biological fluids by furnace atomic absorption spectrophotometry.

PubMed

Johnson, K E; Treble, R G

1992-01-01

Detailed procedures were developed for the furnace atomic absorption spectrophotometry (FAAS) determination of aluminum (Al) in serum, urine, cerebrospinal fluid (CSF), and proportionated dialysate. Of particular note were the use of Mg (NO3)2.6H2O as a matrix modifier and the employment of the standard additions routine in analysis. The accuracy of the method(s) used is supported by work with assayed controls and by recovery studies. The use of a "clean room" was shown to be unnecessary. Normal serum, urine, and CSF Al ranges observed were 4.8-8.9, 5.1-9.1, and 1.0-5.8 micrograms L-1 respectively.

Outcomes of endoscopic repair of cerebrospinal fluid rhinorrhea without lumbar drains.

PubMed

Adams, Austin S; Russell, Paul T; Duncavage, James A; Chandra, Rakesh K; Turner, Justin H

2016-11-01

Lumbar drains (LD) are commonly used during endoscopic repair of cerebrospinal fluid (CSF) rhinorrhea, either to facilitate graft healing or to monitor CSF fluid dynamics. However, the indications and necessity of LD placement remains controversial. The current study sought to evaluate endoscopic CSF leak repair outcomes in the setting of limited LD use. Patients who underwent endoscopic repair of CSF rhinorrhea between 2004 and 2014 were identified by a review of medical records. Demographic and clinical data were extracted and compared between patients who had surgery with and patients who had surgery without a perioperative LD. A univariate analysis was performed to identify factors predictive of recurrence. A total of 107 patients (116 surgical procedures) were identified, with a mean follow-up of 15.8 months. Eighty-eight of 107 patients (82.2%) had surgery without an LD. The mean hospital stay was 4.48 days in the LD group versus 1.03 days in the non-LD group (p < 0.00001). There was no difference in recurrence rate between the LD and non-LD groups. Predictors of recurrence included repair technique (p = 0.04) and size of defect (p = 0.005). Body mass index, leak site (ethmoid, sphenoid, frontal), and etiology (spontaneous, iatrogenic, traumatic) were not predictive of leak recurrence. Use of LDs in endoscopic CSF leak repair was not associated with reduced recurrence rates, regardless of leak etiology, and resulted in a significant increase in hospital length of stay. Although the use of perioperative LDs to monitor CSF dynamics may have some therapeutic and diagnostic advantages, it may not be associated with clinically significant improvements in patient outcomes or recurrence rates.

Assessment of the Utility of Cytology and Flow Cytometry of Cerebrospinal Fluid Samples in Clinical Practice.

PubMed

Nam, Anna S; Giorgadze, Tamara; Tam, Wayne; Chadburn, Amy

2018-01-01

We sought to assess the utility and limitations of both flow cytometry (FC) and cytology for the analysis of cerebrospinal fluid (CSF) in a practical clinical setting. A total of 393 consecutive CSF samples from 171 patients submitted for both cytomorphologic and FC assessments were analyzed. Both FC and cytology findings were negative for malignancy in 315/393 samples (80%), and either positive (POS) or suspicious/atypical (SUSP/AT) in 7% of samples. This resulted in high agreement between FC and cytology (87%). Minor discrepancies were present in 4% of the cases. In 28 samples, an abnormal population was detected by FC but not by cytology. FC and cytology are important complementary methods for analyzing CSF samples. In cases where cytology is SUSP/AT and FC is inconclusive or negative, additional specimens should be submitted for immunostaining, cytogenetics, and/or molecular studies. © 2018 S. Karger AG, Basel.

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.

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.).

Preanalytical Confounding Factors in the Analysis of Cerebrospinal Fluid Biomarkers for Alzheimer’s Disease: The Issue of Diurnal Variation

PubMed Central

Cicognola, Claudia; Chiasserini, Davide; Parnetti, Lucilla

2015-01-01

Given the growing use of cerebrospinal fluid (CSF) beta-amyloid (Aβ) and tau as biomarkers for early diagnosis of Alzheimer’s disease (AD), it is essential that the diagnostic procedures are standardized and the results comparable across different laboratories. Preanalytical factors are reported to be the cause of at least 50% of the total variability. Among them, diurnal variability is a key issue and may have an impact on the comparability of the values obtained. The available studies on this issue are not conclusive so far. Fluctuations of CSF biomarkers in young healthy volunteers have been previously reported, while subsequent studies have not confirmed those observations in older subjects, the ones most likely to receive this test. The observed differences in circadian rhythms need to be further assessed not only in classical CSF biomarkers but also in novel forthcoming biomarkers. In this review, the existing data on the issue of diurnal variations of CSF classical biomarkers for AD will be analyzed, also evaluating the available data on new possible biomarkers. PMID:26175714

Diagnostic Value of Cerebrospinal Fluid T-SPOT.TB for Tuberculousis Meningitis in China.

PubMed

Li, Xue Lian; Xie, Na; Wang, Song Wang; Wu, Qian Hong; Ma, Yan; Shu, Wei; Chen, Hong Mei; Zhang, Li Qun; Wu, Xiao Guang; Ma, Li Ping; Che, Nan Ying; Gao, Meng Qiu

2017-09-01

The aim of this study was to evaluate the diagnostic value of the cerebrospinal fluid (CSF) T-SPOT.TB test for the diagnosis of TB meningitis (TBM). A retrospective analysis of 96 patients with manifested meningitis was conducted; T-SPOT.TB test was performed for diagnosing TBM to determine the diagnostic sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). A receiver operating characteristic (ROC) curve was also drawn to assess the diagnostic accuracy. The sensitivity, specificity, PPV, and NPV of CSF T-SPOT.TB test were 97.8%, 78.0%, 80.3%, and 97.5%, respectively, for 52 patients (54.2%) of the 96 enrolled patients. The area under the curve (AUC) was 0.910, and the sensitivities of CSF T-SPOT.TB for patients with stages I, II, and III of TBM were 96.7%, 97.2%, and 98.9%, respectively. CSF T-SPOT.TB test is a rapid and accurate diagnostic method with higher sensitivity and specificity for diagnosing TBM. Copyright © 2017 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.

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.

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.

Proteomic Analysis of Cerebrospinal Fluid in a Fulminant Case of Multiple Sclerosis

PubMed Central

Füvesi, Judit; Hanrieder, Jörg; Bencsik, Krisztina; Rajda, Cecilia; Kovács, S. Krisztián; Kaizer, László; Beniczky, Sándor; Vécsei, László; Bergquist, Jonas

2012-01-01

Multiple Sclerosis (MS) is a chronic disease, but in rare fulminant cases rapid progression may lead to death shortly after diagnosis. Currently there is no diagnostic test to predict disease course. The aim of this study was to identify potential biomarkers/proteins related to rapid progression. We present the case history of a 15-year-old male MS patient. Cerebrospinal fluid (CSF) was taken at diagnosis and at the time of rapid progression leading to the patient’s death. Using isobaric tag labeling and nanoflow liquid chromatography in conjunction with matrix assisted laser desorption/ionization time of flight tandem mass spectrometry we quantitatively analyzed the protein content of two CSF samples from the patient with fulminant MS as well as one relapsing-remitting (RR) MS patient and one control headache patient, whose CSF analysis was normal. Seventy-eight proteins were identified and seven proteins were found to be more abundant in both fulminant MS samples but not in the RR MS sample compared to the control. These proteins are involved in the immune response, blood coagulation, cell proliferation and cell adhesion. In conclusion, in this pilot study we were able to show differences in the CSF proteome of a rapidly progressing MS patient compared to a more typical clinical form of MS and a control subject. PMID:22837721

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.

The longitudinal cerebrospinal fluid metabolomic profile of amyotrophic lateral sclerosis

PubMed Central

Gray, Elizabeth; Larkin, James R.; Claridge, Tim D. W.; Talbot, Kevin; Sibson, Nicola R.; Turner, Martin R.

2015-01-01

Neurochemical biomarkers are urgently sought in ALS. Metabolomic analysis of cerebrospinal fluid (CSF) using proton nuclear magnetic resonance (1H-NMR) spectroscopy is a highly sensitive method capable of revealing nervous system cellular pathology. The 1H-NMR CSF metabolomic signature of ALS was sought in a longitudinal cohort. Six-monthly serial collection was performed in ALS patients across a range of clinical sub-types (n = 41) for up to two years, and in healthy controls at a single time-point (n = 14). A multivariate statistical approach, partial least squares discriminant analysis, was used to determine differences between the NMR spectra from patients and controls. Significantly predictive models were found using those patients with at least one year's interval between recruitment and the second sample. Glucose, lactate, citric acid and, unexpectedly, ethanol were the discriminating metabolites elevated in ALS. It is concluded that 1H-NMR captured the CSF metabolomic signature associated with derangements in cellular energy utilization connected with ALS, and was most prominent in comparisons using patients with longer disease duration. The specific metabolites identified support the concept of a hypercatabolic state, possibly involving mitochondrial dysfunction specifically. Endogenous ethanol in the CSF may be an unrecognized novel marker of neuronal tissue injury in ALS. PMID:26121274

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

Cerebrospinal fluid cytokines in the diagnosis of bacterial meningitis in infants.

PubMed

Srinivasan, Lakshmi; Kilpatrick, Laurie; Shah, Samir S; Abbasi, Soraya; Harris, Mary C

2016-10-01

Bacterial meningitis poses diagnostic challenges in infants. Antibiotic pretreatment and low bacterial density diminish cerebrospinal fluid (CSF) culture yield, while laboratory parameters do not reliably identify bacterial meningitis. Pro and anti-inflammatory cytokines are elevated in bacterial meningitis and may be useful diagnostic adjuncts when CSF cultures are negative. In a prospective cohort study of infants, we used cytometric bead arrays to measure tumor necrosis factor alpha (TNF-α), interleukin 1 (IL-1), IL-6, IL-8, IL-10, and IL-12 in CSF. Receiver operating characteristic (ROC) analyses and Principal component analysis (PCA) were used to determine cytokine combinations that identified bacterial meningitis. Six hundred and eighty four infants < 6 mo were included; 11 had culture-proven bacterial meningitis. IL-6 and IL-10 were the individual cytokines possessing greatest accuracy in diagnosis of culture proven bacterial meningitis (ROC analyses; area under the concentration-time curve (AUC) 0.91; 0.9103 respectively), and performed as well as, or better than combinations identified using ROC and PCA. CSF cytokines were highly correlated with each other and with CSF white blood cell count (WBC) counts in infants with meningitis. A subset of antibiotic pretreated culture-negative subjects demonstrated cytokine patterns similar to culture positive subjects. CSF cytokine levels may aid diagnosis of bacterial meningitis, and facilitate decision-making regarding treatment for culture negative meningitis.

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.

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

Mathematical Modelling of CSF Pulsatile Flow in Aqueduct Cerebri.

PubMed

Czosnyka, Zofia; Kim, Dong-Joo; Balédent, Olivier; Schmidt, Eric A; Smielewski, Peter; Czosnyka, Marek

2018-01-01

The phase-contrast MRI technique permits the non-invasive assessment of CSF movements in cerebrospinal fluid cavities of the central nervous system. Of particular interest is pulsatile cerebrospinal fluid (CSF) flow through the aqueduct cerebri. It is allegedly increased in hydrocephalus, having potential diagnostic value, although not all scientific reports contain unequivocally positive conclusions. For the mathematical simulation of CSF flow, we used a computational model of cerebrospinal blood/fluid circulation designed by a former student as his PhD project. With this model, cerebral blood flow and CSF may be simulated in various vessels using a system of non-linear differential equations as time-varying signals. The amplitude of CSF flow seems to be positively related to the amplitude of pulse waveforms of intracranial pressure (ICP) in situations where mean ICP increases, such as during simulated infusion tests and following step increases of resistance to CSF outflow. An additional positive association between the pulse amplitude of ICP and CSF flow can be seen during simulated increases in the amplitude of arterial pulses (without changes in mean arterial pressure, MAP). The opposite effect can be observed during step increases in the resistance of the aqueduct cerebri and with decreasing elasticity of the system, where the CSF flow amplitude and the ICP pulse amplitude are related inversely. Vasodilatation caused by both gradual decreases in MAP and by increases in PaCO2 provokes an elevation in the observed amplitude of pulsatile CSF flow. Preliminary results indicate that the pulsations of CSF flow may carry information about both CSF-circulatory and cerebral vasogenic components. In most cases, the pulsations of CSF flow are positively related to the pulse amplitudes of both arterial pressure and ICP and to a degree of cerebrovascular dilatation.

Third Ventricular Cerebrospinal Fluid Cysts of Thalamic Origin: Review of Embryologic Origin, Presentation, and Management Strategies with a Case Series.

PubMed

Vasquez, Ciro A; Casey, Michael; Folzenlogen, Zach; Ormond, David R; Lillehei, Kevin; Youssef, A Samy

2017-07-01

Third ventricular cerebrospinal fluid (CSF) cysts of thalamic origin are rare. The objective of this study is to review their possible pathogenesis, clinical presentation, and management strategies with a case series describing management via an endoscopic approach with fenestration using a single burr-hole technique. A systematic literature review of reported cases of thalamic cysts was conducted with further meta-analysis of CSF cysts that involve the third ventricle. The mode of presentation, pathologic analysis, surgical management, and outcomes were analyzed. Twenty-two studies reported between 1990 and 2013 described 42 cases of thalamic cyst. Of those cases, 13 were consistent with CSF cyst that originated in the thalamus and involved the third ventricle. Eight cases (61.5%) were treated via endoscopic fenestration, 2 cases (15.4%) were surgically drained, 2 cases (15.4%) were stereotactically aspirated, and 1 case (7.69%) was observed. The most common presenting symptoms were gait disturbance (26.3%) and headaches (26.3%) followed by tremors (15.8%) and weakness (15.8%). In our series, a single burr-hole technique was a successful definitive treatment, with an average period of 23 months. Third ventricular CSF cysts of thalamic origin most commonly present with hydrocephalus. They can be safely definitively treated via endoscopic fenestration to the CSF circulation using a single burr-hole technique. Long-term follow-up shows lasting improvement in symptoms without reaccumulation of the cyst. Copyright © 2017 Elsevier Inc. All rights reserved.

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.

Effects of fluid structure interaction in a three dimensional model of the spinal subarachnoid space.

PubMed

Cheng, Shaokoon; Fletcher, David; Hemley, Sarah; Stoodley, Marcus; Bilston, Lynne

2014-08-22

It is unknown whether spinal cord motion has a significant effect on cerebrospinal fluid (CSF) pressure and therefore the importance of including fluid structure interaction (FSI) in computational fluid dynamics models (CFD) of the spinal subarachnoid space (SAS) is unclear. This study aims to determine the effects of FSI on CSF pressure and spinal cord motion in a normal and in a stenosis model of the SAS. A three-dimensional patient specific model of the SAS and spinal cord were constructed from MR anatomical images and CSF flow rate measurements obtained from a healthy human being. The area of SAS at spinal level T4 was constricted by 20% to represent the stenosis model. FSI simulations in both models were performed by running ANSYS CFX and ANSYS Mechanical in tandem. Results from this study show that the effect of FSI on CSF pressure is only about 1% in both the normal and stenosis models and therefore show that FSI has a negligible effect on CSF pressure. Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.

A balanced view of the cerebrospinal fluid composition and functions: Focus on adult humans.

PubMed

Spector, Reynold; Robert Snodgrass, S; Johanson, Conrad E

2015-11-01

In this review, a companion piece to our recent examination of choroid plexus (CP), the organ that secretes the cerebrospinal fluid (CSF), we focus on recent information in the context of reliable older data concerning the composition and functions of adult human CSF. To accomplish this, we define CSF, examine the methodology employed in studying the CSF focusing on ideal or near ideal experiments and discuss the pros and cons of several widely used analogical descriptions of the CSF including: the CSF as the "third circulation," the CSF as a "nourishing liquor," the similarities of the CSF/choroid plexus to the glomerular filtrate/kidney and finally the CSF circulation as part of the "glymphatic system." We also consider the close interrelationship between the CSF and extracellular space of brain through gap junctions and the paucity of data suggesting that the cerebral capillaries secrete a CSF-like fluid. Recently human CSF has been shown to be in dynamic flux with heart-beat, posture and especially respiration. Functionally, the CSF provides buoyancy, nourishment (e.g., vitamins) and endogenous waste product removal for the brain by bulk flow into the venous (arachnoid villi and nerve roots) and lymphatic (nasal) systems, and by carrier-mediated reabsorptive transport systems in CP. The CSF also presents many exogenous compounds to CP for metabolism or removal, indirectly cleansing the extracellular space of brain (e.g., of xenobiotics like penicillin). The CSF also carries hormones (e.g., leptin) from blood via CP or synthesized in CP (e.g., IGF-2) to the brain. In summary the CP/CSF, the third circulation, performs many functions comparable to the kidney including nourishing the brain and contributing to a stable internal milieu for the brain. These tasks are essential to normal adult brain functioning. Copyright © 2015. Published by Elsevier Inc.

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.

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

The Choroid Plexus of the Lateral Ventricle As the Origin of CSF Pulsation Is Questionable.

PubMed

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

2018-01-15

The advent of magnetic resonance imaging (MRI) enables noninvasive measurement of cerebrospinal fluid (CSF) motion, and new information about CSF motion has now been acquired. The driving force of the CSF has long been thought to be choroid plexus (CP) pulsation, but to investigate whether this phenomenon actually occurs, CSF motion was observed in the ventricular system and subarachnoid space using MRI. Eleven healthy volunteers, ranging in age from 23 to 58 years, participated in this study. The MRI sequences used were four-dimensional phase-contrast (4D-PC) and time-spatial labeling inversion pulse (t-SLIP). The 4D-PC images included sagittal images in the cranial midline, coronal images focusing on the foramen of Monro (FOM), and oblique coronal images of the trigone to quantify CSF velocity and acceleration. These values were compared and analyzed as non-parametric data using the Kolmogorov-Smirnov test and the Mann-Whitney U test. 4D-PC showed that the median CSF velocity was significantly lower in the posterior part of the lateral ventricle than in other regions. The quantitative analysis of velocity and acceleration showed that they were decreased around the CP in the trigone. Image analysis of both velocity mapping and t-SLIP showed suppressed CSF motion around the CP in the trigone. These findings cast doubt on CP pulsation being the driving force for CSF motion.

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.

CEREBROSPINAL FLUID STASIS AND ITS CLINICAL SIGNIFICANCE

PubMed Central

Whedon, James M.; Glassey, Donald

2010-01-01

We hypothesize that stasis of the cerebrospinal fluid (CSF) occurs commonly and is detrimental to health. Physiologic factors affecting the normal circulation of CSF include cardiovascular, respiratory, and vasomotor influences. The CSF maintains the electrolytic environment of the central nervous system (CNS), influences systemic acid-base balance, serves as a medium for the supply of nutrients to neuronal and glial cells, functions as a lymphatic system for the CNS by removing the waste products of cellular metabolism, and transports hormones, neurotransmitters, releasing factors, and other neuropeptides throughout the CNS. Physiologic impedance or cessation of CSF flow may occur commonly in the absence of degenerative changes or pathology and may compromise the normal physiologic functions of the CSF. CSF appears to be particularly prone to stasis within the spinal canal. CSF stasis may be associated with adverse mechanical cord tension, vertebral subluxation syndrome, reduced cranial rhythmic impulse, and restricted respiratory function. Increased sympathetic tone, facilitated spinal segments, dural tension, and decreased CSF flow have been described as closely related aspects of an overall pattern of structural and energetic dysfunction in the axial skeleton and CNS. Therapies directed at affecting CSF flow include osteopathic care (especially cranial manipulation), craniosacral therapy, chiropractic adjustment of the spine and cranium, Network Care (formerly Network Chiropractic), massage therapy (including lymphatic drainage techniques), yoga, therapeutic breathwork, and cerebrospinal fluid technique. Further investigation into the nature and causation of CSF stasis, its potential effects upon human health, and effective therapies for its correction is warranted. PMID:19472865

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.

HIV Antibody Test

MedlinePlus

... Free Fetal DNA Cerebrospinal Fluid (CSF) Analysis Ceruloplasmin Chemistry Panels Chickenpox and Shingles Tests Chlamydia Testing Chloride ... D. R., Editors (2006). Contemporary Practice in Clinical Chemistry, AACC Press, Washington, DC. Pp. 487-490. Bennett, ...

Lipase Test

MedlinePlus

... Free Fetal DNA Cerebrospinal Fluid (CSF) Analysis Ceruloplasmin Chemistry Panels Chickenpox and Shingles Tests Chlamydia Testing Chloride ... D. R., Editors (© 2006). Contemporary Practice in Clinical Chemistry: AACC Press, Washington, DC. Pp 281-287. Wu, ...

CK-MB Test

MedlinePlus

... Free Fetal DNA Cerebrospinal Fluid (CSF) Analysis Ceruloplasmin Chemistry Panels Chickenpox and Shingles Tests Chlamydia Testing Chloride ... Missouri. Pp. 312-315. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Burtis CA, Ashwood ER and ...

CSF smear

MedlinePlus

... this page: //medlineplus.gov/ency/article/003768.htm CSF smear To use the sharing features on this ... around the spinal cord and brain. Cerebrospinal fluid (CSF) protects the brain and spinal cord from injury. ...

Acetylcholine and choline in cerebrospinal fluid of patients with Parkinson's disease and Huntington's chorea.

PubMed Central

Welch, M J; Markham, C H; Jenden, D J

1976-01-01

Lumbar cerebrospinal fluid (CSF) acetylcholine (ACh) and choline (Ch) levels were measured in patients with Huntington's chorea (N=11), Parkinson's disease (N=8), and subjects at risk for Huntington's chorea (N=4), and all three groups were found not to differ significantly from normal controls (N=10). The values found for lumbar CSF ACh and Ch levels in the normal subjects were comparable with previously reported values. The use of physostigmine, a cholinesterase inhibitor, in collecting the CSF samples did not appear to make a difference with regard to ACh and Ch concentrations. Evidence suggesting a ventricular-lumbar gradient, with lumbar CSF Ch concentration being less than ventricular CSF Ch concentration, was found. Finally, ACh levels in CSF did not correlate with corresponding Ch levels. PMID:132512

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

Determination of moxifloxacin in human plasma, plasma ultrafiltrate, and cerebrospinal fluid by a rapid and simple liquid chromatography- tandem mass spectrometry method.

PubMed

Pranger, Arianna D; Alffenaar, Jan-Willem C; Wessels, A Mireille A; Greijdanus, Ben; Uges, Donald R A

2010-04-01

Moxifloxacin (MFX) is a useful agent in the treatment of multi-drug-resistant tuberculosis (MDR-TB). At Tuberculosis Centre Beatrixoord, a referral center for tuberculosis in the Netherlands, approximately 36% of the patients have received MFX as treatment. Based on the variability of MFX AUC, the variability of in vitro susceptibility to MFX of M. tuberculosis, and the variability of penetration into sanctuary sites, measuring the concentration of MFX in plasma and cerebrospinal fluid (CSF) could be recommended. Therefore, a rapid and validated liquid chromatography-tandem mass spectrometry (LC-MS-MS) analyzing method with a simple pretreatment procedure was developed for therapeutic drug monitoring of MFX in human plasma and CSF. Because of the potential influence of protein binding on efficacy, we decided to determine both bound and unbound (ultrafiltrate) fraction of MFX. The calibration curves were linear in the therapeutic range of 0.05 to 5.0 mg/L plasma and CSF with CV in the range of -5.4% to 9.3%. MFX ultrafiltrate samples could be determined with the same method setup for analysis of MFX in CSF. The LC-MS-MS method developed in this study is suitable for monitoring MFX in human plasma, plasma ultrafiltrate, and CSF.

Validation of a quantitative cerebrospinal fluid alpha-synuclein assay in a European-wide interlaboratory study.

PubMed

Kruse, Niels; Persson, Staffan; Alcolea, Daniel; Bahl, Justyna M C; Baldeiras, Ines; Capello, Elisabetta; Chiasserini, Davide; Bocchio Chiavetto, Luisella; Emersic, Andreja; Engelborghs, Sebastiaan; Eren, Erden; Fladby, Tormod; Frisoni, Giovanni; García-Ayllón, María-Salud; Genc, Sermin; Gkatzima, Olymbia; Heegaard, Niels H H; Janeiro, André M; Kováčech, Branislav; Kuiperij, H Bea; Leitão, Maria J; Lleó, Alberto; Martins, Madalena; Matos, Mafalda; Mollergard, Hanne M; Nobili, Flavio; Öhrfelt, Annika; Parnetti, Lucilla; de Oliveira, Catarina Resende; Rot, Uros; Sáez-Valero, Javier; Struyfs, Hanne; Tanassi, Julia T; Taylor, Peggy; Tsolaki, Magda; Vanmechelen, Eugeen; Verbeek, Marcel M; Zilka, Norbert; Blennow, Kaj; Zetterberg, Henrik; Mollenhauer, Brit

2015-09-01

Decreased levels of alpha-synuclein (aSyn) in cerebrospinal fluid (CSF) in Parkinson's disease and related synucleinopathies have been reported, however, not consistently in all cross-sectional studies. To test the performance of one recently released human-specific enzyme-linked immunosorbent assay (ELISA) for the quantification of aSyn in CSF, we carried out a round robin trial with 18 participating laboratories trained in CSF ELISA analyses within the BIOMARKAPD project in the EU Joint Program - Neurodegenerative Disease Research. CSF samples (homogeneous aliquots from pools) and ELISA kits (one lot) were provided centrally and data reported back to one laboratory for data analysis. Our study showed that although factors such as preanalytical sample handling and lot-to-lot variability were minimized by our study design, we identified high variation in absolute values of CSF aSyn even when the same samples and same lots of assays were applied. We further demonstrate that although absolute concentrations differ between laboratories the quantitative results are comparable. With further standardization this assay may become an attractive tool for comparing aSyn measurements in diverse settings. Recommendations for further validation experiments and improvement of the interlaboratory results obtained are given. Copyright © 2015 Elsevier Inc. All rights reserved.

Cerebrospinal fluid abacavir concentrations in HIV-positive patients following once-daily administration.

PubMed

Calcagno, A; Pinnetti, C; De Nicolò, A; Scarvaglieri, E; Gisslen, M; Tempestilli, M; D'Avolio, A; Fedele, V; Di Perri, G; Antinori, A; Bonora, S

2018-06-01

Abacavir is a widely used nucleotide reverse transcriptase inhibitor, for which cerebrospinal fluid (CSF) exposure has been previously assessed in twice-daily recipients. We studied abacavir CSF concentrations in 61 and nine HIV-positive patients taking abacavir once daily and twice daily, respectively. Patients on once-daily abacavir had higher plasma and CSF concentrations (96 vs. 22 ng ml -1 , P = 0.038 and 123 vs. 49 ng ml -1 , P = 0.038) but similar CSF-to-plasma ratios (0.8 vs. 0.5, P = 0.500). CSF abacavir concentrations were adequate in patients receiving once-daily treatment. © 2018 The British Pharmacological Society.

Sensitivity of MRI of the spine compared with CT myelography in orthostatic headache with CSF leak.

PubMed

Starling, Amaal; Hernandez, Fatima; Hoxworth, Joseph M; Trentman, Terrence; Halker, Rashmi; Vargas, Bert B; Hastriter, Eric; Dodick, David

2013-11-12

To investigate the sensitivity of MRI of the spine compared with CT myelography (CTM) in detecting CSF leaks. Between July 1998 and October 2010, 12 patients with orthostatic headache and a CTM-confirmed spinal CSF leak underwent an MRI of the spine with and without contrast. Using CTM as the gold standard, we retrospectively investigated the sensitivity of spinal MRI in detecting a CSF leak. Eleven of 12 patients with a CSF leak documented by CTM also had extradural fluid collections on spinal MRI (sensitivity 91.7%). Six patients with extradural fluid collections on spinal MRI also had spinal dural enhancement. When compared with the gold standard of CTM, MRI of the spine appears to be a sensitive and less invasive imaging modality for detecting a spinal CSF leak, suggesting that MRI of the spine should be the imaging modality of first choice for the detection of spinal CSF leaks.

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.

Regulation of cerebrospinal fluid (CSF) flow in neurodegenerative, neurovascular and neuroinflammatory disease

PubMed Central

Simon, Matthew J.; Iliff, Jeffrey J.

2015-01-01

Cerebrospinal fluid (CSF) circulation and turnover provides a sink for the elimination of solutes from the brain interstitium, serving an important homeostatic role for the function of the central nervous system. Disruption of normal CSF circulation and turnover is believed to contribute to the development of many diseases, including neurodegenerative conditions such as Alzheimer’s disease, ischemic and traumatic brain injury, and neuroinflammatory conditions such as multiple sclerosis. Recent insights into CSF biology suggesting that CSF and interstitial fluid exchange along a brain-wide network of perivascular spaces termed the ‘glymphatic’ system suggest that CSF circulation may interact intimately with glial and vascular function to regulate basic aspects of brain function. Dysfunction within this glial vascular network, which is a feature of the aging and injured brain, is a potentially critical link between brain injury, neuroinflammation and the development of chronic neurodegeneration. Ongoing research within this field may provide a powerful new framework for understanding the common links between neurodegenerative, neurovascular and neuroinflammatory disease, in addition to providing potentially novel therapeutic targets for these conditions. PMID:26499397

Detection of central nervous system leukemia in children with acute lymphoblastic leukemia by real-time polymerase chain reaction.

PubMed

Pine, Sharon R; Yin, Changhong; Matloub, Yousif H; Sabaawy, Hatem E; Sandoval, Claudio; Levendoglu-Tugal, Oya; Ozkaynak, M Fevzi; Jayabose, Somasundaram

2005-02-01

Accurate detection of central nervous system (CNS) involvement in children with newly diagnosed acute lymphoblastic leukemia (ALL) could have profound prognostic and therapeutic implications. We examined various cerebrospinal fluid (CSF) preservation methods to yield adequate DNA stability for polymerase chain reaction (PCR) analysis and developed a quantitative real-time PCR assay to detect occult CNS leukemia. Sixty CSF specimens were maintained in several storage conditions for varying amounts of time, and we found that preserving CSF in 1:1 serum-free RPMI tissue culture medium offers the best stability of DNA for PCR analysis. Sixty CSF samples (30 at diagnosis and 30 at the end of induction therapy) from 30 children with ALL were tested for CNS leukemic involvement by real-time PCR using patient-specific antigen receptor gene rearrangement primers. Six of thirty patient diagnosis samples were PCR-positive at levels ranging from 0.5 to 66% leukemic blasts in the CSF. Four of these patients had no clinical or cytomorphological evidence of CNS leukemia involvement at that time. All 30 CSF samples drawn at the end of induction therapy were PCR-negative. The data indicate that real-time PCR analysis of CSF is an excellent tool to assess occult CNS leukemia involvement in patients with ALL and can possibly be used to refine CNS status classification.

Detection of Central Nervous System Leukemia in Children with Acute Lymphoblastic Leukemia by Real-Time Polymerase Chain Reaction

PubMed Central

Pine, Sharon R.; Yin, Changhong; Matloub, Yousif H.; Sabaawy, Hatem E.; Sandoval, Claudio; Levendoglu-Tugal, Oya; Ozkaynak, M. Fevzi; Jayabose, Somasundaram

2005-01-01

Accurate detection of central nervous system (CNS) involvement in children with newly diagnosed acute lymphoblastic leukemia (ALL) could have profound prognostic and therapeutic implications. We examined various cerebrospinal fluid (CSF) preservation methods to yield adequate DNA stability for polymerase chain reaction (PCR) analysis and developed a quantitative real-time PCR assay to detect occult CNS leukemia. Sixty CSF specimens were maintained in several storage conditions for varying amounts of time, and we found that preserving CSF in 1:1 serum-free RPMI tissue culture medium offers the best stability of DNA for PCR analysis. Sixty CSF samples (30 at diagnosis and 30 at the end of induction therapy) from 30 children with ALL were tested for CNS leukemic involvement by real-time PCR using patient-specific antigen receptor gene rearrangement primers. Six of thirty patient diagnosis samples were PCR-positive at levels ranging from 0.5 to 66% leukemic blasts in the CSF. Four of these patients had no clinical or cytomorphological evidence of CNS leukemia involvement at that time. All 30 CSF samples drawn at the end of induction therapy were PCR-negative. The data indicate that real-time PCR analysis of CSF is an excellent tool to assess occult CNS leukemia involvement in patients with ALL and can possibly be used to refine CNS status classification. PMID:15681484

Blood Urea Nitrogen Test

MedlinePlus

... Free Fetal DNA Cerebrospinal Fluid (CSF) Analysis Ceruloplasmin Chemistry Panels Chickenpox and Shingles Tests Chlamydia Testing Chloride ... mmol/L 1 from Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Burtis CA, Ashwood ER, Bruns ...

CSF oligoclonal banding - slideshow

MedlinePlus

... this page: //medlineplus.gov/ency/presentations/100145.htm CSF oligoclonal banding - series—Normal anatomy To use the ... 5 out of 5 Overview The cerebrospinal fluid (CSF) serves to supply nutrients to the central nervous ...

Transcriptomic Analysis Reveals Selective Metabolic Adaptation of Streptococcus suis to Porcine Blood and Cerebrospinal Fluid

PubMed Central

Koczula, Anna; Jarek, Michael; Visscher, Christian; Valentin-Weigand, Peter; Goethe, Ralph; Willenborg, Jörg

2017-01-01

Streptococcus suis is a zoonotic pathogen that can cause severe pathologies such as septicemia and meningitis in its natural porcine host as well as in humans. Establishment of disease requires not only virulence of the infecting strain but also an appropriate metabolic activity of the pathogen in its host environment. However, it is yet largely unknown how the streptococcal metabolism adapts to the different host niches encountered during infection. Our previous isotopologue profiling studies on S. suis grown in porcine blood and cerebrospinal fluid (CSF) revealed conserved activities of central carbon metabolism in both body fluids. On the other hand, they suggested differences in the de novo amino acid biosynthesis. This prompted us to further dissect S. suis adaptation to porcine blood and CSF by RNA deep sequencing (RNA-seq). In blood, the majority of differentially expressed genes were associated with transport of alternative carbohydrate sources and the carbohydrate metabolism (pentose phosphate pathway, glycogen metabolism). In CSF, predominantly genes involved in the biosynthesis of branched-chain and aromatic amino acids were differentially expressed. Especially, isoleucine biosynthesis seems to be of major importance for S. suis in CSF because several related biosynthetic genes were more highly expressed. In conclusion, our data revealed niche-specific metabolic gene activity which emphasizes a selective adaptation of S. suis to host environments. PMID:28212285

Transcriptomic Analysis Reveals Selective Metabolic Adaptation of Streptococcus suis to Porcine Blood and Cerebrospinal Fluid.

PubMed

Koczula, Anna; Jarek, Michael; Visscher, Christian; Valentin-Weigand, Peter; Goethe, Ralph; Willenborg, Jörg

2017-02-15

Streptococcus suis is a zoonotic pathogen that can cause severe pathologies such as septicemia and meningitis in its natural porcine host as well as in humans. Establishment of disease requires not only virulence of the infecting strain but also an appropriate metabolic activity of the pathogen in its host environment. However, it is yet largely unknown how the streptococcal metabolism adapts to the different host niches encountered during infection. Our previous isotopologue profiling studies on S. suis grown in porcine blood and cerebrospinal fluid (CSF) revealed conserved activities of central carbon metabolism in both body fluids. On the other hand, they suggested differences in the de novo amino acid biosynthesis. This prompted us to further dissect S. suis adaptation to porcine blood and CSF by RNA deep sequencing (RNA-seq). In blood, the majority of differentially expressed genes were associated with transport of alternative carbohydrate sources and the carbohydrate metabolism (pentose phosphate pathway, glycogen metabolism). In CSF, predominantly genes involved in the biosynthesis of branched-chain and aromatic amino acids were differentially expressed. Especially, isoleucine biosynthesis seems to be of major importance for S. suis in CSF because several related biosynthetic genes were more highly expressed. In conclusion, our data revealed niche-specific metabolic gene activity which emphasizes a selective adaptation of S. suis to host environments.

Simple and validated UHPLC-MS/MS analysis of nimodipine in plasma and cerebrospinal fluid of patients with subarachnoid haemorrhage.

PubMed

Mohamed, Susan; Riva, Roberto; Contin, Manuela

2016-08-15

We present a simple, fast and validated method for the determination of nimodipine in plasma and cerebrospinal fluid (CSF) of patients with subarachnoid haemorrhage using ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Plasma or CSF 250μL aliquots were pretreated with acetonitrile spiked with lacosamide as internal standard. The chromatographic separation was performed on a Fusion (3μm) 50×2.0mm I.D. column with gradient elution of 0.1% (v/v) formic acid in water and 0.1% (v/v) formic acid in acetonitrile at a flow rate of 0.35mL/min. The MS/MS ion transitions were 419.1→343 for nimodipine and 251.1→91 for the internal standard. The linearity was determined from 2.0 to 40.0ng/mL in plasma and 40.0-800.0pg/mL in CSF. The lower limit of quantitation (LLOQ) of nimodipine was 0.4ng/mL in plasma and 40pg/mL in CSF. The mean recovery for nimodipine was ≥75% in plasma and ≥90% in CSF at all three considered concentrations. Intra- and interassay precision and accuracy were ≤15% at all quality control concentrations in plasma and CSF. The method was applied to measure plasma and CSF concentrations of nimodipine in a series of patients with subarachnoid haemorrhage treated with intravenous nimodipine. The present procedure, omitting time-consuming liquid-liquid extraction and drying steps, is faster, simpler and cheaper than published LC-MS/MS analytical methods for nimodipine in plasma and the first validated one for nimodipine in CSF. Copyright © 2016 Elsevier B.V. All rights reserved.

Is Cerebrospinal Fluid C-reactive Protein a Better Tool than Blood C-reactive Protein in Laboratory Diagnosis of Meningitis in Children?

PubMed Central

Malla, Kalpana K.; Malla, Tejesh; Rao, K. Seshagiri; Basnet, Sahisnuta; Shah, Ravi

2013-01-01

Objectives: This study aimed to test whether C-reactive protein (CRP) measurement could differentiate between different types of meningitis and become a routine test. Methods: A prospective study included 140 children admitted to Manipal Teaching Hospital, Pokhara, Nepal, between July 2009 and June 2011. The subjects had a blood test and detailed cerebrospinal fluid (CSF) analysis, including blood and CSF CRP levels. Results: Of those admitted, 31.1% had pyogenic meningitis (PM), 26.2% partially treated meningitis (PPM), 33% viral meningitis (VM), and 9.7% tubercular meningitis (TBM), with 26.4% controls. Organisms were isolated in 12.5% of the cases by blood culture and 25% of cases through CSF culture. Blood CRP was positive in all groups, with the highest values in PM (53.12 ± 28.88 mg/dl) and PPM (47.55 ± 34.34 mg/dl); this was not statistically significant (P = 0.08). The CSF CRP levels were significantly higher (P <0.001) in PM (45.75 ± 28.50 mg/dl) and PPM (23.11 ± 23.98 mg/dl). The sensitivity and specificity of blood CRP was 90.62%, 88.88%, 64.7%, 70% and 32.4%, 30.97%, 24.52%, 26.12% and that of CSF CRP was 96.87%, 66.66%, 20.58%, 10% and 74.73%, 63.71%, 50.94%, 55.35% for PM, PPM, VM and TBM, respectively. Conclusion: Because of its high sensitivity, both CSF CRP and blood CRP can be used to screen for bacterial meningitis (both PM and PPM). CSF CRP screening yielded results with a higher specificity than blood CRP; hence, it can be a supportive test along with CSF cytology, biochemistry, and microbiology for diagnosing meningitis. PMID:23573388

Evaluation of new monoclonal antibody-based latex agglutination test for detection of cryptococcal polysaccharide antigen in serum and cerebrospinal fluid.

PubMed Central

Kiska, D L; Orkiszewski, D R; Howell, D; Gilligan, P H

1994-01-01

We evaluated the performance of CRYPTO-LEX (Trinity Laboratories, Inc., Raleigh, N. C.), a new mouse immunoglobulin M monoclonal antibody latex agglutination reagent which reacts with the capsular polysaccharide of the four serogroups of Cryptococcus neoformans. This test was compared with CALAS (Meridian Diagnostics, Cincinnati, Ohio) for the ability to detect cryptococcal antigen in serum and cerebrospinal fluid (CSF). A total of 580 clinical specimens (327 serum and 253 CSF samples), primarily from human immunodeficiency virus-infected patients, were tested in this study. Sixty-seven specimens (44 serum and 23 CSF samples) were positive for cryptococcal antigen with both tests, and 511 (282 serum and 229 CSF samples) were negative. The two latex reagents agreed for 326 of 327 serum specimens (44 positives and 282 negatives). One serum specimen with a titer of 1:2 was CALAS positive but CRYPTO-LEX negative. The titer correlation coefficient for the two tests was 0.884 when two highly discordant serum specimens were eliminated from analysis of the data. The two latex tests agreed for 252 of 253 CSF specimens (23 positives and 229 negatives). One specimen with a titer of 1:2 was positive with CALAS and negative by CRYPTO-LEX. The correlation coefficient of the two tests for CSF titers was 0.886. The sensitivity and specificity of CRYPTO-LEX were 97 and 100%, respectively, with a 99.6% correlation with CALAS. These data show that the performance of CRYPTO-LEX is comparable to that of CALAS for detection of cryptococcal antigen in serum and CSF. PMID:7814566

Idiopathic normal pressure hydrocephalus: analysis of factors related to cerebrospinal fluid dynamics determining functional prognosis.

PubMed

Bárcena, A; Mestre, C; Cañizal, J M; Rivero, B; Lobato, R D

1997-01-01

This investigation has been undertaken to analyze the findings with both the cerebrospinal fluid (CSF) pressure (Pcsf) and CSF pulse pressure (PP) in order to predict the outcome of patients with the syndrome of idiopathic normal pressure hydrocephalus (NPH). Accordingly, a prospective clinical study was planned in which two groups of patients with NPH, having analogous prevalence of several matched clinical and radiological parameters, were separated on the basis of their positive or negative response to shunting. Both the resting Pcsf and CSF PP profiles were compared in these two groups, and between them and normal controls. CSF PP amplitude and CSF PP latency correlated directly in conditions associated with either normal or high compliance (controls and patients with Alzheimer-like disorders), whereas this correlation was inverse in states of low compliance (NPH). On the other hand, shunt-responders showed a resting Pcsf significantly higher than both non-responders and controls. The following conclusions were obtained: 1) CSF PP is a high-amplitude and relative low-latency wave in NPH when compared with controls: 2) CSF PP amplitude and latency correlate directly in normal subjects and in those with primary cerebral atrophy; 3) a non-reversible stage of NPH could be conceived in contradistinction to the reversible one, in both of which an inverse correlation between the amplitude and the latency takes place, the main difference between them being the resting Pcsf, which is significantly lower in the former than in the latter, depending on the degree of atrophic changes developed.

Lower body negative pressure reduces optic nerve sheath diameter during head-down tilt.

PubMed

Marshall-Goebel, Karina; Terlević, Robert; Gerlach, Darius A; Kuehn, Simone; Mulder, Edwin; Rittweger, Jörn

2017-11-01

The microgravity ocular syndrome (MOS) results in significant structural and functional ophthalmic changes during 6-mo spaceflight missions consistent with an increase in cerebrospinal fluid (CSF) pressure compared with the preflight upright position. A ground-based study was performed to assess two of the major hypothesized contributors to MOS, headward fluid shifting and increased ambient CO 2 , on intracranial and periorbital CSF. In addition, lower body negative pressure (LBNP) was assessed as a countermeasure to headward fluid shifting. Nine healthy male subjects participated in a crossover design study with five head-down tilt (HDT) conditions: -6, -12, and -18° HDT, -12° HDT with -20 mmHg LBNP, and -12° HDT with a 1% CO 2 environment, each for 5 h total. A three-dimensional volumetric scan of the cranium and transverse slices of the orbita were collected with MRI, and intracranial CSF volume and optic nerve sheath diameter (ONSD) were measured after 4.5 h HDT. ONSD increased during -6° ( P < 0.001), -12° ( P < 0.001), and -18° HDT ( P < 0.001) and intracranial CSF increased during -12° HDT ( P = 0.01) compared with supine baseline. Notably, LBNP was able to reduce the increases in ONSD and intracranial CSF during HDT. The addition of 1% CO 2 during HDT, however, had no further effect on ONSD, but rather ONSD increased from baseline in a similar magnitude to -12° HDT with ambient air ( P = 0.001). These findings demonstrate the ability of LBNP, a technique that targets fluid distribution in the lower limbs, to directly influence CSF and may be a promising countermeasure to help reduce increases in CSF. NEW & NOTEWORTHY This is the first study to demonstrate the ability of lower body negative pressure to directly influence cerebrospinal fluid surrounding the optic nerve, indicating potential use as a countermeasure for increased cerebrospinal fluid on Earth or in space. Copyright © 2017 the American Physiological Society.

CSF smear (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 ...

CSF chemistry (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 ...

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.

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

Treatment of cerebrospinal fluid leak after spine surgery.

PubMed

Fang, Zhao; Tian, Rong; Jia, Yu-Tao; Xu, Tian-Tong; Liu, Yang

2017-04-01

Owing to the complexity of spinal surgery, there is a great prevalence of dural tear causing cerebrospinal fluid (CSF) leakage. Many studies focused on suture repair for dural tear to stop CSF leak. Now some new treatment strategies have shown a promising effect that is listed as follows: 1) creating watertight dural closure to stop CSF leak with the help of dural substitute material; and 2) retarding CSF leak by changing pressure difference, including reducing the subarachnoid fluid pressure, increasing the epidural space pressure and both. In fact several methods mentioned above are usually combined to treat CSF leak. However, no update review summarized the relevant studies implemented in recent years. In this review, the authors would compare the effects of different dural closure techniques, and introduce the latest treatment methods and mechanisms. Copyright © 2017 Daping Hospital and the Research Institute of Surgery of the Third Military Medical University. Production and hosting by Elsevier B.V. All rights reserved.

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.

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).

Dual R3R5 tropism characterizes cerebrospinal fluid HIV-1 isolates from individuals with high cerebrospinal fluid viral load.

PubMed

Karlsson, Ulf; Antonsson, Liselotte; Ljungberg, Bengt; Medstrand, Patrik; Esbjörnsson, Joakim; Jansson, Marianne; Gisslen, Magnus

2012-09-10

To study the use of major and alternative coreceptors by HIV-1 isolates obtained from paired plasma and cerebrospinal fluid (CSF) samples. Paired plasma and CSF isolates from HIV-1-infected individuals with varying clinical, virologic, and immunologic parameters were assessed for the ability to infect indicator cells expressing a panel of coreceptors with documented expression in the central nervous system (CNS). HIV-1 isolates obtained from plasma and CSF in 28 individuals with varying viral load, CD4 T-cell counts, and with or without AIDS-defining disease were analyzed for the ability to infect NP2.CD4 cells stably expressing a panel of HIV coreceptors (CCR5, CXCR4, CCR3, CXCR6, GPR1, APJ, ChemR23, RDC-1 or BLT1). All isolates from both plasma and CSF utilized CCR5 and/or CXCR4. However, the ability to use both CCR3 and CCR5 (R3R5) was more pronounced in CSF isolates and correlated with high CSF viral load and low CD4 T-cell count. Notably, four out of five CSF isolates of subtype C origin exhibited CXCR6 use, which coincided with high CSF viral load despite preserved CD4 T-cell counts. The use of other alternative coreceptors was less pronounced. Dual-tropic R3R5 HIV-1 isolates in CSF coincide with high CSF viral load and low CD4 T-cell counts. Frequent CXCR6 use by CSF-derived subtype C isolates indicates that subtype-specific differences in coreceptor use may exist that will not be acknowledged when assessing plasma virus isolates. The findings may also bare relevance for HIV-1 replication within the CNS, and consequently, for the neuropathogenesis of AIDS.

Diagnostic and prognostic value of procalcitonin for early intracranial infection after craniotomy

PubMed Central

Yu, Y.; Li, H.J.

2017-01-01

Intracranial infection is a common clinical complication after craniotomy. We aimed to explore the diagnostic and prognostic value of dynamic changing procalcitonin (PCT) in early intracranial infection after craniotomy. A prospective study was performed on 93 patients suspected of intracranial infection after craniotomy. Routine peripheral venous blood was collected on the day of admission, and C reactive protein (CRP) and PCT levels were measured. Cerebrospinal fluid (CSF) was collected for routine biochemical, PCT and culture assessment. Serum and CSF analysis continued on days 1, 2, 3, 5, 7, 9, and 11. The patients were divided into intracranial infection group and non-intracranial infection group; intracranial infection group was further divided into infection controlled group and infection uncontrolled group. Thirty-five patients were confirmed with intracranial infection after craniotomy according to the diagnostic criteria. The serum and cerebrospinal fluid PCT levels in the infected group were significantly higher than the non-infected group on day 1 (P<0.05, P<0.01). The area under curve of receiver operating characteristics was 0.803 for CSF PCT in diagnosing intracranial infection. The diagnostic sensitivity and specificity of CSF PCT was superior to other indicators. The serum and CSF PCT levels have potential value in the early diagnosis of intracranial infection after craniotomy. Since CSF PCT levels have higher sensitivity and specificity, dynamic changes in this parameter could be used for early detection of intracranial infection after craniotomy, combined with other biochemical indicators. PMID:28443989

Cerebrospinal fluid analysis for HIV replication and biomarkers of immune activation and neurodegeneration in long-term atazanavir/ritonavir monotherapy treated patients.

PubMed

Ferretti, Francesca; Bigoloni, Alba; Passeri, Laura; Galli, Laura; Longo, Valeria; Gerevini, Simonetta; Spagnuolo, Vincenzo; Gisslen, Magnus; Zetterberg, Henrik; Fuchs, Dietmar; Cattaneo, Dario; Caramatti, Giada; Lazzarin, Adriano; Cinque, Paola; Castagna, Antonella

2016-07-01

Cerebrospinal fluid (CSF) viral escape is a concern in ritonavir-boosted protease inhibitors monotherapy. The aim was to assess HIV-RNA, biomarkers of immune activation and neurodegeneration, and atazanavir concentrations in CSF of patients on successful long-term atazanavir/ritonavir (ATV/r) monotherapy. This is a substudy of the multicentric, randomized, open-label, noninferiority trial monotherapy once a day with atazanavir/ritonavir (NCT01511809), comparing the ongoing ATV/r along with 2 nucleoside retrotranscriptase inhibitors (NRTIs) regimen to a simplified ATV/r monotherapy. Patients with plasma HIV-RNA < 50 copies/mL after at least 96 study weeks were eligible.We assessed HIV-RNA, soluble (s)CD14, sCD163, CCL2, CXCL10, interleukin-6, and YKL40 by enzyme-linked immunosorbent assay; neopterin, tryptophan, kynurenine, and neurofilament by immunoassays; and ATV concentrations by liquid chromatography-mass spectrometry in paired plasma and CSF samples. Variables were compared with Wilcoxon rank-sum or Fisher exact test, as appropriate. HIV-RNA was detected in the CSF of 1/11 patients on ATV/r monotherapy (114 copies/mL), without neurological symptoms, who was successfully reintensified with his previous 2NRTIs, and in none of the 12 patients on ATV/r + 2NRTIs. CSF biomarkers and ATV concentrations did not differ between the 2 arms. CSF escape was uncommon in patients on long-term ATV/r monotherapy and was controlled with reintensification.

Cerebrospinal fluid analysis for HIV replication and biomarkers of immune activation and neurodegeneration in long-term atazanavir/ritonavir monotherapy treated patients

PubMed Central

Ferretti, Francesca; Bigoloni, Alba; Passeri, Laura; Galli, Laura; Longo, Valeria; Gerevini, Simonetta; Spagnuolo, Vincenzo; Gisslen, Magnus; Zetterberg, Henrik; Fuchs, Dietmar; Cattaneo, Dario; Caramatti, Giada; Lazzarin, Adriano; Cinque, Paola; Castagna, Antonella

2016-01-01

Abstract Background: Cerebrospinal fluid (CSF) viral escape is a concern in ritonavir-boosted protease inhibitors monotherapy. The aim was to assess HIV-RNA, biomarkers of immune activation and neurodegeneration, and atazanavir concentrations in CSF of patients on successful long-term atazanavir/ritonavir (ATV/r) monotherapy. Methods: This is a substudy of the multicentric, randomized, open-label, noninferiority trial monotherapy once a day with atazanavir/ritonavir (NCT01511809), comparing the ongoing ATV/r along with 2 nucleoside retrotranscriptase inhibitors (NRTIs) regimen to a simplified ATV/r monotherapy. Patients with plasma HIV-RNA < 50 copies/mL after at least 96 study weeks were eligible. We assessed HIV-RNA, soluble (s)CD14, sCD163, CCL2, CXCL10, interleukin-6, and YKL40 by enzyme-linked immunosorbent assay; neopterin, tryptophan, kynurenine, and neurofilament by immunoassays; and ATV concentrations by liquid chromatography–mass spectrometry in paired plasma and CSF samples. Variables were compared with Wilcoxon rank-sum or Fisher exact test, as appropriate. Results: HIV-RNA was detected in the CSF of 1/11 patients on ATV/r monotherapy (114 copies/mL), without neurological symptoms, who was successfully reintensified with his previous 2NRTIs, and in none of the 12 patients on ATV/r + 2NRTIs. CSF biomarkers and ATV concentrations did not differ between the 2 arms. Conclusions: CSF escape was uncommon in patients on long-term ATV/r monotherapy and was controlled with reintensification. PMID:27428202

Feline meningoencephalomyelitis of unknown origin: A retrospective analysis of 16 cases

PubMed Central

Negrin, Arianna; Spencer, Sarah; Cherubini, Giunio Bruto

2017-01-01

This study aimed to describe the signalment, clinical signs, magnetic resonance imaging (MRI) findings, cerebrospinal fluid (CSF) analysis, treatment, and outcome of feline meningoencephalomyelitis of unknown origin (FMUO). Medical records from 16 cats meeting the inclusion criteria of CSF pleocytosis, negative CSF polymerase chain reaction (PCR)-infectious disease results, and characteristic MRI findings were retrospectively reviewed. Median age was 9.4 years. Clinical signs included ataxia, proprioceptive deficits, seizures, and spinal hyperesthesia. The CSF nucleated cell count was increased (median 70.7 cells/μL), with predominantly mixed pleocytosis and CSF protein concentration was increased in 15/16 cats. Magnetic resonance imaging showed intraparenchymal infiltrative ill-defined lesions in 13 cases. All cats received a corticosteroid-based treatment protocol; additional therapies included lomustine, cytarabine, and anticonvulsant medications. Mild neurological signs were recorded in 5/12 cats but 7/12 cats were neurologically normal at re-examination. This represents the first study of feline MUO, highlighting FMUO as an important differential diagnosis in cats with variable neurological presentation. Prognosis appears to be good with immunomodulatory therapy. PMID:28966357

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).

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.

A fast and reproducible method for albumin isolation and depletion from serum and cerebrospinal fluid.

PubMed

Holewinski, Ronald J; Jin, Zhicheng; Powell, Matthew J; Maust, Matthew D; Van Eyk, Jennifer E

2013-03-01

Analysis of serum and plasma proteomes is a common approach for biomarker discovery, and the removal of high-abundant proteins, such as albumin and immunoglobins, is usually the first step in the analysis. However, albumin binds peptides and proteins, which raises concerns as to how the removal of albumin could impact the outcome of the biomarker study while ignoring the possibility that this could be a biomarker subproteome itself. The first goal of this study was to test a new commercially available affinity capture reagent from Protea Biosciences and to compare the efficiency and reproducibility to four other commercially available albumin depletion methods. The second goal of this study was to determine if there is a highly efficient albumin depletion/isolation system that minimizes sample handling and would be suitable for large numbers of samples. Two of the methods tested (Sigma and ProteaPrep) showed an albumin depletion efficiency of 97% or greater for both serum and cerebrospinal fluid (CSF). Isolated serum and CSF albuminomes from ProteaPrep spin columns were analyzed directly by LC-MS/MS, identifying 128 serum (45 not previously reported) and 94 CSF albuminome proteins (17 unique to the CSF albuminome). Serum albuminome was also isolated using Vivapure anti-HSA columns for comparison, identifying 105 proteins, 81 of which overlapped with the ProteaPrep method. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Tumor-Associated Macrophages Associate with Cerebrospinal Fluid Interleukin-10 and Survival in Primary Central Nervous System Lymphoma (PCNSL).

PubMed

Sasayama, Takashi; Tanaka, Kazuhiro; Mizowaki, Takashi; Nagashima, Hiroaki; Nakamizo, Satoshi; Tanaka, Hirotomo; Nishihara, Masamitsu; Mizukawa, Katsu; Hirose, Takanori; Itoh, Tomoo; Kohmura, Eiji

2016-07-01

Increased tumor-associated macrophages (TAMs) have been reported to be associated with poor prognosis in various tumors; however, the importance of TAMs in primary central nervous system lymphoma (PCNSL) has not been clarified. In 47 patients with PCNSL who were treated with high-dose methotrexate (MTX) and radiotherapy, the relationships between the infiltration levels of TAMs and the clinicopathological parameters were analyzed. Univariate analysis of the Cox proportional hazards model using continuous scales revealed that increased CD68 positive (+) TAMs was significantly associated with inferior progression-free survival (PFS) (P = 0.04), and trends were observed for the increased CD163(+)  TAMs and having shorter PFS (P = 0.05). However, increased TAMs were not associated with overall survival. Because TAMs are known to produce various cytokines, we examined the relationships between cerebrospinal fluid (CSF) cytokines and TAMs. CSF interleukin-6 (IL-6) and soluble IL-2 receptor were not correlated with the infiltration rate of TAMs; however, CSF IL-10 level was correlated with infiltration levels of CD68 and CD163(+)  TAMs. We also confirmed the expression of IL-10 in CD68(+)  and CD163(+)  TAMs by double immunostaining analysis. Our results indicate that a high level of IL-10 in CSF may be positively associated with the infiltration level of TAMs in PCNSLs. © 2015 International Society of Neuropathology.

Approach to Cerebrospinal Fluid (CSF) Biomarker Discovery and Evaluation in HIV Infection

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

Price, Richard W.; Peterson, Julia; Fuchs, Dietmar

2013-12-13

Central nervous system (CNS) infection is a nearly universal facet of systemic HIV infection that varies in character and neurological consequences. While clinical staging and neuropsychological test performance have been helpful in evaluating patients, cerebrospinal fluid (CSF) biomarkers present a valuable and objective approach to more accurate diagnosis, assessment of treatment effects and understanding of evolving pathobiology. We review some lessons from our recent experience with CSF biomarker studies. We have used two approaches to biomarker analysis: targeted, hypothesis-driven and non-targeted exploratory discovery methods. We illustrate the first with data from a cross-sectional study of defined subject groups across themore » spectrum of systemic and CNS disease progression and the second with a longitudinal study of the CSF proteome in subjects initiating antiretroviral treatment. Both approaches can be useful and, indeed, complementary. The first is helpful in assessing known or hypothesized biomarkers while the second can identify novel biomarkers and point to broad interactions in pathogenesis. Common to both is the need for well-defined samples and subjects that span a spectrum of biological activity and biomarker concentrations. Previouslydefined guide biomarkers of CNS infection, inflammation and neural injury are useful in categorizing samples for analysis and providing critical biological context for biomarker discovery studies. CSF biomarkers represent an underutilized but valuable approach to understanding the interactions of HIV and the CNS and to more objective diagnosis and assessment of disease activity. Both hypothesis-based and discovery methods can be useful in advancing the definition and use of these biomarkers.« less

Approach to cerebrospinal fluid (CSF) biomarker discovery and evaluation in HIV infection.

PubMed

Price, Richard W; Peterson, Julia; Fuchs, Dietmar; Angel, Thomas E; Zetterberg, Henrik; Hagberg, Lars; Spudich, Serena; Smith, Richard D; Jacobs, Jon M; Brown, Joseph N; Gisslen, Magnus

2013-12-01

Central nervous system (CNS) infection is a nearly universal facet of systemic HIV infection that varies in character and neurological consequences. While clinical staging and neuropsychological test performance have been helpful in evaluating patients, cerebrospinal fluid (CSF) biomarkers present a valuable and objective approach to more accurate diagnosis, assessment of treatment effects and understanding of evolving pathobiology. We review some lessons from our recent experience with CSF biomarker studies. We have used two approaches to biomarker analysis: targeted, hypothesis-driven and non-targeted exploratory discovery methods. We illustrate the first with data from a cross-sectional study of defined subject groups across the spectrum of systemic and CNS disease progression and the second with a longitudinal study of the CSF proteome in subjects initiating antiretroviral treatment. Both approaches can be useful and, indeed, complementary. The first is helpful in assessing known or hypothesized biomarkers while the second can identify novel biomarkers and point to broad interactions in pathogenesis. Common to both is the need for well-defined samples and subjects that span a spectrum of biological activity and biomarker concentrations. Previously-defined guide biomarkers of CNS infection, inflammation and neural injury are useful in categorizing samples for analysis and providing critical biological context for biomarker discovery studies. CSF biomarkers represent an underutilized but valuable approach to understanding the interactions of HIV and the CNS and to more objective diagnosis and assessment of disease activity. Both hypothesis-based and discovery methods can be useful in advancing the definition and use of these biomarkers.

Spectrophotometry of cerebrospinal fluid in subacute and chronic subdural haematomas

PubMed Central

Kjellin, K. G.; Steiner, L.

1974-01-01

Spectrophotometric examinations were performed on cerebrospinal and subdural fluids in subacute (five patients) and chronic (20 patients) subdural haematomas, with special reference to the diagnostic aid of CSF spectrophotometry. Spectrophotometric xanthochromia of haemorrhagic origin was found in all CSFs examined, while definite visible xanthochromia was observed in only 28% and the CSF was judged as colourless in 52% of those cases. Characteristic bleeding patterns were found spectrophotometrically in all the 20 CSFs examined within 24 hours after lumbar puncture, haematoma patterns being detected in 90-95% of the cases. In many cases the electrophoretically separated protein fractions of CSF and subdural fluids were spectrophotometrically examined. In conclusion, CSF spectrophotometry is a simple, fast, and extremely sensitive method, which in our opinion should be used routinely in the diagnosis of suspected subdural haematomas, if lumbar puncture is not contraindicated. PMID:4140892

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.

Low levels of HIV-1 RNA detected in the cerebrospinal fluid after up to 10 years of suppressive therapy are associated with local immune activation

PubMed Central

Dahl, Viktor; Peterson, Julia; Fuchs, Dietmar; Gisslen, Magnus; Palmer, Sarah; Price, Richard W.

2015-01-01

Objective and design Though combination antiretroviral therapy reduces the concentration of HIV-1 RNA in both plasma and cerebrospinal fluid (CSF) below the detection limit of clinical assays, low levels of HIV-1 RNA are frequently detectable in plasma using more sensitive assays. We examined the frequency and magnitude of persistent low-level HIV-1 RNA in CSF and its relation to the central nervous system (CNS) immune activation. Methods CSF and plasma HIV-1 RNA were measured using the single-copy assay with a detection limit of 0.3 copies/ml in 70 CSF and 68 plasma samples from 45 treated HIV-1-infected patients with less than 40 copies/ml of HIV-1 RNA in both fluids by standard clinical assays. We also measured CSF neopterin to assess intrathecal immune activation. Theoretical drug exposure was estimated using the CNS penetration-efficacy score of treatment regimens. Results CSF HIV-1 RNA was detected in 12 of the 70 CSF samples (17%) taken after up to 10 years of suppressive therapy, compared to 39 of the 68 plasma samples (57%) with a median concentration of less than 0.3 copies/ml in CSF compared to 0.3 copies/ml in plasma (P <0.0001). CSF samples with detectable HIV-1 RNA had higher CSF neopterin levels (mean 8.2 compared to 5.7 nmol/l; P =0.0085). Patients with detectable HIV-1 RNA in CSF did not differ in pretreatment plasma HIV-1 RNA levels, nadir CD4+ cell count or CNS penetration-efficacy score. Conclusion Low-level CSF HIV-1 RNA and its association with elevated CSF neopterin highlight the potential for the CNS to serve as a viral reservoir and for persistent infection to cause subclinical CNS injury. PMID:25022595

Low levels of HIV-1 RNA detected in the cerebrospinal fluid after up to 10 years of suppressive therapy are associated with local immune activation.

PubMed

Dahl, Viktor; Peterson, Julia; Fuchs, Dietmar; Gisslen, Magnus; Palmer, Sarah; Price, Richard W

2014-09-24

Though combination antiretroviral therapy reduces the concentration of HIV-1 RNA in both plasma and cerebrospinal fluid (CSF) below the detection limit of clinical assays, low levels of HIV-1 RNA are frequently detectable in plasma using more sensitive assays. We examined the frequency and magnitude of persistent low-level HIV-1 RNA in CSF and its relation to the central nervous system (CNS) immune activation. CSF and plasma HIV-1 RNA were measured using the single-copy assay with a detection limit of 0.3 copies/ml in 70 CSF and 68 plasma samples from 45 treated HIV-1-infected patients with less than 40 copies/ml of HIV-1 RNA in both fluids by standard clinical assays. We also measured CSF neopterin to assess intrathecal immune activation. Theoretical drug exposure was estimated using the CNS penetration-efficacy score of treatment regimens. CSF HIV-1 RNA was detected in 12 of the 70 CSF samples (17%) taken after up to 10 years of suppressive therapy, compared to 39 of the 68 plasma samples (57%) with a median concentration of less than 0.3 copies/ml in CSF compared to 0.3 copies/ml in plasma (P < 0.0001). CSF samples with detectable HIV-1 RNA had higher CSF neopterin levels (mean 8.2 compared to 5.7 nmol/l; P = 0.0085). Patients with detectable HIV-1 RNA in CSF did not differ in pretreatment plasma HIV-1 RNA levels, nadir CD4 cell count or CNS penetration-efficacy score. Low-level CSF HIV-1 RNA and its association with elevated CSF neopterin highlight the potential for the CNS to serve as a viral reservoir and for persistent infection to cause subclinical CNS injury.

Clinical Value of Assessing Cytokine Levels for the Differential Diagnosis of Bacterial Meningitis in a Pediatric Population

PubMed Central

Ye, Qing; Shao, Wen-Xia; Shang, Shi-Qiang; Shen, Hong-Qiang; Chen, Xue-Jun; Tang, Yong-Min; Yu, Yong-Lin; Mao, Jian-Hua

2016-01-01

Abstract We performed a prospective observational study to evaluate the utility of measuring inflammatory cytokine levels to discriminate bacterial meningitis from similar common pediatric diseases. Inflammatory cytokine levels and other cerebrospinal fluid (CSF) physicochemical indicators were evaluated in 140 patients who were diagnosed with bacterial meningitis via microbiological culture or PCR assay. The CSF concentrations of interleukin (IL)-6 and IL-10, CSF/blood IL-6 and IL-10 ratios, CSF white blood cell count, and CSF micro total protein were significantly elevated in bacterial meningitis patients compared with healthy children or patients with viral encephalitis, epilepsy, or febrile convulsions (P < 0.001). The area under the curve values for CSF concentrations of IL-6 and IL-10, CSF/blood IL-6 and IL-10 ratios, CSF white blood cell count, and CSF micro total protein to identify bacterial meningitis episodes by receiver-operating characteristic analysis were 0.988, 0.949, 0.995, 0.924, 0.945, and 0.928, respectively. The area under the curve for the combination of CSF IL-6 and CSF/blood IL-6 ratio was larger than that for either parameter alone, and the combination exhibited enhanced specificity and positive predictive value. After effective meningitis treatment, CSF IL-6 levels dropped significantly. These results suggest that CSF IL-6 and CSF/blood IL-6 ratio are good biomarkers in discriminating bacterial meningitis. Evaluating CSF IL-6 and CSF/blood IL-6 ratio in combination can improve diagnostic efficiency. Additionally, CSF IL-6 levels can be used to monitor the effects of bacterial meningitis treatment. PMID:27043692

Clinical Value of Assessing Cytokine Levels for the Differential Diagnosis of Bacterial Meningitis in a Pediatric Population.

PubMed

Ye, Qing; Shao, Wen-Xia; Shang, Shi-Qiang; Shen, Hong-Qiang; Chen, Xue-Jun; Tang, Yong-Min; Yu, Yong-Lin; Mao, Jian-Hua

2016-03-01

We performed a prospective observational study to evaluate the utility of measuring inflammatory cytokine levels to discriminate bacterial meningitis from similar common pediatric diseases. Inflammatory cytokine levels and other cerebrospinal fluid (CSF) physicochemical indicators were evaluated in 140 patients who were diagnosed with bacterial meningitis via microbiological culture or PCR assay. The CSF concentrations of interleukin (IL)-6 and IL-10, CSF/blood IL-6 and IL-10 ratios, CSF white blood cell count, and CSF micro total protein were significantly elevated in bacterial meningitis patients compared with healthy children or patients with viral encephalitis, epilepsy, or febrile convulsions (P < 0.001). The area under the curve values for CSF concentrations of IL-6 and IL-10, CSF/blood IL-6 and IL-10 ratios, CSF white blood cell count, and CSF micro total protein to identify bacterial meningitis episodes by receiver-operating characteristic analysis were 0.988, 0.949, 0.995, 0.924, 0.945, and 0.928, respectively. The area under the curve for the combination of CSF IL-6 and CSF/blood IL-6 ratio was larger than that for either parameter alone, and the combination exhibited enhanced specificity and positive predictive value. After effective meningitis treatment, CSF IL-6 levels dropped significantly. These results suggest that CSF IL-6 and CSF/blood IL-6 ratio are good biomarkers in discriminating bacterial meningitis. Evaluating CSF IL-6 and CSF/blood IL-6 ratio in combination can improve diagnostic efficiency. Additionally, CSF IL-6 levels can be used to monitor the effects of bacterial meningitis treatment.

Deregulation of microRNA-181c in cerebrospinal fluid of patients with clinically isolated syndrome is associated with early conversion to relapsing-remitting multiple sclerosis.

PubMed

Ahlbrecht, Jonas; Martino, Filippo; Pul, Refik; Skripuletz, Thomas; Sühs, Kurt-Wolfram; Schauerte, Celina; Yildiz, Özlem; Trebst, Corinna; Tasto, Lars; Thum, Sabrina; Pfanne, Angelika; Roesler, Romy; Lauda, Florian; Hecker, Michael; Zettl, Uwe K; Tumani, Hayrettin; Thum, Thomas; Stangel, Martin

2016-08-01

MiRNA-181c, miRNA-633 and miRNA-922 have been reported to be deregulated in multiple sclerosis. To investigate the association between miRNA-181c, miRNA-633 and miRNA-922 and conversion from clinically isolated syndrome (CIS) to relapsing-remitting multiple sclerosis (RRMS); and to compare microRNAs in cerebrospinal fluid (CSF) and serum with regard to dysfunction of the blood-CSF barrier. CSF and serum miRNA-181c, miRNA-633 and miRNA-922 were retrospectively determined by quantitative real-time polymerase chain reaction in CIS patients with (CIS-RRMS) and without (CIS-CIS) conversion to RRMS within 1 year. Thirty of 58 CIS patients developed RRMS. Cerebrospinal fluid miRNA-922, serum miRNA-922 and cerebrospinal fluid miRNA-181c were significantly higher in CIS-RRMS compared to CIS-CIS (P=0.027, P=0.048, P=0.029, respectively). High levels of cerebrospinal fluid miRNA-181c were independently associated with conversion from CIS to RRMS in multivariate Cox regression analysis (hazard ratio 2.99, 95% confidence interval 1.41-6.34, P=0.005). A combination of high cerebrospinal fluid miRNA-181c, younger age and more than nine lesions on magnetic resonance imaging showed the highest specificity (96%) and positive predictive value (94%) for conversion from CIS to RRMS. MiRNA-181c was higher in serum than in cerebrospinal fluid (P <0.001), while miRNA-633 and miRNA-922 were no different in cerebrospinal fluid and serum. Cerebrospinal fluid/serum albumin quotients did not correlate with microRNAs in cerebrospinal fluid (all P>0.711). Cerebrospinal fluid miRNA-181c might serve as a biomarker for early conversion to RRMS. Moreover, our data suggest an intrathecal origin of microRNAs detected in the cerebrospinal fluid. © The Author(s), 2015.

Intracranial cerebrospinal fluid spaces imaging using a pulse-triggered three-dimensional turbo spin echo MR sequence with variable flip-angle distribution.

PubMed

Hodel, Jérôme; Silvera, Jonathan; Bekaert, Olivier; Rahmouni, Alain; Bastuji-Garin, Sylvie; Vignaud, Alexandre; Petit, Eric; Durning, Bruno; Decq, Philippe

2011-02-01

To assess the three-dimensional turbo spin echo with variable flip-angle distribution magnetic resonance sequence (SPACE: Sampling Perfection with Application optimised Contrast using different flip-angle Evolution) for the imaging of intracranial cerebrospinal fluid (CSF) spaces. We prospectively investigated 18 healthy volunteers and 25 patients, 20 with communicating hydrocephalus (CH), five with non-communicating hydrocephalus (NCH), using the SPACE sequence at 1.5T. Volume rendering views of both intracranial and ventricular CSF were obtained for all patients and volunteers. The subarachnoid CSF distribution was qualitatively evaluated on volume rendering views using a four-point scale. The CSF volumes within total, ventricular and subarachnoid spaces were calculated as well as the ratio between ventricular and subarachnoid CSF volumes. Three different patterns of subarachnoid CSF distribution were observed. In healthy volunteers we found narrowed CSF spaces within the occipital aera. A diffuse narrowing of the subarachnoid CSF spaces was observed in patients with NCH whereas patients with CH exhibited narrowed CSF spaces within the high midline convexity. The ratios between ventricular and subarachnoid CSF volumes were significantly different among the volunteers, patients with CH and patients with NCH. The assessment of CSF spaces volume and distribution may help to characterise hydrocephalus.

[Group A streptococcal meningitis: Streptococcus pneumoniae is not the only one to seep into the CSF fluid leak!].

PubMed

Zappella, N; Barrelet, A; Pangon, B; Laurent, V; Bruneel, F

2013-11-01

We reported a case of group A streptococcal meningitis in a patient with a CSF fluid leak. This case underlined several relevant points: (i) an unfrequent cause of bacterial meningitis; (ii) the main diagnosis to evoke when the direct examination of CSF shows Gram+ cocci with a negative pneumococcal antigen; (iii) that bacteria other than Streptococcus pneumoniae are possible in front of a meningitis associated with a CSF fluif leak. Copyright © 2013 Société française d’anesthésie et de réanimation (Sfar). Published by Elsevier SAS. All rights reserved.

Regulation of cerebrospinal fluid (CSF) flow in neurodegenerative, neurovascular and neuroinflammatory disease.

PubMed

Simon, Matthew J; Iliff, Jeffrey J

2016-03-01

Cerebrospinal fluid (CSF) circulation and turnover provides a sink for the elimination of solutes from the brain interstitium, serving an important homeostatic role for the function of the central nervous system. Disruption of normal CSF circulation and turnover is believed to contribute to the development of many diseases, including neurodegenerative conditions such as Alzheimer's disease, ischemic and traumatic brain injury, and neuroinflammatory conditions such as multiple sclerosis. Recent insights into CSF biology suggesting that CSF and interstitial fluid exchange along a brain-wide network of perivascular spaces termed the 'glymphatic' system suggest that CSF circulation may interact intimately with glial and vascular function to regulate basic aspects of brain function. Dysfunction within this glial vascular network, which is a feature of the aging and injured brain, is a potentially critical link between brain injury, neuroinflammation and the development of chronic neurodegeneration. Ongoing research within this field may provide a powerful new framework for understanding the common links between neurodegenerative, neurovascular and neuroinflammatory disease, in addition to providing potentially novel therapeutic targets for these conditions. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger. Copyright © 2015 Elsevier B.V. All rights reserved.

Attenuated cerebrospinal fluid leukocyte count and sepsis in adults with pneumococcal meningitis: a prospective cohort study

PubMed Central

Weisfelt, Martijn; van de Beek, Diederik; Spanjaard, Lodewijk; Reitsma, Johannes B; de Gans, Jan

2006-01-01

Background A low cerebrospinal fluid (CSF) white-blood cell count (WBC) has been identified as an independent risk factor for adverse outcome in adults with bacterial meningitis. Whereas a low CSF WBC indicates the presence of sepsis with early meningitis in patients with meningococcal infections, the relation between CSF WBC and outcome in patients with pneumococcal meningitis is not understood. Methods We examined the relation between CSF WBC, bacteraemia and sepsis in a prospective cohort study that included 352 episodes of pneumococcal meningitis, confirmed by CSF culture, occurring in patients aged >16 years. Results CSF WBC was recorded in 320 of 352 episodes (91%). Median CSF WBC was 2530 per mm3 (interquartile range 531–6983 per mm3) and 104 patients (33%) had a CSF WBC <1000/mm3. Patients with a CSF WBC <1000/mm3 were more likely to have an unfavourable outcome (defined as a Glasgow Outcome Scale score of 1–4) than those with a higher WBC (74 of 104 [71%] vs. 87 of 216 [43%]; P < 0.001). CSF WBC was significantly associated with blood WBC (Spearman's test 0.29), CSF protein level (0.20), thrombocyte count (0.21), erythrocyte sedimentation rate (-0.15), and C-reactive protein levels (-0.18). Patients with a CSF WBC <1000/mm3 more often had a positive blood culture (72 of 84 [86%] vs. 138 of 196 [70%]; P = 0.01) and more often developed systemic complications (cardiorespiratory failure, sepsis) than those with a higher WBC (53 of 104 [51%] vs. 69 of 216 [32%]; P = 0.001). In a multivariate analysis, advanced age (Odds ratio per 10-year increments 1.22, 95%CI 1.02–1.45), a positive blood culture (Odds ratio 2.46, 95%CI 1.17–5.14), and a low thrombocyte count on admission (Odds ratio per 100,000/mm3 increments 0.67, 95% CI 0.47–0.97) were associated with a CSF WBC <1000/mm3. Conclusion A low CSF WBC in adults with pneumococcal meningitis is related to the presence of signs of sepsis and systemic complications. Invasive pneumococcal infections should possibly be regarded as a continuum from meningitis to sepsis. PMID:17038166

Repair of Spontaneous Cerebrospinal Fluid Otorrhea from Defect of Middle Cranial Fossa

PubMed Central

Goh, Young Bum; Han, Chi-Sung

2013-01-01

Spontaneous cerebrospinal fluid (CSF) otorrhea is defined as CSF otorrhea where there are no identifiable causes including previous trauma, surgery, infection, neoplasm or congenital anomaly. The condition is rare. The origin of CSF leak is commonly a defect in the tegmen of the middle cranial fossa. The pathophysiology of spontaneous CSF otorrhea is unclear. Two theories of the etiology of bony defects of the temporal bone are the congenital bony defect theory and arachnoid granulation theory. The authors experienced a case of a 49-year-old female patient admitted with the complaint of persistent right ear fullness. Computed tomography revealed a large defect of the middle fossa and suspicious CSF otorrhea through the defect of tegmen tympani. Repair was successful with multiple bone chips using the transmastoid approach. The postoperative course was good and there has been no recurrence of the CSF leakage. PMID:24653924

Resistance to outflow of cerebrospinal fluid after central infusions of angiotensin

NASA Technical Reports Server (NTRS)

Morrow, B. A.; Keil, L. C.; Severs, W. B.

1992-01-01

Infusions of artificial cerebrospinal fluid (CSF) into the cerebroventricles of conscious rats can raise CSF pressure (CSFp). This response can be modified by some neuropeptides. One of these, angiotensin, facilitates the rise in CSFp. We measured CSFp in conscious rats with a computerized system and evaluated resistance to CSF outflow during infusion of artificial CSF, with or without angiotensin, from the decay kinetics of superimposed bolus injections. Angiotensin (10 ng/min) raised CSFp (P less than 0.05) compared with solvent, but the resistance to CSF outflow of the two groups was similar (P greater than 0.05). Because CSFp was increased by angiotensin without an increase in the outflow resistance, a change in some volume compartment is likely. Angiotensin may raise CSFp by increasing CSF synthesis; this possibility is supported, since the choroid plexuses contain an intrinsic isorenin-angiotensin system. Alternatively, angiotensin may dilate pial arteries, leading to an increased intracranial blood volume.

Molecular Detection of Leptospira in Two Returned Travelers: Higher Bacterial Load in Cerebrospinal Fluid versus Serum or Plasma

PubMed Central

Waggoner, Jesse J.; Soda, Elizabeth A.; Seibert, Ryan; Grant, Philip; Pinsky, Benjamin A.

2015-01-01

Leptospirosis is a potentially severe illness in returned travelers. Patients often present with fever, headache, and neck pain, which may lead to a workup for meningitis including the acquisition of cerebrospinal fluid (CSF). Although Leptospira DNA has been detected in CSF by polymerase chain reaction (PCR), little data exist regarding the utility of testing CSF in addition to serum or plasma obtained on presentation. In this report, we present two cases of leptospirosis in returned travelers presenting with fever and headache. Our first patient had neutrophilic meningitis, and Leptospira was detectable only in CSF obtained on admission. The second patient had a normal CSF profile, but Leptospira was detected in CSF at a bacterial load 5- to 10-fold higher than that in plasma. CSF is an important specimen for the diagnosis of Leptospira by molecular methods and may yield an actionable diagnosis in the absence of leptospiremia. PMID:26033024

Cerebrospinal Fluid HIV Escape from Antiretroviral Therapy.

PubMed

Ferretti, Francesca; Gisslen, Magnus; Cinque, Paola; Price, Richard W

2015-06-01

CNS infection is a nearly constant facet of systemic CNS infection and is generally well controlled by suppressive systemic antiretroviral therapy (ART). However, there are instances when HIV can be detected in the cerebrospinal fluid (CSF) despite suppression of plasma viruses below the clinical limits of measurement. We review three types of CSF viral escape: asymptomatic, neuro-symptomatic, and secondary. The first, asymptomatic CSF escape, is seemingly benign and characterized by lack of discernable neurological deterioration or subsequent CNS disease progression. Neuro-symptomatic CSF escape is an uncommon, but important, entity characterized by new or progressive CNS disease that is critical to recognize clinically because of its management implications. Finally, secondary CSF escape, which may be even more uncommon, is defined by an increase of CSF HIV replication in association with a concomitant non-HIV infection, as a consequence of the local inflammatory response. Understanding these CSF escape settings not only is important for clinical diagnosis and management but also may provide insight into the CNS HIV reservoir.

BNP and NT-proBNP Test

MedlinePlus

... Free Fetal DNA Cerebrospinal Fluid (CSF) Analysis Ceruloplasmin Chemistry Panels Chickenpox and Shingles Tests Chlamydia Testing Chloride ... 488-95. William Clarke. Contemporary Practice in Clinical Chemistry, 2nd Edition Paperback – February 4, 2011. ISBN-13: ...

Quantifying the influence of respiration and cardiac pulsations on cerebrospinal fluid dynamics using real-time phase-contrast MRI.

PubMed

Yildiz, Selda; Thyagaraj, Suraj; Jin, Ning; Zhong, Xiaodong; Heidari Pahlavian, Soroush; Martin, Bryn A; Loth, Francis; Oshinski, John; Sabra, Karim G

2017-08-01

To validate a real-time phase contrast magnetic resonance imaging (RT-PCMRI) sequence in a controlled phantom model, and to quantify the relative contributions of respiration and cardiac pulsations on cerebrospinal fluid (CSF) velocity at the level of the foramen magnum (FM). To validate the 3T MRI techniques, in vitro studies used a realistic model of the spinal subarachnoid space driven by pulsatile flow waveforms mimicking the respiratory and cardiac components of CSF flow. Subsequently, CSF flow was measured continuously during 1-minute RT-PCMRI acquisitions at the FM while healthy subjects (N = 20) performed natural breathing, deep breathing, breath-holding, and coughing. Conventional cardiac-gated PCMRI was obtained for comparison. A frequency domain power ratio analysis determined the relative contribution of respiration versus cardiac ([r/c]) components of CSF velocity. In vitro studies demonstrating the accuracy of RT-PCMRI within 5% of input values showed that conventional PCMRI measures only the cardiac component of CSF velocity (0.42 ± 0.02 cm/s), averages out respiratory effects, and underestimates the magnitude of CSF velocity (0.96 ± 0.07 cm/s). In vivo RT-PCMRI measurements indicated the ratio of respiratory to cardiac velocity pulsations averaged over all subjects as [r/c = 0.14 ± 0.27] and [r/c = 0.40 ± 0.47] for natural and deep breathing, respectively. During coughing, the peak CSF velocity increased by a factor of 2.27 ± 1.40. RT-PCMRI can noninvasively measure instantaneous CSF velocity driven by cardiac pulsations, respiration, and coughing in real time. A comparable contribution of respiration and cardiac pulsations on CSF velocity was found during deep breathing but not during natural breathing. 1 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2017;46:431-439. © 2017 International Society for Magnetic Resonance in Medicine.

Diagnosis of central nervous system relapse of pediatric acute lymphoblastic leukemia: Impact of routine cytological CSF analysis at the time of intrathecal chemotherapy.

PubMed

Gassas, Adam; Krueger, Joerg; Alvi, Saima; Sung, Lillian; Hitzler, Johanne; Lieberman, Lani

2014-12-01

Despite the success of central nervous system (CNS) directed therapy in pediatric acute lymphoblastic leukemia (ALL), relapse involving the CNS continues to be observed in 5-10% of children when utilizing standard intrathecal prophylactic chemotherapy. While most pediatric ALL treatment protocols mandate regular lumbar punctures (LP) for the intrathecal injection of chemotherapy, the value of routine cytological analysis of cerebrospinal fluid (CSF) during therapy is unknown. Our objective was to assess the diagnostic value of routine CSF analysis during ALL therapy. To allow for at least 10 years of follow up from ALL diagnosis, children (0-18 years) with ALL diagnosed and treated at SickKids, Toronto, Canada between 1994-2004 were studied. Medical records of patients with CNS relapse were examined to determine whether CNS relapse was diagnosed based on cytology of a routinely obtained CSF sample, a CSF sample obtained because of signs and symptoms or a CSF sample obtained after the diagnosis of a bone marrow relapse. Of 494 children treated for ALL, 31 (6.6%) developed a relapse of ALL involving the CNS. Twenty-two had an isolated CNS relapse and nine had a combined bone marrow and CNS relapse. Among patients with isolated CNS relapse, 73% (16/22) were diagnosed based on routine CSF samples obtained from asymptomatic children. Conversely, 89% (8/9) of children with combined bone marrow and CNS relapse presented with symptoms and signs that prompted CSF examination. Routine CSF examination at the time of LP for intrathecal chemotherapy is useful in detecting CNS relapse. © 2014 Wiley Periodicals, Inc.

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.

Clinical characteristics of patients with central nervous system relapse in BCR-ABL1-positive acute lymphoblastic leukemia: the importance of characterizing ABL1 mutations in cerebrospinal fluid.

PubMed

Sanchez, Ricardo; Ayala, Rosa; Alonso, Rafael Alberto; Martínez, María Pilar; Ribera, Jordi; García, Olga; Sanchez-Pina, José; Mercadal, Santiago; Montesinos, Pau; Martino, Rodrigo; Barba, Pere; González-Campos, José; Barrios, Manuel; Lavilla, Esperanza; Gil, Cristina; Bernal, Teresa; Escoda, Lourdes; Abella, Eugenia; Amigo, Ma Luz; Moreno, Ma José; Bravo, Pilar; Guàrdia, Ramón; Hernández-Rivas, Jesús-María; García-Guiñón, Antoni; Piernas, Sonia; Ribera, José-María; Martínez-López, Joaquín

2017-07-01

We investigated the frequency, predictors, and evolution of acute lymphoblastic leukemia (ALL) in patients with CNS relapse and introduced a novel method for studying BCR-ABL1 protein variants in cDNA from bone marrow (BM) and cerebrospinal fluid (CSF) blast cells. A total of 128 patients were analyzed in two PETHEMA clinical trials. All achieved complete remission after imatinib treatment. Of these, 30 (23%) experienced a relapse after achieving complete remission, and 13 (10%) had an isolated CNS relapse or combined CNS and BM relapses. We compared the characteristics of patients with and without CNS relapse and further analyzed CSF and BM samples from two of the 13 patients with CNS relapse. In both patients, classical sequencing analysis of the kinase domain of BCR-ABL1 from the cDNA of CSF blasts revealed the pathogenic variant p.L387M. We also performed ultra-deep next-generation sequencing (NGS) in three samples from one of the relapsed patients. We did not find the mutation in the BM sample, but we did find it in CSF blasts with 45% of reads at the time of relapse. These data demonstrate the feasibility of detecting BCR-ABL1 mutations in CSF blasts by NGS and highlight the importance of monitoring clonal evolution over time.

Simultaneous measurement of monoamine metabolites and 5-methyltetrahydrofolate in the cerebrospinal fluid of children.

PubMed

Akiyama, Tomoyuki; Hayashi, Yumiko; Hanaoka, Yoshiyuki; Shibata, Takashi; Akiyama, Mari; Nakamura, Kazuyuki; Tsuyusaki, Yu; Kubota, Masaya; Yoshinaga, Harumi; Kobayashi, Katsuhiro

2017-02-01

We describe a new method for simultaneous measurement of monoamine metabolites (3-O-methyldopa [3-OMD], 3-methoxy-4-hydroxyphenylethyleneglycol [MHPG], 5-hydroxyindoleacetic acid [5-HIAA], and homovanillic acid [HVA]) and 5-methyltetrahydrofolate (5-MTHF) and its use on cerebrospinal fluid (CSF) samples from pediatric patients. Monoamine metabolites and 5-MTHF were measured by high-performance liquid chromatography with fluorescence detection. CSF samples were prospectively collected from children according to a standardized collection protocol in which the first 1-ml fraction was used for analysis. Monoamine metabolites and 5-MTHF were separated within 10min. They showed linearity from the limit of detection to 1024nmol/l. The limit of quantification of each metabolite was sufficiently low for the CSF sample assay. In 42 CSF samples after excluding cases with possibly altered neurotransmitter profiles, the concentrations of 3-OMD, MHPG, 5-HIAA, HVA, and 5-MTHF showed significant age dependence and their ranges were comparable with the reference values in the literature. The metabolite profiles of aromatic l-amino acid decarboxylase deficiency, Segawa disease, and folate receptor α defect by this method were compatible with those in the literature. This method is a simple means of measuring CSF monoamine metabolites and 5-MTHF, and is especially useful for laboratories not equipped with electrochemical detectors. Copyright © 2016 Elsevier B.V. All rights reserved.

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%.

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.

An Example of Genetically Distinct HIV Type 1 Variants in Cerebrospinal Fluid and Plasma During Suppressive Therapy

PubMed Central

Dahl, Viktor; Gisslen, Magnus; Hagberg, Lars; Peterson, Julia; Shao, Wei; Spudich, Serena; Price, Richard W.; Palmer, Sarah

2014-01-01

We sequenced the genome of human immunodeficiency virus type 1 (HIV-1) recovered from 70 cerebrospinal fluid (CSF) specimens and 29 plasma samples and corresponding samples obtained before treatment initiation from 17 subjects receiving suppressive therapy. More CSF sequences than plasma sequences were hypermutants. We determined CSF sequences and plasma sequences in specimens obtained from 2 subjects after treatment initiation. In one subject, we found genetically distinct CSF and plasma sequences, indicating that they came from HIV-1 from 2 different compartments, one potentially the central nervous system, during suppressive therapy. In addition, there was little evidence of viral evolution in the CSF during therapy, suggesting that continuous virus replication is not the major cause of viral persistence in the central nervous system. PMID:24338353

An example of genetically distinct HIV type 1 variants in cerebrospinal fluid and plasma during suppressive therapy.

PubMed

Dahl, Viktor; Gisslen, Magnus; Hagberg, Lars; Peterson, Julia; Shao, Wei; Spudich, Serena; Price, Richard W; Palmer, Sarah

2014-05-15

We sequenced the genome of human immunodeficiency virus type 1 (HIV-1) recovered from 70 cerebrospinal fluid (CSF) specimens and 29 plasma samples and corresponding samples obtained before treatment initiation from 17 subjects receiving suppressive therapy. More CSF sequences than plasma sequences were hypermutants. We determined CSF sequences and plasma sequences in specimens obtained from 2 subjects after treatment initiation. In one subject, we found genetically distinct CSF and plasma sequences, indicating that they came from HIV-1 from 2 different compartments, one potentially the central nervous system, during suppressive therapy. In addition, there was little evidence of viral evolution in the CSF during therapy, suggesting that continuous virus replication is not the major cause of viral persistence in the central nervous system.

Cerebrospinal fluid as a reflector of central cholinergic and amino acid neurotransmitter activity in cerebellar ataxia.

PubMed

Manyam, B V; Giacobini, E; Ferraro, T N; Hare, T A

1990-11-01

Cerebrospinal fluid (CSF) amino acid neurotransmitters, related compounds, and their precursors, choline levels, and acetylcholinesterase activity were measured in the CSF of patients with cerebellar ataxia during a randomized, double-blind, crossover, placebo-controlled clinical trial of physostigmine salicylate. The CSF gamma-aminobutyric acid, methionine, and choline levels, adjusted for age, were significantly lower in patients with cerebellar ataxia compared with controls. Physostigmine selectively reduced the level of CSF isoleucine and elevated the levels of phosphoethanolamine. No change occurred in CSF acetylcholinesterase activity and in the levels of plasma amino compounds in patients with cerebellar ataxia when compared with controls. Median ataxia scores did not statistically differ between placebo and physostigmine nor did functional improvement occur in any of the patients.

Letter to the editor: Identification of Sarcocystis capracanis in cerebrospinal fluid from sheep with neurological disease

USDA-ARS?s Scientific Manuscript database

A recent report (Formisano et al., 2013) identified clinical sacrocystosis in 2 adult sheep. The diagnosis relied primarily on characterization of DNA extracted from cerebrospinal fluid (CSF) and paraffin-embedded heart tissue. Parasites identified as merozoites were identified in CSF smears stained...

Bioanalytical method development and validation for the determination of glycine in human cerebrospinal fluid by ion-pair reversed-phase liquid chromatography-tandem mass spectrometry.

PubMed

Jiang, Jian; James, Christopher A; Wong, Philip

2016-09-05

A LC-MS/MS method has been developed and validated for the determination of glycine in human cerebrospinal fluid (CSF). The validated method used artificial cerebrospinal fluid as a surrogate matrix for calibration standards. The calibration curve range for the assay was 100-10,000ng/mL and (13)C2, (15)N-glycine was used as an internal standard (IS). Pre-validation experiments were performed to demonstrate parallelism with surrogate matrix and standard addition methods. The mean endogenous glycine concentration in a pooled human CSF determined on three days by using artificial CSF as a surrogate matrix and the method of standard addition was found to be 748±30.6 and 768±18.1ng/mL, respectively. A percentage difference of -2.6% indicated that artificial CSF could be used as a surrogate calibration matrix for the determination of glycine in human CSF. Quality control (QC) samples, except the lower limit of quantitation (LLOQ) QC and low QC samples, were prepared by spiking glycine into aliquots of pooled human CSF sample. The low QC sample was prepared from a separate pooled human CSF sample containing low endogenous glycine concentrations, while the LLOQ QC sample was prepared in artificial CSF. Standard addition was used extensively to evaluate matrix effects during validation. The validated method was used to determine the endogenous glycine concentrations in human CSF samples. Incurred sample reanalysis demonstrated reproducibility of the method. Copyright © 2016 Elsevier B.V. All rights reserved.

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.
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Cerebrospinal Fluid Leak at Percutaneous Exit of Ventricular Catheter as a Crucial Risk Factor for External Ventricular Drainage-Related Infection in Adult Neurosurgical Patients.

PubMed

Park, Jaechan; Choi, Yeon-Ju; Ohk, Boram; Chang, Hyun-Ha

2018-01-01

The placement of a ventricular catheter for temporary cerebrospinal fluid (CSF) diversion is associated with a considerable risk of CSF infection. The authors investigated the effect of a CSF leak on CSF-related infection and the predisposing factors for a CSF leak. Fifty-two patients who underwent external ventricular drainage (EVD) for acute hydrocephalus associated with a subarachnoid hemorrhage or intraventricular hemorrhage (IVH) were enrolled in this prospective study. A CSF leak-detection paper (small sterilized filter paper) was applied at the percutaneous catheter exit site to check for any bloody CSF leak. In addition, radiologic and clinical data were collected. Four of the 52 patients (7.7%) developed an EVD-related CSF infection from organisms including Staphylococcus epidermidis (n = 3) and Staphylococcus hominis (n = 1). A prolonged CSF leak >1 day was detected in 9 patients (17.3%) and revealed as a significant risk factor for CSF infection with a 44.4% positive predictive value. Moreover, an IVH >10 mL was found in 11 patients (21.2%) and revealed as a significant predisposing factor for a CSF leak at the percutaneous catheter exit. A prolonged CSF leak for >1 day at the percutaneous catheter exit site is a crucial risk factor for EVD-related CSF infection and an IVH >10 mL is a predisposing factor for a CSF leak. Copyright © 2017 Elsevier Inc. All rights reserved.

CXCL13 as a Cerebrospinal Fluid Marker for Neurosyphilis in HIV-infected Patients with Syphilis

PubMed Central

Marra, Christina M.; Tantalo, Lauren C.; Sahi, Sharon K.; Maxwell, Clare L.; Lukehart, Sheila A.

2010-01-01

Background Asymptomatic neurosyphilis is more difficult to diagnose in HIV-infected patients because HIV itself can cause cerebrospinal fluid (CSF) pleocytosis. The proportion of CSF lymphocytes that are B cells is elevated in neurosyphilis, suggesting that the CSF concentration of the B cell chemoattractant, chemokine (C-X-C motif) ligand 13 (CXCL13) concentration may also be elevated. Methods CSF and blood were collected from 199 HIV-infected patients with syphilis and neurosyphilis. Serum and CSF CXCL13 concentrations were determined. Results Patients with neurosyphilis had higher CSF and serum CXCL13 concentrations compared to patients with syphilis but not neurosyphilis. The odds of having symptomatic neurosyphilis were increased by 2.23 fold for every log increase in CSF CXCL13 concentration and were independent of CSF WBC and plasma HIV RNA concentrations, peripheral blood CD4+ T cell count and use of antiretroviral medications. A cut-off of 10 pg/mL CSF CXCL13 had high sensitivity and a cut-off of 250 pg/mL or evidence of intrathecal synthesis of CXCL13 had high specificity for diagnosis of both symptomatic and asymptomatic neurosyphilis. CSF concentrations of CXCL13 declined after treatment for neurosyphilis. Conclusions CSF CXCL13 concentration may be particularly useful for diagnosis of neurosyphilis in HIV-infected patients because it is independent of CSF pleocytosis and markers of HIV disease. PMID:20393380

Comparison of the Cerebrospinal Fluid (CSF) Toluidine Red Unheated Serum Test and the CSF Rapid Plasma Reagin Test with the CSF Venereal Disease Research Laboratory Test for Diagnosis of Neurosyphilis among HIV-Negative Syphilis Patients in China

PubMed Central

Zhu, Lin; Gu, Xin; Peng, Rui-Rui; Wang, Cuini; Gao, Zixiao; Gao, Ying; Shi, Mei; Guan, Zhifang; Seña, Arlene C.

2014-01-01

In this study, we aimed to investigate the performance of nontreponemal antibody tests in cerebrospinal fluid (CSF) specimens from syphilis patients. From September 2009 to September 2012, CSF specimens were collected at the Shanghai Skin Disease Hospital in Shanghai, China, from 1,132 syphilis patients without HIV infection, including 154 with symptomatic and 56 with asymptomatic neurosyphilis. All of the CSF specimens underwent testing with a rapid plasma reagin (RPR) test, an RPR-V (commercial RPR antigen diluted 1:2 in 10% saline) test, the toluidine red unheated serum test (TRUST), and the Venereal Disease Research Laboratory (VDRL) test. Specificities, sensitivities, positive predictive values (PPVs), negative predictive values (NPVs), and kappa values were calculated to determine the performances of the tests. We compared results of the CSF-VDRL, CSF-RPR, CSF-RPR-V, and CSF-TRUST among patients with symptomatic and asymptomatic neurosyphilis who had reactive CSF-Treponema pallidum particle agglutination (TPPA) test results. Overall, the CSF-VDRL test was reactive in 261 patients (23.1%). There were no cases in which the CSF-VDRL was nonreactive and CSF-RPR, CSF-RPR-V, or CSF-TRUST was reactive. Agreement between the results of CSF-TRUST and CSF-RPR was almost perfect (κ = 0.861), with substantial agreement between the results of CSF-RPR and CSF-RPR-V (κ = 0.740). The sensitivities of CSF-VDRL, CSF-RPR, CSF-RPR-V, and CSF-TRUST were 81.4%, 76.2%, 79.5%, and 76.2%, respectively. Compared to CSF-VDRL, CSF-RPR, CSF-RPR-V, and CSF-TRUST had comparable PPVs and NPVs. However, the specificity of CSF-VDRL (90.3%) was significantly lower than those of the other tests (92.7 to 93.4%). Therefore, CSF-RPR, CSF-RPR-V, and CSF-TRUST can be considered alternative tests for neurosyphilis diagnosis in HIV-negative populations, particularly when the CSF-VDRL is not available. PMID:24335955

The diagnostic value of cerebrospinal fluid lactate for post-neurosurgical bacterial meningitis: a meta-analysis.

PubMed

Xiao, Xiong; Zhang, Yang; Zhang, Liwei; Kang, Peng; Ji, Nan

2016-09-13

Bacterial meningitis is not rare in post-neurosurgical patients. If patients are not treated promptly, the mortality rate can reach 20 to 50 %. The concentration of cerebrospinal fluid (CSF) lactate has been reported to be helpful in the diagnosis of bacterial meningitis; however, no systematic evaluations have investigated CSF from a postoperative perspective. In this study, we performed a systematic evaluation and meta-analysis of the efficacy of using CSF lactate concentrations in the diagnosis of post-neurosurgical bacterial meningitis. We retrieved studies that investigated the diagnostic value of CSF lactate for the diagnosis of post-neurosurgical bacterial meningitis by searching PubMed, EBSCO, the Cochrane Library and ClinicalTrials.gov. All these databases were searched from inception to November 2015. We used Quality Assessment of Diagnostic Accuracy Studies (QUADAS), a tool for the quality assessment of diagnostic accuracy, to evaluate the quality of the included studies. The Meta-DiSc 1.4 and Review Manager 5.3 software programs were used to analyze the included studies. Forest plots and summary receiver operating characteristics (SROC) curves were also drawn. Five studies, involving a total of 404 post-neurosurgical patients, were selected from 1,672 articles according to the inclusion criteria. The quality of the five included studies was assessed using QUADAS, and the related results are presented in tables. The meta-analysis revealed the following diagnostic values regarding CSF lactate for post-neurosurgical bacterial meningitis: a pooled sensitivity of 0.92 (95 % CI 0.85-0.96), a pooled specificity of 0.88 (95 % CI 0.84-0.92 with significant heterogeneity), a diagnostic odds ratio of 83.09 (95 % CI 36.83-187.46), an area under the curve (AUCSROC) of 0.9601, an SE(AUC) of 0.0122, a Q* of 0.9046 and an SE(Q*) of 0.0179. The meta-analysis indicated that the CSF lactate concentration has relatively high sensitivity and specificity for the diagnosis of post-neurosurgical bacterial meningitis and thus has relatively good efficacy.

[Neopterin in serum and cerebrospinal fluid in Lyme disease].

PubMed

Biesiada, Grazyna; Czepiel, Jacek; Garlicki, Aleksander; Mach, Tomasz

2009-01-01

Lyme disease is a multiorgan disease, caused by spirochetes of Borrelia species. Clinical picture is diverse, borreliosis can affect skin, nervous system, musculoskeletal system and heart. Neopterin is a marker of cytotoxic lymphocytes T activities, it is produced by monocytes/macrophages stimulated with IFNgamma. The aim of our study was to evaluate the level of neopterin in serum and cerebrospinal fluid in borreliosis and correlate it with the symptoms, markers of inflammation in cerebrospinal fluid (CSF), and serological tests against Borrelia burgdorferi. We have enrolled in the study 39 patients treated for Lyme borreliosis. The level of neopterin in serum was assessed in all patients, among patient with suspicion of neuroborreliosis (n = 33) we assessed the level of neopterin, protein, glucose and chlorium in CSF. The level of neopterin in CSF was lower among patients who were treated due to presence of erithema migrans in their past regarding patients who had never had erithema migrans (p = 0.008). The level of neopterin in CSF was higher (6.6 nmol/l) in patients with the presence of inflammation in CSF versus patients with no changes in CSF (3.8 mmol/l; p = 0.019). There was no correlation between neopterin in serum or CSF and Westernblot test. Patients with neuroborreliosis who had lymphocytic meningitis had higher level of neopterin in CSF. We suggest the role of neopterin in pathogenesis on neuroborreliosis. Neopterin as a marker of cytotoxic lymphocytes T activities can be useful in borreliosis diagnosis but more studies regarding this problem should be done.

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

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

Effects of Risperidone and Galantamine Treatment on Alzheimer's Disease Biomarker Levels in Cerebrospinal Fluid.

PubMed

Bloniecki, Victor; Aarsland, Dag; Blennow, Kaj; Cummings, Jeffrey; Falahati, Farshad; Winblad, Bengt; Freund-Levi, Yvonne

2017-01-01

Treatment for neuropsychiatric symptoms (NPS) in dementia is insufficient. Antipsychotics and acetylcholinesterase inhibitors are used generating symptomatic improvements in behavior and cognition, but few studies have investigated their effect on Alzheimer's disease (AD) biomarkers in cerebrospinal fluid (CSF). This is a secondary analysis based on an earlier clinical trial comparing the treatment effects on NPS. The aim of this study was to examine whether treatment with risperidone and galantamine affect levels of the biomarkers T-Tau, P-Tau, Aβ1-42, and Aβ42/40-ratio in CSF. The secondary aim was to test if baseline levels of these biomarkers are associated with the clinical course of NPS. 83 patients (mean + SD 77.9.6±7.7 years) with dementia and NPS were randomized to galantamine (n = 44) or risperidone (n = 39) treatment. CSF samples were collected at baseline and after 12 weeks. Changes in levels of biomarkers between the two treatment groups did not differ significantly. Low baseline levels of Aβ1 - 42 was significantly associated with reduction of irritability at follow up. Low baseline levels of Aβ1-42, Aβ42/40, and P-Tau were significant correlates of reduction in appetite and eating disorders. CSF Aβ1-42 levels in patients treated with risperidone were significantly decreased at follow up, showing an 8% (40 pg/mL) reduction as compared with baseline (p = 0.03). Our results suggest that risperidone may affect the CSF profile of AD biomarkers indicating more amyloid pathology. Treatment with galantamine did not affect the CSF biomarkers in any direction. The AD CSF biomarkers displayed correlations with specific NPS suggesting potential research questions to be pursued.

Factors impacting cerebrospinal fluid leak rates in endoscopic sellar surgery.

PubMed

Karnezis, Tom T; Baker, Andrew B; Soler, Zachary M; Wise, Sarah K; Rereddy, Shruthi K; Patel, Zara M; Oyesiku, Nelson M; DelGaudio, John M; Hadjipanayis, Constantinos G; Woodworth, Bradford A; Riley, Kristen O; Lee, John; Cusimano, Michael D; Govindaraj, Satish; Psaltis, Alkis; Wormald, Peter John; Santoreneos, Steve; Sindwani, Raj; Trosman, Samuel; Stokken, Janalee K; Woodard, Troy D; Recinos, Pablo F; Vandergrift, W Alexander; Schlosser, Rodney J

2016-11-01

In patients undergoing transnasal endoscopic sellar surgery, an analysis of risk factors and predictors of intraoperative and postoperative cerebrospinal fluid leak (CSF) would provide important prognostic information. A retrospective review of patients undergoing endoscopic sellar surgery for pituitary adenomas or craniopharyngiomas between 2002 and 2014 at 7 international centers was performed. Demographic, comorbidity, and tumor characteristics were evaluated to determine the associations between intraoperative and postoperative CSF leaks. Correlations between reconstructive and CSF diversion techniques were associated with postoperative CSF leak rates. Odds ratios (OR) were identified using a multivariate logistic regression model. Data were collected on 1108 pituitary adenomas and 53 craniopharyngiomas. Overall, 30.1% of patients had an intraoperative leak and 5.9% had a postoperative leak. Preoperative factors associated with increased intraoperative leaks were mild liver disease, craniopharyngioma, and extension into the anterior cranial fossa. In patients with intraoperative CSF leaks, postoperative leaks occurred in 10.3%, with a higher postoperative leak rate in craniopharyngiomas (20.8% vs 5.1% in pituitary adenomas). Once an intraoperative leak occurred, craniopharyngioma (OR = 4.255, p = 0.010) and higher body mass index (BMI) predicted postoperative leak (OR = 1.055, p = 0.010). In patients with an intraoperative leak, the use of septal flaps reduced the occurrence of postoperative leak (OR = 0.431, p = 0.027). Rigid reconstruction and CSF diversion techniques did not impact postoperative leak rates. Intraoperative CSF leaks can occur during endoscopic sellar surgery, especially in larger tumors or craniopharyngiomas. Once an intraoperative leak occurs, risk factors for postoperative leaks include craniopharyngiomas and higher BMI. Use of septal flaps decreases this risk. © 2016 ARS-AAOA, LLC.

Biological false-positive venereal disease research laboratory test in cerebrospinal fluid in the diagnosis of neurosyphilis - a case-control study.

PubMed

Zheng, S; Lin, R J; Chan, Y H; Ngan, C C L

2018-03-01

There is no clear consensus on the diagnosis of neurosyphilis. The Venereal Disease Research Laboratory (VDRL) test from cerebrospinal fluid (CSF) has traditionally been considered the gold standard for diagnosing neurosyphilis but is widely known to be insensitive. In this study, we compared the clinical and laboratory characteristics of true-positive VDRL-CSF cases with biological false-positive VDRL-CSF cases. We retrospectively identified cases of true and false-positive VDRL-CSF across a 3-year period received by the Immunology and Serology Laboratory, Singapore General Hospital. A biological false-positive VDRL-CSF is defined as a reactive VDRL-CSF with a non-reactive Treponema pallidum particle agglutination (TPPA)-CSF and/or negative Line Immuno Assay (LIA)-CSF IgG. A true-positive VDRL-CSF is a reactive VDRL-CSF with a concordant reactive TPPA-CSF and/or positive LIA-CSF IgG. During the study period, a total of 1254 specimens underwent VDRL-CSF examination. Amongst these, 60 specimens from 53 patients tested positive for VDRL-CSF. Of the 53 patients, 42 (79.2%) were true-positive cases and 11 (20.8%) were false-positive cases. In our setting, a positive non-treponemal serology has 97.6% sensitivity, 100% specificity, 100% positive predictive value and 91.7% negative predictive value for a true-positive VDRL-CSF based on our laboratory definition. HIV seropositivity was an independent predictor of a true-positive VDRL-CSF. Biological false-positive VDRL-CSF is common in a setting where patients are tested without first establishing a serological diagnosis of syphilis. Serological testing should be performed prior to CSF evaluation for neurosyphilis. © 2017 European Academy of Dermatology and Venereology.

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.

Neuroactive steroid levels in plasma and cerebrospinal fluid of male multiple sclerosis patients.

PubMed

Caruso, Donatella; Melis, Marta; Fenu, Giuseppe; Giatti, Silvia; Romano, Simone; Grimoldi, Maria; Crippa, Donatella; Marrosu, Maria Giovanna; Cavaletti, Guido; Melcangi, Roberto Cosimo

2014-08-01

Neuroactive steroid family includes molecules synthesized in peripheral glands (i.e., hormonal steroids) and directly in the nervous system (i.e., neurosteroids) which are key regulators of the nervous function. As already reported in clinical and experimental studies, neurodegenerative diseases affect the levels of neuroactive steroids. However, a careful analysis comparing the levels of these molecules in cerebrospinal fluid (CSF) and in plasma of multiple sclerosis (MS) patients is still missing. To this aim, the levels of neuroactive steroids were evaluated by liquid chromatography-tandem mass spectrometry in CSF and plasma of male adults affected by Relapsing-Remitting MS and compared with those collected in control patients. An increase in pregnenolone and isopregnanolone levels associated with a decrease in progesterone metabolites, dihydroprogesterone, and tetrahydroprogesterone was observed in CSF of MS patients. Moreover, an increase of 5α-androstane-3α,17β-diol and of 17β-estradiol levels associated with a decrease of dihydrotestosterone also occurred. In plasma, an increase in pregnenolone, progesterone, and dihydrotestosterone and a decrease in dihydroprogesterone and tetrahydroprogesterone levels were reported. This study shows for the first time that the levels of several neuroactive steroids, and particularly those of progesterone and testosterone metabolites, are deeply affected in CSF of relapsing-remitting MS male patients. We here demonstrated that, the cerebrospinal fluid and plasma levels of several neuroactive steroids are modified in relapsing remitting multiple sclerosis male patients. Interestingly, we reported for the first time that, the levels of progesterone and testosterone metabolites are deeply affected in cerebrospinal fluid. These findings may have an important relevance in therapeutic and/or diagnostic field of multiple sclerosis. © 2014 International Society for Neurochemistry.

Infections in the differential diagnosis of Bell's palsy: a plea for performing CSF analysis.

PubMed

Henkel, Katrin; Lange, Peter; Eiffert, Helmut; Nau, Roland; Spreer, Annette

2017-04-01

Peripheral facial nerve palsy (FP) is the most common single nerve affection. Most cases are idiopathic, but a relevant fraction is caused by potentially treatable aetiologies including infections. Not all current diagnosis and treatment guidelines recommend routine cerebrospinal fluid (CSF) analysis in the diagnostic workup of this symptom. In this study, we evaluated frequency of aetiologies and relevance of CSF analysis in an interdisciplinary cohort. We retrospectively analysed all cases of newly diagnosed FP treated at a German university medical centre in a 3-year period. Diagnostic certainty was classified for infectious aetiologies according to clinical and CSF parameters. 380 patients with FP were identified, 63 children and 317 adults. Idiopathic Bell´s palsy was predominant in 61 %. 25 % of FP was attributed to infections, and other causes were identified in 14 %. Clinical presentation alone was not conclusive for infectious aetiology, in almost half of patients with infection-attributed FP the reported symptoms or clinical signs did not differ from common symptoms of idiopathic Bell`s palsy. Determination of C-reactive protein or white blood cell count was not helpful in the identification of infectious causes, and radiological imaging was performed in a high proportion of adult patients without conclusive results. Nuchal rigidity was found only in 7 % of patients with CSF pleocytosis. The predominant infectious agents were Borrelia burgdorferi, VZV and HSV, and in most of these cases diagnosis relied on the findings of CSF analysis. This study outlines the importance of careful differential diagnosis to identify infectious causes of facial nerve palsy. The high incidence and frequent unspecific clinical presentation of infectious FP underlines the importance of including CSF analysis in the diagnostic routine workup of FP.

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

Comparison of ventricular and lumbar cerebrospinal fluid T cells in non-inflammatory neurological disorder (NIND) patients.

PubMed

Provencio, J Javier; Kivisäkk, Pia; Tucky, Barbara H; Luciano, Mark G; Ransohoff, Richard M

2005-06-01

The aim of the present study was to define the cellular composition of ventricular, as compared with lumbar, cerebrospinal fluid (CSF) in patients with non-inflammatory neurological disorders (NIND). We addressed this issue by determining the cellular composition of lumbar CSF from patients with normal pressure hydrocephalus (NPH) who were undergoing lumbar CSF drainage during evaluation for shunting procedures, and evaluating ventricular CSF from a subset of these who underwent subsequent placement of ventriculoperitoneal shunts. We determined the cellular composition of lumbar CSF from 18 patients with NPH, and found that the leukocyte differentials, and relative proportions of CD4+ and CD8+ central memory (TCM), effector memory (TEM) and naive cell (TNaive) populations, were equivalent to those found previously in studies of CSF from patients with NIND. We further evaluated cells in the ventricular CSF of five patients who had previously undergone lumbar drainage. Leukocyte differential counts, as well as CD4+ and CD8+ TCM, TEM, and TNaive proportions, were equivalent in matched ventricular and lumbar CSF samples. These observations support the hypothesis that leukocytes enter the CSF in a selective fashion, at its site of formation in the choroid plexus. The results implicate CSF T cells in the immune surveillance of the central nervous system.

CSF glucose test

MedlinePlus

Glucose test - CSF; Cerebrospinal fluid glucose test ... The glucose level in the CSF should be 50 to 80 mg/100 mL (or greater than 2/3 ... Abnormal results include higher and lower glucose levels. Abnormal ... or fungus) Inflammation of the central nervous system Tumor

Early post-operative cerebrospinal fluid hypovolemia: Report of 7 cases.

PubMed

Hou, Kun; Zhu, Xiaobo; Zhang, Yang; Gao, Xianfeng; Suo, Shihuan; Zhao, Jinchuan; Li, Guichen

2018-06-01

Cerebrospinal fluid (CSF) hypovolemia is a common neurosurgical condition, which may be spontaneous or iatrogenic. At our institution, a substantial number of the reported cases of early post-operative CSF hypovolemia were identified to have unintentional or unrecognized post-operative continuous excessive CSF leakage. Cases who presented with post-operative CSF hypovolemia several days after uneventful intracranial surgeries without continuous CSF leakage were rarely reported. A retrospective review of the medical records of these patients was performed to identify those patients who developed early post-operative CSF hypovolemia without the presence of post-operative continuous CSF leakage. A total of 7 patients, 5 of which were males, were identified in this retrospective study. They experienced CSF hypovolemia between days 1 and 7 after emergency or scheduled intracranial surgeries. Ventricular collapse, cisternal effacement and midline shift are the most common radiological observations. With early diagnosis and management, 4 of the patients achieved a Glasgow Outcome Scale (GOS) score of 5, 1 achieved a GOS score of 4 and the remaining 2 had a GOS score of 3. No mortality was noted in this series. Although rare in incidence, early post-operative CSF hypovolemia may occur without the existence of post-operative continuous CSF leakage. When the diagnosis of CSF hypovolemia is reached, factors that may exacerbate CSF compensation should be promptly terminated. Trendelenburg position and sufficient intravenous hydration are practical and effective managements, and CSF hypovolemia may thereby be reversed in a substantial number of patients.

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

Correlation of Lactate Concentration in Peripheral Plasma and Cerebrospinal Fluid with Glasgow Outcome Scale for Patients with Tuberculous Meningitis Complicated by Acute Hydrocephalus Treated with Fluid Diversions.

PubMed

Faried, Ahmad; Arief, Gusman; Arifin, Muhammad Z; Nataprawira, Heda M

2018-03-01

Tuberculous meningitis (TBM) is an endemic infectious disease in developing countries, and it can become a serious illness in children. Treatment of TBM is more difficult and prone to failure than treatment of pulmonary tuberculosis. TBM causes hydrocephalus, cerebral edema, increased intracranial pressure, global ischemia, and neurologic deficits, which disturb cellular metabolism and increase lactate levels. A reliable, widely available clinical indicator of TBM severity is needed. Successful treatment of TBM is assessed using the Glasgow Outcome Scale (GOS). This prospective cohort study included 34 patients with TBM and acute hydrocephalus who had undergone fluid diversions and were admitted to Dr. Hasan Sadikin Hospital in Bandung from 2014 to 2015. A portable machine for blood glucose measurement was used to measure lactate concentrations. Statistical significance was defined as P ≤ 0.05. Average levels of plasma and cerebrospinal fluid (CSF) lactate were 1.99 ± 0.70 mmol/L and 3.04 ± 1.05 mmol/L, respectively. A significantly higher level of lactate was observed in CSF compared with plasma. Preoperative plasma lactate was negatively correlated to GOS (r = -0.539; P = 0.013), and CSF lactate was negatively correlated to GOS (r = -0.412; P = 0.027). Average lactate levels in CSF (central) were higher than plasma (peripheral) levels. GOS scale of patients decreased with increased plasma and CSF lactate levels. Examination of plasma and CSF lactate levels should be included in routine examinations to determine extent of cellular damage and GOS score in patients with TBM and acute hydrocephalus who have undergone fluid diversions. Copyright © 2017 Elsevier Inc. All rights reserved.

Cerebrospinal fluid eosinophilia and sterile shunt malfunction.

PubMed

Traynelis, V C; Powell, R G; Koss, W; Schochet, S S; Kaufman, H H

1988-11-01

Cerebrospinal fluid (CSF) eosinophilia is a rare finding most often associated with central nervous system inflammatory processes, including parasitic, bacterial, and mycotic infections. It has also been seen as an allergic phenomenon. We present two cases of CSF eosinophilia occurring concurrently with sterile shunt malfunction. We speculate that CSF eosinophilia in our patients might have resulted from an allergic response to a foreign material such as suture, surgical glove powder, hair, cotton fibers, antibiotics, or silicone rubber. The incidence of sterile CSF eosinophilia after shunting is not known. Information concerning the role of eosinophilia in the development of shunt malfunctions is also lacking. An increased awareness of this possibility and further investigation are warranted.

[Cerebral vasospasm and lipid peroxidation--lipid peroxides in the cerebrospinal fluid after subarachnoid hemorrhage].

PubMed

Sasaki, T; Asano, T; Takakura, K; Sano, K; Nakamura, T; Suzuki, N; Imabayashi, S; Ishikawa, Y

1982-12-01

The relationship between lipid peroxides in cerebrospinal fluid (CSF) and the occurrence of cerebral vasospasm following subarachnoid hemorrhage (SAH) was evaluated by analyzing CSF with high-performance liquid chromatography (HPLC) and gas chromatography mass spectrometry (GC-MS). Hydroperoxy eicosatetraenoic acids (HPETEs) and hydroxy eicosatetraenoic acids (HETEs) were synthesized by the treatment of arachidonic acid with hydrogen peroxide and cupric chloride. The retention time of these HPETEs and HETEs were determined on HPLC. The position of oxydation occurred was determined after methylation, reduction and trimethyl silylation using GC-MS. Thus the elucidation of positional isomers of HPETEs and HETEs was made possible by the retention time on HPLC. The supernant of CSF after SAH was adjusted to pH 3.0 and then absorbed to octadecyl silyl silica column. The eluted fraction with 15% ethanol-water from octadecyl silyl silica column was analyzed by HPLC detecting at 238 nm. No peak was observed on HPLC at the region of HPETEs and HETEs in the CSF obtained from healthy person. In SAH patients, several peaks were recognized in accordance with the occurrence of cerebral vasospasm. One of the peaks was identified as 5-HETE by HPLC and GC-MS. In 10 SAH patients, semi-quantitative analysis of 5-HETE in the CSF was performed by measuring the height of the peak identified as 5-HETE on HPLC. The close correlation was recognized between the occurrence of cerebral vasospasm and the appearance of 5-HETE in the CSF. The results of the present study suggest that lipid peroxidation is involved in the pathogenesis of chronic vasospasm after SAH.

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.

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

Immunophenotyping of the cerebrospinal fluid as a prognostic factor at diagnosis of acute lymphoblastic leukemia in children and adolescents.

PubMed

Cancela, Camila Silva Peres; Murao, Mitiko; Assumpção, Juliana Godoy; Souza, Marcelo Eduardo de Lima; de Macedo, Antonio Vaz; Viana, Marcos Borato; De Oliveira, Benigna Maria

2017-03-01

This study aimed at evaluating the use of immunophenotyping (IMP) in the identification of blast cells in the cerebrospinal fluid (CSF) of children and adolescents with acute lymphoblastic leukemia (ALL). Sixty-seven patients aged 18 years or younger were included. Fifty-five CSF samples were analyzed at initial diagnosis and 17 at the time of relapse. A cytological analysis (CA) was performed in all 72 samples, while IMP was done in 63. Blasts were identified in only three samples by CA, whereas all three samples were found negative by IMP, one of which had no isolation of nucleated cells after centrifugation. Among the samples analyzed by IMP, 11 showed a positive blast count, two of which had been inconclusive using CA. No equivalence was found between CA and IMP results (p = 0.55). CSF IMP positivity was not associated with other risk factors for ALL relapse. Among the 55 patients included at the time of diagnosis of ALL, eight relapsed during follow-up. Considering the cases of central nervous system (CNS) relapse, one of the patients belonged to the CSF IMP-positive group (11%) at diagnosis, and the other two cases, to the IMP-negative (5%) group. Detection of CSF blast cells using IMP was associated with a worse overall (p < 0.0001) and event-free survival (p < 0.0001). These results show that CSF IMP may be a useful additional method to conventional CA in the diagnosis of CNS involvement in ALL, and for the identification of high-risk subgroups that would benefit from an intensified therapy.

CSF profile in primary progressive multiple sclerosis: Re-exploring the basics.

PubMed

Abdelhak, Ahmed; Hottenrott, Tilman; Mayer, Christoph; Hintereder, Gudrun; Zettl, Uwe K; Stich, Oliver; Tumani, Hayrettin

2017-01-01

The aim of this study was to report the basic cerebrospinal fluid (CSF) profile in patients with primary progressive multiple sclerosis (PPMS). The results of CSF analysis from 254 patients with PPMS were collected at four university hospitals in Germany. Routine CSF parameters and different indices of intrathecal immunoglobulin synthesis were evaluated. We assessed possible correlations between the various CSF parameters and the expanded disability status scale (EDSS) both at the time of lumbar puncture and during the course of the disease. The median cell count and albumin concentration in the CSF did not deviate from normal values. The CSF-serum albumin-quotient (QALB) was elevated in 29.6% of the patients, while intrathecal immunoglobulin G (IgG) oligoclonal bands (OCBs) were detected in 91.1% of the patients. CSF-lactate levels as well as local IgM- and IgA-synthesis were correlated with the yearly disease progression rate, as assessed by EDSS. We present the results of the hitherto largest and most detailed CSF biomarker profile in a cohort of 254 patients with PPMS. As reported previously, OCBs are the most sensitive marker for intrathecal IgG synthesis. CSF-lactate concentrations are positively correlated with the progression rate, which might suggest that mitochondrial dysfunction plays a relevant role in PPMS. The negative correlation between intrathecally produced IgM and IgA and disease progression may indicate their hitherto unexplored protective role.

Effects of blood contamination of cerebrospinal fluid on results of indirect fluorescent antibody tests for detection of antibodies against Sarcocystis neurona and Neospora hughesi.

PubMed

Finno, Carrie J; Packham, Andrea E; David Wilson, W; Gardner, Ian A; Conrad, Patricia A; Pusterla, Nicola

2007-05-01

The purpose of this study was to determine the effect of blood contamination of cerebrospinal fluid (CSF) on the results of indirect fluorescent antibody tests (IFATs) for Sarcocystis neurona and Neospora hughesi. The in vitro study used antibody-negative CSF collected from non-neurologic horses immediately after euthanasia and blood samples from 40 healthy horses that had a range of IFAT antibody titers against S. neurona and N. hughesi. Serial dilutions of whole blood were made in seronegative CSF to generate blood-contaminated CSF with red blood cell (RBC) concentrations ranging from 10 to 100,000 RBCs/microl. The blood-contaminated CSF samples were then tested for antibodies against both pathogens using IFAT. Blood contamination of CSF had no detectable effect on IFAT results for S. neurona or N. hughesi at any serologic titer when the RBC concentration in CSF was <10,000 RBCs/microl. At concentrations of 10,000-100,000 RBCs/microl of CSF, positive CSF results (IFAT titer >or=5) for S. neurona and N. hughesi were detected only when the corresponding serum titers were >or=160 and >or=80, respectively. The IFAT performed on CSF is reliable for testing horses for equine protozoal myeloencephalitis caused by S. neurona or N. hughesi, even when blood contamination causes the RBC concentration in CSF to be up to 10,000 RBCs/microl.

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.

Is it possible to differentiate tuberculous and cryptococcal meningitis in HIV-infected patients using only clinical and basic cerebrospinal fluid characteristics?

PubMed

Vidal, J E; Peixoto de Miranda, E J F; Gerhardt, J; Croda, M; Boulware, D R

2017-01-30

Tuberculous and cryptococcal meningitis (TBM and CM) are the most common causes of opportunistic meningitis in HIVinfected patients from resource-limited settings, and the differential diagnosis is challenging. To compare clinical and basic cerebrospinal fluid (CSF) characteristics between TBM and CM in HIV-infected patients. A retrospective analysis was conducted of clinical, radiological and laboratory records of 108 and 98 HIV-infected patients with culture-proven diagnosis of TBM and CM, respectively. The patients were admitted at a tertiary centre in São Paulo, Brazil. A logistic regression model was used to distinguish TBM from CM and derive a diagnostic index based on the adjusted odds ratio (OR) to differentiate these two diseases. In multivariate analysis, TBM was independently associated with: CSF with neutrophil predominance (odds ratio (OR) 35.81, 95% confidence interval (CI) 3.80 - 341.30, p=0.002), CSF pleocytosis (OR 9.43, 95% CI 1.30 - 68.70, p=0.027), CSF protein >1.0 g/L (OR 5.13, 95% CI 1.38 - 19.04, p=0.032) and Glasgow Coma Scale <15 (OR 3.10, 95% CI 1.03 - 9.34, p=0.044). Nausea and vomiting (OR 0.27, 95% CI 0.08 - 0.90, p=0.033) were associated with CM. Algorithm-related area under the receiver operating characteristics curve was 0.815 (95% CI 0.758 - 0.873, p<0.0001), but an accurate cut-off was not derived. Although some clinical and basic CSF characteristics appear useful in the differential diagnosis of TBM and CM in HIVinfected patients, an accurate algorithm was not identified. Optimised access to rapid, sensitive and specific laboratory tests is essential.

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.

Enfuvirtide cerebrospinal fluid (CSF) pharmacokinetics and potential use in defining CSF HIV-1 origin.

PubMed

Price, Richard W; Parham, Robin; Kroll, Jing Lu; Wring, Stephen A; Baker, Brian; Sailstad, Jeff; Hoh, Rebecca; Liegler, Teri; Spudich, Serena; Kuritzkes, Daniel R; Deeks, Steven G

2008-01-01

Enfuvirtide is a potent inhibitor of systemic HIV-1 replication, but its penetration into the human central nervous system (CNS) has not been analysed. Here, we define cerebrospinal fluid (CSF) enfuvirtide pharmacokinetics and present a case illustrating the use of enfuvirtide as a probe to trace the origins of CSF HIV-1 quasispecies. Enfuvirtide CSF pharmacokinetics were assessed in 18 CSF and plasma sample pairs from four HIV-1-infected individuals. Enfuvirtide levels were measured by liquid chromatography tandem mass spectrometry using known standards and controls that included spiked CSF samples from untreated, HIV-negative individuals. A segment of the gp41 coding region encompassing the heptad repeat HR-1 and HR-2 domains was amplified from selected CSF and plasma samples and independent clones sequenced to assess resistance-associated mutations. CSF and plasma samples obtained between 2 and 20 h after enfuvirtide injection showed plasma concentrations similar to previous reports (mean 3.687 SD +/- 1.828 mg/ml) with prolonged decay. By contrast, enfuvirtide in all CSF samples was below the assay detection limit of 0.025 mg/ml. In one individual, who developed a transient increase in CSF HIV-1 RNA, seven of seven CSF and plasma clones had identical enfuvirtide resistance-associated V38A mutations, suggesting that the CSF quasispecies derived from that of blood. Enfuvirtide penetration into CSF is negligible; thus, in clinical settings, where direct CNS drug exposure is crucial, this drug Is not likely to directly contribute to the local therapeutic effect. Enfuvirtide can be used as a tool to dissect the origin of the CNS virus.

Associations between [18F]AV1451 tau PET and CSF measures of tau pathology in a clinical sample.

PubMed

La Joie, Renaud; Bejanin, Alexandre; Fagan, Anne M; Ayakta, Nagehan; Baker, Suzanne L; Bourakova, Viktoriya; Boxer, Adam L; Cha, Jungho; Karydas, Anna; Jerome, Gina; Maass, Anne; Mensing, Ashley; Miller, Zachary A; O'Neil, James P; Pham, Julie; Rosen, Howard J; Tsai, Richard; Visani, Adrienne V; Miller, Bruce L; Jagust, William J; Rabinovici, Gil D

2018-01-23

To assess the relationships between fluid and imaging biomarkers of tau pathology and compare their diagnostic utility in a clinically heterogeneous sample. Fifty-three patients (28 with clinical Alzheimer disease [AD] and 25 with non-AD clinical neurodegenerative diagnoses) underwent β-amyloid (Aβ) and tau ([ 18 F]AV1451) PET and lumbar puncture. CSF biomarkers (Aβ 42 , total tau [t-tau], and phosphorylated tau [p-tau]) were measured by multianalyte immunoassay (AlzBio3). Receiver operator characteristic analyses were performed to compare discrimination of Aβ-positive AD from non-AD conditions across biomarkers. Correlations between CSF biomarkers and PET standardized uptake value ratios (SUVR) were assessed using skipped Pearson correlation coefficients. Voxelwise analyses were run to assess regional CSF-PET associations. [ 18 F]AV1451-PET cortical SUVR and p-tau showed excellent discrimination between Aβ-positive AD and non-AD conditions (area under the curve 0.92-0.94; ≤0.83 for other CSF measures), and reached 83% classification agreement. In the full sample, cortical [ 18 F]AV1451 was associated with all CSF biomarkers, most strongly with p-tau ( r = 0.75 vs 0.57 for t-tau and -0.49 for Aβ 42 ). When restricted to Aβ-positive patients with AD, [ 18 F]AV1451 SUVR correlated modestly with p-tau and t-tau (both r = 0.46) but not Aβ 42 ( r = 0.02). On voxelwise analysis, [ 18 F]AV1451 correlated with CSF p-tau in temporoparietal cortices and with t-tau in medial prefrontal regions. Within AD, Mini-Mental State Examination scores were associated with [ 18 F]AV1451-PET, but not CSF biomarkers. [ 18 F]AV1451-PET and CSF p-tau had comparable value for differential diagnosis. Correlations were robust in a heterogeneous clinical group but attenuated (although significant) in AD, suggesting that fluid and imaging biomarkers capture different aspects of tau pathology. This study provides Class III evidence that, in a clinical sample of patients with a variety of suspected neurodegenerative diseases, both CSF p-tau and [ 18 F]AV1451 distinguish AD from non-AD conditions. Copyright © 2017 American Academy of Neurology.

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.

Longitudinal Analysis of Cerebrospinal Fluid and Plasma HIV-1 Envelope Sequences Isolated From a Single Donor with HIV Asymptomatic Neurocognitive Impairment.

PubMed

Vázquez-Santiago, Fabián; García, Yashira; Rivera-Román, Ivelisse; Noel, Richard J; Wojna, Valerie; Meléndez, Loyda M; Rivera-Amill, Vanessa

Combined antiretroviral treatment (cART) has changed the clinical presentation of HIV-associated neurocognitive disorders (HAND) to that of the milder forms of the disease. Asymptomatic neurocognitive impairment (ANI) is now more prevalent and is associated with increased morbidity and mortality risk in HIV-1-infected people. HIV-1 envelope ( env ) genetic heterogeneity has been detected within the central nervous system (CNS) of individuals with ANI. Changes within env determine co-receptor use, cellular tropism, and neuropathogenesis. We hypothesize that compartmental changes are associated with HIV-1 env C2V4 during ANI and sought to analyze paired HIV-1 env sequences from plasma and cerebrospinal fluid (CSF) of a female subject undergoing long-term cART. Paired plasma and CSF samples were collected at 12-month intervals and HIV-1 env C2V4 was cloned and sequenced. Phylogenetic analysis of paired samples consistently showed genetic variants unique to the CSF. Phenotypic prediction showed CCR5 (R5) variants for all CSF-derived sequences and showed minor X4 variants (or dual-tropic) in the plasma at later time points. Viral compartmentalization was evident throughout the study, suggesting that the occurrence of distinctive env strains may contribute to the neuropathogenesis of HAND. Our study provides new insights about the genetic characteristics within the C2V4 of HIV-1 env that persist after long-term cART and during the course of persistent ANI.

Decreased Expression of hsa-miR-4274 in Cerebrospinal Fluid of Normal Pressure Hydrocephalus Mimics with Parkinsonian Syndromes

PubMed Central

Jurjević, Ivana; Miyajima, Masakazu; Ogino, Ikuko; Akiba, Chihiro; Nakajima, Madoka; Kondo, Akihide; Kikkawa, Mika; Kanai, Mitsuyasu; Hattori, Nobutaka; Arai, Hajime

2016-01-01

Background: Patients presenting with the classical idiopathic normal pressure hydrocephalus (iNPH) triad often show additional parkinsonian spectrum signs. Accurate differential diagnosis strongly influences the long-term outcome of cerebrospinal fluid (CSF) shunting. Objective: The aim of this study was to find potential CSF microRNA (miRNA) biomarkers for NPH mimics with parkinsonian syndromes that can reliably distinguish them from iNPH patients. Methods: Two cohorts of 81 patients (cohort 1, n = 55; cohort 2, n = 26) with possible iNPH who were treated in two centers between January 2011 and May 2014 were studied. In both cohorts, CSF samples were obtained from patients clinically diagnosed with iNPH (n = 21 and n = 10, respectively), possible iNPH with parkinsonian spectrum (PS) (n = 18, n = 10, respectively), possible iNPH with Alzheimer’s disease (AD) (n = 16), and non-affected elderly individuals (NC) (n = 6). A three-step qRT-PCR analysis of the CSF samples was performed to detect miRNAs that were differentially expressed in the groups. Results: The expression of hsa-miR-4274 in CSF was decreased in both cohorts of PS group patients (cohort 1: p < 0.0001, cohort 2: p < 0.0001), and was able to distinguish PS from iNPH with high accuracy (area under the curve = 0.908). The CSF concentration of hsa-miR-4274 also correlated with the specific binding ratio of ioflupane (123I) dopamine transporter scan (r = –0.494, p = 0.044). By contrast, the level of hsa-miR-4274 was significantly increased in the PS group after CSF diversion. Conclusion: Levels of CSF hsa-miR-4274 can differentiate PS from patients with iNPH, AD, and NC. This may be clinically useful for diagnostic purposes and predicting shunt treatment responses. PMID:27911315

Decreased Expression of hsa-miR-4274 in Cerebrospinal Fluid of Normal Pressure Hydrocephalus Mimics with Parkinsonian Syndromes.

PubMed

Jurjević, Ivana; Miyajima, Masakazu; Ogino, Ikuko; Akiba, Chihiro; Nakajima, Madoka; Kondo, Akihide; Kikkawa, Mika; Kanai, Mitsuyasu; Hattori, Nobutaka; Arai, Hajime

2017-01-01

Patients presenting with the classical idiopathic normal pressure hydrocephalus (iNPH) triad often show additional parkinsonian spectrum signs. Accurate differential diagnosis strongly influences the long-term outcome of cerebrospinal fluid (CSF) shunting. The aim of this study was to find potential CSF microRNA (miRNA) biomarkers for NPH mimics with parkinsonian syndromes that can reliably distinguish them from iNPH patients. Two cohorts of 81 patients (cohort 1, n = 55; cohort 2, n = 26) with possible iNPH who were treated in two centers between January 2011 and May 2014 were studied. In both cohorts, CSF samples were obtained from patients clinically diagnosed with iNPH (n = 21 and n = 10, respectively), possible iNPH with parkinsonian spectrum (PS) (n = 18, n = 10, respectively), possible iNPH with Alzheimer's disease (AD) (n = 16), and non-affected elderly individuals (NC) (n = 6). A three-step qRT-PCR analysis of the CSF samples was performed to detect miRNAs that were differentially expressed in the groups. The expression of hsa-miR-4274 in CSF was decreased in both cohorts of PS group patients (cohort 1: p < 0.0001, cohort 2: p < 0.0001), and was able to distinguish PS from iNPH with high accuracy (area under the curve = 0.908). The CSF concentration of hsa-miR-4274 also correlated with the specific binding ratio of ioflupane (123I) dopamine transporter scan (r = -0.494, p = 0.044). By contrast, the level of hsa-miR-4274 was significantly increased in the PS group after CSF diversion. Levels of CSF hsa-miR-4274 can differentiate PS from patients with iNPH, AD, and NC. This may be clinically useful for diagnostic purposes and predicting shunt treatment responses.

Cerebrospinal fluid lactate: a differential biomarker for bacterial and viral meningitis in children.

PubMed

Nazir, Mudasir; Wani, Wasim Ahmad; Malik, Muzaffar Ahmad; Mir, Mohd Rafiq; Ashraf, Younis; Kawoosa, Khalid; Ali, Syed Wajid

To assess the performance of cerebrospinal fluid (CSF) lactate as a biomarker to differentiate bacterial meningitis from viral meningitis in children, and to define an optimal CSF lactate concentration that can be called significant for the differentiation. Children with clinical findings compatible with meningitis were studied. CSF lactate and other conventional CSF parameters were recorded. At a cut-off value of 3mmol/L, CSF lactate had a sensitivity of 0.90, specificity of 1.0, positive predictive value of 1.0, and negative predictive value of 0.963, with an accuracy of 0.972. The positive and negative likelihood ratios were 23.6 and 0.1, respectively. When comparing between bacterial and viral meningitis, the area under the curve for CSF lactate was 0.979. The authors concluded that CSF lactate has high sensitivity and specificity in differentiating bacterial from viral meningitis. While at a cut-off value of 3mmol/L, CSF lactate has high diagnostic accuracy for bacterial meningitis, mean levels in viral meningitis remain essentially below 2mmol/L. Copyright © 2017 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

CSF lactate alone is not a reliable indicator of bacterial ventriculitis in patients with ventriculostomies.

PubMed

Hill, Emily; Bleck, Thomas P; Singh, Kamaljit; Ouyang, Bichun; Busl, Katharina M

2017-06-01

In a febrile patient with a ventriculostomy, diagnosing or excluding bacterial or microbial ventriculitis is difficult, as conventional markers in analysis of cerebrospinal fluid (CSF) are not applicable due to presence of blood and inflammation. CSF lactate has been shown to be a useful indicator of bacterial meningitis in CSF obtained via lumbar puncture, but little and heterogenous data exist on patients with ventriculostomies. We reviewed all CSF analyses obtained via ventriculostomy in patients admitted to our tertiary medical center between 2008 and 2013, and constructed receiver operating characteristic (ROC) curves to evaluate the accuracy of CSF lactate concentration in discriminating a positive CSF culture from a negative one in setting of ventriculostomy and prophylactic antibiosis. Among 467 CSF lactate values, there were 22 corresponding CSF cultures with bacterial growth. Sensitivities and specificities for CSF lactate at threshold values 3, 4, 5 and 6mmol/L showed sensitivity and specificity greater than 70% for CSF lactate threshold 4mmol/L. The lowest threshold value of 3mmol/L resulted in higher sensitivity of 81.8%, and the highest chosen threshold value resulted in high specificity of 94.2%, but these values had poor corresponding specificity and sensitivity, respectively. The area under the curve was 0.82 (95% CI 0.72, 0.91). Our data from a large sample of CSF studies in patients with ventriculostomy indicate that no single value of CSF lactate provided both sensitivity and specificity high enough to be regarded as reliable test. Copyright © 2017 Elsevier B.V. All rights reserved.

Subarachnoid Hemorrhage Severely Impairs Brain Parenchymal Cerebrospinal Fluid Circulation in Nonhuman Primate.

PubMed

Goulay, Romain; Flament, Julien; Gauberti, Maxime; Naveau, Michael; Pasquet, Nolwenn; Gakuba, Clement; Emery, Evelyne; Hantraye, Philippe; Vivien, Denis; Aron-Badin, Romina; Gaberel, Thomas

2017-08-01

Subarachnoid hemorrhage (SAH) is a devastating form of stroke with neurological outcomes dependent on the occurrence of delayed cerebral ischemia. It has been shown in rodents that some of the mechanisms leading to delayed cerebral ischemia are related to a decreased circulation of the cerebrospinal fluid (CSF) within the brain parenchyma. Here, we evaluated the cerebral circulation of the CSF in a nonhuman primate in physiological condition and after SAH. We first evaluated in physiological condition the circulation of the brain CSF in Macaca facicularis , using magnetic resonance imaging of the temporal DOTA-Gd distribution after its injection into the CSF. Then, animals were subjected to a minimally invasive SAH before an MRI evaluation of the impact of SAH on the brain parenchymal CSF circulation. We first demonstrate that the CSF actively penetrates the brain parenchyma. Two hours after injection, almost the entire brain is labeled by DOTA-Gd. We also show that our model of SAH in nonhuman primate displays the characteristics of SAH in humans and leads to a dramatic impairment of the brain parenchymal circulation of the CSF. The CSF actively penetrates within the brain parenchyma in the gyrencephalic brain, as described for the glymphatic system in rodent. This parenchymal CSF circulation is severely impaired by SAH. © 2017 American Heart Association, Inc.

Quantification of γ-Aminobutyric Acid in Cerebrospinal Fluid Using Liquid Chromatography-Electrospray Tandem Mass Spectrometry.

PubMed

Arning, Erland; Bottiglieri, Teodoro

2016-01-01

We describe a simple stable isotope dilution method for accurate and precise measurement of γ-aminobutyric acid (GABA), a major inhibitory neurotransmitter in human cerebrospinal fluid (CSF) as a clinical diagnostic test. Determination of GABA in CSF (50 μL) was performed utilizing high performance liquid chromatography coupled with electrospray positive ionization tandem mass spectrometry (HPLC-ESI-MS/MS). Analysis of free and total GABA requires two individual sample preparations and mass spectrometry analyses. Free GABA in CSF is determined by a 1:2 dilution with internal standard (GABA-D2) and injected directly onto the HPLC-ESI-MS/MS system. Determination of total GABA in CSF requires additional sample preparation in order to hydrolyze all the bound GABA in the sample to the free form. This requires hydrolyzing the sample by boiling in acidic conditions (hydrochloric acid) for 4 h. The sample is then further diluted 1:10 with a 90 % acetonitrile/0.1 % formic acid solution and injected into the HPLC-ESI-MS/MS system. Each assay is quantified using a five-point standard curve and is linear from 6 nM to 1000 nM and 0.63 μM to 80 μM for free and total GABA, respectively.

Multiple reaction monitoring assay based on conventional liquid chromatography and electrospray ionization for simultaneous monitoring of multiple cerebrospinal fluid biomarker candidates for Alzheimer's disease

PubMed Central

Choi1, Yong Seok; Lee, Kelvin H.

2016-01-01

Alzheimer's disease (AD) is the most common type of dementia, but early and accurate diagnosis remains challenging. Previously, a panel of cerebrospinal fluid (CSF) biomarker candidates distinguishing AD and non-AD CSF accurately (> 90%) was reported. Furthermore, a multiple reaction monitoring (MRM) assay based on nano liquid chromatography tandem mass spectrometry (nLC-MS/MS) was developed to help validate putative AD CSF biomarker candidates including proteins from the panel. Despite the good performance of the MRM assay, wide acceptance may be challenging because of limited availability of nLC-MS/MS systems laboratories. Thus, here, a new MRM assay based on conventional LC-MS/MS is presented. This method monitors 16 peptides representing 16 (of 23) biomarker candidates that belonged to the previous AD CSF panel. A 30-times more concentrated sample than the sample used for the previous study was loaded onto a high capacity trap column, and all 16 MRM transitions showed good linearity (average R2 = 0.966), intra-day reproducibility (average coefficient of variance (CV) = 4.78%), and inter-day reproducibility (average CV = 9.85%). The present method has several advantages such as a shorter analysis time, no possibility of target variability, and no need for an internal standard. PMID:26404792

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.

Steady-streaming effects on the motion of the cerebrospinal fluid (CSF) in the spinal canal

NASA Astrophysics Data System (ADS)

Lawrence, Jenna; Coenen, Wilfried; Sanchez, Antonio; Lasheras, Juan

2017-11-01

With each heart beat the oscillatory blood supply to the rigid cranial vault produces a time-periodic variation of the intracranial pressure that drives the cerebrospinal fluid (CSF) periodically in and out of the compliant spinal canal. We have recently conducted an analysis of this flow-structure interaction problem taking advantage of the small compliance of the dura membrane bounding externally the CSF and of the disparity of length scales associated with the geometry of the subarachnoid space. We have shown in an idealized geometry that the steady-streaming motion associated with this periodic flow, resulting from the nonlinear cumulative effects of convective acceleration, causes a bulk recirculation of CSF inside the spinal canal, which has been observed in many radiological studies. We extend here our study to investigate the possible contribution arising from the flow around the nerve roots protruding from the spinal cord, an effect that was neglected in our previous work. For this purpose, we consider the oscillatory motion around a cylindrical post confined between two parallel plates. For large values of the relevant Strouhal number we find at leading order a harmonic Stokes flow, whereas steady-streaming effects enter in the first-order corrections, which are computed for realistic values of the Womersley number and of the cylinder height-to-radius ratio.

Rapid determination of piracetam in human plasma and cerebrospinal fluid by micellar electrokinetic chromatography with sample direct injection.

PubMed

Yeh, Hsin-Hua; Yang, Yuan-Han; Ko, Ju-Yun; Chen, Su-Hwei

2006-07-07

A simple micellar electrokinetic chromatography (MEKC) method with UV detection at 200 nm for analysis of piracetam in plasma and in cerebrospinal fluid (CSF) by direct injection without any sample pretreatment is described. The separation of piracetam from biological matrix was performed at 25 degrees C using a background electrolyte consisting of Tris buffer with sodium dodecyl sulfate (SDS) as the electrolyte solution. Several parameters affecting the separation of the drug from biological matrix were studied, including the pH and concentrations of the Tris buffer and SDS. Under optimal MEKC condition, good separation with high efficiency and short analyses time is achieved. Using imidazole as an internal standard (IS), the linear ranges of the method for the determination of piracetam in plasma and in CSF were all between 5 and 500 microg/mL; the detection limit of the drug in plasma and in CSF (signal-to-noise ratio=3; injection 0.5 psi, 5s) was 1.0 microg/mL. The applicability of the proposed method for determination of piracetam in plasma and CSF collected after intravenous administration of 3g piracetam every 6h and oral administration 1.2g every 6h in encephalopathy patients with aphasia was demonstrated.

The effectiveness of the liquid-based preparation method in cerebrospinal fluid cytology.

PubMed

Argon, Asuman; Uyaroğlu, Mehmet Ali; Nart, Deniz; Veral, Ali; Kitapçıoğlu, Gül

2013-01-01

Since malignant cells were first detected in the cerebrospinal fluid (CSF), numerous methods have been used for CSF examination. The cytocentrifugation and liquid-based cytology (LBC) methods are two of these. We aimed to investigate whether the results from the LBC method were different from the results of the cytological diagnosis of the CSF materials that were prepared using the cytocentrifugation method. A retrospective analysis was conducted using the pathological records of 3,491 (cytocentrifugation on 1,306 and LBC on 2,185) cytological specimens of CSF which were diagnosed over a 4-year period between January 2007 and December 2011. The Fisher exact test was used to compare the results of the LBC and cytocentrifugation methods. While there was a noticeable decrease in nondiagnostic diagnosis and a slight decrease in suspicious diagnosis, there was an increase in malignant and benign diagnosis with the LBC method in comparison to the centrifugation method. Statistically, the decrease in nondiagnostic diagnosis was considered significant (p < 0.0001). The LBC method seems like a better option than the cytocentrifugation method, because of many preparatory, screening and diagnostic advantages, especially in pathology departments where materials come from far away and large volumes are examined. Copyright © 2013 S. Karger AG, Basel.

Multiple reaction monitoring assay based on conventional liquid chromatography and electrospray ionization for simultaneous monitoring of multiple cerebrospinal fluid biomarker candidates for Alzheimer's disease.

PubMed

Choi, Yong Seok; Lee, Kelvin H

2016-03-01

Alzheimer's disease (AD) is the most common type of dementia, but early and accurate diagnosis remains challenging. Previously, a panel of cerebrospinal fluid (CSF) biomarker candidates distinguishing AD and non-AD CSF accurately (>90 %) was reported. Furthermore, a multiple reaction monitoring (MRM) assay based on nano liquid chromatography tandem mass spectrometry (nLC-MS/MS) was developed to help validate putative AD CSF biomarker candidates including proteins from the panel. Despite the good performance of the MRM assay, wide acceptance may be challenging because of limited availability of nLC-MS/MS systems in laboratories. Thus, here, a new MRM assay based on conventional LC-MS/MS is presented. This method monitors 16 peptides representing 16 (of 23) biomarker candidates that belonged to the previous AD CSF panel. A 30-times more concentrated sample than the sample used for the previous study was loaded onto a high capacity trap column, and all 16 MRM transitions showed good linearity (average R(2) = 0.966), intra-day reproducibility (average coefficient of variance (CV) = 4.78 %), and inter-day reproducibility (average CV = 9.85 %). The present method has several advantages such as a shorter analysis time, no possibility of target variability, and no need for an internal standard.

Enfuvirtide Cerebrospinal Fluid (CSF) Pharmacokinetics and Potential Use in Defining CSF HIV-1 Origin

PubMed Central

Price, Richard W; Parham, Robin; Lu, Jing; Wring, Stephen A.; Baker, Brian; Sailstad, Jeff; Hoh, Rebecca; Liegler, Teri; Spudich, Serena; Kuritzkes, Daniel R; Deeks, Steven G

2009-01-01

Background Enfuvirtide is a potent inhibitor of systemic HIV-1 replication, but its penetration into the human central nervous system (CNS) has not been analyzed. Here, we define cerebrospinal fluid (CSF) enfuvirtide pharmacokinetics and present a case illustrating the use of enfuvirtide as a probe to trace the origins of CSF HIV-1 quasispecies. Methods Enfuvirtide CSF PK was assessed in 18 CSF and plasma sample pairs from 4 HIV-1-infected subjects. Enfuvirtide levels were measured by liquid chromatography tandem mass spectrometry using known standards and controls that including spiked CSF samples from untreated, HIV-negative subjects. A segment of the gp41-coding region encompassing the heptad repeat (HR)-1 and HR-2 domains was amplified from selected CSF and plasma samples, and independent clones sequenced to assess resistance-associated mutations. Results CSF and plasma samples obtained between 2 and 20 hrs after enfuvirtide injection showed plasma concentrations similar to previous reports (mean 3.687 +/−1.828 µg/ml SD) with prolonged decay. By contrast, enfuvirtide in all CSF samples was below the assay detection limit of 0.025 µg/ml. In one subject, who developed a transient increase in CSF HIV-1 RNA, 7 of 7 CSF and plasma clones had identical enfuvirtide resistance-associated V38A mutation, suggesting that the CSF quasispecies derived from that of blood. Conclusions Enfuvirtide CSF penetration into CSF is negligible, and thus in clinical settings where direct CNS drug exposure is critical, this drug will likely not directly contribute to the local therapeutic effect. Enfuvirtide can be used as a tool to dissect the origin of the CNS virus. PMID:18572749

BEAMing and Droplet Digital PCR Analysis of Mutant IDH1 mRNA in Glioma Patient Serum and Cerebrospinal Fluid Extracellular Vesicles

PubMed Central

Chen, Walter W; Balaj, Leonora; Liau, Linda M; Samuels, Michael L; Kotsopoulos, Steve K; Maguire, Casey A; LoGuidice, Lori; Soto, Horacio; Garrett, Matthew; Zhu, Lin Dan; Sivaraman, Sarada; Chen, Clark; Wong, Eric T; Carter, Bob S; Hochberg, Fred H; Breakefield, Xandra O; Skog, Johan

2013-01-01

Development of biofluid-based molecular diagnostic tests for cancer is an important step towards tumor characterization and real-time monitoring in a minimally invasive fashion. Extracellular vesicles (EVs) are released from tumor cells into body fluids and can provide a powerful platform for tumor biomarkers because they carry tumor proteins and nucleic acids. Detecting rare point mutations in the background of wild-type sequences in biofluids such as blood and cerebrospinal fluid (CSF) remains a major challenge. Techniques such as BEAMing (beads, emulsion, amplification, magnetics) PCR and droplet digital PCR (ddPCR) are substantially more sensitive than many other assays for mutant sequence detection. Here, we describe a novel approach that combines biofluid EV RNA and BEAMing RT-PCR (EV-BEAMing), as well droplet digital PCR to interrogate mutations from glioma tumors. EVs from CSF of patients with glioma were shown to contain mutant IDH1 transcripts, and we were able to reliably detect and quantify mutant and wild-type IDH1 RNA transcripts in CSF of patients with gliomas. EV-BEAMing and EV-ddPCR represent a valuable new strategy for cancer diagnostics, which can be applied to a variety of biofluids and neoplasms. PMID:23881452

Persistence of Pneumolysin in the Cerebrospinal Fluid of Patients With Pneumococcal Meningitis Is Associated With Mortality

PubMed Central

Wall, Emma C.; Hussain, Samia; Goonetilleke, Upali R. S.; Gritzfeld, Jenna; Scarborough, Matthew; Kadioglu, Aras

2012-01-01

Poor prognosis in Pneumococcal meningitis may be associated with high pneumolysin levels in cerebrospinal fluid (CSF). In patient samples we showed that pneumolysin levels in CSF remained high after 48 hours in nonsurvivors of meningitis compared with survivors. Selective antipneumolysin treatment may present a novel therapeutic option. PMID:22238165

Asymptomatic Cerebrospinal Fluid HIV-1 Viral Blips and Viral Escape During Antiretroviral Therapy: A Longitudinal Study.

PubMed

Edén, Arvid; Nilsson, Staffan; Hagberg, Lars; Fuchs, Dietmar; Zetterberg, Henrik; Svennerholm, Bo; Gisslén, Magnus

2016-12-15

We examined longitudinal cerebrospinal fluid (CSF) samples (median, 5 samples/patients; interquartile range [IQR], 3-8 samples/patient) in 75 neurologically asymptomatic human immunodeficiency virus (HIV)-infected patients receiving antiretroviral therapy. Twenty-seven patients (36%) had ≥1 CSF HIV RNA load of >20 copies/mL (23% had ≥1 load of >50 copies/mL), with a median HIV RNA load of 50 copies/mL (IQR, 32-77 copies/mL). In plasma, 42 subjects (52%) and 22 subjects (29%) had an HIV RNA load of >20 and >50 copies/mL, respectively. Two subjects had an increasing virus load in consecutive CSF samples, representing possible CSF escape. Of 418 samples, 9% had a CSF HIV RNA load of >20 copies/mL (5% had a load of >50 copies/mL) and 19% had a plasma HIV RNA load of >20 copies/mL (8% had a load of >50 copies/mL). A CSF-associated virus load of >20 copies/mL was associated with higher CSF level of neopterin. In conclusion, CSF escape was rare, and increased CSF HIV RNA loads usually represented CSF virus load blips. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

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

Isobaric Quantification of Cerebrospinal Fluid Amyloid-β Peptides in Alzheimer's Disease: C-Terminal Truncation Relates to Early Measures of Neurodegeneration.

PubMed

Rogeberg, Magnus; Almdahl, Ina Selseth; Wettergreen, Marianne; Nilsson, Lars N G; Fladby, Tormod

2015-11-06

The amyloid beta (Aβ) peptide is the main constituent of the plaques characteristic of Alzheimer's disease (AD). Measurement of Aβ1-42 in cerebrospinal fluid (CSF) is a valuable marker in AD research, where low levels indicate AD. Although the use of immunoassays measuring Aβ1-38 and Aβ1-40 in addition to Aβ1-42 has increased, quantitative assays of other Aβ peptides remain rarely explored. We recently discovered novel Aβ peptides in CSF using antibodies recognizing the Aβ mid-domain region. Here we have developed a method using both Aβ N-terminal and mid-domain antibodies for immunoprecipitation in combination with isobaric labeling and liquid chromatography-tandem mass spectrometry (LC-MS/MS) for relative quantification of endogenous Aβ peptides in CSF. The developed method was used in a pilot study to produce Aβ peptide profiles from 38 CSF samples. Statistical comparison between CSF samples from 19 AD patients and 19 cognitively healthy controls revealed no significant differences at group level. A significant correlation was found between several larger C-terminally truncated Aβ peptides and protein biomarkers for neuronal damage, particularly prominent in the control group. Comparison of the isobaric quantification with immunoassays measuring Aβ1-38 or Aβ1-40 showed good correlation (r(2) = 0.84 and 0.85, respectively) between the two analysis methods. The developed method could be used to assess disease-modifying therapies directed at Aβ production or degradation.

Imaging diagnosis--necrotizing meningomyelitis and polyarthritis.

PubMed

Parry, Andrew T; Penning, Victoria A; Smith, Ken C; Kenny, Patrick J; Lamb, Christopher R

2009-01-01

A vaccinated 2-year-old female neutered Weimaraner had bilateral pelvic limb ataxia that progressed over 12 h. The dog became nonambulatory, with signs of pain on palpation of the lumbar spine. The dog also developed multiple joint effusions. On magnetic resonance (MR) imaging, there was a diffuse, asymmetric T2-hyperintensity in the thoracolumbar spinal cord which was characterized by contrast enhancement. Lumbar cerebrospinal fluid (CSF) analysis had an elevated white blood cell count and protein. On the basis of MR images and CSF analysis, a presumptive diagnosis of diffuse myelitis was made. The dog became paraplegic and was euthanized. Postmortem examination confirmed the presence of myelitis with vasculitis and nonerosive polyarthritis.

CSF 5-HIAA Predicts Suicide Risk after Attempted Suicide.

ERIC Educational Resources Information Center

Nordstrom, Peter; And Others

1994-01-01

Studied suicide risk after attempted suicide, as predicted by cerebrospinal fluid (CSF) monoamine metabolite concentrations, in 92 psychiatric mood disorder inpatients admitted shortly after attempting suicide. Results revealed that low CSF 5-hydroxyindoleacetic acid (5-HIAA) predicted short-range suicide risk after attempted suicide in mood…

Oligoclonal bands in cerebrospinal fluid in patients with Tourette's syndrome.

PubMed

Wenzel, Claudia; Wurster, Ulrich; Müller-Vahl, Kirsten R

2011-02-01

Since a postinfectious or autoimmune etiology is suggested to be involved in the pathogenesis of Tourette's syndrome (TS), we investigated oligoclonal bands (OB) of immunoglobulin G (IgG) in cerebrospinal fluid (CSF), indicating a humoral immune response in the central nervous system. CSF examinations including isoelectric focusing to analyze the presence of OB were performed in 21 TS patients [17 men/4 women, mean age = 29 ± 12 (SD) years]. Isoelectric focusing showed the presence of positive OB in 6, borderline bands in 2, and serum and CSF bands ("mirrored pattern") in another 2 patients. Clinical data did not correlate with CSF findings. Thus, 38% (8 of 21) of our patients exhibited pathological CSF bands. Since none of them suffered from another disease known to be associated with OB, our results suggest an association with the pathogenesis of TS itself and point to an involvement of immunological mechanisms in TS pathology. Copyright © 2010 Movement Disorder Society.

Metal concentrations in cerebrospinal fluid and blood plasma from patients with amyotrophic lateral sclerosis.

PubMed

Roos, Per M; Vesterberg, Olof; Syversen, Tore; Flaten, Trond Peder; Nordberg, Monica

2013-02-01

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal degenerative disorder of motor neurons. The cause of this degeneration is unknown, and different causal hypotheses include genetic, viral, traumatic and environmental mechanisms. In this study, we have analyzed metal concentrations in cerebrospinal fluid (CSF) and blood plasma in a well-defined cohort (n = 17) of ALS patients diagnosed with quantitative electromyography. Metal analyses were performed with high-resolution inductively coupled plasma mass spectrometry. Statistically significant higher concentrations of manganese, aluminium, cadmium, cobalt, copper, zinc, lead, vanadium and uranium were found in ALS CSF compared to control CSF. We also report higher concentrations of these metals in ALS CSF than in ALS blood plasma, which indicate mechanisms of accumulation, e.g. inward directed transport. A pattern of multiple toxic metals is seen in ALS CSF. The results support the hypothesis that metals with neurotoxic effects are involved in the pathogenesis of ALS.

False-positive cerebrospinal fluid cryptococcus antigen in Libman-Sacks endocarditis.

PubMed

Isseh, Iyad N; Bourgi, Kassem; Nakhle, Asaad; Ali, Mahmoud; Zervos, Marcus J

2016-12-01

Cryptococcus meningoencephalitis is a serious opportunistic infection associated with high morbidity and mortality in immunocompromised hosts, particularly patients with advanced AIDS disease. The diagnosis is established through cerebrospinal fluid (CSF) cryptococcus antigen detection and cultures. Cryptococcus antigen testing is usually the initial test of choice due its high sensitivity and specificity along with the quick availability of the results. We hereby report a case of a false-positive CSF cryptococcus antigen assay in a patient with systemic lupus erythematosus presenting with acute confusion. While initial CSF evaluation revealed a positive cryptococcus antigen assay, the patient's symptoms were inconsistent with cryptococcus meningoencephalitis. A repeat CSF evaluation, done 3 days later, revealed a negative CSF cryptococcus antigen assay. Given the patient's active lupus disease and the elevated antinuclear antibody titers, we believe that the initial positive result was a false positive caused by interference from autoantibodies.

Osteopontin (OPN) as a CSF and blood biomarker for multiple sclerosis: A systematic review and meta-analysis.

PubMed

Agah, Elmira; Zardoui, Arshia; Saghazadeh, Amene; Ahmadi, Mona; Tafakhori, Abbas; Rezaei, Nima

2018-01-01

Identifying a reliable biomarker may accelerate diagnosis of multiple sclerosis (MS) and lead to early management of the disease. Accumulating evidence suggest that cerebrospinal fluid (CSF) and peripheral blood concentration of osteopontin (OPN) may have diagnostic and prognostic value in MS. We conducted a systematic review and meta-analysis of studies that measured peripheral blood and CSF levels of OPN in MS patients and controls to evaluate the diagnostic potential of this biomarker better. We searched PubMed, Web of Science and Scopus databases to find articles that measured OPN concentration in peripheral blood and CSF samples from MS patients up to October 19, 2016. Q statistic tests and the I2 index were applied for heterogeneity assessment. If the I2 index was less than 40%, the fixed-effects model was used for meta-analysis. Random-effects meta-analysis was chosen if the I2 value was greater than 40%. After removal of duplicates, 918 articles were identified, and 27 of them fulfilled the inclusion criteria. We included 22 eligible studies in the final meta-analysis. MS patients, in general, had considerably higher levels of OPN in their CSF and blood when compared to all types of controls (p<0.05). When the comparisons were made between different subtypes of MS patients and controls, the results pointed to significantly higher levels of OPN in CSF of MS subgroups (p<0.05). All subtypes of MS patients, except CIS patients, had increased blood levels of OPN compared to controls (p<0.05). In the second set of meta-analyses, we compared the peripheral blood and CSF concentrations of OPN between MS patient subtypes. CIS patients had significantly lower levels of OPN both in their peripheral blood and CSF compared to patients with progressive subtypes of MS (p<0.05). CSF concentration of OPN was significantly higher among RRMS patients compared to the CIS patients and SPMS patients (P<0.05). Finally, patients with active MS had significantly higher OPN levels in their CSF compared to patients with stable disease (P = 0.007). The result of this study confirms that increased levels of OPN exist in CSF and peripheral blood of MS patients and strengthens the evidence regarding the clinical utility of OPN as a promising and validated biomarker for MS.

[Endonasal endoscopic surgery in the treatment of spontaneous or post-traumatic cerebrospinal fluid (csf) leaks].

PubMed

Nallet, E; Decq, P; Bezzo, A; Le Lievre, G; Peynegre, R; Coste, A

1998-10-01

The incidence and the risk of meningitidis justify treatment in all cases of cerebrospinal fluid rhinorrhea with spontaneous etiology or after traumatic injury. Endonasal surgery with endoscopic instruments provides many advantages compared with transcranial or transfacial approach used by neurosurgeons. We report our experience and our surgical technique in the treatment of CSF leaks in 5 patients. Intrathecal injection of fluoresceine was very useful in all cases for detecting the CSF leak. Total or selected ethmoidectomy depended on the localization of the leakage. Wide sphenoidotomy enables detection and repair of CSF leaks from the sphenoid cavity. A free graft of inferior turbinal mucosal was used to repair the breache. This rapid low morbidity surgery offered secure closure of rhinorrhea in 4 cases after one procedure and in 1 case after two procedures with an average follow up of 22 months. Cerebrospinal fluid rhinorrhea can be managed in first line therapy with endoscopic intranasal surgical techniques when they are localized in the anterior ethmoid or in the sphenoid cavity.

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.

The First Isolation and Whole Genome Sequencing of Murray Valley Encephalitis Virus from Cerebrospinal Fluid of a Patient with Encephalitis.

PubMed

Russell, Jessica S; Caly, Leon; Kostecki, Renata; McGuinness, Sarah L; Carter, Glen; Bulach, Dieter; Seemann, Torsten; Stinear, Tim P; Baird, Rob; Catton, Mike; Druce, Julian

2018-06-11

Murray Valley Encephalitis virus (MVEV) is a mosquito-borne Flavivirus. Clinical presentation is rare but severe, with a case fatality rate of 15⁻30%. Here we report a case of MVEV from the cerebrospinal fluid (CSF) of a patient in the Northern Territory in Australia. Initial diagnosis was performed using both MVEV-specific real-time, and Pan- Flavivirus conventional, Polymerase Chain Reaction (PCR), with confirmation by Sanger sequencing. Subsequent isolation, the first from CSF, was conducted in Vero cells and the observed cytopathic effect was confirmed by increasing viral titre in the real-time PCR. Isolation allowed for full genome sequencing using the Scriptseq V2 RNASeq library preparation kit. A consensus genome for VIDRL-MVE was generated and phylogenetic analysis identified it as Genotype 2. This is the first reported isolation, and full genome sequencing of MVEV from CSF. It is also the first time Genotype 2 has been identified in humans. As such, this case has significant implications for public health surveillance, epidemiology, and the understanding of MVEV evolution.

CSF/plasma ratios of amino acids: reference data and transports in children.

PubMed

Akiyama, Tomoyuki; Kobayashi, Katsuhiro; Higashikage, Akihito; Sato, Junko; Yoshinaga, Harumi

2014-01-01

We intended to investigate the effects of age, gender, and medications on amino acid cerebrospinal fluid (CSF)/plasma ratios in children, and to determine whether amino acid transports across the blood-CSF barrier in children differ from those in adults. Amino acid concentrations measured by ion-exchange high-performance liquid chromatography were used (CSF from 99 children, simultaneously collected plasma from 76 children). Influence of age, gender, and medications on the amino acid CSF concentrations and CSF/plasma ratios were analyzed by linear multiple regression. Interactions of amino acid transports were analyzed by correlation analysis of CSF/plasma ratios. CSF/plasma ratios of serine, valine, histidine, and arginine were higher in younger children. The glutamate CSF/plasma ratio was higher in older children. Serine, alanine, threonine, valine, and histidine CSF/plasma ratios were lower in females. Glutamine, methionine, tyrosine, and phenylalanine CSF/plasma ratios were elevated with valproate therapy. Serine, threonine, valine, leucine, and tyrosine CSF/plasma ratios were lower with clobazam therapy. The asparagine CSF/plasma ratio was elevated with pyridoxal phosphate therapy. Transports of most essential neutral amino acids interacted with each other, as did neutral amino acids with low molecular weights. Cationic amino acids interacted with each other and some essential neutral amino acids. Acidic amino acids had no interactions with other amino acids. Age, gender, and anti-epileptic drugs affect amino acid CSF/plasma ratios in children. Transport interactions between amino acids in children showed no remarkable difference from those of adults and generally followed the substrate specificities of multiple amino acid transport systems. Copyright © 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Expanding the cerebrospinal fluid endopeptidome.

PubMed

Hansson, Karl T; Skillbäck, Tobias; Pernevik, Elin; Kern, Silke; Portelius, Erik; Höglund, Kina; Brinkmalm, Gunnar; Holmén-Larsson, Jessica; Blennow, Kaj; Zetterberg, Henrik; Gobom, Johan

2017-03-01

Biomarkers of neurodegenerative disorders are needed to assist in diagnosis, to monitor disease progression and therapeutic interventions, and to provide insight into disease mechanisms. One route to identify such biomarkers is by proteomic and peptidomic analysis of cerebrospinal fluid (CSF). In the current study, we performed an in-depth analysis of the human CSF endopeptidome to establish an inventory that may serve as a basis for future targeted biomarker studies. High-pH RP HPLC was employed for off-line sample prefractionation followed by low-pH nano-LC-MS analysis. Different software programs and scoring algorithms for peptide identification were employed and compared. A total of 18 031 endogenous peptides were identified at a FDR of 1%, increasing the number of known endogenous CSF peptides 10-fold compared to previous studies. The peptides were derived from 2 053 proteins of which more than 60 have been linked to neurodegeneration. Notably, among the findings were six peptides derived from microtubule-associated protein tau, three of which span the diagnostically interesting threonine-181 (Tau-F isoform). Also, 213 peptides from amyloid precursor protein were identified, 58 of which were partially or completely within the sequence of amyloid β 1-40/42, as well as 109 peptides from apolipoprotein E, spanning sequences that discriminate between the E2/E3/E4 isoforms of the protein. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

Closed-Suction Drainage and Cerebrospinal Fluid Leakage Following Microvascular Decompression : A Retrospective Comparison Study

PubMed Central

Kim, Young-Hoon; Kim, Chae-Yong; Oh, Chang Wan

2013-01-01

Objective We performed this study to investigate whether the use of closed-suction drainage following microvascular decompression (MVD) causes cerebrospinal fluid (CSF) leakage. Methods Between 2004 and 2011, a total of 157 patients with neurovascular compression were treated with MVD. MVD was performed for hemifacial spasm in 150 (95.5%) cases and for trigeminal neuralgia in 7 (4.5%) cases. The mean age of the patients was 49.8±9.6 years (range, 20-69). Dural substitutes were used in 44 (28.0%) patients. Ninety-two patients (58.6%) were underwent a 4-5 cm craniotomy using drainage (drainage group), and 65 (41.4%) did a small 2-2.5 cm retromastoid craniectomy without closed-suction drainage (no-drainage group). Results Eleven (7.0%) patients experienced CSF leakage following MVD based on the criteria of this study; all of these patients were in the drainage group. In the unadjusted analyses, the incidence of CSF leakage was significantly related with the use of closed-suction drainage following MVD (12.0% in the drainage group vs. 0% in the no-drainage group, respectively; p=0.003; Fisher's exact test). Those who received dural substitutes and the elderly (cut-off value=60 years) exhibited a tendency to develop CSF leakage (p=0.075 and p=0.090, respectively; Fisher's exact test). In the multivariate analysis, only the use of closed-suction drainage was significantly and independently associated with the development of CSF leakage following MVD (odds ratio=9.900; 95% confidence interval, 1.418 to infinity; p=0.017). Conclusion The use of closed-suction drainage following MVD appears to be related to the development of CSF leakage. PMID:24175025

Diagnostic value of cerebrospinal fluid Aβ ratios in preclinical Alzheimer's disease.

PubMed

Adamczuk, Katarzyna; Schaeverbeke, Jolien; Vanderstichele, Hugo M J; Lilja, Johan; Nelissen, Natalie; Van Laere, Koen; Dupont, Patrick; Hilven, Kelly; Poesen, Koen; Vandenberghe, Rik

2015-12-18

In this study of preclinical Alzheimer's disease (AD) we assessed the added diagnostic value of using cerebrospinal fluid (CSF) Aβ ratios rather than Aβ42 in isolation for detecting individuals who are positive on amyloid positron emission tomography (PET). Thirty-eight community-recruited cognitively intact older adults (mean age 73, range 65-80 years) underwent (18)F-flutemetamol PET and CSF measurement of Aβ1-42, Aβ1-40, Aβ1-38, and total tau (ttau). (18)F-flutemetamol retention was quantified using standardized uptake value ratios in a composite cortical region (SUVRcomp) with reference to cerebellar grey matter. Based on a prior autopsy validation study, the SUVRcomp cut-off was 1.57. Sensitivities, specificities and cut-offs were defined based on receiver operating characteristic analysis with CSF analytes as variables of interest and (18)F-flutemetamol positivity as the classifier. We also determined sensitivities and CSF cut-off values at fixed specificities of 90 % and 95 %. Seven out of 38 subjects (18 %) were positive on amyloid PET. Aβ42/ttau, Aβ42/Aβ40, Aβ42/Aβ38, and Aβ42 had the highest accuracy to identify amyloid-positive subjects (area under the curve (AUC) ≥ 0.908). Aβ40 and Aβ38 had significantly lower discriminative power (AUC = 0.571). When specificity was fixed at 90 % and 95 %, Aβ42/ttau had the highest sensitivity among the different CSF markers (85.71 % and 71.43 %, respectively). Sensitivity of Aβ42 alone was significantly lower under these conditions (57.14 % and 42.86 %, respectively). For the CSF-based definition of preclinical AD, if a high specificity is required, our data support the use of Aβ42/ttau rather than using Aβ42 in isolation.

Application of κ free light chains in cerebrospinal fluid as a biomarker in multiple sclerosis diagnosis: development of a diagnosis algorithm.

PubMed

Valencia-Vera, Estefania; Martinez-Escribano Garcia-Ripoll, Ana; Enguix, Alfredo; Abalos-Garcia, Carmen; Segovia-Cuevas, Maria Jesus

2018-03-28

The determination of κ free light chains (KFLC) in cerebrospinal fluid (CSF) by nephelometry is a feasible alternative to immunoglobulin G oligoclonal bands (OCB) in the evaluation of intrathecal synthesis of immunoglobulin in multiple sclerosis (MS) and other demyelinating diseases. The aim of this study was to assess the diagnostic value of KFLC and its inclusion in a procedure algorithm along with OCB interpretation. A cross-sectional study, which included 123 patients with a CSF OCB request, was carried out. Isoelectric focusing followed by immunofixation was used to detect OCB, and nephelometry was used to analyze KFLC. The KFLC index was calculated using CSF/serum quotient of KFLC and albumin. The KFLC index was compared with MS diagnosis to find the optimal cutoff. It was obtained from the receiver operating characteristic (ROC) curves and the Youden method. The CSF KFLC median was 1.66 mg/L in the MS group, whereas in other central nervous system diseases, KFLC showed generally no or only moderate increase in CSF (median 0.10 mg/L). KFLC index showed a significant difference between groups. ROC analysis for CSF KFLC concentration, and KFLC indexes were 91.88% and 93.94%, respectively. The best cutoff for the KFLC index was 2.91 for MS diagnosis (sensitivity: 83.78%; specificity: 85.88%). The proposed algorithm showed high sensitivity (89.19%) and specificity (84.71%). KFLC determination is rapid and automatized, but it has no higher sensitivity and specificity than OCB in MS diagnosis. Nevertheless, when used in screening, it could reduce the number of manual OCB tests.

Diagnostic and prognostic value of human prion detection in cerebrospinal fluid.

PubMed

Foutz, Aaron; Appleby, Brian S; Hamlin, Clive; Liu, Xiaoqin; Yang, Sheng; Cohen, Yvonne; Chen, Wei; Blevins, Janis; Fausett, Cameron; Wang, Han; Gambetti, Pierluigi; Zhang, Shulin; Hughson, Andrew; Tatsuoka, Curtis; Schonberger, Lawrence B; Cohen, Mark L; Caughey, Byron; Safar, Jiri G

2017-01-01

Several prion amplification systems have been proposed for detection of prions in cerebrospinal fluid (CSF), most recently, the measurements of prion seeding activity with second-generation real-time quaking-induced conversion (RT-QuIC). The objective of this study was to investigate the diagnostic performance of the RT-QuIC prion test in the broad phenotypic spectrum of prion diseases. We performed CSF RT-QuIC testing in 2,141 patients who had rapidly progressive neurological disorders, determined diagnostic sensitivity and specificity in 272 cases that were autopsied, and evaluated the impact of mutations and polymorphisms in the PRNP gene, and type 1 or type 2 human prions on diagnostic performance. The 98.5% diagnostic specificity and 92% sensitivity of CSF RT-QuIC in a blinded retrospective analysis matched the 100% specificity and 95% sensitivity of a blind prospective study. The CSF RT-QuIC differentiated 94% of cases of sporadic Creutzfeldt-Jakob disease (sCJD) MM1 from the sCJD MM2 phenotype, and 80% of sCJD VV2 from sCJD VV1. The mixed prion type 1-2 and cases heterozygous for codon 129 generated intermediate CSF RT-QuIC patterns, whereas genetic prion diseases revealed distinct profiles for each PRNP gene mutation. The diagnostic performance of the improved CSF RT-QuIC is superior to surrogate marker tests for prion diseases such as 14-3-3 and tau proteins, and together with PRNP gene sequencing the test allows the major prion subtypes to be differentiated in vivo. This differentiation facilitates prediction of the clinicopathological phenotype and duration of the disease-two important considerations for envisioned therapeutic interventions. ANN NEUROL 2017;81:79-92. © 2016 American Neurological Association.

Diagnostic and Prognostic Value of Human Prion Detection in Cerebrospinal Fluid

PubMed Central

Foutz, Aaron; Appleby, Brian S.; Hamlin, Clive; Liu, Xiaoqin; Yang, Sheng; Cohen, Yvonne; Chen, Wei; Blevins, Janis; Fausett, Cameron; Wang, Han; Gambetti, Pierluigi; Zhang, Shulin; Hughson, Andrew; Tatsuoka, Curtis; Schonberger, Lawrence B.; Cohen, Mark L.; Caughey, Byron; Safar, Jiri G.

2016-01-01

Objective Several prion amplification systems have been proposed for detection of prions in cerebrospinal fluid (CSF), most recently, the measurements of prion seeding activity with second-generation real-time quaking-induced conversion (RT-QuIC). The objective of this study was to investigate the diagnostic performance of the RT-QuIC prion test in the broad phenotypic spectrum of prion diseases. Methods We performed CSF RT-QuIC testing in 2,141 patients who had rapidly progressive neurological disorders, determined diagnostic sensitivity and specificity in 272 cases which were autopsied, and evaluated the impact of mutations and polymorphisms in the PRNP gene, and Type 1 or Type 2 of human prions on diagnostic performance. Results The 98.5% diagnostic specificity and 92% sensitivity of CSF RT-QuIC in a blinded retrospective analysis matched the 100% specificity and 95% sensitivity of a blind prospective study. The CSF RT-QuIC differentiated 94% of cases of sporadic Creutzfeldt-Jakob disease (sCJD) MM1 from the sCJD MM2 phenotype, and 80% of sCJD VV2 from sCJD VV1. The mixed prion type 1–2 and cases heterozygous for codon 129 generated intermediate CSF RT-QuIC patterns, while genetic prion diseases revealed distinct profiles for each PRNP gene mutation. Interpretation The diagnostic performance of the improved CSF RT-QuIC is superior to surrogate marker tests for prion diseases such as 14-3-3 and Tau proteins and together with PRNP gene sequencing, the test allows the major prion subtypes to be differentiated in vivo. This differentiation facilitates prediction of the clinicopathological phenotype and duration of the disease—two important considerations for envisioned therapeutic interventions. PMID:27893164

Cerebrospinal fluid HIV RNA in persons living with HIV.

PubMed

Di Carlofelice, M; Everitt, A; Muir, D; Winston, A

2018-05-01

Despite adequate suppression of plasma HIV RNA, viral escape in cerebrospinal fluid (CSF) is widely reported. Rates of CSF HIV RNA escape vary in the literature. In persons living with HIV (PLWH) undergoing lumbar puncture examination for clinical reasons, we assessed rates of CSF HIV RNA escape. Persons living with HIV attending a designated HIV neurology service undergoing CSF assessment for clinical reasons between January 2015 and April 2017 were included in the study. CSF HIV RNA escape was defined as HIV RNA ≥ 0.5 log 10 HIV-1 RNA copies/mL higher than plasma HIV RNA or detectable CSF HIV RNA when plasma HIV RNA was < 20 copies/mL. Clinical factors associated with CSF HIV RNA were assessed using logistic regression modelling. Of 38 individuals, 35 were receiving antiretroviral therapy, 30 were male and their mean age was 51 years. Clinical reasons for CSF assessment included investigation for cognitive decline (n = 25), early syphilis (n = 4) and other central nervous system (CNS) conditions (n = 9). HIV RNA was detectable in plasma and CSF in seven and six individuals, respectively, with two individuals (5.3%) meeting the definition of CSF escape. Detectable CSF HIV RNA was associated with a detectable plasma HIV RNA (P < 0.001) and a history of known antiretroviral drug resistance mutations (P = 0.021). The prevalence of CSF viral escape in PLWH undergoing lumbar puncture examination for clinical reasons is lower than previously reported. © 2018 British HIV Association.

CCR6+ Th cells in the cerebrospinal fluid of persons with multiple sclerosis are dominated by pathogenic non-classic Th1 cells and GM-CSF-only-secreting Th cells.

PubMed

Restorick, S M; Durant, L; Kalra, S; Hassan-Smith, G; Rathbone, E; Douglas, M R; Curnow, S J

2017-08-01

Considerable attention has been given to CCR6 + IL-17-secreting CD4 + T cells (Th17) in the pathology of a number of autoimmune diseases including multiple sclerosis (MS). However, other Th subsets also play important pathogenic roles, including those that secrete IFNγ and GM-CSF. CCR6 expression by Th17 cells allows their migration across the choroid plexus into the cerebrospinal fluid (CSF), where they are involved in the early phase of experimental autoimmune encephalomyelitis (EAE), and in MS these cells are elevated in the CSF during relapses and contain high frequencies of autoreactive cells. However, the relatively low frequency of Th17 cells suggests they cannot by themselves account for the high percentage of CCR6 + cells in MS CSF. Here we identify the dominant CCR6 + T cell subsets in both the blood and CSF as non-classic Th1 cells, including many that secrete GM-CSF, a key encephalitogenic cytokine. In addition, we show that Th cells secreting GM-CSF but not IFNγ or IL-17, a subset termed GM-CSF-only-secreting Th cells, also accumulate in the CSF. Importantly, in MS the proportion of IFNγ- and GM-CSF-secreting T cells expressing CCR6 was significantly enriched in the CSF, and was elevated in MS, suggesting these cells play a pathogenic role in this disease. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

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

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 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

Confocal Raman microscopy of pathologic cells in cerebrospinal fluid

NASA Astrophysics Data System (ADS)

Gonchukov, S. A.; Lonkina, T. V.; Minaeva, S. A.; Sundukov, A. V.; Migmanov, T. E.; Lademann, J.; Darvin, M. E.; Bagratashvili, V. N.

2014-01-01

In this work, the spatial localization of leucocytes, bacteria, and erythrocytes in the crystal pattern of a dried droplet of cerebrospinal fluid (CSF) is established. Characteristic lines are detected and identified in the Raman spectrum of the CSF that point to the presence of pathologic cells therein and can be used in a timely way to diagnose meningitis, the spectroscopic sample preparation procedure being simple enough. A dry CSF sample retains its characteristic spectral features for no less than three days, which is important for its safe keeping and transportation, and also for the computer processing of its spectra.

Use of Fetal Magnetic Resonance Image Analysis and Machine Learning to Predict the Need for Postnatal Cerebrospinal Fluid Diversion in Fetal Ventriculomegaly.

PubMed

Pisapia, Jared M; Akbari, Hamed; Rozycki, Martin; Goldstein, Hannah; Bakas, Spyridon; Rathore, Saima; Moldenhauer, Julie S; Storm, Phillip B; Zarnow, Deborah M; Anderson, Richard C E; Heuer, Gregory G; Davatzikos, Christos

2018-02-01

Which children with fetal ventriculomegaly, or enlargement of the cerebral ventricles in utero, will develop hydrocephalus requiring treatment after birth is unclear. To determine whether extraction of multiple imaging features from fetal magnetic resonance imaging (MRI) and integration using machine learning techniques can predict which patients require postnatal cerebrospinal fluid (CSF) diversion after birth. This retrospective case-control study used an institutional database of 253 patients with fetal ventriculomegaly from January 1, 2008, through December 31, 2014, to generate a predictive model. Data were analyzed from January 1, 2008, through December 31, 2015. All 25 patients who required postnatal CSF diversion were selected and matched by gestational age with 25 patients with fetal ventriculomegaly who did not require CSF diversion (discovery cohort). The model was applied to a sample of 24 consecutive patients with fetal ventriculomegaly who underwent evaluation at a separate institution (replication cohort) from January 1, 1998, through December 31, 2007. Data were analyzed from January 1, 1998, through December 31, 2009. To generate the model, linear measurements, area, volume, and morphologic features were extracted from the fetal MRI, and a machine learning algorithm analyzed multiple features simultaneously to find the combination that was most predictive of the need for postnatal CSF diversion. Accuracy, sensitivity, and specificity of the model in correctly classifying patients requiring postnatal CSF diversion. A total of 74 patients (41 girls [55%] and 33 boys [45%]; mean [SD] gestational age, 27.0 [5.6] months) were included from both cohorts. In the discovery cohort, median time to CSF diversion was 6 days (interquartile range [IQR], 2-51 days), and patients with fetal ventriculomegaly who did not develop symptoms were followed up for a median of 29 months (IQR, 9-46 months). The model correctly classified patients who required CSF diversion with 82% accuracy, 80% sensitivity, and 84% specificity. In the replication cohort, the model achieved 91% accuracy, 75% sensitivity, and 95% specificity. Image analysis and machine learning can be applied to fetal MRI findings to predict the need for postnatal CSF diversion. The model provides prognostic information that may guide clinical management and select candidates for potential fetal surgical intervention.

Effect of cerebral spinal fluid suppression for diffusional kurtosis imaging.

PubMed

Yang, Alicia W; Jensen, Jens H; Hu, Caixia C; Tabesh, Ali; Falangola, Maria F; Helpern, Joseph A

2013-02-01

To evaluate the cerebral spinal fluid (CSF) partial volume effect on diffusional kurtosis imaging (DKI) metrics in white matter and cortical gray matter. Four healthy volunteers participated in this study. Standard DKI and fluid-attenuated inversion recovery (FLAIR) DKI experiments were performed using a twice-refocused-spin-echo diffusion sequence. The conventional diffusion tensor imaging (DTI) metrics of fractional anisotropy (FA), mean, axial, and radial diffusivity (MD, D[symbol in text], D[symbol in text] together with DKI metrics of mean, axial, and radial kurtosis (MK, K[symbol in text], K[symbol in text], were measured and compared. Single image slices located above the lateral ventricles, with similar anatomical features for each subject, were selected to minimize the effect of CSF from the ventricles. In white matter, differences of less than 10% were observed between diffusion metrics measured with standard DKI and FLAIR-DKI sequences, suggesting minimal CSF contamination. For gray matter, conventional DTI metrics differed by 19% to 52%, reflecting significant CSF partial volume effects. Kurtosis metrics, however, changed by 11% or less, indicating greater robustness with respect to CSF contamination. Kurtosis metrics are less sensitive to CSF partial voluming in cortical gray matter than conventional diffusion metrics. The kurtosis metrics may then be more specific indicators of changes in tissue microstructure, provided the effect sizes for the changes are comparable. Copyright © 2012 Wiley Periodicals, Inc.

Paracetamol plasma and cerebrospinal fluid pharmacokinetics in children

PubMed Central

Anderson, B J; Holford, N H G; Woollard, G A; Chan, P L S

1998-01-01

Aims Paracetamol has a central action for both antipyresis and analgesia. Maximum temperature decrease and peak analgesia are reported at 1–2 h after peak plasma paracetamol concentration. We wished to determine the relationship between plasma and cerebrospinal fluid (CSF) pharmacokinetics in children. Methods Concentration-time profiles in plasma and CSF after nasogastric paracetamol 40 mg kg−1 were measured in nine children who had indwelling ventricular drains. Estimation of population pharmacokinetic parameters was made using both a standard two-stage population approach (MKMODEL) and a nonlinear mixed effect model (NONMEM). Results were standardized to a 70 kg person using an allometric power model. Results Both approaches gave similar estimates. NONMEM parameter estimates were clearance 10.2 l h−1 (CV 47%), volume of distribution 67.1 l (CV 58%) and absorption rate constant 0.77 h−1 (CV 49%). Cerebrospinal fluid concentrations lagged behind those of plasma. The equilibration half time was 0.72 h (CV 117%). The CSF/plasma partition coefficient was 1.18 (CV 8%). Conclusions Higher concentrations in the CSF probably reflect the lower free water volume of plasma. The CSF equilibration half time suggests that CSF kinetics approximate more closely to the effect compartment than plasma, but further time is required for paracetamol to exert its effects. Effect site concentrations equilibrate slowly with plasma. Paracetamol should be given 1–2 h before anticipated pain or fever in children. PMID:9764964

The role of ICP monitoring in patients with persistent cerebrospinal fluid leak following spinal surgery: a case series.

PubMed

Craven, Claudia; Toma, Ahmed K; Khan, Akbar A; Watkins, Laurence D

2016-09-01

Cerebrospinal fluid (CSF) leak following spinal surgery is a relatively common surgical complication. A disturbance in the underlying CSF dynamics could be the causative factor in a small group of patients with refractory CSF leaks that require multiple surgical repairs and prolonged hospital admission. A retrospective case series of patients with persistent post spinal surgery CSF leak referred to the hydrocephalus service for continuous intracranial pressure (ICP) monitoring. Patients' notes were reviewed for medical history, ICP data, radiological data, and subsequent management and outcome. Five patients (two males/three females, mean age, 35.4 years) were referred for ICP monitoring over a 12-month period. These patients had prolonged CSF leak despite multiple repair attempts 252 ± 454 days (mean ± SD). On ICP monitoring, all five patients had abnormal results, with the mean ICP 8.95 ± 4.41 mmHg. Four had abnormal pulse amplitudes, mean 6.15 mmHg ± 1.22 mmHg. All five patients underwent an intervention. Three patients underwent insertion of ventriculoperitoneal (VP) shunts. One patient had venous sinus stent insertion and one patient underwent medical management with acetazolamide. All five of the patients' CSF leak resolved post intervention. The mean time to resolution of CSF leak post intervention was 10.8  ± 12.9 days. Abnormal cerebrospinal fluid dynamics could be the underlying factor in patients with a persistent and treatment-refractory CSF leak post spinal surgery. Treatments aimed at lowering ICP may be beneficial in this group of patients. Whether abnormal pressure and dynamics represent a pre-existing abnormality or is induced by spinal surgery should be a subject of further study.

Truncated cystatin C in cerebrospiral fluid: Technical [corrected] artefact or biological process?

PubMed

Carrette, Odile; Burkhard, Pierre R; Hughes, Severine; Hochstrasser, Denis F; Sanchez, Jean-Charles

2005-08-01

Cystatin C, a low molecular weight cysteine proteinase inhibitor present in human body fluids at physiological concentrations, is more expressed in cerebrospinal fluid (CSF) than in plasma. Mass spectrometric characterization showed that after 3 months of storage of human CSF at -20 degrees C, cystatin C was cleaved in the peptide bond between R8 and L9 and lost its eight N-termini amino acids, whereas this cleavage did not occur when stored at -80 degrees C. This truncation occurred in all CSF samples studied irrespective of the underlying neurological status, indicating a storage-related artefact rather than a physiological or pathological processing of the protein. These results stress the importance of optimal preanalytical storage conditions of any sample prior to proteomics studies.

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.

Elevated host lipid metabolism revealed by iTRAQ-based quantitative proteomic analysis of cerebrospinal fluid of tuberculous meningitis patients

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

Mu, Jun; Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing; Chongqing Key Laboratory of Neurobiology, Chongqing

Purpose: Tuberculous meningitis (TBM) remains to be one of the most deadly infectious diseases. The pathogen interacts with the host immune system, the process of which is largely unknown. Various cellular processes of Mycobacterium tuberculosis (MTB) centers around lipid metabolism. To determine the lipid metabolism related proteins, a quantitative proteomic study was performed here to identify differential proteins in the cerebrospinal fluid (CSF) obtained from TBM patients (n = 12) and healthy controls (n = 12). Methods: CSF samples were desalted, concentrated, labelled with isobaric tags for relative and absolute quantitation (iTRAQ™), and analyzed by multi-dimensional liquid chromatography-tandem mass spectrometry (LC-MS/MS). Gene ontology andmore » proteomic phenotyping analysis of the differential proteins were conducted using Database for Annotation, Visualization, and Integrated Discovery (DAVID) Bioinformatics Resources. ApoE and ApoB were selected for validation by ELISA. Results: Proteomic phenotyping of the 4 differential proteins was invloved in the lipid metabolism. ELISA showed significantly increased ApoB levels in TBM subjects compared to healthy controls. Area under the receiver operating characteristic curve analysis demonstrated ApoB levels could distinguish TBM subjects from healthy controls and viral meningitis subjects with 89.3% sensitivity and 92% specificity. Conclusions: CSF lipid metabolism disregulation, especially elevated expression of ApoB, gives insights into the pathogenesis of TBM. Further evaluation of these findings in larger studies including anti-tuberculosis medicated and unmedicated patient cohorts with other center nervous system infectious diseases is required for successful clinical translation. - Highlights: • The first proteomic study on the cerebrospinal fluid of tuberculous meningitis patients using iTRAQ. • Identify 4 differential proteins invloved in the lipid metabolism. • Elevated expression of ApoB gives insights into the pathogenesis of TBM.« less

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.

Detection of cerebrospinal fluid leakage by specific measurement of transferrin glycoforms.

PubMed

Kwon, Seok-Joon; Zhang, Fuming; Dordick, Jonathan S; Sonstein, William J; Linhardt, Robert J

2015-10-01

A simple and rapid detection of cerebrospinal fluid (CSF) leakage would benefit spine surgeons making critical postoperative decisions on patient care. We have assessed novel approaches to selectively determine CSF β2-transferrin (β2TF), an asialo-transferrin (aTF) biomarker, without interference from serum sialo-transferrin (sTF) in test samples. First, we performed mild periodate oxidation to selectively generate aldehyde groups in sTF for capture with magnetic hydrazide microparticles, and selective removal with a magnetic separator. Using this protocol sTF was selectively removed from mixtures of CSF and serum containing CSF aTF (β2TF) and serum sTF, respectively. Second, a two-step enzymatic method was developed with neuraminidase and galactose oxidase for generating aldehyde groups in sTF present in CSF and serum mixtures for magnetic hydrazide microparticle capture. After selectively removing sTF from mixtures of CSF and serum, ELISA could detect significant TF signal only in CSF, while the TF signal in serum was negligible. The new approach for selective removal of only sTF in test samples will be promising for the required intervention by a spine surgeon. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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.

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

Effect of protein binding on unbound atazanavir and darunavir cerebrospinal fluid concentrations.

PubMed

Delille, Cecile A; Pruett, Sarah T; Marconi, Vincent C; Lennox, Jeffrey L; Armstrong, Wendy S; Arrendale, Richard F; Sheth, Anandi N; Easley, Kirk A; Acosta, Edward P; Vunnava, Aswani; Ofotokun, Ighovwerha

2014-09-01

HIV-1 protease inhibitors (PIs) exhibit different protein binding affinities and achieve variable plasma and tissue concentrations. Degree of plasma protein binding may impact central nervous system penetration. This cross-sectional study assessed cerebrospinal fluid (CSF) unbound PI concentrations, HIV-1 RNA, and neopterin levels in subjects receiving either ritonavir-boosted darunavir (DRV), 95% plasma protein bound, or atazanavir (ATV), 86% bound. Unbound PI trough concentrations were measured using rapid equilibrium dialysis and liquid chromatography/tandem mass spectrometry. Plasma and CSF HIV-1 RNA and neopterin were measured by Ampliprep/COBAS® Taqman® 2.0 assay (Roche) and enzyme-linked immunosorbent assay (ALPCO), respectively. CSF/plasma unbound drug concentration ratio was higher for ATV, 0.09 [95% confidence interval (CI) 0.06-0.12] than DRV, 0.04 (95%CI 0.03-0.06). Unbound CSF concentrations were lower than protein adjusted wild-type inhibitory concentration-50 (IC50 ) in all ATV and 1 DRV-treated subjects (P < 0.001). CSF HIV-1 RNA was detected in 2/15 ATV and 4/15 DRV subjects (P = 0.65). CSF neopterin levels were low and similar between arms. ATV relative to DRV had higher CSF/plasma unbound drug ratio. Low CSF HIV-1 RNA and neopterin suggest that both regimens resulted in CSF virologic suppression and controlled inflammation. © 2014, The American College of Clinical Pharmacology.

Effect of Protein Binding on Unbound Atazanavir and Darunavir Cerebrospinal Fluid Concentrations

PubMed Central

Delille, Cecile A.; Pruett, Sarah T.; Marconi, Vincent C.; Lennox, Jeffrey L.; Armstrong, Wendy S.; Arrendale, Richard F.; Sheth, Anandi N.; Easley, Kirk A.; Acosta, Edward P.; Vunnava, Aswani; Ofotokun, Ighovwerha

2015-01-01

HIV-1 protease inhibitors (PIs) exhibit different protein binding affinities and achieve variable plasma and tissue concentrations. Degree of plasma protein binding may impact central nervous system penetration. This cross-sectional study assessed cerebrospinal fluid (CSF) unbound PI concentrations, HIV-1 RNA, and neopterin levels in subjects receiving either ritonavir-boosted darunavir (DRV), 95% plasma protein bound, or atazanavir (ATV), 86% bound. Unbound PI trough concentrations were measured using rapid equilibrium dialysis and liquid chromatography/tandem mass spectrometry. Plasma and CSF HIV-1 RNA and neopterin were measured by Ampliprep/COBAS® Taqman® 2.0 assay (Roche) and enzyme-linked immunosorbent assay (ALPCO), respectively. CSF/plasma unbound drug concentration ratio was higher for ATV, 0.09 [95% confidence interval (CI) 0.06–0.12] than DRV, 0.04 (95%CI 0.03–0.06). Unbound CSF concentrations were lower than protein adjusted wild-type inhibitory concentration-50 (IC50) in all ATV and 1 DRV-treated subjects (P < 0.001). CSF HIV-1 RNA was detected in 2/15 ATV and 4/15 DRV subjects (P = 0.65). CSF neopterin levels were low and similar between arms. ATV relative to DRV had higher CSF/plasma unbound drug ratio. Low CSF HIV-1 RNA and neopterin suggest that both regimens resulted in CSF virologic suppression and controlled inflammation. PMID:24691856

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.

Cerebrospinal Fluid Levels of Amyloid Beta 1-43 Mirror 1-42 in Relation to Imaging Biomarkers of Alzheimer’s Disease

PubMed Central

Almdahl, Ina S.; Lauridsen, Camilla; Selnes, Per; Kalheim, Lisa F.; Coello, Christopher; Gajdzik, Beata; Møller, Ina; Wettergreen, Marianne; Grambaite, Ramune; Bjørnerud, Atle; Bråthen, Geir; Sando, Sigrid B.; White, Linda R.; Fladby, Tormod

2017-01-01

Introduction: Amyloid beta 1-43 (Aβ43), with its additional C-terminal threonine residue, is hypothesized to play a role in early Alzheimer’s disease pathology possibly different from that of amyloid beta 1-42 (Aβ42). Cerebrospinal fluid (CSF) Aβ43 has been suggested as a potential novel biomarker for predicting conversion from mild cognitive impairment (MCI) to dementia in Alzheimer’s disease. However, the relationship between CSF Aβ43 and established imaging biomarkers of Alzheimer’s disease has never been assessed. Materials and Methods: In this observational study, CSF Aβ43 was measured with ELISA in 89 subjects; 34 with subjective cognitive decline (SCD), 51 with MCI, and four with resolution of previous cognitive complaints. All subjects underwent structural MRI; 40 subjects on a 3T and 50 on a 1.5T scanner. Forty subjects, including 24 with SCD and 12 with MCI, underwent 18F-Flutemetamol PET. Seventy-eight subjects were assessed with 18F-fluorodeoxyglucose PET (21 SCD/7 MCI and 11 SCD/39 MCI on two different scanners). Ten subjects with SCD and 39 with MCI also underwent diffusion tensor imaging. Results: Cerebrospinal fluid Aβ43 was both alone and together with p-tau a significant predictor of the distinction between SCD and MCI. There was a marked difference in CSF Aβ43 between subjects with 18F-Flutemetamol PET scans visually interpreted as negative (37 pg/ml, n = 27) and positive (15 pg/ml, n = 9), p < 0.001. Both CSF Aβ43 and Aβ42 were negatively correlated with standardized uptake value ratios for all analyzed regions; CSF Aβ43 average rho -0.73, Aβ42 -0.74. Both CSF Aβ peptides correlated significantly with hippocampal volume, inferior parietal and frontal cortical thickness and axial diffusivity in the corticospinal tract. There was a trend toward CSF Aβ42 being better correlated with cortical glucose metabolism. None of the studied correlations between CSF Aβ43/42 and imaging biomarkers were significantly different for the two Aβ peptides when controlling for multiple testing. Conclusion: Cerebrospinal fluid Aβ43 appears to be strongly correlated with cerebral amyloid deposits in the same way as Aβ42, even in non-demented patients with only subjective cognitive complaints. Regarding imaging biomarkers, there is no evidence from the present study that CSF Aβ43 performs better than the classical CSF biomarker Aβ42 for distinguishing SCD and MCI. PMID:28223932

Inflammation in complex regional pain syndrome

PubMed Central

Parkitny, Luke; McAuley, James H.; Di Pietro, Flavia; Stanton, Tasha R.; O’Connell, Neil E.; Marinus, Johan; van Hilten, Jacobus J.

2013-01-01

Objectives: We conducted a systematic review of the literature with meta-analysis to determine whether complex regional pain syndrome (CRPS) is associated with a specific inflammatory profile and whether this is dependent on the duration of the condition. Methods: Comprehensive searches of the literature using MEDLINE, Embase, Scopus, Web of Science, and reference lists from published reviews identified articles that measured inflammatory factors in CRPS. Two independent investigators screened titles and abstracts, and performed data extraction and risk of bias assessments. Studies were subgrouped by medium (blood, blister fluid, and CSF) and duration (acute and chronic CRPS). Where possible, meta-analyses of inflammatory factor concentrations were performed and pooled effect sizes were calculated using random-effects models. Results: Twenty-two studies were included in the systematic review and 15 in the meta-analysis. In acute CRPS, the concentrations of interleukin (IL)-8 and soluble tumor necrosis factor receptors I (sTNF-RI) and II (sTNF-RII) were significantly increased in blood. In chronic CRPS, significant increases were found in 1) TNFα, bradykinin, sIL-1RI, IL-1Ra, IL-2, sIL-2Ra, IL-4, IL-7, interferon-γ, monocyte chemoattractant protein-1 (MCP-1), and sRAGE (soluble receptor for advanced glycation end products) in blood; 2) IL-1Ra, MCP-1, MIP-1β, and IL-6 in blister fluid; and 3) IL-1β and IL-6 in CSF. Chronic CRPS was also associated with significantly decreased 1) substance P, sE-selectin, sL-selectin, sP-selectin, and sGP130 in blood; and 2) soluble intercellular adhesion molecule-1 (sICAM-1) in CSF. Most studies failed to meet 3 or more of our quality criteria. Conclusion: CRPS is associated with the presence of a proinflammatory state in the blood, blister fluid, and CSF. Different inflammatory profiles were found for acute and chronic cases. PMID:23267031

CSF beta-amyloid 1–42 – what are we measuring in Alzheimer's disease?

PubMed Central

Hu, William T; Watts, Kelly D; Shaw, Leslie M; Howell, Jennifer C; Trojanowski, John Q; Basra, Sundeep; Glass, Jonathan D; Lah, James J; Levey, Allan I

2015-01-01

Objective To characterize biological and technical factors which influence cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarker levels, including the presence of apolipoprotein E (APOE) ε4 allele, AD diagnosis, Aβ-binding proteins, sample processing, and preanalytical handling. Methods CSF was collected from 140 subjects with normal cognition, mild cognitive impairment, AD, and non-AD dementia. CSF levels of beta-amyloid 1–42 (Aβ42), total Tau (t-Tau), and Tau phosphorylated at threonine 181 (p-Tau181) were analyzed following the standard and modified protocols. CSF levels of apoJ, apoE, albumin, and α-synuclein were measured in a subgroup (n = 69), and their effects on measured AD biomarker levels were also determined in vitro using human CSF samples. Results CSF Aβ42 levels measured using the AD Neuro-imaging Initiative (ADNI) protocol (which we call suspended Aβ42 or susAβ) were lower than total measurable CSF Aβ42 in all groups, and on average represents 57% of the latter. Logistic regression analysis showed this proportion (% susAβ) to be directly correlated with CSF Aβ42 and apoJ levels, but inversely correlated with CSF t-Tau levels. Finally, we showed in vitro that increasing apoE and apoJ levels directly increased % susAβ. Conclusion CSF susAβ levels are influenced by biological and technical factors, and may represent a marker of Aβ susceptible to lipoprotein-mediated clearance. Clinical trials should include total measurable Aβ42 and susAβ to better inform outcomes. PMID:25750918

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.

Clinical evaluation of a loop-mediated isothermal amplification (LAMP) assay for rapid detection of Neisseria meningitidis in cerebrospinal fluid.

PubMed

Lee, DoKyung; Kim, Eun Jin; Kilgore, Paul E; Kim, Soon Ae; Takahashi, Hideyuki; Ohnishi, Makoto; Anh, Dang Duc; Dong, Bai Qing; Kim, Jung Soo; Tomono, Jun; Miyamoto, Shigehiko; Notomi, Tsugunori; Kim, Dong Wook; Seki, Mitsuko

2015-01-01

Neisseria meningitidis (Nm) is a leading causative agent of bacterial meningitis in humans. Traditionally, meningococcal meningitis has been diagnosed by bacterial culture. However, isolation of bacteria from patients' cerebrospinal fluid (CSF) is time consuming and sometimes yields negative results. Recently, polymerase chain reaction (PCR)-based diagnostic methods of detecting Nm have been considered the gold standard because of their superior sensitivity and specificity compared with culture. In this study, we developed a loop-mediated isothermal amplification (LAMP) method and evaluated its ability to detect Nm in cerebrospinal fluid (CSF). We developed a meningococcal LAMP assay (Nm LAMP) that targets the ctrA gene. The primer specificity was validated using 16 strains of N. meningitidis (serogroup A, B, C, D, 29-E, W-135, X, Y, and Z) and 19 non-N. meningitidis species. Within 60 min, the Nm LAMP detected down to ten copies per reaction with sensitivity 1000-fold more than that of conventional PCR. The LAMP assays were evaluated using a set of 1574 randomly selected CSF specimens from children with suspected meningitis collected between 1998 and 2002 in Vietnam, China, and Korea. The LAMP method was shown to be more sensitive than PCR methods for CSF samples (31 CSF samples were positive by LAMP vs. 25 by PCR). The detection rate of the LAMP method was substantially higher than that of the PCR method. In a comparative analysis of the PCR and LAMP assays, the clinical sensitivity, specificity, positive predictive value, and negative predictive value of the LAMP assay were 100%, 99.6%, 80.6%, and 100%, respectively. Compared to PCR, LAMP detected Nm with higher analytical and clinical sensitivity. This sensitive and specific LAMP method offers significant advantages for screening patients on a population basis and for diagnosis in clinical settings.

Connective tissue spectrum abnormalities associated with spontaneous cerebrospinal fluid leaks: a prospective study.

PubMed

Reinstein, Eyal; Pariani, Mitchel; Bannykh, Serguei; Rimoin, David L; Schievink, Wouter I

2013-04-01

We aimed to assess the frequency of connective tissue abnormalities among patients with cerebrospinal fluid (CSF) leaks in a prospective study using a large cohort of patients. We enrolled a consecutive group of 50 patients, referred for consultation because of CSF leak. All patients have been carefully examined for the presence of connective tissue abnormalities, and based on findings, patients underwent genetic testing. Ancillary diagnostic studies included echocardiography, eye exam, and histopathological examinations of skin and dura biopsies in selected patients. We identified nine patients with heritable connective tissue disorders, including Marfan syndrome, Ehlers-Danlos syndrome and other unclassified forms. In seven patients, spontaneous CSF leak was the first noted manifestation of the genetic disorder. We conclude that spontaneous CSF leaks are associated with a spectrum of connective tissue abnormalities and may be the first noted clinical presentation of the genetic disorder. We propose that there is a clinical basis for considering spontaneous CSF leak as a clinical manifestation of heritable connective tissue disorders, and we suggest that patients with CSF leaks should be screened for connective tissue and vascular abnormalities.

Cerebrospinal fluid and plasma C-reactive protein and aggression in personality-disordered subjects: a pilot study.

PubMed

Coccaro, Emil F; Lee, Royce; Coussons-Read, Mary

2015-02-01

C-reactive protein (CRP), in the plasma, serves as a marker of systemic inflammation and has been shown to correlate with history of actual aggressive behavior, and as a personality trait of aggressive tendency, in human subjects. This pilot study was conducted to determine if plasma CRP levels are correlated with cerebrospinal fluid levels (CSF CRP) and if CSF CRP also correlates with aggression. If so, this would suggest a role for central inflammatory processes in human aggression. Both plasma and basal lumbar CSF samples were obtained from 17 subjects with DSM-5 personality disorder and assayed for CRP. Plasma and CSF CRP levels were correlated (r = 0.65, p = 0.005) and each correlated with aggression (Plasma: r = 0.53, p = 0.029; CSF: r = 0.84, p < 0.001). When considered simultaneously, CSF CRP, but not plasma CRP, uniquely correlated with aggression. No relationship was seen with other measures of psychopathology. These data suggest a positive relationship between central nervous system CRP and aggression in humans.

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.

Rostral cranial fossa as a site for cerebrospinal fluid drainage - volumetric studies in dog breeds of different size and morphotype.

PubMed

Sokołowski, Wojciech; Czubaj, Norbert; Skibniewski, Michał; Barszcz, Karolina; Kupczyńska, Marta; Kinda, Wojciech; Kiełbowicz, Zdzisław

2018-05-18

Hydrocephalus is a multifactorial condition, whose aetiology is not fully understood. Congenital hydrocephalus frequently occurs in small and brachycephalic dog breeds. Although it is widely accepted that the cribriform plate located in the rostral cranial fossa (RCF) is a site of cerebrospinal fluid (CSF) drainage, the RCF has not been studied extensively. Literature reports indicate that a decreased caudal cranial fossa (CCF) volume in the course of the Chiari-like malformation may obstruct CSF circulation. We hypothesised that morphological diversity among different breeds in the volume of the RCF may affect CSF circulation. The aim of the study was to carry out a volumetric analysis of the RCF and the cranial cavity and to determine the ratio between them in dog breeds of different size and morphotype. We performed computed tomography (CT) morphometric analysis of the RCF compartment by obtaining volume measurements from the transverse and reformatted sagittal and dorsal planes. The rostral cranial fossa percentage - volume of the rostral cranial fossa/volume of cranial cavity × 100 (volRCF/volCC × 100) was lower in small and brachycephalic dog breeds than in the other dogs. A reduced RCF volume was detected in small and brachycephalic dog breeds, some of which are predisposed to congenital hydrocephalus. This may lead to overcrowding of brain parenchyma in the RCF and may impede CSF circulation. Our observations may be useful for future studies focusing on the causes and new therapies to treat conditions such as hydrocephalus and syringomyelia.

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).

Longitudinal Analysis of Cerebrospinal Fluid and Plasma HIV-1 Envelope Sequences Isolated From a Single Donor with HIV Asymptomatic Neurocognitive Impairment

PubMed Central

Vázquez-Santiago, Fabián; García, Yashira; Rivera-Román, Ivelisse; Noel, Richard J.; Wojna, Valerie; Meléndez, Loyda M.; Rivera-Amill, Vanessa

2015-01-01

Objective Combined antiretroviral treatment (cART) has changed the clinical presentation of HIV-associated neurocognitive disorders (HAND) to that of the milder forms of the disease. Asymptomatic neurocognitive impairment (ANI) is now more prevalent and is associated with increased morbidity and mortality risk in HIV-1–infected people. HIV-1 envelope (env) genetic heterogeneity has been detected within the central nervous system (CNS) of individuals with ANI. Changes within env determine co-receptor use, cellular tropism, and neuropathogenesis. We hypothesize that compartmental changes are associated with HIV-1 env C2V4 during ANI and sought to analyze paired HIV-1 env sequences from plasma and cerebrospinal fluid (CSF) of a female subject undergoing long-term cART. Methods Paired plasma and CSF samples were collected at 12-month intervals and HIV-1 env C2V4 was cloned and sequenced. Results Phylogenetic analysis of paired samples consistently showed genetic variants unique to the CSF. Phenotypic prediction showed CCR5 (R5) variants for all CSF-derived sequences and showed minor X4 variants (or dual-tropic) in the plasma at later time points. Viral compartmentalization was evident throughout the study, suggesting that the occurrence of distinctive env strains may contribute to the neuropathogenesis of HAND. Conclusions Our study provides new insights about the genetic characteristics within the C2V4 of HIV-1 env that persist after long-term cART and during the course of persistent ANI. PMID:26167513

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.

Flow cytometry analysis of T-cell subsets in cerebrospinal fluid of narcolepsy type 1 patients with long-lasting disease.

PubMed

Moresco, Monica; Lecciso, Mariangela; Ocadlikova, Darina; Filardi, Marco; Melzi, Silvia; Kornum, Birgitte Rahbek; Antelmi, Elena; Pizza, Fabio; Mignot, Emmanuel; Curti, Antonio; Plazzi, Giuseppe

2018-04-01

Type 1 narcolepsy (NT1) is a central hypersomnia linked to the destruction of hypocretin-producing neurons. A great body of genetic and epidemiological data points to likely autoimmune disease aetiology. Recent reports have characterized peripheral blood T-cell subsets in NT1, whereas data regarding the cerebrospinal fluid (CSF) immune cell composition are lacking. The current study aimed to characterize the T-cell and natural killer (NK) cell subsets in NT1 patients with long disease course. Immune cell subsets from CSF and peripheral blood mononuclear cell (PBMC) samples were analysed by flow cytometry in two age-balanced and sex-balanced groups of 14 NT1 patients versus 14 healthy controls. The frequency of CSF cell groups was compared with PBMCs. Non-parametric tests were used for statistical analyses. The NT1 patients did not show significant differences of CSF immune cell subsets compared to controls, despite a trend towards higher CD4 + terminally differentiated effector memory T cells. T cells preferentially displayed a memory phenotype in the CSF compared to PBMCs. Furthermore, a reduced frequency of CD4 + terminally differentiated effector memory T cells and an increased frequency of NK CD56 bright cells was observed in PBMCs from patients compared to controls. Finally, the ratio between CSF and peripheral CD4 + terminally differentiated effector memory T cells was two-fold increased in NT1 patients versus controls. Significant differences in PBMCs and in CSF/PBMC ratios of immune cell profile were found in NT1 patients compared to healthy controls. These differences might have arisen from the different HLA status, or be primary or secondary to hypocretin deficiency. Further functional studies in patients close to disease onset are required to understand NT1 pathophysiology. Copyright © 2017 Elsevier B.V. All rights reserved.

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

Effect of epileptic seizures on the cerebrospinal fluid--A systematic retrospective analysis.

PubMed

Tumani, Hayrettin; Jobs, Catherine; Brettschneider, Johannes; Hoppner, Anselm C; Kerling, Frank; Fauser, Susanne

2015-08-01

Analyses of the cerebrospinal fluid (CSF) are obligatory when epileptic seizures manifest for the first time in order to exclude life-threatening causes or treatable diseases such as acute infections or autoimmune encephalitis. However, there are only few systematic investigations on the effect of seizures themselves on CSF parameters and the significance of these parameters in differential diagnosis. CSF samples of 309 patients with epileptic and 10 with psychogenic seizures were retrospectively analyzed. CSF samples were collected between 1999 and 2008. Cell counts, the albumin quotient, lactate and Tau-protein levels were determined. Findings were correlated with seizure types, seizure etiology (symptomatic, cryptogenic, occasional seizure), and seizure duration. Pathological findings were only observed in patients with epileptic but not with psychogenic seizures. The lactate concentration was elevated in 14%, the albumin quotient in 34%, and the Tau protein level in 36% of CSF samples. Cell counts were only slightly elevated in 6% of patients. Different seizure types influenced all parameters except for the cell count: In status epilepticus highest, in simple partial seizures lowest values were seen. Symptomatic partial and generalized epileptic seizures had significantly higher Tau-protein levels than cryptogenic partial seizures. In patients with repetitive and occasional epileptic seizures, higher Tau-protein levels were seen than in those with psychogenic seizures. Duration of epileptic seizures was positively correlated with the albumin quotient, lactate and Tau-protein levels. High variability of investigated CSF parameters within each subgroup rendered a clear separation between epileptic and psychogenic seizures impossible. Elevated cell counts are infrequently observed in patients with epileptic seizures and should therefore not uncritically be interpreted as a postictal phenomenon. However, blood-CSF barrier disruption, increased glucose metabolism and elevation of neuronal damage markers are observed in considerable percentages of patients and depend on many factors such as etiology, seizure type and duration. Copyright © 2015 Elsevier B.V. All rights reserved.

Evaluation of putative neurochemical intermediaries in space/motion sickness

NASA Technical Reports Server (NTRS)

Lucot, James B.; Crampton, George H.

1991-01-01

The topics covered include the following: the emetic stimuli used on the cats in the study; analysis of the constituents of the cerebral spinal fluid (CSF) during motion sickness; evaluation of serotonin-1A agonists; other 5-HT receptors; and additional studies and activities.

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.

Therapeutic Amprenavir Concentrations in Cerebrospinal Fluid

PubMed Central

Letendre, Scott; Best, Brookie M.; Rossi, Steven S.; Ellis, Ronald J.; Clifford, David B.; Collier, Ann C.; Gelman, Benjamin B.; Marra, Christina M.; McArthur, Justin; McCutchan, J. Allen; Morgello, Susan; Simpson, David M.; Way, Lauren; Capparelli, Edmund; Grant, Igor

2012-01-01

Antiretrovirals that reach higher concentrations in cerebrospinal fluid (CSF) are associated with better control of HIV in CSF and possibly better neurocognitive performance. The objective of this study was to determine whether amprenavir (APV) concentrations in CSF are in the therapeutic range. Individuals were selected based on the use of regimens that included fosamprenavir (FPV), a prodrug of APV, and the availability of stored CSF and matched plasma. Total APV was measured in 119 matched CSF-plasma pairs from 75 subjects by high-performance liquid chromatography (HPLC) (plasma) or liquid chromatography tandem mass spectrometry (LC/MS/MS) (CSF). Concentrations were compared to the 50% inhibitory concentration (IC50) for wild-type HIV (5.6 ng/ml). Subjects were predominantly middle-aged (median 44 years) white (57%) men (78%) with AIDS (77%). APV was detected in all but 4 CSF specimens, with a median concentration of 24.8 ng/ml (interquartile range [IQR], 16.2 to 44.0). The median CSF-to-plasma ratio was 0.012 (IQR, 0.008 to 0.018). CSF concentrations correlated with plasma concentrations (rho = 0.61; P < 0.0001) and with postdose sampling interval (rho = −0.29; P = 0.0019). APV concentrations in CSF exceeded the median IC50 for wild-type HIV in more than 97% of CSF specimens with detectable APV by a median of 4.4-fold (IQR, 2.9 to 7.9). We conclude that administration of fosamprenavir should contribute to control of HIV replication in the central nervous system (CNS) as a component of effective antiretroviral regimens. PMID:22290964

Sustained high-pressure in the spinal subarachnoid space while arterial expansion is low may be linked to syrinx development.

PubMed

Clarke, Elizabeth C; Fletcher, David F; Bilston, Lynne E

2017-04-01

Syringomyelia (a spinal cord cyst) usually develops as a result of conditions that cause cerebrospinal fluid (CSF) obstruction. The mechanism of syrinx formation and enlargement remains unclear, though previous studies suggest that the fluid enters via the perivascular spaces (PVS) of the penetrating arteries of the spinal cord, and that alterations in the CSF pulse timing and pressure could contribute to enhanced PVS inflow. This study uses an idealised computational model of the PVS to investigate the factors that influence peri-arterial fluid flow. First, we used three sample patient-specific models to explore whether changes in subarachnoid space (SAS) pressures in individuals with and without syringomyelia could influence PVS inflow. Second we conducted a parametric study to determine how features of the CSF pulse altered perivascular fluid, including alterations to timing and magnitude of the peak SAS pressure, the timing of reversal from high to low pressure (diastolic phase), and the area under the pressure-time curve. The model for the patient with syringomyelia had higher net CSF inflow to the PVS than the two subjects without syringomyelia. In the parametric study, only increasing the area under the high pressure region of the SAS pulse substantially increased PVS inflow, when coupled with a temporal shift in arterial and SAS pulses. This suggests that a period of sustained high SAS pressure while arterial diameter is low may increase net CSF pumping into the PVS.

Experimental hydrocephalus following mechanical increment of intraventricular pulse pressure.

PubMed

Di Rocco, C; Pettorossi, V E; Caldarelli, M; Mancinelli, R; Velardi, F

1977-11-15

Experimental hydrocephalus has been induced in lambs by artificial increase of the amplitude of intraventricular cerebrospinal fluid (CSF) oscillations related to arterial pulsations, without concomitant changes of the mean CSF-pressure. The characteristics of this hydrocephalus demonstrate that the intraventricular CSF-pulsations can play a role in the genesis of ventricular dilation. Such a method may be used to produce an original model of hydrocephalus independent of changes of CSF-circulation or absorption.

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

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.

Bilateral meningoencephaloceles with cerebrospinal fluid rhinorrhea after facial advancement in the Crouzon syndrome.

PubMed

Panuganti, Bharat A; Leach, Matthew; Antisdel, Jastin

2015-01-01

Cerebrospinal fluid (CSF) rhinorrhea and encephaloceles are rare complications of craniofacial advancement procedures performed in patients with craniofacial dysostoses (CD) to address the ramifications of their midface hypoplasia including obstructed nasal airway, exorbitism, and impaired mastication. Surgical repair of this CSF rhinorrhea is complicated by occult elevations in intracranial pressure (ICP), potentially necessitating open, transcranial repair. We report the first case in otolaryngology literature of a patient with Crouzon syndrome with late CSF rhinorrhea and encephalocele formation after previous LeFort III facial advancement surgery. Describe the case of a patient with Crouzon syndrome who presented with CSF rhinorrhea and encephaloceles as complications of Le Fort III facial advancement surgery. Review the literature pertaining to the incidence and management of post-operative CSF rhinorrhea and encephaloceles. Analyze issues related to repair of these complications, including occult elevations in ICP, the utility of perioperative CSF shunts, and the importance of considering alternative repair schemes to the traditional endonasal, endoscopic approach. Review of the literature describing CSF rhinorrhea and encephalocele formation following facial advancement in CD, focusing on management strategies. CSF rhinorrhea and encephalocele formation are rare complications of craniofacial advancement procedures. Occult elevations in ICP complicate the prospect of permanent surgical repair, potentially necessitating transcranial repair and the use of CSF shunts. Though no consensus exists regarding the utility of perioperative CSF drains, strong associations exist between elevated ICP and failed surgical repair. Additionally, the anatomic changes in the frontal and ethmoid sinuses after facial advancement present a challenge to endoscopic repair. Otolaryngologists should be aware of the possibility of occult elevations in ICP and sinonasal anatomic abnormalities when repairing CSF rhinorrhea in patients with CD. Clinicians should consider CSF shunt placement and carefully weigh the advantages of the transcranial approach versus endonasal, endoscopic techniques.

[Rapid identification of meningitis due to bacterial pathogens].

PubMed

Ubukata, Kimiko

2013-01-01

We constructed a new real-time PCR method to detect causative pathogens in cerebrospinal fluid (CSF) from patient due to bacterial meningitis. The eight pathogens targeted in the PCR are Streptococcus pneumoniae, Haemophilus influenzae, Streptococcus agalactiae, Staphylococcus aurues, Neisseria meningitides, Listeria monocytogenes, Esherichia coli, and Mycoplasma pneumoniae. The total time from DNA extraction from CSF to PCR analysis was 1.5 hour. The pathogens were detected in 72% of the CSF samples (n=115) by real-time PCR, but in only 48% by culture, although the microorganisms were completely concordant. The detection rate of pathogens with PCR was significantly better than that with cultures in patients with antibiotic administration.In conclusion, detection with real-time PCR is useful for rapidly identifying the causative pathogens of meningitis and for examining the clinical course of chemotherapy.

Analysis of various tracts of mastoid air cells related to CSF leak after the anterior transpetrosal approach.

PubMed

Tamura, Ryota; Tomio, Ryosuke; Mohammad, Farrag; Toda, Masahiro; Yoshida, Kazunari

2018-03-16

OBJECTIVE The anterior transpetrosal approach (ATPA) was established in 1984 and has been particularly effective for petroclival tumors. Although some complications associated with this approach, such as venous hemorrhage in the temporal lobe and nervous disturbances, have been resolved over the years, the incidence rate of CSF leaks has not greatly improved. In this study, some varieties of air cell tracts that are strongly related to CSF leaks are demonstrated. In addition, other pre- and postoperative risk factors for CSF leakage after ATPA are discussed. METHODS Preoperative and postoperative target imaging of the temporal bone was performed in a total of 117 patients who underwent ATPA, and various surgery-related parameters were analyzed. RESULTS The existence of air cells at the petrous apex, as well as fluid collection in the mastoid antrum detected by a postoperative CT scan, were possible risk factors for CSF leakage. Tracts that directly connected to the antrum from the squamous part of the temporal bone and petrous apex, rather than through numerous air cells, were significantly related to CSF leak and were defined as "direct tract." All patients with a refractory CSF leak possessed "unusual tracts" that connected to the attic, tympanic cavity, or eustachian tube, rather than through the mastoid antrum. CONCLUSIONS Preoperative assessment of petrous pneumatization types is necessary to prevent CSF leaks. Direct and unusual tracts are particularly strong risk factors for CSF leaks.

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.

Patients with depression display cytokine levels in serum and cerebrospinal fluid similar to patients with diffuse neurological symptoms without a defined diagnosis.

PubMed

Hestad, Knut A; Engedal, Knut; Whist, Jon Elling; Aukrust, Pål; Farup, Per G; Mollnes, Tom Eirik; Ueland, Thor

2016-01-01

Several reports indicate that inflammation may play a role in depression and demonstrate enhanced systemic levels of inflammatory mediators. We hypothesized that 44 patients with a diagnosis of depression would present with a specific and different serum and cerebrospinal fluid (CSF) cytokine profile compared to 21 patients with diffuse neurological symptoms, of whom 15 had fatigue as a major symptom, but no change in emotional state. The diagnoses of the patients with depression were according to the International Classification of Diseases, tenth edition (F32-34 spectra). Cytokine profiles in serum and CSF were determined by multiplex analysis, including 27 cytokines, chemokines, and growth factors. No differences could be found between the two groups studied regarding cytokine levels in serum or CSF except for serum interleukin (IL)-1 receptor antagonist that was lower in the depression group. There were only four high correlations (>0.4) between serum and CSF levels of the cytokines, reflecting independent synthesis and turnover in these two compartments. In the control group, fatigue was associated with increased IL-1 receptor antagonist, IL-10, granulocyte-colony stimulating factor, and interferon-γ (all P<0.01). Patients with depression had a similar cytokine profile as nondepressive patients, both systemically and in CSF. Fatigue was associated with higher levels of some inflammatory markers in the control group. It is possible that the presence of fatigue in a large proportion of patients and controls could contribute to the lack of difference in cytokine levels between these two groups.

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.

Cerebrospinal fluid rhinorrhea: An institutional perspective from Pakistan.

PubMed

Tahir, Muhammad Zubair; Khan, Muhammad Babar; Bashir, Muhammad Umair; Akhtar, Shabbir; Bari, Ehsan

2011-01-01

The management of cerebrospinal fluid (CSF) rhinorrhea has evolved over the last two decades. We present here a review of our 11-year data on CSF rhinorrhea and its management at a tertiary care hospital in a developing country, with particular reference to the diagnosis, surgical management and outcome of the disease. The medical charts of all patients with a diagnosis of CSF rhinorrhea over an 11-year period were reviewed. The etiology of CSF rhinorrhea was classified into three categories: spontaneous, iatrogenic and traumatic. All the patients were divided into three categories based on the type of management as conservative, intracranial and transnasal endoscopic groups. A total of 43 patients fulfilled our inclusion criteria and were included in the final analysis. Eleven of the 43 patients were managed conservatively, while 22 underwent intracranial repairs; 10 patients had transnasal endoscopic repairs. The primary success rate for the transnasal approach was 70% compared to 86% for the intracranial repair. Blood loss, special care unit (SCU) stay and total cost were found to be significantly less in the transnasal endoscopic group. Computed tomography (CT) cisternography was found to have the highest sensitivity and specificity. Further, no postoperative complications were found in the transnasal endoscopic group, while five patients from the intracranial group developed various complications. We conclude that the transnasal endoscopic approach has comparable success rates with the intracranial approach and significantly lower morbidity.

Cerebral spinal fluid (CSF) collection

MedlinePlus

... establish the diagnosis of normal pressure hydrocephalus. Normal Results Normal values typically range as follows: Pressure: 70 ... measurements or may test different specimens. What Abnormal Results Mean If the CSF looks cloudy, it could ...

Validation of α-Synuclein as a CSF Biomarker for Sporadic Creutzfeldt-Jakob Disease.

PubMed

Llorens, Franc; Kruse, Niels; Karch, André; Schmitz, Matthias; Zafar, Saima; Gotzmann, Nadine; Sun, Ting; Köchy, Silja; Knipper, Tobias; Cramm, Maria; Golanska, Ewa; Sikorska, Beata; Liberski, Pawel P; Sánchez-Valle, Raquel; Fischer, Andre; Mollenhauer, Brit; Zerr, Inga

2018-03-01

The analysis of cerebrospinal fluid (CSF) biomarkers gains importance in the differential diagnosis of prion diseases. However, no single diagnostic tool or combination of them can unequivocally confirm prion disease diagnosis. Electrochemiluminescence (ECL)-based immunoassays have demonstrated to achieve high diagnostic accuracy in a variety of sample types due to their high sensitivity and dynamic range. Quantification of CSF α-synuclein (a-syn) by an in-house ECL-based ELISA assay has been recently reported as an excellent approach for the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD), the most prevalent form of human prion disease. In the present study, we validated a commercially available ECL-based a-syn ELISA platform as a diagnostic test for correct classification of sCJD cases. CSF a-syn was analysed in 203 sCJD cases with definite diagnosis and in 445 non-CJD cases. We investigated reproducibility and stability of CSF a-syn and made recommendations for its analysis in the sCJD diagnostic workup. A sensitivity of 98% and a specificity of 97% were achieved when using an optimal cut-off of 820 pg/mL a-syn. Moreover, we were able to show a negative correlation between a-syn levels and disease duration suggesting that CSF a-syn may be a good prognostic marker for sCJD patients. The present study validates the use of a-syn as a CSF biomarker of sCJD and establishes the clinical and pre-analytical parameters for its use in differential diagnosis in clinical routine. Additionally, the current test presents some advantages compared to other diagnostic approaches: it is fast, economic, requires minimal amount of CSF and a-syn levels are stable along disease progression.

BEAMing and Droplet Digital PCR Analysis of Mutant IDH1 mRNA in Glioma Patient Serum and Cerebrospinal Fluid Extracellular Vesicles.

PubMed

Chen, Walter W; Balaj, Leonora; Liau, Linda M; Samuels, Michael L; Kotsopoulos, Steve K; Maguire, Casey A; Loguidice, Lori; Soto, Horacio; Garrett, Matthew; Zhu, Lin Dan; Sivaraman, Sarada; Chen, Clark; Wong, Eric T; Carter, Bob S; Hochberg, Fred H; Breakefield, Xandra O; Skog, Johan

2013-07-23

Development of biofluid-based molecular diagnostic tests for cancer is an important step towards tumor characterization and real-time monitoring in a minimally invasive fashion. Extracellular vesicles (EVs) are released from tumor cells into body fluids and can provide a powerful platform for tumor biomarkers because they carry tumor proteins and nucleic acids. Detecting rare point mutations in the background of wild-type sequences in biofluids such as blood and cerebrospinal fluid (CSF) remains a major challenge. Techniques such as BEAMing (beads, emulsion, amplification, magnetics) PCR and droplet digital PCR (ddPCR) are substantially more sensitive than many other assays for mutant sequence detection. Here, we describe a novel approach that combines biofluid EV RNA and BEAMing RT-PCR (EV-BEAMing), as well droplet digital PCR to interrogate mutations from glioma tumors. EVs from CSF of patients with glioma were shown to contain mutant IDH1 transcripts, and we were able to reliably detect and quantify mutant and wild-type IDH1 RNA transcripts in CSF of patients with gliomas. EV-BEAMing and EV-ddPCR represent a valuable new strategy for cancer diagnostics, which can be applied to a variety of biofluids and neoplasms.Molecular Therapy-Nucleic Acids (2013) 2, e109; doi:10.1038/mtna.2013.28; published online 23 July 2013.

Evaluation of Mucorales DNA load in cerebrospinal fluid in a patient with possible cerebral mucormycosis treated with intravenous liposomal amphotericin B.

PubMed

Shigemura, Tomonari; Nakazawa, Yozo; Matsuda, Kazuyuki; Motobayashi, Mitsuo; Saito, Shoji; Koike, Kenichi

2014-12-01

We report the case of a 19-year-old male with possible cerebral mucormycosis following chemotherapy. We detected a Lichtheimia DNA load of 2.0×10(4) copies/ml in cerebrospinal fluid (CSF), although a CSF culture showed no growth. After treatment with intravenous liposomal amphotericin B, the Lichtheimia DNA load fell below the detection limit, and at the same time the patient's headache and imaging findings improved. The quantification of Mucorales DNA in CSF may be useful for evaluating cerebral mucormycosis. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Real-Time Polymerase Chain Reaction Detection of Angiostrongylus cantonensis DNA in Cerebrospinal Fluid from Patients with Eosinophilic Meningitis

PubMed Central

Qvarnstrom, Yvonne; Xayavong, Maniphet; da Silva, Ana Cristina Aramburu; Park, Sarah Y.; Whelen, A. Christian; Calimlim, Precilia S.; Sciulli, Rebecca H.; Honda, Stacey A. A.; Higa, Karen; Kitsutani, Paul; Chea, Nora; Heng, Seng; Johnson, Stuart; Graeff-Teixeira, Carlos; Fox, LeAnne M.; da Silva, Alexandre J.

2016-01-01

Angiostrongylus cantonensis is the most common infectious cause of eosinophilic meningitis. Timely diagnosis of these infections is difficult, partly because reliable laboratory diagnostic methods are unavailable. The aim of this study was to evaluate the usefulness of a real-time polymerase chain reaction (PCR) assay for the detection of A. cantonensis DNA in human cerebrospinal fluid (CSF) specimens. A total of 49 CSF specimens from 33 patients with eosinophilic meningitis were included: A. cantonensis DNA was detected in 32 CSF specimens, from 22 patients. Four patients had intermittently positive and negative real-time PCR results on subsequent samples, indicating that the level of A. cantonensis DNA present in CSF may fluctuate during the course of the illness. Immunodiagnosis and/or supplemental PCR testing supported the real-time PCR findings for 30 patients. On the basis of these observations, this real-time PCR assay can be useful to detect A. cantonensis in the CSF from patients with eosinophilic meningitis. PMID:26526920

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

PubMed

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.

Predicting progression to dementia in persons with mild cognitive impairment using cerebrospinal fluid markers.

PubMed

Handels, Ron L H; Vos, Stephanie J B; Kramberger, Milica G; Jelic, Vesna; Blennow, Kaj; van Buchem, Mark; van der Flier, Wiesje; Freund-Levi, Yvonne; Hampel, Harald; Olde Rikkert, Marcel; Oleksik, Ania; Pirtosek, Zvezdan; Scheltens, Philip; Soininen, Hilkka; Teunissen, Charlotte; Tsolaki, Magda; Wallin, Asa K; Winblad, Bengt; Verhey, Frans R J; Visser, Pieter Jelle

2017-08-01

We aimed to determine the added value of cerebrospinal fluid (CSF) to clinical and imaging tests to predict progression from mild cognitive impairment (MCI) to any type of dementia. The risk of progression to dementia was estimated using two logistic regression models based on 250 MCI participants: the first included standard clinical measures (demographic, clinical, and imaging test information) without CSF biomarkers, and the second included standard clinical measures with CSF biomarkers. Adding CSF improved predictive accuracy with 0.11 (scale from 0-1). Of all participants, 136 (54%) had a change in risk score of 0.10 or higher (which was considered clinically relevant), of whom in 101, it was in agreement with their dementia status at follow-up. An individual person's risk of progression from MCI to dementia can be improved by relying on CSF biomarkers in addition to recommended clinical and imaging tests for usual care. Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

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

National audit of cerebrospinal fluid testing.

PubMed

Holbrook, Ian; Beetham, Robert; Cruickshank, Anne; Egner, William; Fahie-Wilson, Mike; Keir, Geoff; Patel, Dina; Watson, Ian; White, Peter

2007-09-01

UK National External Quality Assessment Service (NEQAS) Specialist Advisory Group for EQA of CSF Proteins and Biochemistry was interested in current practice for the biochemical investigation of cerebrospinal fluid (CSF) in the UK. A questionnaire was sent to laboratories via regional audit committees and the results collated. Most laboratories were analysing CSF in a satisfactory manner. There was some variation in the reference ranges used for glucose, protein and lactate. There was concern about the rejection policies of some laboratories on these unrepeatable samples and the wavelengths used to measure bilirubin. The survey revealed the lack of spectrophotometric scanning for haem pigments and bilirubin in some hospitals. The current practice for the measurement of CSF samples in the UK is satisfactory in most laboratories responding to the questionnaire. National agreement on reference ranges for glucose, protein and lactate should be achievable. Those performing spectrophotometric scanning of the CSF were doing so in concordance with the national guidelines. Some hospitals in the UK may not have responded to the questionnaire because they did not offer spectrophotometric scanning.

A programmable point-of-care device for external CSF drainage and monitoring.

PubMed

Simkins, Jeffrey R; Subbian, Vignesh; Beyette, Fred R

2014-01-01

This paper presents a prototype of a programmable cerebrospinal fluid (CSF) external drainage system that can accurately measure the dispensed fluid volume. It is based on using a miniature spectrophotometer to collect color data to inform drain rate and pressure monitoring. The prototype was machined with 1 μm dimensional accuracy. The current device can reliably monitor the total accumulated fluid volume, the drain rate, the programmed pressure, and the pressure read from the sensor. Device requirements, fabrication processes, and preliminary results with an experimental set-up are also presented.

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.

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 ...

[Creatine kinase BB and lactate in the cerebrospinal fluid of neonates and infants with perinatal injuries of the CNS].

PubMed

Alatyrtsev, V V; Iakunin, Iu A; Burkova, A S; Podkopaev, V N; Afonina, L G

1989-01-01

A study was made of the content of creatine kinase-BB (CK-BB) and lactate in cerebrospinal fluid (CSF) of 202 neonates and infants with perinatal CNS injuries. The relationship was found between the rise of the CK-BB content and the gravity of perinatal CNS injuries. The highest content of CK-BB in CSF was marked in neonates with cerebral disorders complicated by infectious and inflammatory diseases (pneumonia, sepsis). Within the first 5 days of life, the children of this group demonstrated the relationship between the content of CK-BB and lactate of CSF. The measurement of the content of CK-BB in CSF should be used for early diagnosis, assessment of the gravity and course of perinatal CNS injuries in neonates and in infants.

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.

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

Anti-Human Immunodeficiency Virus Antibodies in the Cerebrospinal Fluid: Evidence of Early Treatment Impact on Central Nervous System Reservoir?

PubMed Central

Burbelo, Peter D; Price, Richard W; Hagberg, Lars; Hatano, Hiroyu; Spudich, Serena; Deeks, Steven G; Gisslén, Magnus

2018-01-01

Abstract Background Despite effective antiretroviral therapy (ART), human immunodeficiency virus (HIV) likely persists in the central nervous system (CNS) in treated individuals. We examined anti-HIV antibodies in cerebrospinal fluid (CSF) and blood as markers of persistence. Methods Human immunodeficiency virus antibodies were measured in paired CSF and serum before and after long-term treatment of chronic (n = 10) and early infection (n = 12), along with untreated early infection (n = 10). Results Treatment of chronic infection resulted in small reductions of anti-HIV antibodies in CSF and serum despite >10 years of suppressive ART. In untreated early infection, anti-HIV antibodies emerged in blood by day 30, whereas CSF antibodies reached similar levels 2 weeks later. Compared with long-term treatment of chronic infection, early ART initiation reduced CSF antibodies by 43-fold (P > .0001) and blood antibodies by 7-fold (P = .0003). Two individuals receiving pre-exposure prophylaxis and then ART early after infection failed to develop antibodies in CSF or blood, whereas CSF antibodies were markedly reduced in the Berlin patient. Conclusions To the extent that differential CSF and blood antibodies indicate HIV persistence, these data suggest a relative delay in establishment of the CNS compared with the systemic HIV reservoir that provides an opportunity for early treatment to have a greater impact on the magnitude of long-term CNS infection. PMID:29401308

Anti-Human Immunodeficiency Virus Antibodies in the Cerebrospinal Fluid: Evidence of Early Treatment Impact on Central Nervous System Reservoir?

PubMed

Burbelo, Peter D; Price, Richard W; Hagberg, Lars; Hatano, Hiroyu; Spudich, Serena; Deeks, Steven G; Gisslén, Magnus

2018-03-13

Despite effective antiretroviral therapy (ART), human immunodeficiency virus (HIV) likely persists in the central nervous system (CNS) in treated individuals. We examined anti-HIV antibodies in cerebrospinal fluid (CSF) and blood as markers of persistence. Human immunodeficiency virus antibodies were measured in paired CSF and serum before and after long-term treatment of chronic (n = 10) and early infection (n = 12), along with untreated early infection (n = 10). Treatment of chronic infection resulted in small reductions of anti-HIV antibodies in CSF and serum despite >10 years of suppressive ART. In untreated early infection, anti-HIV antibodies emerged in blood by day 30, whereas CSF antibodies reached similar levels 2 weeks later. Compared with long-term treatment of chronic infection, early ART initiation reduced CSF antibodies by 43-fold (P > .0001) and blood antibodies by 7-fold (P = .0003). Two individuals receiving pre-exposure prophylaxis and then ART early after infection failed to develop antibodies in CSF or blood, whereas CSF antibodies were markedly reduced in the Berlin patient. To the extent that differential CSF and blood antibodies indicate HIV persistence, these data suggest a relative delay in establishment of the CNS compared with the systemic HIV reservoir that provides an opportunity for early treatment to have a greater impact on the magnitude of long-term CNS infection.

Simulation of Two-Fluid Flows by the Least-Squares Finite Element Method Using a Continuum Surface Tension Model

NASA Technical Reports Server (NTRS)

Wu, Jie; Yu, Sheng-Tao; Jiang, Bo-nan

1996-01-01

In this paper a numerical procedure for simulating two-fluid flows is presented. This procedure is based on the Volume of Fluid (VOF) method proposed by Hirt and Nichols and the continuum surface force (CSF) model developed by Brackbill, et al. In the VOF method fluids of different properties are identified through the use of a continuous field variable (color function). The color function assigns a unique constant (color) to each fluid. The interfaces between different fluids are distinct due to sharp gradients of the color function. The evolution of the interfaces is captured by solving the convective equation of the color function. The CSF model is used as a means to treat surface tension effect at the interfaces. Here a modified version of the CSF model, proposed by Jacqmin, is used to calculate the tension force. In the modified version, the force term is obtained by calculating the divergence of a stress tensor defined by the gradient of the color function. In its analytical form, this stress formulation is equivalent to the original CSF model. Numerically, however, the use of the stress formulation has some advantages over the original CSF model, as it bypasses the difficulty in approximating the curvatures of the interfaces. The least-squares finite element method (LSFEM) is used to discretize the governing equation systems. The LSFEM has proven to be effective in solving incompressible Navier-Stokes equations and pure convection equations, making it an ideal candidate for the present applications. The LSFEM handles all the equations in a unified manner without any additional special treatment such as upwinding or artificial dissipation. Various bench mark tests have been carried out for both two dimensional planar and axisymmetric flows, including a dam breaking, oscillating and stationary bubbles and a conical liquid sheet in a pressure swirl atomizer.

Fibrinolytic activity in cerebrospinal fluid of dogs with different neurological disorders.

PubMed

de la Fuente, C; Monreal, L; Cerón, J; Pastor, J; Viu, J; Añor, S

2012-01-01

Fibrinolytic activity in cerebrospinal fluid (CSF) is activated in humans by different pathologic processes. To investigate fibrinolytic activity in the CSF of dogs with neurological disorders by measuring CSF D-dimer concentrations. One hundred and sixty-nine dogs with neurological disorders, 7 dogs with systemic inflammatory diseases without central nervous system involvement (SID), and 7 healthy Beagles were included in the study. Dogs with neurological disorders included 11 with steroid-responsive meningitis-arteritis (SRMA), 37 with other inflammatory neurological diseases (INF), 38 with neoplasia affecting the central nervous system (NEO), 28 with spinal compressive disorders (SCC), 15 with idiopathic epilepsy (IE), and 40 with noninflammatory neurological disorders (NON-INF). Prospective observational study. D-dimers and C-reactive protein (CRP) were simultaneously measured in paired CSF and blood samples. D-dimers and CRP were detected in 79/183 (43%) and in 182/183 (99.5%) CSF samples, respectively. All dogs with IE, SID, and controls had undetectable concentrations of D-dimers in the CSF. CSF D-dimer concentrations were significantly (P < .001) higher in dogs with SRMA than in dogs with other diseases and controls. CSF CRP concentration in dogs with SRMA was significantly (P < .001) higher than in dogs of other groups and controls, except for the SID group. No correlation was found between blood and CSF D-dimer concentrations. Intrathecal fibrinolytic activity seems to be activated in some canine neurological disorders, and it is high in severe meningeal inflammatory diseases. CSF D-dimer concentrations may be considered a diagnostic marker for SRMA. Copyright © 2012 by the American College of Veterinary Internal Medicine.

Cerebrospinal fluid interferon-gamma-inducible protein 10 (IP-10, CXCL10) in HIV-1 infection.

PubMed

Cinque, Paola; Bestetti, Arabella; Marenzi, Roberta; Sala, Serena; Gisslen, Magnus; Hagberg, Lars; Price, Richard W

2005-11-01

Interferon-gamma-inducible protein (IP-10 or CXCL10) is a potent chemoattractant and has been suggested to enhance retrovirus infection and mediate neuronal injury. In order to assess this chemokine in central nervous system (CNS) HIV infection, we measured the cerebrospinal fluid (CSF) and plasma concentrations of CXCL10 by immunoassay in samples derived from 97 HIV-infected subjects across a spectrum of immunological progression and CNS complications and from 16 HIV seronegative control subjects studied at three clinical centers between 1994 and 2001. We also examined changes in the CSF and plasma CXCL10 concentrations in 30 subjects starting and three stopping antiretroviral therapy. CSF CXCL10 concentrations: (1) correlated with CSF HIV RNA and white blood cell (WBC) counts, but not with blood CXCL10, HIV RNA, or CD4 counts; (2) were increased in subjects with primary and asymptomatic HIV infections and AIDS dementia complex, but less frequently in those with more advanced infection, with or without CNS opportunistic diseases except cytomegalovirus encephalitis; (3) decreased in subjects starting antiretroviral in association with decreases in CSF and plasma HIV RNA and CSF WBCs; and (4) conversely, increased in subjects stopping treatment in parallel with CSF HIV RNA and WBCs. These results confirm that CSF CXCL10 associates closely with both CSF HIV and WBCs and suggest that this chemokine may be both a response to and contributing determinant of local infection. High CSF levels may be useful in the diagnosis of ADC in subjects with advanced immunosuppression in whom CMV encephalitis has been ruled out, though this issue requires further study.

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

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.

A pilot study on the use of cerebrospinal fluid cell-free DNA in intramedullary spinal ependymoma.

PubMed

Connolly, Ian David; Li, Yingmei; Pan, Wenying; Johnson, Eli; You, Linya; Vogel, Hannes; Ratliff, John; Hayden Gephart, Melanie

2017-10-01

Cerebrospinal fluid (CSF) represents a promising source of cell-free DNA (cfDNA) for tumors of the central nervous system. A CSF-based liquid biopsy may obviate the need for riskier tissue biopsies and serve as a means for monitoring tumor recurrence or response to therapy. Spinal ependymomas most commonly occur in adults, and aggressive resection must be delicately balanced with the risk of injury to adjacent normal tissue. In patients with subtotal resection, recurrence commonly occurs. A CSF-based liquid biopsy matched to the patient's spinal ependymoma mutation profile has potential to be more sensitive then surveillance MRI, but the utility has not been well characterized for tumors of the spinal cord. In this study, we collected matched blood, tumor, and CSF samples from three adult patients with WHO grade II intramedullary spinal ependymoma. We performed whole exome sequencing on matched tumor and normal DNA to design Droplet Digital™ PCR (ddPCR) probes for tumor and wild-type mutations. We then interrogated CSF samples for tumor-derived cfDNA by performing ddPCR on extracted cfDNA. Tumor cfDNA was not reliably detected in the CSF of our cohort. Anatomic sequestration and low grade of intramedullary spinal cord tumors likely limits the role of CSF liquid biopsy.

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.

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.

Lower CSF Aβ is Associated with HAND in HIV-Infected Adults with a Family History of Dementia

PubMed Central

Fazeli, Pariya. L.; Moore, David J.; Franklin, Donald R.; Umlauf, Anya; Heaton, Robert K.; Collier, Ann C.; Marra, Christina M.; Clifford, David B.; Gelman, Benjamin B.; Sacktor, Ned C.; Morgello, Susan; Simpson, David M.; McCutchan, John A.; Grant, Igor; Letendre, Scott L.

2015-01-01

Background Both family history of dementia (FHD) and lower levels of Aβ-42 are indepentently associated with worse neurocognitive functioning in HIV-infected patients. Objective To examine the relationships between cerebrospinal fluid (CSF) Aβ-42 and FHD with HIV-associated neurocognitive disorders (HAND). Methods One hundred eighty-three HIV+ adults underwent neuropsychological and neuromedical assessments, and determination of CSF Aβ-42 concentration and FHD (defined as a self-reported first or second-degree relative with a dementia diagnosis). Univariate analyses and multivariable logistic regressions were used. Results FHD was not associated with HAND (p = 0.24); however, CSF Aβ-42 levels were lower (p = 0.03) in the HAND group, but were not associated with FHD (p = 0.89). Multivariable models showed a main effect of CSF Aβ-42 (p = 0.03) and a trend-level (p = 0.06) interaction between FHD and CSF Aβ-42, such that lower CSF Aβ-42 was associated with HAND in those with FHD (p < 0.01) compared to those without FHD (p = 0.83). An analysis in those with follow-up data showed that higher baseline CSF Aβ-42 was associated with lower risk of neurocognitive decline (p = 0.02). While we did not find an FHD X CSF Aβ-42 interaction (p = 0.83), when analyses were stratified by FHD, lower CSF Aβ-42 was associated at the trend-level with neurocognitive decline in the FHD group (p = 0.08) compared to the no FHD group (p = 0.15). Conclusions FHD moderates the relationship between of CSF Aβ-42 and HAND. The findings highlight the complexities in interpreting the relationships between biomarkers of age-related neurodegeneration and HAND. PMID:26673902

Does Caffeine Consumption Modify Cerebrospinal Fluid Amyloid-β Levels in Patients with Alzheimer's Disease?

PubMed

Travassos, Maria; Santana, Isabel; Baldeiras, Inês; Tsolaki, Magda; Gkatzima, Olymbia; Sermin, Genc; Yener, Görsev G; Simonsen, Anja; Hasselbalch, Steen G; Kapaki, Elisabeth; Mara, Bourbouli; Cunha, Rodrigo A; Agostinho, Paula; Blennow, Kaj; Zetterberg, Henrik; Mendes, Vera M; Manadas, Bruno; de Mendon, Alexandreça

2015-01-01

Caffeine may be protective against Alzheimer's disease (AD) by modulating amyloid-β (Aβ) metabolic pathways. The present work aimed to study a possible association of caffeine consumption with the cerebrospinal fluid (CSF) biomarkers, particularly Aβ. The study included 88 patients with AD or mild cognitive impairment. The consumption of caffeine and theobromine was evaluated using a validated food questionnaire. Quantification of caffeine and main active metabolites was performed with liquid chromatography coupled to tandem mass spectrometry. The levels of A(1-42), total tau, and phosphorylated tau in the CSF were determined using sandwich ELISA methods and other Aβ species, Aβ(X-38), Aβ(X-40), and Aβ(X-42), with the MSD Aβ Triplex assay. The concentration of caffeine was 0.79±1.15 μg/mL in the CSF and 1.20±1.88 μg/mL in the plasma. No correlation was found between caffeine consumption and Aβ42 in the CSF. However, a significant positive correlation was found between the concentrations of theobromine, both in the CSF and in the plasma, with Aβ42 in the CSF. Theobromine in the CSF was positively correlated with the levels of other xanthines in the CSF, but not in the plasma, suggesting that it may be formed by central metabolic pathways. In conclusion, caffeine consumption does not modify the levels of CSF biomarkers, and does not require to be controlled for when measuring CSF biomarkers in a clinical setting. Since theobromine is associated with a favorable Aβ profile in the CSF, the possibility that it might have a protective role in AD should be further investigated.

Cerebrospinal fluid rhinorrhoea following transsphenoidal surgery for pituitary adenoma: experience in a Chinese centre.

PubMed

Zhang, C; Ding, X; Lu, Y; Hu, L; Hu, G

2017-08-01

The aim of this study was to elucidate the risk factors for cerebrospinal fluid (CSF) rhinorrhoea following transsphenoidal surgery and discuss its prevention and treatments. We retrospectively reviewed 474 consecutive cases of pituitary adenoma treated with 485 transsphenoidal surgical procedures from January 2008 to December 2011 in our department. We analysed the incidence of intra- and post-operative CSF leakage and outcomes of various repair strategies. Intra-operative CSF leakage was encountered in 85 cases (17.9%), and post-operative CSF rhinorrhoea in 13 cases (2.7%). Seven of the 13 patients with post-operative CSF rhinorrhoea did not experience intra-operative CSF leakage; three of these patients had adrenocorticotropic hormone-secreting adenomas. Of the remaining 6 patients with both intra- and post-operative CSF leakage, 2 were treated for giant invasive prolactinomas, and 2 had previously undergone transsphenoidal surgery. In eight patients, the leak was resolved by lumbar puncture, lumbar external drainage, resting in a semi-reclining position, or other conservative treatment. Two CSF leaks were repaired with gelatine foam and fibrin glue using a transsphenoidal approach, and two with autologous fat graft and sellar floor reconstruction using a transnasal endoscopic approach. After undergoing two transnasal endoscopic repairs, one patient with post-operative CSF rhinorrhoea was successfully treated by further lumbar subarachnoid drainage. In conclusion, procedures using gelatine foam, fibrin glue and autologous fat graft are common and effective techniques for the management of CSF rhinorrhoea after transsphenoidal surgery. When a CSF leak is detected during transsphenoidal surgery, thorough sellar reconstruction and long-term follow-up are necessary. © Copyright by Società Italiana di Otorinolaringologia e Chirurgia Cervico-Facciale, Rome, Italy.

Perilymph sampling from the cochlear apex: a reliable method to obtain higher purity perilymph samples from scala tympani.

PubMed

Salt, Alec N; Hale, Shane A; Plonkte, Stefan K R

2006-05-15

Measurements of drug levels in the fluids of the inner ear are required to establish kinetic parameters and to determine the influence of specific local delivery protocols. For most substances, this requires cochlear fluids samples to be obtained for analysis. When auditory function is of primary interest, the drug level in the perilymph of scala tympani (ST) is most relevant, since drug in this scala has ready access to the auditory sensory cells. In many prior studies, ST perilymph samples have been obtained from the basal turn, either by aspiration through the round window membrane (RWM) or through an opening in the bony wall. A number of studies have demonstrated that such samples are likely to be contaminated with cerebrospinal fluid (CSF). CSF enters the basal turn of ST through the cochlear aqueduct when the bony capsule is perforated or when fluid is aspirated. The degree of sample contamination has, however, not been widely appreciated. Recent studies have shown that perilymph samples taken through the round window membrane are highly contaminated with CSF, with samples greater than 2microL in volume containing more CSF than perilymph. In spite of this knowledge, many groups continue to sample from the base of the cochlea, as it is a well-established method. We have developed an alternative, technically simple method to increase the proportion of ST perilymph in a fluid sample. The sample is taken from the apex of the cochlea, a site that is distant from the cochlear aqueduct. A previous problem with sampling through a perforation in the bone was that the native perilymph rapidly leaked out driven by CSF pressure and was lost to the middle ear space. We therefore developed a procedure to collect all the fluid that emerged from the perforated apex after perforation. We evaluated the method using a marker ion trimethylphenylammonium (TMPA). TMPA was applied to the perilymph of guinea pigs either by RW irrigation or by microinjection into the apical turn. The TMPA concentration of the fluid sample was compared with that measured in perilymph prior to taking the sample using a TMPA-selective microelectrode sealed into ST. Data were interpreted with a finite element model of the cochlear fluids that was used to simulate each aspect of the experiment. The correction of sample concentration back to the perilymph concentration prior to sampling can be performed based on the known ST volume (4.7microL in the guinea pig) and the sample volume. A more precise correction requires some knowledge of the profile of drug distribution along the cochlear prior to sampling. This method of sampling from the apex is technically simple and provides a larger sample volume with a greater proportion of perilymph compared to sampling through the RW.

Perilymph Sampling from the Cochlear Apex: A Reliable Method to Obtain Higher Purity Perilymph Samples from Scala Tympani

PubMed Central

Salt, Alec N.; Hale, Shane A.; Plontke, Stefan K. R.

2006-01-01

Measurements of drug levels in the fluids of the inner ear are required to establish kinetic parameters and to determine the influence of specific local delivery protocols. For most substances, this requires cochlear fluids samples to be obtained for analysis. When auditory function is of primary interest, the drug level in the perilymph of scala tympani (ST) is most relevant, since drug in this scala has ready access to the auditory sensory cells. In many prior studies, ST perilymph samples have been obtained from the basal turn, either by aspiration through the round window membrane (RWM) or through an opening in the bony wall. A number of studies have demonstrated that such samples are likely to be contaminated with cerebrospinal fluid (CSF). CSF enters the basal turn of ST through the cochlear aqueduct when the bony capsule is perforated or when fluid is aspirated. The degree of sample contamination has, however, not been widely appreciated. Recent studies have shown that perilymph samples taken through the round window membrane are highly contaminated with CSF, with samples greater than 2 μL in volume containing more CSF than perilymph. In spite of this knowledge, many groups continue to sample from the base of the cochlea, as it is a well-established method. We have developed an alternative, technically simple method to increase the proportion of ST perilymph in a fluid sample. The sample is taken from the apex of the cochlea, a site that is distant from the cochlear aqueduct. A previous problem with sampling through a perforation in the bone was that the native perilymph rapidly leaked out driven by CSF pressure and was lost to the middle ear space. We therefore developed a procedure to collect all the fluid that emerged from the perforated apex after perforation. We evaluated the method using a marker ion trimethylphenylammonium (TMPA). TMPA was applied to the perilymph of guinea pigs either by RW irrigation or by microinjection into the apical turn. The TMPA concentration of the fluid sample was compared with that measured in perilymph prior to taking the sample using a TMPA-selective microelectrode sealed into ST. Data were interpreted with a finite element model of the cochlear fluids that was used to simulate each aspect of the experiment. The correction of sample concentration back to the perilymph concentration prior to sampling can be performed based on the known ST volume (4.7 μL in the guinea pig) and the sample volume. A more precise correction requires some knowledge of the profile of drug distribution along the cochlear prior to sampling. This method of sampling from the apex is technically simple and provides a larger sample volume with a greater proportion of perilymph compared to sampling through the RW. PMID:16310856

Correlation mapping for visualizing propagation of pulsatile CSF motion in intracranial space based on magnetic resonance phase contrast velocity images: preliminary results.

PubMed

Yatsushiro, Satoshi; Hirayama, Akihiro; Matsumae, Mitsunori; Kajiwara, Nao; Abdullah, Afnizanfaizal; Kuroda, Kagayaki

2014-01-01

Correlation time mapping based on magnetic resonance (MR) velocimetry has been applied to pulsatile cerebrospinal fluid (CSF) motion to visualize the pressure transmission between CSF at different locations and/or between CSF and arterial blood flow. Healthy volunteer experiments demonstrated that the technique exhibited transmitting pulsatile CSF motion from CSF space in the vicinity of blood vessels with short delay and relatively high correlation coefficients. Patient and healthy volunteer experiments indicated that the properties of CSF motion were different from the healthy volunteers. Resultant images in healthy volunteers implied that there were slight individual difference in the CSF driving source locations. Clinical interpretation for these preliminary results is required to apply the present technique for classifying status of hydrocephalus.

Quantification of thymosin beta(4) in human cerebrospinal fluid using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

PubMed

Urso, Elena; Le Pera, Maria; Bossio, Sabrina; Sprovieri, Teresa; Qualtieri, Antonio

2010-07-01

Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) has been applied to the analysis of a wide range of biomolecules. To date, there are two specific areas of application where MALDI-TOF-MS is viewed as impractical: analysis of low-mass analytes and relative quantitative applications. However, these limitations can be overcome and quantification can be routine. Increased levels of thymosin beta(4) (TB4) have been recently found in cerebrospinal fluid (CSF) from Creutzfeldt-Jakob disease (CJD) patients. Our objective was to apply a label-free quantitative application of MALDI-TOF-MS to measure TB4 levels in human CSF by adding the oxidized form of TB4 as an internal standard. The relative peak area or peak height ratios of the native TB4 to the added oxidized form were evaluated. Considering the relative peak area ratios, healthy individuals showed a mean value of 40.8+/-21.27 ng/ml, whereas CJD patients showed high values with a mean of 154+/-59.07 ng/ml, in agreement with the previous observation found in CJD patients. Similar results were obtained considering peak height ratios. The proposed method may provide a simple and rapid screening method for quantification on CSF of TB4 levels suitable for diagnostic purposes. 2010 Elsevier Inc. All rights reserved.

Simultaneous determination of vancomycin and ceftazidime in cerebrospinal fluid in craniotomy patients by high-performance liquid chromatography.

PubMed

Ye, Guangming; Cai, Xuejian; Wang, Biao; Zhou, Zhongxian; Yu, Xiaohua; Wang, Weibin; Zhang, Jiandong; Wang, Yuhai; Dong, Jierong; Jiang, Yunyun

2008-11-04

A simple, accurate and rapid method for simultaneous analysis of vancomycin and ceftazidime in cerebrospinal fluid (CSF), utilizing high-performance liquid chromatography (HPLC), has been developed and thoroughly validated to satisfy strict FDA guidelines for bioanalytical methods. Protein precipitation was used as the sample pretreatment method. In order to increase the accuracy, tinidazole was chosen as the internal standard. Separation was achieved on a Diamonsil C18 column (200 mm x 4.6mm I.D., 5 microm) using a mobile phase composed of acetonitrile and acetate buffer (pH 3.5) (8:92, v/v) at room temperature (25 degrees C), and the detection wavelength was 240 nm. All the validation data, such as accuracy, precision, and inter-day repeatability, were within the required limits. The method was applied to determine vancomycin and ceftazidime concentrations in CSF in five craniotomy patients.

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

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.

Cerebrospinal Fluid Aβ40 Improves the Interpretation of Aβ42 Concentration for Diagnosing Alzheimer’s Disease

PubMed Central

Dorey, Aline; Perret-Liaudet, Armand; Tholance, Yannick; Fourier, Anthony; Quadrio, Isabelle

2015-01-01

The combination of decreased amyloid β42 (Aβ42) and increased total tau proteins (T-Tau) and phosphorylated tau (P-Tau) in cerebrospinal fluid (CSF) has recently been considered as a biological diagnostic criterion of Alzheimer’s disease (AD). Previous studies showed significant heterogeneity in CSF Aβ42 levels to discriminate AD from non-AD patients. It was also suggested that the CSF amyloid peptide β42/β40 ratio has better diagnostic performance than Aβ42 alone. The objective of the present study was to investigate the potential added value of determining CSF amyloid β40 peptide (Aβ40) for biological diagnosis of AD when CSF Aβ42 levels failed. CSF AD biomarkers were run in 2,171 samples from 1,499 AD and 672 non-AD patients. The following pathologic thresholds were used to define an AD-positive CSF biomarker profile: T-Tau ≥ 400 ng/L, P-Tau181 ≥ 60 ng/L, and Aβ42 ≤ 700 ng/L. CSF Aβ40 was assayed in AD patients with CSF Aβ42 levels above 700 ng/L and non-AD patients with CSF Aβ42 levels below 700 ng/L. CSF Aβ40 levels were higher in AD than non-AD patients. The receiver operator characteristic curves of CSF Aβ40 and the Aβ42/Aβ40 ratio defined AD cut-off values at 12,644 ng/L and 0.06, respectively. In AD patients with non-pathological CSF Aβ42, CSF Aβ40 concentration was able to correct 76.2% of cases when expressed as CSF Aβ42/Aβ40 ratio and 94.7% of cases when used alone. Using CSF Aβ42 and then CSF Aβ40, the percentage of misinterpreted AD patients fell to 1.0%. CSF Aβ40 concentration improved interpretation of Aβ42 level for the diagnosis of AD. CSF Aβ40 alone showed better diagnostic performance than the amyloid peptide Aβ42/Aβ40 ratio. The added value of determining CSF Aβ40 in AD diagnosis now needs confirming in a cohort of definite AD patients and to be completed with novel amyloid cascade biomarkers. PMID:26640457

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

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

Flow cytometric characterization of cerebrospinal fluid cells.

PubMed

de Graaf, Marieke T; de Jongste, Arjen H C; Kraan, Jaco; Boonstra, Joke G; Sillevis Smitt, Peter A E; Gratama, Jan W

2011-09-01

Flow cytometry facilitates the detection of a large spectrum of cellular characteristics on a per cell basis, determination of absolute cell numbers and detection of rare events with high sensitivity and specificity. White blood cell (WBC) counts in cerebrospinal fluid (CSF) are important for the diagnosis of many neurological disorders. WBC counting and differential can be performed by microscopy, hematology analyzers, or flow cytometry. Flow cytometry of CSF is increasingly being considered as the method of choice in patients suspected of leptomeningeal localization of hematological malignancies. Additionally, in several neuroinflammatory diseases such as multiple sclerosis and paraneoplastic neurological syndromes, flow cytometry is commonly performed to obtain insight into the immunopathogenesis of these diseases. Technically, the low cellularity of CSF samples, combined with the rapidly declining WBC viability, makes CSF flow cytometry challenging. Comparison of flow cytometry with microscopic and molecular techniques shows that each technique has its own advantages and is ideally combined. We expect that increasing the number of flow cytometric parameters that can be simultaneously studied within one sample, will further refine the information on CSF cell subsets in low-cellular CSF samples and enable to define cell populations more accurately. Copyright © 2011 International Clinical Cytometry Society.

Use of duraseal in repair of cerebrospinal fluid leaks.

PubMed

Chin, Christopher J; Kus, Lukas; Rotenberg, Brian W

2010-10-01

The purpose of our article is to review the use of the DuraSeal Sealant System (Confluent Surgical Inc., Waltham, MA) in the repair of complex cerebrospinal fluid (CSF) leaks in endoscopic skull-base surgery. Retrospective chart review. London Health Sciences Centre. A database of endoscopic skull-base cases between 2007 and 2009 that involved CSF leakage repaired with DuraSeal was created. Demographic data and operative reports were collected and analyzed qualitatively. Recurrence of CSF leak after repair. Five cases were identified that met study criteria. In four of the five cases, the repair was successful. There were no complications related to DuraSeal use. Comparison to a subset of patients using Tisseel Fibrin Sealant (Baxter, Toronto, ON) for repair did not show a significant difference in failure rate (χ2 = 0.029, p = .858). There are a variety of techniques described to repair CSF rhinorrhea, with various studies demonstrating the advantages of using tissue glues in CSF leak repairs. We used DuraSeal in five patients to enhance graft strength and form a watertight seal. The system was effective in the majority of patients. Our study is the first to report on endoscopic endonasal repair of CSF leaks using DuraSeal.

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.

The Value of Changing Position in the Detection of CSF Leakage in Spontaneous Intracranial Hypotension Using Tc-99m DTPA Scintigraphy: Two Case Reports.

PubMed

Lu, Yu Yu; Wang, Hsin Yi; Lin, Ying; Lin, Wan Yu

2012-09-01

Radionuclide Cisternography (RNC) is of potential value in pointing out the sites of cerebrospinal fluid (CSF) leakage in patients with spontaneous intracranial hypotension (SIH). In the current report, we present two patients who underwent RNC for suspected CSF leakage. Both patients underwent magnetic resonance imaging (MRI) and RNC for evaluation. We describe a simple method to increase the detection ability of RNC for CSF leakage in patients with SIH.

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

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.

Quantitative measurement of intervertebral disc signal using MRI.

PubMed

Niemeläinen, R; Videman, T; Dhillon, S S; Battié, M C

2008-03-01

To investigate the spinal cord as an alternative intra-body reference to cerebrospinal fluid (CSF) in evaluating thoracic disc signal intensity. T2-weighted magnetic resonance imaging (MRI) images of T6-T12 were obtained using 1.5 T machines for a population-based sample of 523 men aged 35-70 years. Quantitative data on the signal intensities were acquired using an image analysis program (SpEx). A random sample of 30 subjects and intraclass correlation coefficients (ICC) were used to examine the repeatability of the spinal cord measurements. The validity of using the spinal cord as a reference was examined by correlating cord and CSF samples. Finally, thoracic disc signal was validated by correlating it with age without adjustment and adjusting for either cord or CSF. Pearson's r was used for correlational analyses. The repeatability of the spinal cord signal measurements was extremely high (>or=0.99). The correlations between the signals of spinal cord and CSF by level were all above 0.9. The spinal cord-adjusted disc signal and age correlated similarly with CSF-adjusted disc signal and age (r=-0.30 to -0.40 versus r=-0.26 to -0.36). Adjacent spinal cord is a good alternative reference to the current reference standard, CSF, for quantitative measurements of disc signal intensity. Clearly fewer levels were excluded when using spinal cord as compared to CSF due to missing reference samples.

Impact of cerebro-spinal fluid biomarkers of Alzheimer's disease in clinical practice: a multicentric study.

PubMed

Mouton-Liger, François; Wallon, David; Troussière, Anne-Cécile; Yatimi, Rachida; Dumurgier, Julien; Magnin, Eloi; de la Sayette, Vincent; Duron, Emannuelle; Philippi, Nathalie; Beaufils, Emilie; Gabelle, Audrey; Croisile, Bernard; Robert, Philippe; Pasquier, Florence; Hannequin, Didier; Hugon, Jacques; Paquet, Claire

2014-01-01

CSF biomarkers of Alzheimer's disease are well validated in clinical research; however, their pragmatic utility in daily practice is still unappreciated. These biomarkers are used in routine practice according to Health Authority Recommendations. In 604 consecutive patients explored for cognitive disorders, questionnaires were prospectively proposed and filled. Before and after CSF biomarker results, clinicians provided a diagnosis and an estimate of their diagnostic confidence. Analysis has compared the frequency of diagnosis before and after CSF biomarker results using the net reclassification improvement (NRI) method. We have evaluated external validity comparing with data of French Bank National of AD (BNA). A total of 561 patients [Alzheimer's disease (AD), n = 253; non-AD, n = 308] were included (mean age, 68.6 years; women, 52 %). Clinically suspected diagnosis and CSF results were concordant in 65.2 % of cases. When clinical hypothesis and biological results were discordant, a reclassification occurred in favour of CSF biomarkers results in 76.9 %. The NRI was 39.5 %. In addition, the results show a statistically significant improvement in clinician confidence for their diagnosis. In comparison with BNA data, patients were younger and more frequently diagnosed with AD. Clinicians tend to heavily rely on the CSF AD biomarkers results and are more confident in their diagnoses using CSF AD biomarkers. Thus, these biomarkers appear as a key tool in clinical practice.

Optical analysis of suspended particles in the cerebrospinal fluid obtained by puncture from patients diagnosed with the disorders of cerebrospinal fluid (CSF) circulation

NASA Astrophysics Data System (ADS)

Staroń, Waldemar; Herbowski, Leszek; Gurgul, Henryk

2007-04-01

The goal of the work was to determine the values of cumulative parameters of the cerebrospinal fluid. Values of the parameters characterise statistical cerebrospinal fluid obtained by puncture from the patients diagnosed due to suspicion of normotensive hydrocephalus. The cerebrospinal fluid taken by puncture for the routine examinations carried out at the patients suspected of normotensive hydrocephalus was analysed. In the paper there are presented results of examinations of several dozens of puncture samples of the cerebrospinal fluid coming from various patients. Each sample was examined under the microscope and photographed in 20 randomly chosen places. On the basis of analysis of the pictures showing the area of 100 x 100μm, the selected cumulative parameters such as count, numerical density, field area and field perimeter were determined for each sample. Then the average value of the parameters was determined as well.

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.

Herpes Zoster Meningitis Presenting With a Cerebrospinal Fluid Leukemoid Reaction in an Adolescent With preB-ALL in Remission.

PubMed

Adachi, Kristina; Song, Sophie X; Kao, Roy L; Van Dyne, Elizabeth; Kempert, Pamela; Deville, Jaime G

2016-08-01

A 19-year-old girl with a history of precursor B acute lymphoblastic leukemia in remission presented with fever, headache, and a skin rash. Cerebrospinal fluid (CSF) examination reported pleocytosis with blast-like cells concerning for a central nervous system leukemic relapse. After the patient showed significant improvement on intravenous acyclovir, a repeat lumbar puncture revealed normalization of CSF. The abnormal CSF cells were reviewed and ultimately determined to be activated and atypical lymphocytes. The patient recovered uneventfully. Atypical lymphocytes resembling leukemic blasts are an unusual finding in viral meningitis. Varicella zoster virus reactivation should be considered during initial evaluation for central nervous system relapse of leukemia.

Pre-cut Filter Paper for Detecting Anti-Japanese Encephalitis Virus IgM from Dried Cerebrospinal Fluid Spots

PubMed Central

Bharucha, Tehmina; Chanthongthip, Anisone; Phuangpanom, Soumphou; Phonemixay, Ooyanong; Sengvilaipaseuth, Onanong; Vongsouvath, Manivanh; Lee, Sue; Newton, Paul N.; Dubot-Pérès, Audrey

2016-01-01

Background The use of filter paper as a simple, inexpensive tool for storage and transportation of blood, ‘Dried Blood Spots’ or Guthrie cards, for diagnostic assays is well-established. In contrast, there are a paucity of diagnostic evaluations of dried cerebrospinal fluid (CSF) spots. These have potential applications in low-resource settings, such as Laos, where laboratory facilities for central nervous system (CNS) diagnostics are only available in Vientiane. In Laos, a major cause of CNS infection is Japanese encephalitis virus (JEV). We aimed to develop a dried CSF spot protocol and to evaluate its diagnostic performance using the World Health Organisation recommended anti-JEV IgM antibody capture enzyme-linked immunosorbent assay (JEV MAC-ELISA). Methodology and Principal Findings Sample volumes, spotting techniques and filter paper type were evaluated using a CSF-substitute of anti-JEV IgM positive serum diluted in Phosphate Buffer Solution (PBS) to end-limits of detection by JEV MAC-ELISA. A conventional protocol, involving eluting one paper punch in 200μl PBS, did not detect the end-dilution, nor did multiple punches utilising diverse spotting techniques. However, pre-cut filter paper enabled saturation with five times the volume of CSF-substitute, sufficiently improving sensitivity to detect the end-dilution. The diagnostic accuracy of this optimised protocol was compared with routine, neat CSF in a pilot, retrospective study of JEV MAC-ELISA on consecutive CSF samples, collected 2009–15, from three Lao hospitals. In comparison to neat CSF, 132 CSF samples stored as dried CSF spots for one month at 25–30°C showed 81.6% (65.7–92.3 95%CI) positive agreement, 96.8% (91.0–99.3 95%CI) negative agreement, with a kappa coefficient of 0.81 (0.70–0.92 95%CI). Conclusions/Significance The novel design of pre-cut filter paper saturated with CSF could provide a useful tool for JEV diagnostics in settings with limited laboratory access. It has the potential to improve national JEV surveillance and inform vaccination policies. The saturation of filter paper has potential use in the wider context of pathogen detection, including dried spots for detecting other analytes in CSF, and other body fluids. PMID:26986061

Penetration of amoxicillin and potassium clavulanate into the cerebrospinal fluid of patients with inflamed meninges.

PubMed Central

Bakken, J S; Bruun, J N; Gaustad, P; Tasker, T C

1986-01-01

A single intravenous dose of 2.0 g of amoxicillin and 0.2 g of potassium clavulanate was given to patients with bacterial meningitis, and the pharmacokinetics of both drugs in the cerebrospinal fluid (CSF) and plasma were evaluated. Twenty-one patients aged 14 to 76 years were studied. Both amoxicillin and potassium clavulanate were detectable in the CSF as early as 1 h and reached peak concentrations by approximately 2 h. The highest mean CSF concentrations were 2.25 micrograms/ml for amoxicillin and 0.25 micrograms/ml for potassium clavulanate and were found in patients with moderately or severely inflamed meninges. The CSF penetration relative to plasma for amoxicillin and potassium clavulanate was 5.8 and 8.4%, respectively. These levels suggest that the amoxicillin-potassium clavulanate combination may be effective for the treatment of bacterial meningitis caused by beta-lactamase-producing pathogens. PMID:3777911

Cerebrospinal Fluid Shunting Complications in Children

PubMed Central

Hanak, Brian W.; Bonow, Robert H.; Harris, Carolyn A.; Browd, Samuel R.

2018-01-01

Although cerebrospinal fluid (CSF) shunt placement is the most common procedure performed by pediatric neurosurgeons, shunts remain among the most failure-prone life-sustaining medical devices implanted in modern medical practice. This article provides an overview of the mechanisms of CSF shunt failure for the 3 most commonly employed definitive CSF shunts in the practice of pediatric neurosurgery: ventriculoperitoneal, ventriculopleural, and ventriculoatrial. The text has been partitioned into the broad modes of shunt failure: obstruction, infection, mechanical shunt failure, overdrainage, and distal catheter site-specific failures. Clinical management strategies for the various modes of shunt failure are discussed as are research efforts directed towards reducing shunt complication rates. As it is unlikely that CSF shunting will become an obsolete procedure in the foreseeable future, it is incumbent on the pediatric neurosurgery community to maintain focused efforts to improve our understanding of and management strategies for shunt failure and shunt-related morbidity. PMID:28249297

The predictive value of cerebrospinal fluid tap-test in normal pressure hydrocephalus.

PubMed

Damasceno, B P; Carelli, E F; Honorato, D C; Facure, J J

1997-06-01

Eighteen patients (mean age of 66.5 years) with normal pressure hydrocephalus (NPH) underwent a ventriculo-peritoneal shunt surgery. Prior to operation a cerebrospinal fluid tap-test (CSF-TT) was performed with measurements of gait pattern and psychometric functions (memory, visuo-motor speed and visuo-constructive skills) before and after the removal of 50 ml CSF by lumbar puncture (LP). Fifteen patients improved and 3 were unchanged after surgery. Short duration of disease, gait disturbance preceding mental deterioration, wide temporal horns and small sulci on CT-scan were associated with good outcome after shunting. There was a good correlation between the results of CSF-TT and shunt surgery (chi 2 = 4.11, phi = 0.48, p < 0.05), with gait test showing highest correlation (r = 0.99, p = 0.01). In conclusion, this version of CSF-TT proved to be an effective test to predict improvement after shunting in patients with NPH.

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.

Network-based analysis of differentially expressed genes in cerebrospinal fluid (CSF) and blood reveals new candidate genes for multiple sclerosis

PubMed Central

Safari-Alighiarloo, Nahid; Taghizadeh, Mohammad; Tabatabaei, Seyyed Mohammad; Namaki, Saeed

2016-01-01

Background The involvement of multiple genes and missing heritability, which are dominant in complex diseases such as multiple sclerosis (MS), entail using network biology to better elucidate their molecular basis and genetic factors. We therefore aimed to integrate interactome (protein–protein interaction (PPI)) and transcriptomes data to construct and analyze PPI networks for MS disease. Methods Gene expression profiles in paired cerebrospinal fluid (CSF) and peripheral blood mononuclear cells (PBMCs) samples from MS patients, sampled in relapse or remission and controls, were analyzed. Differentially expressed genes which determined only in CSF (MS vs. control) and PBMCs (relapse vs. remission) separately integrated with PPI data to construct the Query-Query PPI (QQPPI) networks. The networks were further analyzed to investigate more central genes, functional modules and complexes involved in MS progression. Results The networks were analyzed and high centrality genes were identified. Exploration of functional modules and complexes showed that the majority of high centrality genes incorporated in biological pathways driving MS pathogenesis. Proteasome and spliceosome were also noticeable in enriched pathways in PBMCs (relapse vs. remission) which were identified by both modularity and clique analyses. Finally, STK4, RB1, CDKN1A, CDK1, RAC1, EZH2, SDCBP genes in CSF (MS vs. control) and CDC37, MAP3K3, MYC genes in PBMCs (relapse vs. remission) were identified as potential candidate genes for MS, which were the more central genes involved in biological pathways. Discussion This study showed that network-based analysis could explicate the complex interplay between biological processes underlying MS. Furthermore, an experimental validation of candidate genes can lead to identification of potential therapeutic targets. PMID:28028462

Limited geographic distribution of the novel cyclovirus CyCV-VN.

PubMed

Le, Van Tan; de Jong, Menno D; Nguyen, Van Kinh; Nguyen, Vu Trung; Taylor, Walter; Wertheim, Heiman F L; van der Ende, Arie; van der Hoek, Lia; Canuti, Marta; Crusat, Martin; Sona, Soeng; Nguyen, Hanh Uyen; Giri, Abhishek; Nguyen, Thi Thuy Chinh Bkrong; Ho, Dang Trung Nghia; Farrar, Jeremy; Bryant, Juliet E; Tran, Tinh Hien; Nguyen, Van Vinh Chau; van Doorn, H Rogier

2014-02-05

A novel cyclovirus, CyCV-VN, was recently identified in cerebrospinal fluid (CSF) from patients with central nervous system (CNS) infections in central and southern Vietnam. To explore the geographic distribution of this novel virus, more than 600 CSF specimens from patients with suspected CNS infections in northern Vietnam, Cambodia, Nepal and The Netherlands were screened for the presence of CyCV-VN but all were negative. Sequence comparison and phylogenetic analysis between CyCV-VN and another novel cyclovirus recently identified in CSF from Malawian patients indicated that these represent distinct cycloviral species, albeit phylogenetically closely related. The data suggest that CyCV-VN has a limited geographic distribution within southern and central Vietnam. Further research is needed to determine the global distribution and diversity of cycloviruses and importantly their possible association with human disease.

Population Pharmacokinetics of Combined Intravenous and Local Intrathecal Administration of Meropenem in Aneurysm Patients with Suspected Intracranial Infections After Craniotomy.

PubMed

Li, Xingang; Sun, Shusen; Wang, Qiang; Zhao, Zhigang

2018-02-01

For patients with intracranial infection, local intrathecal administration of meropenem may be a useful method to obtain a sufficient drug concentration in the cerebral spinal fluid (CSF). However, a large inter-individual variability may pose treatment efficacy at risk. This study aimed to identify factors affecting drug concentration in the CSF using population pharmacokinetics method. After craniotomy, aneurysm patients with an indwelling lumbar cistern drainage tube who received a combined intravenous and intrathecal administration of meropenem for the treatment of suspected intracranial infection were enrolled. Venous blood and CSF specimens were collected for determining meropenem concentrations. Nonlinear mixed-effects modeling method was used to fit blood and CSF concentrations simultaneously and to develop the population pharmacokinetic model. The proposed model was applied to simulate dosage regimens. A three-compartmental model was established to describe meropenem in vivo behavior. Lumbar CSF drainage resulted in a drug loss, and drug clearance in CSF (CL CSF ) was employed to describe this. The covariate analysis found that the drainage volume (mL/day) was strongly associated with CL CSF , and the effect of creatinine clearance was significant on the clearance of meropenem in blood (CL). Visual predictive check suggested that the proposed pharmacokinetic model agreed well with the observations. Simulation showed that both intravenous and intrathecal doses should be increased with the increases of minimum inhibitory concentration and daily CSF drainage volume. This model incorporates covariates of the creatinine clearance and the drainage volume, and a simple to use dosage regimen table was created to guide clinicians with meropenem dosing.

Meta-Review of CSF Core Biomarkers in Alzheimer’s Disease: The State-of-the-Art after the New Revised Diagnostic Criteria

PubMed Central

Ferreira, Daniel; Perestelo-Pérez, Lilisbeth; Westman, Eric; Wahlund, Lars-Olof; Sarría, Antonio; Serrano-Aguilar, Pedro

2014-01-01

Background: Current research criteria for Alzheimer’s disease (AD) include cerebrospinal fluid (CSF) biomarkers into the diagnostic algorithm. However, spreading their use to the clinical routine is still questionable. Objective: To provide an updated, systematic and critical review on the diagnostic utility of the CSF core biomarkers for AD. Data sources: MEDLINE, PreMedline, EMBASE, PsycInfo, CINAHL, Cochrane Library, and CRD. Eligibility criteria: (1a) Systematic reviews with meta-analysis; (1b) Primary studies published after the new revised diagnostic criteria; (2) Evaluation of the diagnostic performance of at least one CSF core biomarker. Results: The diagnostic performance of CSF biomarkers is generally satisfactory. They are optimal for discriminating AD patients from healthy controls. Their combination may also be suitable for mild cognitive impairment (MCI) prognosis. However, CSF biomarkers fail to distinguish AD from other forms of dementia. Limitations: (1) Use of clinical diagnosis as standard instead of pathological postmortem confirmation; (2) variability of methodological aspects; (3) insufficiently long follow-up periods in MCI studies; and (4) lower diagnostic accuracy in primary care compared with memory clinics. Conclusion: Additional work needs to be done to validate the application of CSF core biomarkers as they are proposed in the new revised diagnostic criteria. The use of CSF core biomarkers in clinical routine is more likely if these limitations are overcome. Early diagnosis is going to be of utmost importance when effective pharmacological treatment will be available and the CSF core biomarkers can also be implemented in clinical trials for drug development. PMID:24715863

Post craniotomy extra-ventricular drain (EVD) associated nosocomial meningitis: CSF diagnostic criteria.

PubMed

Muñoz-Gómez, Sigridh; Wirkowski, Elizabeth; Cunha, Burke A

2015-01-01

Because external ventricular drains (EVDs) provide access to cerebrospinal fluid (CSF), there is potential for EVD associated acute bacterial meningitis (EVD-AM). Post-craniotomy, in patients with EVDs, one or more CSF abnormalities are commonly present making the diagnosis of EVD-AM problematic. EVD-AM was defined as elevated CSF lactic acid (>6 nmol/L), plus CSF marked pleocytosis (>50 WBCs/mm(3)), plus a positive Gram stain (same morphology as CSF isolate), plus a positive CSF culture of neuropathogen (same morphology as Gram stained organism). We reviewed 22 adults with EVDs to determine if our four CSF parameters combined accurately identified EVD-AM. No single or combination of <4 CSF parameters correctly diagnosed or ruled out EVD-AM. Combined our four CSF parameters clearly differentiated EVD-AM from one case of pseudomeningitis due to E. cloacae. We conclude that our four CSF criteria combined are useful in diagnosing EVD-AM in adults. Copyright © 2015 Elsevier Inc. All rights reserved.

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.

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.

Mortality of Dandy-Walker syndrome in the United States: Analysis by race, gender, and insurance status.

PubMed

McClelland, Shearwood; Ukwuoma, Onyinyechi I; Lunos, Scott; Okuyemi, Kolawole S

2015-01-01

Dandy-Walker syndrome (DWS) is a congenital disorder often diagnosed in early childhood. Typically manifesting with signs/symptoms of increased intracranial pressure, DWS is catastrophic unless timely neurosurgical care can be administered via cerebrospinal fluid (CSF) drainage. The rates of mortality, adverse discharge disposition (ADD), and CSF drainage in DWS may not be uniform regardless of race, gender or insurance status; such differences could reflect disparities in access to neurosurgical care. This study examines these issues on a nationwide level. The Kids' Inpatient Database spanning 1997-2003 was used for analysis. Only patients admitted for DWS (ICD-9-CM = 742.3) were included. Multivariate analysis was adjusted for several variables, including patient age, race, sex, admission type, primary payer, income, and hospital volume. More than 14,000 DWS patients were included. Increasing age predicted reduced mortality (OR = 0.87; P < 0.05), ADD (OR = 0.96; P < 0.05), and decreased likelihood of receiving CSF drainage (OR = 0.86; P < 0.0001). Elective admission type predicted reduced mortality (OR = 0.29; P = 0.0008), ADD (OR = 0.68; P < 0.05), and increased CSF drainage (OR = 2.02; P < 0.0001). African-American race (OR = 1.20; P < 0.05) and private insurance (OR = 1.18; P < 0.05) each predicted increased likelihood of receiving CSF drainage, but were not predictors of mortality or ADD. Gender, income, and hospital volume were not significant predictors of DWS outcome. Increasing age and elective admissions each decrease mortality and ADD associated with DWS. African-American race and private insurance status increase access to CSF drainage. These findings contradict previous literature citing African-American race as a risk factor for mortality in DWS, and emphasize the role of private insurance in obtaining access to potentially lifesaving operative care.

Preservation of the Myofascial Cuff During Posterior Fossa Surgery to Reduce the Rate of Pseudomeningocele Formation and Cerebrospinal Fluid Leak: A Technical Note.

PubMed

Felbaum, Daniel R; Mueller, Kyle; Anaizi, Amjad; Mason, Robert B; Jean, Walter C; Voyadzis, Jean M

2016-12-28

 Suboccipital craniotomy is a workhorse neurosurgical operation for approaching the posterior fossa but carries a high risk of pseudomeningocele and cerebrospinal fluid (CSF) leak. We describe our experience with a simple T-shaped fascial opening that preserves the occipital myofascial cuff as compared to traditional methods to reduce this risk.  A single institution, retrospective review of prospectively collected database was performed of patients that underwent a suboccipital craniectomy or craniotomy. Patient data was reviewed for craniotomy or craniectomy, dural graft, and/or sealant use as well as CSF complications. A pseudomeningocele was defined as a subcutaneous collection of cerebrospinal fluid palpable clinically and confirmed on imaging. A CSF leak was defined as a CSF-cutaneous fistula manifested by CSF leaking through the wound. All patients underwent regular postoperative visits of two weeks, one month, and three months.  Our retrospective review identified 33 patients matching the inclusion criteria. Overall, our cohort had a 21% (7/33) rate of clinical and radiographic pseudomeningocele formation with 9% (3/33) requiring surgical revision or a separate procedure. The rate of clinical and radiographic pseudomeningocele formation in the myofascial cuff preservation technique was less than standard techniques (12% and 31%, respectively). Revision or further surgical procedures were also reduced in the myofascial cuff preservation technique vs. the standard technique (6% vs 13%).  Preservation of the myofascial cuff during posterior fossa surgery is a simple and adoptable technique that reduces the rate of pseudomeningocele formation and CSF leak as compared with standard techniques.

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.

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

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

Anti-Correlated Cerebrospinal Fluid Biomarker Trajectories in Preclinical Alzheimer's Disease.

PubMed

Gomar, Jesus J; Conejero-Goldberg, Concepcion; Davies, Peter; Goldberg, Terry E

2016-01-01

The earliest stage of preclinical Alzheimer's disease (AD) is defined by low levels of cerebrospinal fluid (CSF) amyloid-β (Aβ42). However, covariance in longitudinal dynamic change of Aβ42 and tau in incipient preclinical AD is poorly understood. To examine dynamic interrelationships between Aβ42 and tau in preclinical AD. We followed 47 cognitively intact participants (CI) with available CSF data over four years in ADNI. Based on longitudinal Aβ42 levels in CSF, CI were classified into three groups: 1) Aβ42 stable with normal levels of Aβ42 over time (n = 15); 2) Aβ42 declining with normal Aβ42 levels at baseline but showing decline over time (n = 14); and 3) Aβ42 levels consistently abnormal (n = 18). In the Aβ42 declining group, suggestive of incipient preclinical AD, CSF phosphorylated tau (p-tau) showed a similar longitudinal pattern of increasing abnormality over time (p = 0.0001). Correlation between longitudinal slopes of Aβ42 and p-tau confirmed that both trajectories were anti-correlated (rho = -0.60; p = 0.02). Regression analysis showed that Aβ42 slope (decreasing Aβ42) predicted p-tau slope (increasing p-tau) (R2 = 0.47, p = 0.03). Atrophy in the hippocampus was predicted by the interaction of Aβ42 and p-tau slopes (p <  0.0001) only in this incipient preclinical AD group. In all groups combined, memory decline was predicted by p-tau. The evolution of Aβ42 and p-tau CSF biomarkers in CI subjects follows an anti-correlated trajectory, i.e., as Aβ42 declined, p-tau increased, and thus was suggestive of strong temporal coincidence. Rapid pathogenic cross-talk between Aβ42 and p-tau thus may be evident in very early stages of preclinical AD.

Large-Scale Evaluation of the Immuno-Mycologics Lateral Flow and Enzyme-Linked Immunoassays for Detection of Cryptococcal Antigen in Serum and Cerebrospinal Fluid

PubMed Central

Hansen, Jessica; Slechta, E. Susan; Gates-Hollingsworth, Marcellene A.; Neary, Brandon; Barker, Adam P.; Bauman, Sean; Kozel, Thomas R.

2013-01-01

Cryptococcosis is a systemic infection caused by the pathogenic yeasts Cryptococcus neoformans and C. gattii. Detection of cryptococcal capsular antigen (CrAg) in serum and cerebrospinal fluid (CSF) plays an important diagnostic role. We prospectively compared the new Immuno-Mycologics Inc. (IMMY) lateral flow assay (LFA) and enzyme immunoassay (EIA) to our current CrAg test (Premier EIA; Meridian Bioscience Inc.). Discordant samples were retested with the latex-Cryptococcus antigen test (IMMY) and using serotype-specific monoclonal antibodies (MAbs). A total of 589 serum and 411 CSF specimens were tested in parallel. Qualitative agreement across assays was 97.7%. In all, 56 (41 serum and 15 CSF) samples were positive and 921 (527 serum and 394 CSF) samples were negative by all three assays. The 23 discrepant specimens were all Meridian EIA negative. Of 23 discordant specimens, 20 (87.0%) were positive by both the IMMY LFA and EIA, 2 were LFA positive only, and 1 was EIA positive only. Eleven discrepant specimens had adequate volume for latex agglutination (LA) testing; 8 were LA positive, and 3 were LA negative. LA-negative samples (2 CSF samples and 1 serum) had low IMMY LFA/EIA titers (≤1:10). Serotype-specific MAb analysis of the LA-positive samples suggested that these specimens contained CrAg epitopes similar to those of serotype C strains. In conclusion, the IMMY assays showed excellent overall concordance with the Meridian EIA. Assay performance differences were related to issues of analytic sensitivity and possible serotype bias. Incomplete access to patient-level data combined with low specimen volumes limited our ability to fully resolve discrepant results. PMID:23114703

Large-scale evaluation of the immuno-mycologics lateral flow and enzyme-linked immunoassays for detection of cryptococcal antigen in serum and cerebrospinal fluid.

PubMed

Hansen, Jessica; Slechta, E Susan; Gates-Hollingsworth, Marcellene A; Neary, Brandon; Barker, Adam P; Bauman, Sean; Kozel, Thomas R; Hanson, Kimberly E

2013-01-01

Cryptococcosis is a systemic infection caused by the pathogenic yeasts Cryptococcus neoformans and C. gattii. Detection of cryptococcal capsular antigen (CrAg) in serum and cerebrospinal fluid (CSF) plays an important diagnostic role. We prospectively compared the new Immuno-Mycologics Inc. (IMMY) lateral flow assay (LFA) and enzyme immunoassay (EIA) to our current CrAg test (Premier EIA; Meridian Bioscience Inc.). Discordant samples were retested with the latex-Cryptococcus antigen test (IMMY) and using serotype-specific monoclonal antibodies (MAbs). A total of 589 serum and 411 CSF specimens were tested in parallel. Qualitative agreement across assays was 97.7%. In all, 56 (41 serum and 15 CSF) samples were positive and 921 (527 serum and 394 CSF) samples were negative by all three assays. The 23 discrepant specimens were all Meridian EIA negative. Of 23 discordant specimens, 20 (87.0%) were positive by both the IMMY LFA and EIA, 2 were LFA positive only, and 1 was EIA positive only. Eleven discrepant specimens had adequate volume for latex agglutination (LA) testing; 8 were LA positive, and 3 were LA negative. LA-negative samples (2 CSF samples and 1 serum) had low IMMY LFA/EIA titers (≤1:10). Serotype-specific MAb analysis of the LA-positive samples suggested that these specimens contained CrAg epitopes similar to those of serotype C strains. In conclusion, the IMMY assays showed excellent overall concordance with the Meridian EIA. Assay performance differences were related to issues of analytic sensitivity and possible serotype bias. Incomplete access to patient-level data combined with low specimen volumes limited our ability to fully resolve discrepant results.

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.

Cerebrospinal fluid neural cell adhesion molecule levels and their correlation with clinical variables in patients with schizophrenia, bipolar disorder, and major depressive disorder.

PubMed

Hidese, Shinsuke; Hattori, Kotaro; Sasayama, Daimei; Miyakawa, Tomoko; Matsumura, Ryo; Yokota, Yuuki; Ishida, Ikki; Matsuo, Junko; Noda, Takamasa; Yoshida, Sumiko; Teraishi, Toshiya; Hori, Hiroaki; Ota, Miho; Kunugi, Hiroshi

2017-06-02

Neural cell adhesion molecule (NCAM) plays an important role in neural plasticity, and its altered function has been implicated in psychiatric disorders. However, previous studies have yielded inconsistent results on cerebrospinal fluid (CSF) NCAM levels in psychiatric disorders. The aim of our study was to examine CSF NCAM levels in patients with schizophrenia, bipolar disorder (BD), and major depressive disorder (MDD), and their possible relationship with clinical variables. The participants comprised 85 patients with schizophrenia, 57 patients with BD, 83 patients with MDD and 111 healthy controls, all matched for age, sex, and Japanese ethnicity. The CSF samples were drawn using a lumbar puncture and NCAM levels were quantified by an enzyme-linked immunosorbent assay. Analysis of covariance controlling for age and sex revealed that CSF NCAM levels were lower in all patients (p=0.033), and in those with BD (p=0.039), than in the controls. NCAM levels positively correlated with age in patients with BD (p<0.01), MDD (p<0.01), and the controls (p<0.01). NCAM levels negatively correlated with depressive symptom scores in patients with BD (p=0.040). In patients with schizophrenia, NCAM levels correlated negatively with negative symptom scores (p=0.029), and correlated positively with scores for cognitive functions such as category fluency (p=0.011) and letter fluency (p=0.023) scores. We showed that CSF NCAM levels were lower in psychiatric patients, particularly bipolar patients than in the controls. Furthermore, we found correlations of NCAM levels with clinical symptoms in patients with BD and in those with schizophrenia, suggesting the involvement of central NCAM in the symptom formation of severe psychiatric disorders. Copyright © 2017 Elsevier Inc. All rights reserved.

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.

Obstructive Sleep Apnea is Associated With Early but Possibly Modifiable Alzheimer's Disease Biomarkers Changes.

PubMed

Liguori, Claudio; Mercuri, Nicola Biagio; Izzi, Francesca; Romigi, Andrea; Cordella, Alberto; Sancesario, Giuseppe; Placidi, Fabio

2017-05-01

Obstructive sleep apnea (OSA) is a common sleep disorder. The, literature lacks studies examining sleep, cognition, and Alzheimer's Disease (AD) cerebrospinal fluid (CSF) biomarkers in OSA patients. Therefore, we first studied cognitive performances, polysomnographic sleep, and CSF β-amyloid42, tau proteins, and lactate levels in patients affected by subjective cognitive impairment (SCI) divided in three groups: OSA patients (showing an Apnea-Hypopnea Index [AHI] ≥15/hr), controls (showing an AHI < 15/hr), and patients with OSA treated by continuous positive airway pressure (CPAP). We compared results among 25 OSA, 10 OSA-CPAP, and 15 controls who underwent a protocol counting neuropsychological testing in the morning, 48-hr polysomnography followed by CSF analysis. OSA patients showed lower CSF Aβ42 concentrations, higher CSF lactate levels, and higher t-tau/Aβ42 ratio compared to controls and OSA-CPAP patients. OSA patients also showed reduced sleep quality and continuity and lower performances at memory, intelligence, and executive tests than controls and OSA-CPAP patients. We found significant relationships among higher CSF tau proteins levels, sleep impairment, and increased CSF lactate levels in the OSA group. Moreover, lower CSF Aβ42 levels correlate with memory impairment and nocturnal oxygen saturation parameters in OSA patients. We hypothesize that OSA reducing sleep quality and producing intermittent hypoxia lowers CSF Aβ42 levels, increases CSF lactate levels, and alters cognitive performances in SCI patients, thus inducing early AD clinical and neuropathological biomarkers changes. Notably, controls as well as OSA-CPAP SCI patients did not show clinical and biochemical AD markers. Therefore, OSA may induce early but possibly CPAP-modifiable AD biomarkers changes. © Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

Detection of cerebrospinal fluid leakage: initial experience with three-dimensional fast spin-echo magnetic resonance myelography.

PubMed

Tomoda, Y; Korogi, Y; Aoki, T; Morioka, T; Takahashi, H; Ohno, M; Takeshita, I

2008-03-01

The pathogenesis of cerebrospinal fluid (CSF) hypovolemia is supposed to be caused by CSF leakage through small dural defects. To compare source three-dimensional (3D) fast spin-echo (FSE) images of magnetic resonance (MR) myelography with radionuclide cisternography findings, and to evaluate the feasibility of MR myelography in the detection of CSF leakage. A total of 67 patients who were clinically suspected of CSF hypovolemia underwent indium-111 radionuclide cisternography, and 27 of those who had direct findings of CSF leakage were selected for evaluation. MR myelography with 3D FSE sequences (TR/TE 6000/203 ms) was performed at the lumbar spine for all patients. We evaluated source images and maximum intensity projection (MIP) images of MR myelography, and the findings were correlated with radionuclide cisternography findings. MR myelography of five healthy volunteers was used as a reference. The MR visibility of the CSF leakage was graded as definite (leakage clearly visible), possible (leakage poorly seen), or absent (not shown). CSF leakage was identified with source 3D FSE images in 22 (81.5%) of 27 patients. Of the 22 patients, 16 were graded as definite and six were graded as possible. For the definite cases, 3D FSE images clearly showed the extent of the leaked CSF in the paraspinal structures. In the remaining five patients with absent findings, radionuclide cisternography showed only slight radionuclide activity out of the arachnoid space. Source 3D FSE images of MR myelography seem useful in the detection of CSF leakage. Invasive radionuclide cisternography may be reserved for equivocal cases only.

Cerebrospinal fluid neopterin decay characteristics after initiation of antiretroviral therapy.

PubMed

Yilmaz, Aylin; Yiannoutsos, Constantin T; Fuchs, Dietmar; Price, Richard W; Crozier, Kathryn; Hagberg, Lars; Spudich, Serena; Gisslén, Magnus

2013-05-10

Neopterin, a biomarker of macrophage activation, is elevated in the cerebrospinal fluid (CSF) of most HIV-infected individuals and decreases after initiation of antiretroviral therapy (ART). We studied decay characteristics of neopterin in CSF and blood after commencement of ART in HIV-infected subjects and estimated the set-point levels of CSF neopterin after ART-mediated viral suppression. CSF and blood neopterin were longitudinally measured in 102 neurologically asymptomatic HIV-infected subjects who were treatment-naïve or had been off ART for ≥ 6 months. We used a non-linear model to estimate neopterin decay in response to ART and a stable neopterin set-point attained after prolonged ART. Seven subjects with HIV-associated dementia (HAD) who initiated ART were studied for comparison. Non-HAD patients were followed for a median 84.7 months. Though CSF neopterin concentrations decreased rapidly after ART initiation, it was estimated that set-point levels would be below normal CSF neopterin levels (<5.8 nmol/L) in only 60/102 (59%) of these patients. Pre-ART CSF neopterin was the primary predictor of set-point (P <0.001). HAD subjects had higher baseline median CSF neopterin levels than non-HAD subjects (P <0.0001). Based on the non-HAD model, only 14% of HAD patients were predicted to reach normal levels. After virologically suppressive ART, abnormal CSF neopterin levels persisted in 41% of non-HAD and the majority of HAD patients. ART is not fully effective in ameliorating macrophage activation in CNS as well as blood, especially in subjects with higher pre-ART levels of immune activation.

Usefulness of interleukin 6 levels in the cerebrospinal fluid for the diagnosis of bacterial meningitis.

PubMed

Takahashi, Waka; Nakada, Taka-aki; Abe, Ryuzo; Tanaka, Kumiko; Matsumura, Yosuke; Oda, Shigeto

2014-08-01

Interleukin 6 (IL-6) is a proinflammatory cytokine produced during infections. We hypothesized that IL-6 levels in the cerebrospinal fluid (CSF) would be elevated in bacterial meningitis and useful for diagnosing and predicting neurologic outcomes. For the differentiation of bacterial meningitis, serum and CSF samples were obtained from patients with an altered level of consciousness. Patients were classified into 3 groups: bacterial meningitis, nonbacterial central nervous system disease, and other site sepsis. Of the 70 patients included in this study, there were 13 in the bacterial meningitis group, 21 in the nonbacterial central nervous system disease group, and 36 in the other site sepsis group. The CSF IL-6 level was significantly higher in the bacterial meningitis group than in the other 2 groups (P<.0001). Of the 5 CSF parameters assessed, CSF IL-6 level exhibited the largest area under the receiver operating characteristic curve (0.962), with a cut-off value of 644 pg/mL (sensitivity, 92.3%; specificity, 89.5%). To examine a potential association between a high CSF level and neurologic outcome, CSF IL-6 levels were divided into 4 quartiles, and each level was compared with the frequency of a good neurologic outcome. The frequency of a good neurologic outcome was significantly lower in the highest CSF IL-6 quartile than in the other 3 quartiles (odds ratio, 0.18; 95% confidence interval, 0.05-0.69; P=.013). Measurement of the CSF IL-6 level is useful for diagnosing bacterial meningitis. Copyright © 2014 Elsevier Inc. All rights reserved.

Cerebrospinal fluid levels of amyloid precursor protein are associated with ventricular size in post-hemorrhagic hydrocephalus of prematurity.

PubMed

Morales, Diego M; Holubkov, Richard; Inder, Terri E; Ahn, Haejun C; Mercer, Deanna; Rao, Rakesh; McAllister, James P; Holtzman, David M; Limbrick, David D

2015-01-01

Neurological outcomes of preterm infants with post-hemorrhagic hydrocephalus (PHH) remain among the worst in infancy, yet there remain few instruments to inform the treatment of PHH. We previously observed PHH-associated elevations in cerebrospinal fluid (CSF) amyloid precursor protein (APP), neural cell adhesion molecule-L1 (L1CAM), neural cell adhesion molecule-1 (NCAM-1), and other protein mediators of neurodevelopment. The objective of this study was to examine the association of CSF APP, L1CAM, and NCAM-1 with ventricular size as an early step toward developing CSF markers of PHH. CSF levels of APP, L1CAM, NCAM-1, and total protein (TP) were measured in 12 preterm infants undergoing PHH treatment. Ventricular size was determined using cranial ultrasounds. The relationships between CSF APP, L1CAM, and NCAM-1, occipitofrontal circumference (OFC), volume of CSF removed, and ventricular size were examined using correlation and regression analyses. CSF levels of APP, L1CAM, and NCAM-1 but not TP paralleled treatment-related changes in ventricular size. CSF APP demonstrated the strongest association with ventricular size, estimated by frontal-occipital horn ratio (FOR) (Pearson R = 0.76, p = 0.004), followed by NCAM-1 (R = 0.66, p = 0.02) and L1CAM (R = 0.57,p = 0.055). TP was not correlated with FOR (R = 0.02, p = 0.95). Herein, we report the novel observation that CSF APP shows a robust association with ventricular size in preterm infants treated for PHH. The results from this study suggest that CSF APP and related proteins at once hold promise as biomarkers of PHH and provide insight into the neurological consequences of PHH in the preterm infant.

G-CSF suppresses allergic pulmonary inflammation, downmodulating cytokine, chemokine and eosinophil production.

PubMed

Queto, Túlio; Vasconcelos, Zilton F M; Luz, Ricardo Alves; Anselmo, Carina; Guiné, Ana Amélia A; e Silva, Patricia Machado R; Farache, Júlia; Cunha, José Marcos T; Bonomo, Adriana C; Gaspar-Elsas, Maria Ignez C; Xavier-Elsas, Pedro

2011-05-09

Granulocyte Colony-Stimulating Factor (G-CSF), which mobilizes hemopoietic stem cells (HSC), is believed to protect HSC graft recipients from graft-versus-host disease by enhancing Th2 cytokine secretion. Accordingly, G-CSF should aggravate Th2-dependent allergic pulmonary inflammation and the associated eosinophilia. We evaluated the effects of G-CSF in a model of allergic pulmonary inflammation. Allergic pulmonary inflammation was induced by repeated aerosol allergen challenge in ovalbumin-sensitized C57BL/6J mice. The effects of allergen challenge and of G-CSF pretreatment were evaluated by monitoring: a) eosinophilia and cytokine/chemokine content of bronchoalveolar lavage fluid, pulmonary interstitium, and blood; b) changes in airway resistance; and c) changes in bone-marrow eosinophil production. Contrary to expectations, G-CSF pretreatment neither induced nor enhanced allergic pulmonary inflammation. Instead, G-CSF: a) suppressed accumulation of infiltrating eosinophils in bronchoalveolar, peribronchial and perivascular spaces of challenged lungs; and b) prevented ovalbumin challenge-induced rises in airway resistance. G-CSF had multiple regulatory effects on cytokine and chemokine production: in bronchoalveolar lavage fluid, levels of IL-1 and IL-12 (p40), eotaxin and MIP-1a were decreased; in plasma, KC, a neutrophil chemoattractant, was increased, while IL-5 was decreased and eotaxin was unaffected. In bone-marrow, G-CSF: a) prevented the increase in bone-marrow eosinophil production induced by ovalbumin challenge of sensitized mice; and b) selectively stimulated neutrophil colony formation. These observations challenge the view that G-CSF deviates cytokine production towards a Th2 profile in vivo, and suggest that this neutrophil-selective hemopoietin affects eosinophilic inflammation by a combination of effects on lung cytokine production and bone-marrow hemopoiesis. Copyright © 2011 Elsevier Inc. All rights reserved.

UPLC-MS/MS assay of riluzole in human plasma and cerebrospinal fluid (CSF): Application in samples from spinal cord injured patients.

PubMed

Sarkar, Mahua; Grossman, Robert G; Toups, Elizabeth G; Chow, Diana S-L

2017-11-30

In the present study, a sensitive and robust LC-MS/MS method has been developed and validated for the quantification of riluzole in human plasma and cerebrospinal fluid (CSF) in clinical samples from patients with spinal cord injury (SCI). Riluzole and its labeled internal standard (IS) were isolated from plasma and CSF by liquid-liquid extraction using ethyl acetate. Riluzole (m/z 235→166) and IS (m/z 238→169) were detected by electrospray ionization (ESI) using multiple reaction monitoring (MRM) in a positive mode. The assay was linear in the concentration range of 0.5 (LLOQ, signal/noise ratio>10)-800ng/ml in plasma, and 1.0 (LLOQ)-800ng/ml in CSF samples. The intra- and inter-day accuracy in plasma were 94.2-110.0% and 97.8-102.0%, respectively, and those in CSF were 87.6-105.1% and 91.9-98.8%, respectively. The intra- and inter-day precision were 2.2-7.2% and 4.0-9.1%, respectively, in plasma, and 1.4-14.1% and 2.6-11.5%, respectively in CSF. Matrix effect was negligible from both matrices with signal percentages of 97.6-100.6% in plasma and 99.4-106.4% in CSF. The recoveries were >75% in plasma, >84% in CSF with low protein (53.9mg/dl), and >68% in CSF with high protein (348.2mg/dl). This method was successfully applied to quantify riluzole concentrations in plasma and CSF from patients with SCI. Copyright © 2017 Elsevier B.V. All rights reserved.

Cerebrospinal fluid markers of neuronal and glial cell damage to monitor disease activity and predict long-term outcome in patients with autoimmune encephalitis.

PubMed

Constantinescu, R; Krýsl, D; Bergquist, F; Andrén, K; Malmeström, C; Asztély, F; Axelsson, M; Menachem, E B; Blennow, K; Rosengren, L; Zetterberg, H

2016-04-01

Clinical symptoms and long-term outcome of autoimmune encephalitis are variable. Diagnosis requires multiple investigations, and treatment strategies must be individually tailored. Better biomarkers are needed for diagnosis, to monitor disease activity and to predict long-term outcome. The value of cerebrospinal fluid (CSF) markers of neuronal [neurofilament light chain protein (NFL), and total tau protein (T-tau)] and glial cell [glial fibrillary acidic protein (GFAP)] damage in patients with autoimmune encephalitis was investigated. Demographic, clinical, magnetic resonance imaging, CSF and antibody-related data of 25 patients hospitalized for autoimmune encephalitis and followed for 1 year were retrospectively collected. Correlations between these data and consecutive CSF levels of NFL, T-tau and GFAP were investigated. Disability, assessed by the modified Rankin scale, was used for evaluation of disease activity and long-term outcome. The acute stage of autoimmune encephalitis was accompanied by high CSF levels of NFL and T-tau, whereas normal or significantly lower levels were observed after clinical improvement 1 year later. NFL and T-tau reacted in a similar way but at different speeds, with T-tau reacting faster. CSF levels of GFAP were initially moderately increased but did not change significantly later on. Final outcome (disability at 1 year) directly correlated with CSF-NFL and CSF-GFAP levels at all time-points and with CSF-T-tau at 3 ± 1 months. This correlation remained significant after age adjustment for CSF-NFL and T-tau but not for GFAP. In autoimmune encephalitis, CSF levels of neuronal and glial cell damage markers appear to reflect disease activity and long-term disability. © 2016 EAN.

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.

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.

Cerebrospinal fluid HIV escape associated with progressive neurologic dysfunction in patients on antiretroviral therapy with well controlled plasma viral load.

PubMed

Peluso, Michael J; Ferretti, Francesca; Peterson, Julia; Lee, Evelyn; Fuchs, Dietmar; Boschini, Antonio; Gisslén, Magnus; Angoff, Nancy; Price, Richard W; Cinque, Paola; Spudich, Serena

2012-09-10

To characterize HIV-infected patients with neurosymptomatic cerebrospinal fluid (CSF) 'escape', defined as detectable CSF HIV RNA in the setting of treatment-suppressed plasma levels or CSF RNA more than 1-log higher than plasma RNA. Retrospective case series. Four urban medical centers in the United States and Europe. Virologically controlled HIV-infected patients on antiretroviral therapy (ART) with progressive neurologic abnormalities who were determined to have CSF 'escape'. INTERVENTION Optimization of ART based upon drug susceptibility and presumed central nervous system exposure. Levels of CSF HIV RNA and inflammatory markers, clinical signs and symptoms, and MRI findings. Ten patients presented with new neurologic abnormalities, which included sensory, motor, and cognitive manifestations. Median CSF HIV RNA was 3900 copies/ml (range 134-9056), whereas median plasma HIV RNA was 62 copies/ml (range <50 to 380). Median CD4 T-cell count was 482 cells/μl (range 290-660). All patients had been controlled to less than 500 copies/ml for median 27.5 months (range 2-96) and five of 10 had been suppressed to less than 50 copies/ml for median 19.5 months (range 2-96). Patients had documentation of a stable ART regimen for median 21 months (range 9-60). All had CSF pleocytosis or elevated CSF protein; seven of eight had abnormalities on MRI; and six of seven harbored CSF resistance mutations. Following optimization of ART, eight of nine patients improved clinically. The development of neurologic symptoms in patients on ART with low or undetectable plasma HIV levels may be an indication of CSF 'escape'. This study adds to a growing body of literature regarding this rare condition in well controlled HIV infection.

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.

[Lessening effect of hypoxia-preconditioned rat cerebrospinal fluid on oxygen-glucose deprivation-induced injury of cultured hippocampal neurons in neonate rats and possible mechanism].

PubMed

Niu, Jing-Zhong; Zhang, Yan-Bo; Li, Mei-Yi; Liu, Li-Li

2011-12-25

The present study was to investigate the effect of cerebrospinal fluid (CSF) from the rats with hypoxic preconditioning (HPC) on apoptosis of cultured hippocampal neurons in neonate rats under oxygen glucose deprivation (OGD). Adult Wistar rats were exposed to 3 h of hypoxia for HPC, and then their CSF was taken out. Cultured hippocampal neurons from the neonate rats were randomly divided into four groups (n = 6): normal control group, OGD group, normal CSF group and HPC CSF group. OGD group received 1.5 h of incubation in glucose-free Earle's solution containing 1 mmol/L Na2S2O4, and normal and HPC CSF groups were subjected to 1 d of corresponding CSF treatments followed by 1.5 h OGD. The apoptosis of neurons was analyzed by confocal laser scanning microscope and flow cytometry using Annexin V/PI double staining. Moreover, protein expressions of Bcl-2 and Bax were detected by immunofluorescence. The results showed that few apoptotic cells were observed in normal control group, whereas the number of apoptotic cells was greatly increased in OGD group. Both normal and HPC CSF could decrease the apoptosis of cultured hippocampal neurons injured by OGD (P < 0.01). Notably, the protective effect of HPC CSF was stronger than that of normal one (P < 0.01). Compared to OGD group, normal and HPC CSF groups both showed significantly higher levels of Bcl-2 (P < 0.01), and Bcl-2 expression level in HPC CSF group was even higher than that in normal CSF group (P < 0.01). Whereas the expressions of Bax in normal and HPC CSF groups were significantly lower than that in OGD group (P < 0.01), and the Bax expression in HPC CSF group was even lower than that in normal CSF group (P < 0.01). These results suggest that CSF from hypoxic-preconditioned rats could degrade apoptotic rate of OGD-injured hippocampal neurons by up-regulating expression of Bcl-2 and down-regulating expression of Bax.

Characteristic Cytokine and Chemokine Profiles in Encephalitis of Infectious, Immune-Mediated, and Unknown Aetiology

PubMed Central

Michael, Benedict D.; Griffiths, Michael J.; Granerod, Julia; Brown, David; Davies, Nicholas W. S.; Borrow, Ray; Solomon, Tom

2016-01-01

Background Encephalitis is parenchymal brain inflammation due to infectious or immune-mediated processes. However, in 15–60% the cause remains unknown. This study aimed to determine if the cytokine/chemokine-mediated host response can distinguish infectious from immune-mediated cases, and whether this may give a clue to aetiology in those of unknown cause. Methods We measured 38 mediators in serum and cerebrospinal fluid (CSF) of patients from the Health Protection Agency Encephalitis Study. Of serum from 78 patients, 38 had infectious, 20 immune-mediated, and 20 unknown aetiology. Of CSF from 37 patients, 20 had infectious, nine immune-mediated and eight unknown aetiology. Results Heat-map analysis of CSF mediator interactions was different for infectious and immune-mediated cases, and that of the unknown aetiology group was similar to the infectious pattern. Higher myeloperoxidase (MPO) concentrations were found in infectious than immune-mediated cases, in serum and CSF (p = 0.01 and p = 0.006). Serum MPO was also higher in unknown than immune-mediated cases (p = 0.03). Multivariate analysis selected serum MPO; classifying 31 (91%) as infectious (p = 0.008) and 17 (85%) as unknown (p = 0.009) as opposed to immune-mediated. CSF data also selected MPO classifying 11 (85%) as infectious as opposed to immune-mediated (p = 0.036). CSF neutrophils were detected in eight (62%) infective and one (14%) immune-mediated cases (p = 0.004); CSF MPO correlated with neutrophils (p<0.0001). Conclusions Mediator profiles of infectious aetiology differed from immune-mediated encephalitis; and those of unknown cause were similar to infectious cases, raising the hypothesis of a possible undiagnosed infectious cause. Particularly, neutrophils and MPO merit further investigation. PMID:26808276

Characteristic Cytokine and Chemokine Profiles in Encephalitis of Infectious, Immune-Mediated, and Unknown Aetiology.

PubMed

Michael, Benedict D; Griffiths, Michael J; Granerod, Julia; Brown, David; Davies, Nicholas W S; Borrow, Ray; Solomon, Tom

2016-01-01

Encephalitis is parenchymal brain inflammation due to infectious or immune-mediated processes. However, in 15-60% the cause remains unknown. This study aimed to determine if the cytokine/chemokine-mediated host response can distinguish infectious from immune-mediated cases, and whether this may give a clue to aetiology in those of unknown cause. We measured 38 mediators in serum and cerebrospinal fluid (CSF) of patients from the Health Protection Agency Encephalitis Study. Of serum from 78 patients, 38 had infectious, 20 immune-mediated, and 20 unknown aetiology. Of CSF from 37 patients, 20 had infectious, nine immune-mediated and eight unknown aetiology. Heat-map analysis of CSF mediator interactions was different for infectious and immune-mediated cases, and that of the unknown aetiology group was similar to the infectious pattern. Higher myeloperoxidase (MPO) concentrations were found in infectious than immune-mediated cases, in serum and CSF (p = 0.01 and p = 0.006). Serum MPO was also higher in unknown than immune-mediated cases (p = 0.03). Multivariate analysis selected serum MPO; classifying 31 (91%) as infectious (p = 0.008) and 17 (85%) as unknown (p = 0.009) as opposed to immune-mediated. CSF data also selected MPO classifying 11 (85%) as infectious as opposed to immune-mediated (p = 0.036). CSF neutrophils were detected in eight (62%) infective and one (14%) immune-mediated cases (p = 0.004); CSF MPO correlated with neutrophils (p<0.0001). Mediator profiles of infectious aetiology differed from immune-mediated encephalitis; and those of unknown cause were similar to infectious cases, raising the hypothesis of a possible undiagnosed infectious cause. Particularly, neutrophils and MPO merit further investigation.

Postoperative Central Nervous System Infection After Neurosurgery in a Modernized, Resource-Limited Tertiary Neurosurgical Center in South Asia.

PubMed

Chidambaram, Swathi; Nair, M Nathan; Krishnan, Shyam Sundar; Cai, Ling; Gu, Weiling; Vasudevan, Madabushi Chakravarthy

2015-12-01

Postoperative central nervous system infections (PCNSIs) are rare but serious complications after neurosurgery. The purpose of this study was to examine the prevalence and causative pathogens of PCNSIs at a modernized, resource-limited neurosurgical center in South Asia. A retrospective analysis was conducted of the medical records of all 363 neurosurgical cases performed between June 1, 2012, and June 30, 2013, at a neurosurgical center in South Asia. Data from all operative neurosurgical cases during the 13-month period were included. Cerebrospinal fluid (CSF) analysis indicated that 71 of the 363 surgical cases had low CSF glucose or CSF leukocytosis. These 71 cases were categorized as PCNSIs. The PCNSIs with positive CSF cultures (9.86%) all had gram-negative bacteria with Pseudomonas aeruginosa (n = 5), Escherichia coli (n = 1), or Klebsiella pneumoniae (n = 1). The data suggest a higher rate of death (P = 0.031), a higher rate of CSF leak (P < 0.001), and a higher rate of cranial procedures (P < 0.001) among the infected patients and a higher rate of CSF leak among the patients with culture-positive infections (P = 0.038). This study summarizes the prevalence, causative organism of PCNSI, and antibiotic usage for all of the neurosurgical cases over a 13-month period in a modernized yet resource-limited neurosurgical center located in South Asia. The results from this study highlight the PCNSI landscape in an area of the world that is often underreported in the neurosurgical literature because of the paucity of clinical neurosurgical research undertaken there. This study shows an increasing prevalence of gram-negative organisms in CSF cultures from PCNSIs, which supports a trend in the recent literature of increasing gram-negative bacillary meningitis. Copyright © 2015 Elsevier Inc. All rights reserved.

Anxiety in major depression and cerebrospinal fluid free gamma-aminobutyric acid.

PubMed

Mann, J John; Oquendo, Maria A; Watson, Kalycia Trishana; Boldrini, Maura; Malone, Kevin M; Ellis, Steven P; Sullivan, Gregory; Cooper, Thomas B; Xie, Shan; Currier, Dianne

2014-10-01

Low gamma-aminobutyric acid (GABA) is implicated in both anxiety and depression pathophysiology. They are often comorbid, but most clinical studies have not examined these relationships separately. We investigated the relationship of cerebrospinal fluid (CSF) free GABA to the anxiety and depression components of a major depressive episode (MDE) and to monoamine systems. Patients with a DSM-IV major depressive episode (N = 167: 130 major depressive disorder; 37 bipolar disorder) and healthy volunteers (N = 38) had CSF free GABA measured by gas chromatography mass spectroscopy. Monoamine metabolites were assayed by high performance liquid chromatography. Symptomatology was assessed by Hamilton depression rating scale. Psychic anxiety severity increased with age and correlated with lower CSF free GABA, controlling for age. CSF free GABA declined with age but was not related to depression severity. Other monoamine metabolites correlated positively with CSF GABA but not with psychic anxiety or depression severity. CSF free GABA was lower in MDD compared with bipolar disorder and healthy volunteers. GABA levels did not differ based on a suicide attempt history in mood disorders. Recent exposure to benzodiazepines, but not alcohol or past alcoholism, was associated with a statistical trend for more severe anxiety and lower CSF GABA. Lower CSF GABA may explain increasing severity of psychic anxiety in major depression with increasing age. This relationship is not seen with monoamine metabolites, suggesting treatments targeting the GABAergic system should be evaluated in treatment-resistant anxious major depression and in older patients. © 2014 Wiley Periodicals, Inc.

Cerebrospinal fluid corticotropin-releasing factor and perceived early-life stress in depressed patients and healthy control subjects.

PubMed

Carpenter, Linda L; Tyrka, Audrey R; McDougle, Christopher J; Malison, Robert T; Owens, Michael J; Nemeroff, Charles B; Price, Lawrence H

2004-04-01

Previous studies have reported elevated concentrations of cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF) in patients with major depression. Elevations of CSF CRF have also been reported in adult laboratory animals exposed to the stress of brief maternal deprivation or maternal neglect in the neonatal or preweaning period. The present study was designed to determine whether major depression and a history of perceived early adversity in childhood are independently associated with elevated CSF CRF concentrations in adults. In this case-control study, 27 medication-free adults with major depression and 25 matched controls underwent standardized lumbar puncture for collection of a single CSF sample at 1200. Subjects provided data about significant adverse early-life experiences and rated their global perceived level of stress during pre-school and preteen years on a six-point Likert scale. The mean difference in CSF CRF between depressed patients and controls did not reach statistical significance. In a regression model, perceived early-life stress was a significant predictor of CSF CRF, but depression was not. Perinatal adversity and perceived adversity in the preteen adversity years (ages 6-13 years) were both independently associated with decreasing CSF CRF concentrations. The relationship observed between perceived early-life stress and adult CSF CRF concentrations in this study closely parallels recent preclinical findings. More work is needed to elucidate the critical nature and timing of early events that may be associated with enduring neuroendocrine changes in humans.

Cerebrospinal fluid biomarkers of simian immunodeficiency virus encephalitis

PubMed Central

Bissel, Stephanie J.; Kofler, Julia; Nyaundi, Julia; Murphey-Corb, Michael; Wisniewski, Stephen R.; Wiley, Clayton A.

2016-01-01

Antiretroviral therapy has led to increased survival of HIV-infected patients but also increased prevalence of HIV-associated neurocognitive disorders. We previously identified YKL40 as a potential cerebrospinal fluid (CSF) biomarker of lentiviral central nervous system (CNS) disease in HIV-infected patients and in the macaque model of HIV encephalitis. The aim of this study was to define the specificity and sensitivity along with the predictive value of YKL40 as a biomarker of encephalitis and to assess its relationship to CSF viral load. CSF YKL40 and SIV RNA concentrations were analyzed over the course of infection in 19 SIV-infected pigtailed macaques and statistical analyses were performed to evaluate the relationship to encephalitis. Using these relationships, CSF alterations of 31 neuroimmune markers were studied pre-infection, during acute and asymptomatic infection, at the onset of encephalitis, and at necropsy. YKL40 CSF concentrations above 1122 ng/ml were found to be a specific and sensitive biomarker for the presence of encephalitis and were highly correlated with CSF viral load. Macaques that developed encephalitis had evidence of chronic CNS immune activation during early, asymptomatic, and end stages of infection. At the onset of encephalitis, CSF demonstrated a rise of neuroimmune markers associated with macrophage recruitment, activation and interferon response. CSF YKL40 concentration and viral load are valuable biomarkers to define the onset of encephalitis. Chronic CNS immune activation precedes the development of encephalitis while some responses suggest protection from CNS lentiviral disease. PMID:27059917

The late and dual origin of cerebrospinal fluid-contacting neurons in the mouse spinal cord

PubMed Central

Petracca, Yanina L.; Sartoretti, Maria Micaela; Di Bella, Daniela J.; Marin-Burgin, Antonia; Carcagno, Abel L.; Schinder, Alejandro F.; Lanuza, Guillermo M.

2016-01-01

Considerable progress has been made in understanding the mechanisms that control the production of specialized neuronal types. However, how the timing of differentiation contributes to neuronal diversity in the developing spinal cord is still a pending question. In this study, we show that cerebrospinal fluid-contacting neurons (CSF-cNs), an anatomically discrete cell type of the ependymal area, originate from surprisingly late neurogenic events in the ventral spinal cord. CSF-cNs are identified by the expression of the transcription factors Gata2 and Gata3, and the ionic channels Pkd2l1 and Pkd1l2. Contrasting with Gata2/3+ V2b interneurons, differentiation of CSF-cNs is independent of Foxn4 and takes place during advanced developmental stages previously assumed to be exclusively gliogenic. CSF-cNs are produced from two distinct dorsoventral regions of the mouse spinal cord. Most CSF-cNs derive from progenitors circumscribed to the late-p2 and the oligodendrogenic (pOL) domains, whereas a second subset of CSF-cNs arises from cells bordering the floor plate. The development of these two subgroups of CSF-cNs is differentially controlled by Pax6, they adopt separate locations around the postnatal central canal and they display electrophysiological differences. Our results highlight that spatiotemporal mechanisms are instrumental in creating neural cell diversity in the ventral spinal cord to produce distinct classes of interneurons, motoneurons, CSF-cNs, glial cells and ependymal cells. PMID:26839365

ANXIETY IN MAJOR DEPRESSION AND CEREBROSPINAL FLUID FREE GAMMA-AMINOBUTYRIC ACID

PubMed Central

Mann, J. John; Oquendo, Maria A.; Watson, Kalycia Trishana; Boldrini, Maura; Malone, Kevin M.; Ellis, Steven P.; Sullivan, Gregory; Cooper, Thomas B.; Xie, Shan; Currier, Dianne

2016-01-01

Background Low gamma-aminobutyric acid (GABA) is implicated in both anxiety and depression pathophysiology. They are often comorbid, but most clinical studies have not examined these relationships separately. We investigated the relationship of cerebrospinal fluid (CSF) free GABA to the anxiety and depression components of a major depressive episode (MDE) and to monoamine systems. Methods and Materials Patients with a DSM-IV major depressive episode (N = 167: 130 major depressive disorder; 37 bipolar disorder) and healthy volunteers (N = 38) had CSF free GABA measured by gas chromatography mass spectroscopy. Monoamine metabolites were assayed by high performance liquid chromatography. Symptomatology was assessed by Hamilton depression rating scale. Results Psychic anxiety severity increased with age and correlated with lower CSF free GABA, controlling for age. CSF free GABA declined with age but was not related to depression severity. Other monoamine metabolites correlated positively with CSF GABA but not with psychic anxiety or depression severity. CSF free GABA was lower in MDD compared with bipolar disorder and healthy volunteers. GABA levels did not differ based on a suicide attempt history in mood disorders. Recent exposure to benzodiazepines, but not alcohol or past alcoholism, was associated with a statistical trend for more severe anxiety and lower CSF GABA. Conclusions Lower CSF GABA may explain increasing severity of psychic anxiety in major depression with increasing age. This relationship is not seen with monoamine metabolites, suggesting treatments targeting the GABAergic system should be evaluated in treatment-resistant anxious major depression and in older patients. PMID:24865448

A potential endophenotype for Alzheimer's disease: cerebrospinal fluid clusterin.

PubMed

Deming, Yuetiva; Xia, Jian; Cai, Yefei; Lord, Jenny; Holmans, Peter; Bertelsen, Sarah; Holtzman, David; Morris, John C; Bales, Kelly; Pickering, Eve H; Kauwe, John; Goate, Alison; Cruchaga, Carlos

2016-01-01

Genome-wide association studies have associated clusterin (CLU) variants with Alzheimer's disease (AD). However, the role of CLU on AD pathogenesis is not totally understood. We used cerebrospinal fluid (CSF) and plasma CLU levels as endophenotypes for genetic studies to understand the role of CLU in AD. CSF, but not plasma, CLU levels were significantly associated with AD status and CSF tau/amyloid-beta ratio, and highly correlated with CSF apolipoprotein E (APOE) levels. Several loci showed almost genome-wide significant associations including LINC00917 (p = 3.98 × 10(-7)) and interleukin 6 (IL6, p = 9.94 × 10(-6), in the entire data set and in the APOE ε4- individuals p = 7.40 × 10(-8)). Gene ontology analyses suggest that CSF CLU levels may be associated with wound healing and immune response which supports previous functional studies that demonstrated an association between CLU and IL6. CLU may play a role in AD by influencing immune system changes that have been observed in AD or by disrupting healing after neurodegeneration. Copyright © 2016 Elsevier Inc. All rights reserved.

Real-Time Polymerase Chain Reaction Detection of Angiostrongylus cantonensis DNA in Cerebrospinal Fluid from Patients with Eosinophilic Meningitis.

PubMed

Qvarnstrom, Yvonne; Xayavong, Maniphet; da Silva, Ana Cristina Aramburu; Park, Sarah Y; Whelen, A Christian; Calimlim, Precilia S; Sciulli, Rebecca H; Honda, Stacey A A; Higa, Karen; Kitsutani, Paul; Chea, Nora; Heng, Seng; Johnson, Stuart; Graeff-Teixeira, Carlos; Fox, LeAnne M; da Silva, Alexandre J

2016-01-01

Angiostrongylus cantonensis is the most common infectious cause of eosinophilic meningitis. Timely diagnosis of these infections is difficult, partly because reliable laboratory diagnostic methods are unavailable. The aim of this study was to evaluate the usefulness of a real-time polymerase chain reaction (PCR) assay for the detection of A. cantonensis DNA in human cerebrospinal fluid (CSF) specimens. A total of 49 CSF specimens from 33 patients with eosinophilic meningitis were included: A. cantonensis DNA was detected in 32 CSF specimens, from 22 patients. Four patients had intermittently positive and negative real-time PCR results on subsequent samples, indicating that the level of A. cantonensis DNA present in CSF may fluctuate during the course of the illness. Immunodiagnosis and/or supplemental PCR testing supported the real-time PCR findings for 30 patients. On the basis of these observations, this real-time PCR assay can be useful to detect A. cantonensis in the CSF from patients with eosinophilic meningitis. © The American Society of Tropical Medicine and Hygiene.

[Bath Plug Closure Method for Cerebrospinal Fluid Leakage by Endoscopic Endonasal Approach:Cooperative Treatment by Neurosurgeons and Otolaryngologists].

PubMed

Kawaguchi, Tomohiro; Arakawa, Kazuya; Nomura, Kazuhiro; Ogawa, Yoshikazu; Katori, Yukio; Tominaga, Teiji

2017-12-01

Endoscopic endonasal surgery, an innovative surgical technique, is used to approach sinus lesions, lesions of the skull base, and intradural tumors. The cooperation of experienced otolaryngologists and neurosurgeons is important to achieve safe and reliable surgical results. The bath plug closure method is a treatment option for patients with cerebrospinal fluid(CSF)leakage. Although it includes dural and/or intradural procedures, surgery tends to be performed by otolaryngologists because its indications, detailed maneuvers, and pitfalls are not well recognized by neurosurgeons. We reviewed the cases of patients with CSF leakage treated by using the bath plug closure method with an endoscopic endonasal approach at our institution. Three patients were treated using the bath plug closure method. CSF leakage was caused by a meningocele in two cases and trauma in one case. No postoperative intracranial complications or recurrence of CSF leakage were observed. The bath plug closure method is an effective treatment strategy and allows neurosurgeons to gain in-depth knowledge of the treatment options for CSF leakage by using an endoscopic endonasal approach.

Cerebrospinal Fluid Biomarkers of Alzheimer's Disease Correlate With Electroencephalography Parameters Assessed by Exact Low-Resolution Electromagnetic Tomography (eLORETA).

PubMed

Hata, Masahiro; Tanaka, Toshihisa; Kazui, Hiroaki; Ishii, Ryouhei; Canuet, Leonides; Pascual-Marqui, Roberto D; Aoki, Yasunori; Ikeda, Shunichiro; Sato, Shunsuke; Suzuki, Yukiko; Kanemoto, Hideki; Yoshiyama, Kenji; Iwase, Masao

2017-09-01

Recently, cerebrospinal fluid (CSF) biomarkers related to Alzheimer's disease (AD) have garnered a lot of clinical attention. To explore neurophysiological traits of AD and parameters for its clinical diagnosis, we examined the association between CSF biomarkers and electroencephalography (EEG) parameters in 14 probable AD patients. Using exact low-resolution electromagnetic tomography (eLORETA), artifact-free 40-sesond EEG data were estimated with current source density (CSD) and lagged phase synchronization (LPS) as the EEG parameters. Correlations between CSF biomarkers and the EEG parameters were assessed. Patients with AD showed significant negative correlation between CSF beta-amyloid (Aβ)-42 concentration and the logarithms of CSD over the right temporal area in the theta band. Total tau concentration was negatively correlated with the LPS between the left frontal eye field and the right auditory area in the alpha-2 band in patients with AD. Our study results suggest that AD biomarkers, in particular CSF Aβ42 and total tau concentrations are associated with the EEG parameters CSD and LPS, respectively. Our results could yield more insights into the complicated pathology of AD.

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

Neurotoxicity of cerebro-spinal fluid from patients with Parkinson's disease on mesencephalic primary cultures as an in vitro model of dopaminergic neurons.

PubMed

Kong, Ping; Zhang, Ben-Shu; Lei, Ping; Kong, Xiao-Dong; Zhang, Shi-Shuang; Li, Dai; Zhang, Yun

2015-08-01

Parkinson's disease is a degenerative disorder of the central nervous system. In spite of extensive research, neither the cause nor the mechanisms have been firmly established thus far. One assumption is that certain toxic substances may exist in the cerebro-spinal fluid (CSF) of Parkinson's disease patients. To confirm the neurotoxicity of CSF and study the potential correlation between neurotoxicity and the severity of Parkinson's disease, CSF was added to cultured cells. By observation of cell morphology, changes in the levels of lactate dehydrogenase, the ratio of tyrosine hydroxylase-positive cells, and the expression of tyrosine hydroxylase mRNA and protein, the differences between the two groups were shown. The created in vitro model of dopaminergic neurons using primary culture of mouse embryonic mesencephalic tissue is suitable for the study of neurotoxicity. The observations of the present study indicated that CSF from Parkinson's disease patients contains factors that can cause specific injury to cultured dopaminergic neurons. However, no obvious correlation was found between the neurotoxicity of CSF and the severity of Parkinson's disease.

Detection of Antibodies to Brucella Cytoplasmic Proteins in the Cerebrospinal Fluid of Patients with Neurobrucellosis

PubMed Central

Baldi, Pablo C.; Araj, George F.; Racaro, Graciela C.; Wallach, Jorge C.; Fossati, Carlos A.

1999-01-01

The diagnosis of human neurobrucellosis usually relies on the detection of antibodies to Brucella lipopolysaccharide (LPS) in cerebrospinal fluid (CSF) by agglutination tests or enzyme-linked immunosorbent assay (ELISA). Here we describe the detection of immunoglobulin G (IgG) to cytoplasmic proteins (CP) of Brucella spp. by ELISA and Western blotting in seven CSF samples from five patients with neurobrucellosis. While IgG to CP (titers of 200 to 12,800) and IgG to LPS (800 to 6,400) were found in the CSF of these patients, these antibodies were not detected in CSF samples from two patients who had systemic brucellosis without neurological involvement. The latter, however, had serum IgG and IgM to both LPS and CP. No reactivity to these antigens was found in CSF samples from 14 and 20 patients suffering from nonbrucellar meningitis and noninfectious diseases, respectively. These findings suggest that, in addition to its usefulness in the serological diagnosis of human systemic brucellosis, the ELISA with CP antigen can be used for the specific diagnosis of human neurobrucellosis. PMID:10473531

Investigation of spinal cerebrospinal fluid-contacting neurons expressing PKD2L1: evidence for a conserved system from fish to primates

PubMed Central

Djenoune, Lydia; Khabou, Hanen; Joubert, Fanny; Quan, Feng B.; Nunes Figueiredo, Sophie; Bodineau, Laurence; Del Bene, Filippo; Burcklé, Céline; Tostivint, Hervé; Wyart, Claire

2014-01-01

Over 90 years ago, Kolmer and Agduhr identified spinal cerebrospinal fluid-contacting neurons (CSF-cNs) based on their morphology and location within the spinal cord. In more than 200 vertebrate species, they observed ciliated neurons around the central canal that extended a brush of microvilli into the cerebrospinal fluid (CSF). Although their morphology is suggestive of a primitive sensory cell, their function within the vertebrate spinal cord remains unknown. The identification of specific molecular markers for these neurons in vertebrates would benefit the investigation of their physiological roles. PKD2L1, a transient receptor potential channel that could play a role as a sensory receptor, has been found in cells contacting the central canal in mouse. In this study, we demonstrate that PKD2L1 is a specific marker for CSF-cNs in the spinal cord of mouse (Mus musculus), macaque (Macaca fascicularis) and zebrafish (Danio rerio). In these species, the somata of spinal PKD2L1+ CSF-cNs were located below or within the ependymal layer and extended an apical bulbous extension into the central canal. We found GABAergic PKD2L1-expressing CSF-cNs in all three species. We took advantage of the zebrafish embryo for its transparency and rapid development to identify the progenitor domains from which pkd2l1+ CSF-cNs originate. pkd2l1+ CSF-cNs were all GABAergic and organized in two rows—one ventral and one dorsal to the central canal. Their location and marker expression is consistent with previously described Kolmer–Agduhr cells. Accordingly, pkd2l1+ CSF-cNs were derived from the progenitor domains p3 and pMN defined by the expression of nkx2.2a and olig2 transcription factors, respectively. Altogether our results suggest that a system of CSF-cNs expressing the PKD2L1 channel is conserved in the spinal cord across bony vertebrate species. PMID:24834029

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.

Cerebrospinal Fluid (CSF) Neuronal Biomarkers across the Spectrum of HIV Infection: Hierarchy of Injury and Detection

PubMed Central

Peterson, Julia; Gisslen, Magnus; Zetterberg, Henrik; Fuchs, Dietmar; Shacklett, Barbara L.; Hagberg, Lars; Yiannoutsos, Constantin T.; Spudich, Serena S.; Price, Richard W.

2014-01-01

The character of central nervous system (CNS) HIV infection and its effects on neuronal integrity vary with evolving systemic infection. Using a cross-sectional design and archived samples, we compared concentrations of cerebrospinal fluid (CSF) neuronal biomarkers in 143 samples from 8 HIV-infected subject groups representing a spectrum of untreated systemic HIV progression and viral suppression: primary infection; four groups of chronic HIV infection neuroasymptomatic (NA) subjects defined by blood CD4+ T cells of >350, 200–349, 50–199, and <50 cells/µL; HAD; treatment-induced viral suppression; and ‘elite’ controllers. Samples from 20 HIV-uninfected controls were also examined. The neuronal biomarkers included neurofilament light chain protein (NFL), total and phosphorylated tau (t-tau, p-tau), soluble amyloid precursor proteins alpha and beta (sAPPα, sAPPβ) and amyloid beta (Aβ) fragments 1–42, 1–40 and 1–38. Comparison of the biomarker changes showed a hierarchy of sensitivity in detection and suggested evolving mechanisms with progressive injury. NFL was the most sensitive neuronal biomarker. Its CSF concentration exceeded age-adjusted norms in all HAD patients, 75% of NA CD4<50, 40% of NA CD4 50–199, and 42% of primary infection, indicating common neuronal injury with untreated systemic HIV disease progression as well as transiently during early infection. By contrast, only 75% of HAD subjects had abnormal CSF t-tau levels, and there were no significant differences in t-tau levels among the remaining groups. sAPPα and β were also abnormal (decreased) in HAD, showed less marked change than NFL with CD4 decline in the absence of HAD, and were not decreased in PHI. The CSF Aβ peptides and p-tau concentrations did not differ among the groups, distinguishing the HIV CNS injury profile from Alzheimer's disease. These CSF biomarkers can serve as useful tools in selected research and clinical settings for patient classification, pathogenetic analysis, diagnosis and management. PMID:25541953

Cerebrospinal fluid (CSF) neuronal biomarkers across the spectrum of HIV infection: hierarchy of injury and detection.

PubMed

Peterson, Julia; Gisslen, Magnus; Zetterberg, Henrik; Fuchs, Dietmar; Shacklett, Barbara L; Hagberg, Lars; Yiannoutsos, Constantin T; Spudich, Serena S; Price, Richard W

2014-01-01

The character of central nervous system (CNS) HIV infection and its effects on neuronal integrity vary with evolving systemic infection. Using a cross-sectional design and archived samples, we compared concentrations of cerebrospinal fluid (CSF) neuronal biomarkers in 143 samples from 8 HIV-infected subject groups representing a spectrum of untreated systemic HIV progression and viral suppression: primary infection; four groups of chronic HIV infection neuroasymptomatic (NA) subjects defined by blood CD4+ T cells of >350, 200-349, 50-199, and <50 cells/µL; HAD; treatment-induced viral suppression; and 'elite' controllers. Samples from 20 HIV-uninfected controls were also examined. The neuronal biomarkers included neurofilament light chain protein (NFL), total and phosphorylated tau (t-tau, p-tau), soluble amyloid precursor proteins alpha and beta (sAPPα, sAPPβ) and amyloid beta (Aβ) fragments 1-42, 1-40 and 1-38. Comparison of the biomarker changes showed a hierarchy of sensitivity in detection and suggested evolving mechanisms with progressive injury. NFL was the most sensitive neuronal biomarker. Its CSF concentration exceeded age-adjusted norms in all HAD patients, 75% of NA CD4<50, 40% of NA CD4 50-199, and 42% of primary infection, indicating common neuronal injury with untreated systemic HIV disease progression as well as transiently during early infection. By contrast, only 75% of HAD subjects had abnormal CSF t-tau levels, and there were no significant differences in t-tau levels among the remaining groups. sAPPα and β were also abnormal (decreased) in HAD, showed less marked change than NFL with CD4 decline in the absence of HAD, and were not decreased in PHI. The CSF Aβ peptides and p-tau concentrations did not differ among the groups, distinguishing the HIV CNS injury profile from Alzheimer's disease. These CSF biomarkers can serve as useful tools in selected research and clinical settings for patient classification, pathogenetic analysis, diagnosis and management.

Leptomeningeal metastases: a RANO proposal for response criteria

PubMed Central

Junck, Larry; Brandsma, Dieta; Soffietti, Riccardo; Rudà, Roberta; Raizer, Jeffrey; Boogerd, Willem; Taillibert, Sophie; Groves, Morris D.; Rhun, Emilie Le; Walker, Julie; van den Bent, Martin; Wen, Patrick Y.; Jaeckle, Kurt A.

2017-01-01

Abstract Leptomeningeal metastases (LM) currently lack standardization with respect to response assessment. A Response Assessment in Neuro-Oncology (RANO) working group with expertise in LM developed a consensus proposal for evaluating patients treated for this disease. Three basic elements in assessing response in LM are proposed: a standardized neurological examination, cerebral spinal fluid (CSF) cytology or flow cytometry, and radiographic evaluation. The group recommends that all patients enrolling in clinical trials undergo CSF analysis (cytology in all cancers; flow cytometry in hematologic cancers), complete contrast-enhanced neuraxis MRI, and in instances of planned intra-CSF therapy, radioisotope CSF flow studies. In conjunction with the RANO Neurological Assessment working group, a standardized instrument was created for assessing the neurological exam in patients with LM. Considering that most lesions in LM are nonmeasurable and that assessment of neuroimaging in LM is subjective, neuroimaging is graded as stable, progressive, or improved using a novel radiological LM response scorecard. Radiographic disease progression in isolation (ie, negative CSF cytology/flow cytometry and stable neurological assessment) would be defined as LM disease progression. The RANO LM working group has proposed a method of response evaluation for patients with LM that will require further testing, validation, and likely refinement with use. PMID:28039364

Innovative real CSF leak simulation model for rhinology training: human cadaveric design.

PubMed

AlQahtani, Abdulaziz A; Albathi, Abeer A; Alhammad, Othman M; Alrabie, Abdulkarim S

2018-04-01

To study the feasibility of designing a human cadaveric simulation model of real CSF leak for rhinology training. The laboratory investigation took place at the surgical academic center of Prince Sultan Military Medical City between 2016 and 2017. Five heads of human cadaveric specimens were cannulated into the intradural space through two frontal bone holes. Fluorescein-dyed fluid was injected intracranialy, then endoscopic endonasal iatrogenic skull base defect was created with observation of fluid leak, followed by skull base reconstruction. The outcome measures included subjective assessment of integrity of the design, the ability of creating real CSF leak in multiple site of skull base and the possibility of watertight closure by various surgical techniques. The fluid filled the intradural space in all specimens without spontaneous leak from skull base or extra sinus areas. Successfully, we demonstrated fluid leak from all areas after iatrogenic defect in the cribriform plate, fovea ethmoidalis, planum sphenoidale sellar and clival regions. Watertight closure was achieved in all defects using different reconstruction techniques (overly, underlay and gasket seal closure). The design is simulating the real patient with CSF leak. It has potential in the learning process of acquiring and maintaining the surgical skills of skull base reconstruction before direct involvement of the patient. This model needs further evaluation and competence measurement as training tools in rhinology training.

EEG and Neuronal Activity Topography analysis can predict effectiveness of shunt operation in idiopathic normal pressure hydrocephalus patients☆

PubMed Central

Aoki, Yasunori; Kazui, Hiroaki; Tanaka, Toshihisa; Ishii, Ryouhei; Wada, Tamiki; Ikeda, Shunichiro; Hata, Masahiro; Canuet, Leonides; Musha, Toshimitsu; Matsuzaki, Haruyasu; Imajo, Kaoru; Yoshiyama, Kenji; Yoshida, Tetsuhiko; Shimizu, Yoshiro; Nomura, Keiko; Iwase, Masao; Takeda, Masatoshi

2013-01-01

Idiopathic normal pressure hydrocephalus (iNPH) is a neuropsychiatric syndrome characterized by gait disturbance, cognitive impairment and urinary incontinence that affect elderly individuals. These symptoms can potentially be reversed by cerebrospinal fluid (CSF) drainage or shunt operation. Prior to shunt operation, drainage of a small amount of CSF or “CSF tapping” is usually performed to ascertain the effect of the operation. Unfortunately, conventional neuroimaging methods such as single photon emission computed tomography (SPECT) and functional magnetic resonance imaging (fMRI), as well as electroencephalogram (EEG) power analysis seem to have failed to detect the effect of CSF tapping on brain function. In this work, we propose the use of Neuronal Activity Topography (NAT) analysis, which calculates normalized power variance (NPV) of EEG waves, to detect cortical functional changes induced by CSF tapping in iNPH. Based on clinical improvement by CSF tapping and shunt operation, we classified 24 iNPH patients into responders (N = 11) and nonresponders (N = 13), and performed both EEG power analysis and NAT analysis. We also assessed correlations between changes in NPV and changes in functional scores on gait and cognition scales before and after CSF tapping. NAT analysis showed that after CSF tapping there was a significant decrease in alpha NPV at the medial frontal cortex (FC) (Fz) in responders, while nonresponders exhibited an increase in alpha NPV at the right dorsolateral prefrontal cortex (DLPFC) (F8). Furthermore, we found correlations between cortical functional changes and clinical symptoms. In particular, delta and alpha NPV changes in the left-dorsal FC (F3) correlated with changes in gait status, while alpha and beta NPV changes in the right anterior prefrontal cortex (PFC) (Fp2) and left DLPFC (F7) as well as alpha NPV changes in the medial FC (Fz) correlated with changes in gait velocity. In addition, alpha NPV changes in the right DLPFC (F8) correlated with changes in WMS-R Mental Control scores in iNPH patients. An additional analysis combining the changes in values of alpha NPV over the left-dorsal FC (∆alpha-F3-NPV) and the medial FC (∆alpha-Fz-NPV) induced by CSF tapping (cut-off value of ∆alpha-F3-NPV + ∆alpha-Fz-NPV = 0), could correctly identified “shunt responders” and “shunt nonresponders” with a positive predictive value of 100% (10/10) and a negative predictive value of 66% (2/3). In contrast, EEG power spectral analysis showed no function related changes in cortical activity at the frontal cortex before and after CSF tapping. These results indicate that the clinical changes in gait and response suppression induced by CSF tapping in iNPH patients manifest as NPV changes, particularly in the alpha band, rather than as EEG power changes. Our findings suggest that NAT analysis can detect CSF tapping-induced functional changes in cortical activity, in a way that no other neuroimaging methods have been able to do so far, and can predict clinical response to shunt operation in patients with iNPH. PMID:24273735

EEG and Neuronal Activity Topography analysis can predict effectiveness of shunt operation in idiopathic normal pressure hydrocephalus patients.

PubMed

Aoki, Yasunori; Kazui, Hiroaki; Tanaka, Toshihisa; Ishii, Ryouhei; Wada, Tamiki; Ikeda, Shunichiro; Hata, Masahiro; Canuet, Leonides; Musha, Toshimitsu; Matsuzaki, Haruyasu; Imajo, Kaoru; Yoshiyama, Kenji; Yoshida, Tetsuhiko; Shimizu, Yoshiro; Nomura, Keiko; Iwase, Masao; Takeda, Masatoshi

2013-01-01

Idiopathic normal pressure hydrocephalus (iNPH) is a neuropsychiatric syndrome characterized by gait disturbance, cognitive impairment and urinary incontinence that affect elderly individuals. These symptoms can potentially be reversed by cerebrospinal fluid (CSF) drainage or shunt operation. Prior to shunt operation, drainage of a small amount of CSF or "CSF tapping" is usually performed to ascertain the effect of the operation. Unfortunately, conventional neuroimaging methods such as single photon emission computed tomography (SPECT) and functional magnetic resonance imaging (fMRI), as well as electroencephalogram (EEG) power analysis seem to have failed to detect the effect of CSF tapping on brain function. In this work, we propose the use of Neuronal Activity Topography (NAT) analysis, which calculates normalized power variance (NPV) of EEG waves, to detect cortical functional changes induced by CSF tapping in iNPH. Based on clinical improvement by CSF tapping and shunt operation, we classified 24 iNPH patients into responders (N = 11) and nonresponders (N = 13), and performed both EEG power analysis and NAT analysis. We also assessed correlations between changes in NPV and changes in functional scores on gait and cognition scales before and after CSF tapping. NAT analysis showed that after CSF tapping there was a significant decrease in alpha NPV at the medial frontal cortex (FC) (Fz) in responders, while nonresponders exhibited an increase in alpha NPV at the right dorsolateral prefrontal cortex (DLPFC) (F8). Furthermore, we found correlations between cortical functional changes and clinical symptoms. In particular, delta and alpha NPV changes in the left-dorsal FC (F3) correlated with changes in gait status, while alpha and beta NPV changes in the right anterior prefrontal cortex (PFC) (Fp2) and left DLPFC (F7) as well as alpha NPV changes in the medial FC (Fz) correlated with changes in gait velocity. In addition, alpha NPV changes in the right DLPFC (F8) correlated with changes in WMS-R Mental Control scores in iNPH patients. An additional analysis combining the changes in values of alpha NPV over the left-dorsal FC (∆alpha-F3-NPV) and the medial FC (∆alpha-Fz-NPV) induced by CSF tapping (cut-off value of ∆alpha-F3-NPV + ∆alpha-Fz-NPV = 0), could correctly identified "shunt responders" and "shunt nonresponders" with a positive predictive value of 100% (10/10) and a negative predictive value of 66% (2/3). In contrast, EEG power spectral analysis showed no function related changes in cortical activity at the frontal cortex before and after CSF tapping. These results indicate that the clinical changes in gait and response suppression induced by CSF tapping in iNPH patients manifest as NPV changes, particularly in the alpha band, rather than as EEG power changes. Our findings suggest that NAT analysis can detect CSF tapping-induced functional changes in cortical activity, in a way that no other neuroimaging methods have been able to do so far, and can predict clinical response to shunt operation in patients with iNPH.

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.

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

Predictive value of cerebrospinal fluid parameters in neonates with intraventricular drainage devices.

PubMed

Lenfestey, Robert W; Smith, P Brian; Moody, M Anthony; Clark, Reese H; Cotten, C Michael; Seed, Patrick C; Benjamin, Daniel K

2007-09-01

Infection is a common and potentially devastating complication following placement of ventriculoperitoneal (VP) shunts and cerebrospinal fluid (CSF) reservoirs in neonates. The goal of this study was to determine the normal ranges for cell count parameters in neonates with VP shunts and CSF reservoirs, as well as to determine the predictive value of CSF parameters as markers of infection. The authors evaluated neonates from 150 different neonatal intensive care units of the Pediatrix Medical Group who had undergone a lumbar puncture, VP shunt insertion, or CSF reservoir placement between 1997 and 2004. Data were collected from 9704 neonates with a mean birthweight of 2573 g and a mean gestational age of 35 weeks. Of these neonates, 181 had VP shunt insertions or CSF reservoir placements. In neonates with negative CSF cultures, significant differences were found between those with and without VP shunts or CSF reservoirs when comparing red blood cell (RBC) count (620/mm' compared with 155/mm3, p < 0.05), absolute eosinophil count (4/mm3 compared with 2/mm3, p < 0.001), protein levels (179 mg/dl compared with 115 mg/dl, p < 0.001), and glucose levels (27.5 mg/dl compared with 49 mg/dl, p < 0.001). No significant difference was found between white blood cell (WBC) counts in neonates with or without VP shunts who had negative CSF cultures. The sensitivity and specificity of a cutoff value of 20 WBCs/mm3 for diagnosing meningitis in neonates with positive cultures and intraventricular drainage devices were 67% and 62%, respectively. Although differences exist between CSF parameters found in neonates with or without VP shunts or CSF reservoirs, only the difference in RBC count is large enough to be clinically significant. The authors found that the utility of CSF parameters in neonates with VP shunts or CSF reservoirs was limited due to poor diagnostic sensitivity and specificity.

Novel dural closure technique using polyglactin acid sheet prevents cerebrospinal fluid leakage after spinal surgery.

PubMed

Sugawara, Taku; Itoh, Yasunobu; Hirano, Yoshitaka; Higashiyama, Naoki; Shimada, Yoichi; Kinouchi, Hiroyuki; Mizoi, Kazuo

2005-10-01

Extradural or subcutaneous cerebrospinal fluid (CSF) leakage is a common complication after spinal surgery and is associated with the risks of poor wound healing, meningitis, and pseudomeningocele. Numerous methods to prevent postoperative CSF leakage are available, but pressure-tight dural closure remains difficult, especially with synthetic surgical membranes. The efficacy of a novel dural closure technique was assessed by detecting extradural or subcutaneous CSF leakage on magnetic resonance imaging. The novel dural closure technique using absorbable polyglactin acid sheet and fibrin glue and the conventional procedure using only fibrin glue were evaluated retrospectively by identifying extradural or subcutaneous CSF leakage on magnetic resonance imaging scans in the acute (2-7 d) and chronic (3-6 mo) postoperative stages after spinal intradural surgery in 53 patients. The incidence of extradural and subcutaneous CSF leakage was significantly lower (P < 0.05) in the acute (20%) and chronic (0%) stages using polyglactin acid sheet and fibrin glue in 15 patients compared with that in the acute (81%) and chronic (24%) stages using only fibrin glue in 38 patients. One patient in the fibrin glue-only group required repair surgery for cutaneous CSF leakage. The combination of polyglactin acid sheet and fibrin glue can achieve water-tight closure after spinal intradural surgery and can minimize the risk of intractable postoperative CSF leakage. This simple, economical technique is recommended for dural closure after spinal intradural surgery.

Cerebrospinal fluid leptin in anorexia nervosa: correlation with nutritional status and potential role in resistance to weight gain.

PubMed

Mantzoros, C; Flier, J S; Lesem, M D; Brewerton, T D; Jimerson, D C

1997-06-01

Studies in rodents have shown that leptin acts in the central nervous system to modulate food intake and energy metabolism. To evaluate the possible role of leptin in the weight loss of anorexia nervosa, this study compared cerebrospinal fluid (CSF) and plasma leptin concentrations in anorexic patients and controls. Subjects included 11 female patients with anorexia nervosa studied at low weight and after treatment, and 15 healthy female controls. Concentrations of leptin in blood and CSF were measured by RIA. Patients with anorexia nervosa, compared to controls, had decreased concentrations of leptin in CSF (98 +/- 26 vs. 160 +/- 58 pg/mL; P < 0.0005) and plasma (1.75 +/- 0.46 vs. 7.01 +/- 3.92 ng/mL; P < 0.005). The CSF to plasma leptin ratio, however, was higher for patients (0.060 +/- 0.023) than for controls (0.025 +/- 0.007; P < 0.0001). At posttreatment testing, although patients had not yet reached normal body weight, CSF and plasma leptin concentrations had increased to normal levels. These results demonstrate the dynamic changes in plasma and CSF leptin during positive energy balance in anorexia nervosa. The results further suggest that normalization of CSF leptin levels before full weight restoration during treatment of anorexic patients could contribute to resistance to weight gain and/or incomplete weight recovery.

The Management of Cerebrospinal Fluid Leak After Anterior Cervical Decompression Surgery.

PubMed

Zhai, Jiliang; Panchal, Ripul R; Tian, Ye; Wang, Shujie; Zhao, Lijuan

2018-03-01

Cerebrospinal fluid (CSF) leak is a rare but potentially troublesome and occasionally catastrophic complication after anterior cervical decompression surgery. There is limited literature describing this complication, and the management of CSF leak varies. The aim of this study was to retrospectively review the treatment of cases with CSF leak and develop a management algorithm. A series of 14 patients with CSF leak from January 2011 to May 2016 were included in this study. Their characteristics, management of CSF leak, and outcomes were documented. There were 5 male and 9 female patients. Mean age at surgery was 57.1±9.9 years (range, 37-76 years). All instances of CSF leak, except 1 noted postoperatively, were indirectly repaired intraoperatively. A closed straight wound drain was placed for all patients. A lumbar subarachnoid drain was placed immediately after surgery in 4 patients and postoperatively in 7 patients. In 1 patient, lumbar drain placement was unsuccessful. In 2 additional patients, the surgeon decided not to place a lumbar drain. One patient developed meningitis and recovered after antibiotic therapy with meropenem and vancomycin. Another patient had a deep wound infection and required a revision surgery. Wound drains and lumbar drains should be immediately considered when CSF leak is identified. Antibiotics also should be considered to prevent intradural infection. [Orthopedics. 2018; 41(2):e283-e288.]. Copyright 2018, SLACK Incorporated.

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.

Intramedullary placement of ventricular shunts: a review of using bone as a distal cerebrospinal absorption site in treating hydrocephalus.

PubMed

Kassem, Mohammad W; Chern, Joshua; Loukas, Marios; Tubbs, R Shane

2017-12-01

Intraosseous (IO) vascular access has been used since the Second World War and is warranted when there is an emergency and/or urgent need to replenish the vascular pool. Despite long-term and satisfactory results from delivering large quantities of intravenous fluid via the medullary space of bone, use of this space for a distant receptacle for cerebrospinal fluid (CSF) diversion has seldom been considered. The current paper reviews the literature regarding the bony medullary space as a receptacle for intravenous fluid and CSF. Previous authors have demonstrated the potential of the diploic space of the calvaria for CSF shunting. Pugh and colleagues tested the ability of the cranium to receive and absorb a small amount of tracer fluid. The literature suggests that intraosseous placement of ventricular diversionary shunts is an alternative to more traditional sites such as the pleural cavity and peritoneum. When these latter locations are not available or are contraindicated, placement in the medullary space of bone is another option available to the surgeon.

Intrathecal oligoclonal IgG synthesis in multiple sclerosis.

PubMed

Petzold, Axel

2013-09-15

The diagnosis of multiple sclerosis is based on dissemination in time and space. Before 2010 lack of evidence for dissemination in space could be substituted by a paraclinical test, cerebrospinal fluid (CSF) oligoclonal bands (OCBs). The present meta-analysis (13,467 patients) shows that the diagnostic specificity of OCB drops from 94% to 61% if inflammatory etiologies are considered. Importantly, this was not caused by poor laboratory practice. This review on CSF OCB further illustrates the conceptional problem of substituting dissemination in space with a biomarker. The potential prognostic value of intrathecal OCB will need to be tested prospectively. © 2013 Elsevier B.V. All rights reserved.

Chronic Subdural Hematoma Preceded by High-Impact Trauma: Does the Intensity of Trauma Influence the Pathogenesis of Traumatic Chronic Subdural Hematoma?

PubMed

Park, Ki-Su; Lee, Chang-Heon; Park, Seong-Hyun; Hwang, Sung-Kyoo; Hwang, Jeong-Hyun

2017-01-01

The purpose of this study was to investigate whether the intensity of trauma influences the pathogenesis of traumatic chronic subdural hematoma (CSDH). Thirty-one patients treated surgically for traumatic CSDH were divided into high-impact and lowimpact groups according to the intensity of trauma. They were respectively evaluated with respect to clinical and radiological findings at presentation, and the subdural concentrations of interleukin-6 (IL-6), interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), basic fibroblast growth factor, and beta-trace protein (ΒTP) [a highly specific protein in the cerebrospinal fluid (CSF)] related to the pathogenesis of CSDH. If ΒTP (subdural fluid/serum) was > 2, an admixture of CSF to the subdural fluid was indicated. The ΒTP (subdural fluid/serum) was > 2 in all patients with a traumatic CSDH. The mean concentration of subdural ΒTP in the high-impact group was higher than in the low-impact group (6.1 mg/L versus 3.9 mg/L), and the difference was statistically significant (p=0.02). In addition, mean concentrations of IL-6, IL-8 and VEGF were higher in the high-impact group, as compared to the low-impact group, though the differences did not reach statistical significance. Trauma may be related to CSF leakage into the subdural space in CSDH, and the intensity of trauma may influence the amount of CSF leakage. Although there is no direct correlation between the amount of CSF leakage and other subdural molecules, the intensity of trauma may be associated with larger concentrations of molecules in traumatic CSDH.

Changes in sensorimotor-related thalamic diffusion properties and cerebrospinal fluid hydrodynamics predict gait responses to tap test in idiopathic normal-pressure hydrocephalus.

PubMed

Tsai, Ping-Huei; Chen, Yung-Chieh; Chiang, Shih-Wei; Huang, Teng-Yi; Chou, Ming-Chung; Liu, Hua-Shan; Chung, Hsiao-Wen; Peng, Giia-Sheun; Ma, Hsin-I; Kao, Hung-Wen; Chen, Cheng-Yu

2018-05-07

To compare diffusion tensor (DT)-derived indices from the thalamic nuclei and cerebrospinal fluid (CSF) hydrodynamic parameters for the prediction of gait responsiveness to the CSF tap test in early iNPH patients. In this study, 22 patients with iNPH and 16 normal controls were enrolled with the approval of an institutional review board. DT imaging and phase-contrast magnetic resonance imaging were performed in patients and controls to determine DT-related indices of the sensorimotor-related thalamic nuclei and CSF hydrodynamics. Gait performance was assessed in patients using gait scale before and after the tap test. The Mann-Whitney U test and receiver operating characteristic (ROC) curve analysis were applied to compare group differences between patients and controls and assess the predictive performance of gait responsiveness to the tap test in the patients. Fractional anisotropy (FA) and axial diffusivity showed significant increases in the ventrolateral (VL) and ventroposterolateral (VPL) nuclei of the iNPH group compared with those of the control group (p < 0.05). The predictions of gait responsiveness of ventral thalamic FA alone (area under the ROC curve [AUC] < 0.8) significantly outperformed those of CSF hydrodynamics alone (AUC < 0.6). The AUC curve was elevated to 0.812 when the CSF peak systolic velocity and FA value were combined for the VPL nucleus, yielding the highest sensitivity (0.769) and specificity (0.778) to predict gait responses. Combined measurements of sensorimotor-related thalamic FA and CSF hydrodynamics can provide potential biomarkers for gait response to the CSF tap test in patients with iNPH. • Ventrolateral and ventroposterolateral thalamic FA may predict gait responsiveness to tap test. • Thalamic neuroplasticity can be assessed through DTI in idiopathic normal-pressure hydrocephalus. • Changes in the CST associated with gait control could trigger thalamic neuroplasticity. • Activities of sensorimotor-related circuits could alter in patients with gait disturbance. • Management of patients with iNPH could be more appropriate.

Risk factors for suicide among patients with schizophrenia: a cohort study focused on cerebrospinal fluid levels of homovanillic acid and 5-hydroxyindoleacetic acid

PubMed Central

Neider, Daniel; Lindström, Leif H; Bodén, Robert

2016-01-01

Background The objective of this study was to investigate the association between 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in cerebrospinal fluid (CSF), bullying, and later suicide among patients with schizophrenia. Methods Ninety-nine patients with schizophrenia were included. Correlations of clinical factors, 5-HIAA and HVA, and later suicide were investigated. Results Twelve patients committed suicide (12%) during a 28-year follow-up period. Later suicide was correlated to bullying in childhood (P=0.02) and a lower quotient of HVA/5-HIAA in CSF (P<0.05). Conclusion Suicide in schizophrenia is related to childhood exposedness and CSF neurotransmitter levels. PMID:27468235

Plasma and cerebrospinal fluid amyloid-β levels in late-life depression: a systematic review and meta-analysis

PubMed Central

do Nascimento, Kenia Kelly Fiaux; Silva, Kelly P.; Malloy-Diniz, Leandro F.; Butters, Meryl A.; Diniz, Breno S.

2016-01-01

This study aimed to evaluate differences in plasma and cerebrospinal fluid (CSF) levels of Aβ peptides in older adults with late-life depression compared to non-depressed older controls. We conducted a systematic review and meta-analysis of the literature using PubMed, Web of science and Scopus databases with no search limits for publication dates or languages. Two independent reviewers extracted data and assessed quality. Six hundred references were retrieved, and we included 12 studies in the meta-analysis after eligibility screening. Older adults with late-life depression (LLD) had a higher plasma Aβ40:Aβ42 ratio compared to non-depressed participants (SMD= 1.10, CI95% [0.28; 1.96], p=0.01), and marginally significant reduction of CSF Aβ42 levels (SMD= −1.12, CI95% [−2.47; 0.22], p=0.1). The present results evidence that older adults with depression have significant differences in Aβ metabolism, in the same direction observed in individuals with AD. These differences in the Aβ metabolism may help identify a subgroup of subjects with LLD at higher risk of developing AD. PMID:26343592

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

Update on the core and developing cerebrospinal fluid biomarkers for Alzheimer disease

PubMed Central

Babić, Mirjana; Švob Štrac, Dubravka; Mück-Šeler, Dorotea; Pivac, Nela; Stanić, Gabrijela; Hof, Patrick R.; Šimić, Goran

2014-01-01

Alzheimer disease (AD) is a complex neurodegenerative disorder, whose prevalence will dramatically rise by 2050. Despite numerous clinical trials investigating this disease, there is still no effective treatment. Many trials showed negative or inconclusive results, possibly because they recruited only patients with severe disease, who had not undergone disease-modifying therapies in preclinical stages of AD before severe degeneration occurred. Detection of AD in asymptomatic at risk individuals (and a few presymptomatic individuals who carry an autosomal dominant monogenic AD mutation) remains impractical in many of clinical situations and is possible only with reliable biomarkers. In addition to early diagnosis of AD, biomarkers should serve for monitoring disease progression and response to therapy. To date, the most promising biomarkers are cerebrospinal fluid (CSF) and neuroimaging biomarkers. Core CSF biomarkers (amyloid β1-42, total tau, and phosphorylated tau) showed a high diagnostic accuracy but were still unreliable for preclinical detection of AD. Hence, there is an urgent need for detection and validation of novel CSF biomarkers that would enable early diagnosis of AD in asymptomatic individuals. This article reviews recent research advances on biomarkers for AD, focusing mainly on the CSF biomarkers. In addition to core CSF biomarkers, the potential usefulness of novel CSF biomarkers is discussed. PMID:25165049

Fibrinogen is not elevated in the cerebrospinal fluid of patients with multiple sclerosis

PubMed Central

2011-01-01

Background Elevated plasma fibrinogen levels are a well known finding in acute infectious diseases, acute stroke and myocardial infarction. However its role in the cerebrospinal fluid (CSF) of acute and chronic central (CNS) and peripheral nervous system (PNS) diseases is unclear. Findings We analyzed CSF and plasma fibrinogen levels together with routine parameters in patients with multiple sclerosis (MS), acute inflammatory diseases of the CNS (bacterial and viral meningoencephalitis, BM and VM) and PNS (Guillain-Barré syndrome; GBS), as well as in non-inflammatory neurological controls (OND) in a total of 103 patients. Additionally, MS patients underwent cerebral MRI scans at time of lumbar puncture. CSF and plasma fibrinogen levels were significantly lower in patients with MS and OND patients as compared to patients with BM, VM and GBS. There was a close correlation between fibrinogen levels and albumin quotient (rho = 0.769, p < 0.001) which strongly suggests passive transfer of fibrinogen through the blood-CSF-barrier during acute inflammation. Hence, in MS, the prototype of chronic neuroinflammation, CSF fibrinogen levels were not elevated and could not be correlated to clinical and neuroradiological outcome parameters. Conclusions Although previous work has shown clear evidence of the involvement of fibrinogen in MS pathogenesis, this is not accompanied by increased fibrinogen in the CSF compartment. PMID:22029888

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

Detection by PCR of Enteroviruses in Cerebrospinal Fluid during a Summer Outbreak of Aseptic Meningitis in Switzerland

PubMed Central

Gorgievski-Hrisoho, Meri; Schumacher, Jean-Daniel; Vilimonovic, Nevenka; Germann, Daniel; Matter, Lukas

1998-01-01

Enteroviruses (EV) are among the most common causes of aseptic meningitis. Standard diagnostic techniques are often too slow and lack sensitivity to be of clinical relevance. EV RNA can be detected within 5 h by a commercially available reverse transcription-PCR (RT-PCR) test kit. Cerebrospinal fluid (CSF) samples from 68 patients presenting with aseptic meningitis during a summer outbreak in Switzerland were examined in parallel with cell culture and commercial RT-PCR. RT-PCR was positive in all 16 CSF specimens positive by cell culture (100%). In addition, 42 of 52 (80%) CSF samples negative by cell culture were PCR positive. In 26 of these 42 (62%) patients, viral culture from other sites (throat swab or stool) was also positive. The CSF virus culture took 3 to 7 days to become positive. Echovirus 30 was the type most often isolated in this outbreak. The sensitivity of CSF RT-PCR based on clinical diagnosis during this aseptic meningitis outbreak in patients with negative bacterial culture results was 85%, i.e., considerably higher than the sensitivity of CSF virus culture (24%). We conclude that this commercial RT-PCR assay allows a positive diagnosis with minimal delay and may thus influence clinical decisions. PMID:9705364

Cerebrospinal fluid leakage and Chiari I malformation with Gorham's disease of the skull base: A case report.

PubMed

Nagashima, Hiroaki; Mizukawa, Katsu; Taniguchi, Masaaki; Yamamoto, Yusuke; Kohmura, Eiji

Gorham's syndrome is a rare bone disorder characterized by massive osteolysis of unknown etiology. There are no reports of comorbidity involving cerebrospinal fluid (CSF) leakage and Chiari I malformation with Gorham's syndrome. Here, we report an unusual case of an acute presyrinx state complicated by bacterial meningitis due to CSF leakage and Chiari I malformation associated with Gorham's disease of the skull base. A 25-year-old woman with Chiari I malformation associated with Gorham's syndrome presented with aggressive paresthesia following bacterial meningitis. Axial magnetic resonance imaging (MRI) and computed tomography (CT) cisternography revealed CSF leakage in the right petrous apex. A presyrinx state was diagnosed based on the clinical symptoms and MRI findings. With resolution of the bacterial meningitis, the spinal edema and tonsillar ectopia also improved. Surgical repair of the CSF leakage was performed by an endoscopic endonasal transsphenoidal approach to prevent recurrence of meningitis. The postoperative course was uneventful. Skull base osteolysis in Gorham's syndrome may induce Chiari I malformation and CSF leakage. We should pay attention to acute progression of clinical symptoms because Gorham's syndrome may predispose to development of Chiari I malformation and may be complicated by CSF leakage. Copyright © 2017 Polish Neurological Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Application of targeted quantitative proteomics analysis in human cerebrospinal fluid using a liquid chromatography matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometer (LC MALDI TOF/TOF) platform.

PubMed

Pan, Sheng; Rush, John; Peskind, Elaine R; Galasko, Douglas; Chung, Kathryn; Quinn, Joseph; Jankovic, Joseph; Leverenz, James B; Zabetian, Cyrus; Pan, Catherine; Wang, Yan; Oh, Jung Hun; Gao, Jean; Zhang, Jianpeng; Montine, Thomas; Zhang, Jing

2008-02-01

Targeted quantitative proteomics by mass spectrometry aims to selectively detect one or a panel of peptides/proteins in a complex sample and is particularly appealing for novel biomarker verification/validation because it does not require specific antibodies. Here, we demonstrated the application of targeted quantitative proteomics in searching, identifying, and quantifying selected peptides in human cerebrospinal spinal fluid (CSF) using a matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometer (MALDI TOF/TOF)-based platform. The approach involved two major components: the use of isotopic-labeled synthetic peptides as references for targeted identification and quantification and a highly selective mass spectrometric analysis based on the unique characteristics of the MALDI instrument. The platform provides high confidence for targeted peptide detection in a complex system and can potentially be developed into a high-throughput system. Using the liquid chromatography (LC) MALDI TOF/TOF platform and the complementary identification strategy, we were able to selectively identify and quantify a panel of targeted peptides in the whole proteome of CSF without prior depletion of abundant proteins. The effectiveness and robustness of the approach associated with different sample complexity, sample preparation strategies, as well as mass spectrometric quantification were evaluated. Other issues related to chromatography separation and the feasibility for high-throughput analysis were also discussed. Finally, we applied targeted quantitative proteomics to analyze a subset of previously identified candidate markers in CSF samples of patients with Parkinson's disease (PD) at different stages and Alzheimer's disease (AD) along with normal controls.

Intact protein analysis of ubiquitin in cerebrospinal fluid by multiple reaction monitoring reveals differences in Alzheimer's disease and frontotemporal lobar degeneration.

PubMed

Oeckl, Patrick; Steinacker, Petra; von Arnim, Christine A F; Straub, Sarah; Nagl, Magdalena; Feneberg, Emily; Weishaupt, Jochen H; Ludolph, Albert C; Otto, Markus

2014-11-07

The impairment of the ubiquitin-proteasome system (UPS) is thought to be an early event in neurodegeneration, and monitoring UPS alterations might serve as a disease biomarker. Our aim was to establish an alternate method to antibody-based assays for the selective measurement of free monoubiquitin in cerebrospinal fluid (CSF). Free monoubiquitin was measured with liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MS/MS) in CSF of patients with Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), behavioral variant of frontotemporal dementia (bvFTD), Creutzfeldt-Jakob disease (CJD), Parkinson's disease (PD), primary progressive aphasia (PPA), and progressive supranuclear palsy (PSP). The LC-MS/MS method showed excellent intra- and interassay precision (4.4-7.4% and 4.9-10.3%) and accuracy (100-107% and 100-106%). CSF ubiquitin concentration was increased compared with that of controls (33.0 ± 9.7 ng/mL) in AD (47.5 ± 13.1 ng/mL, p < 0.05) and CJD patients (171.5 ± 103.5 ng/mL, p < 0.001) but not in other neurodegenerative diseases. Receiver operating characteristic curve (ROC) analysis of AD vs control patients revealed an area under the curve (AUC) of 0.832, and the specificity and sensitivity were 75 and 75%, respectively. ROC analysis of AD and FTLD patients yielded an AUC of 0.776, and the specificity and sensitivity were 53 and 100%, respectively. In conclusion, our LC-MS/MS method may facilitate ubiquitin determination to a broader community and might help to discriminate AD, CJD, and FTLD patients.

Elevated host lipid metabolism revealed by iTRAQ-based quantitative proteomic analysis of cerebrospinal fluid of tuberculous meningitis patients.

PubMed

Mu, Jun; Yang, Yongtao; Chen, Jin; Cheng, Ke; Li, Qi; Wei, Yongdong; Zhu, Dan; Shao, Weihua; Zheng, Peng; Xie, Peng

2015-10-30

Tuberculous meningitis (TBM) remains to be one of the most deadly infectious diseases. The pathogen interacts with the host immune system, the process of which is largely unknown. Various cellular processes of Mycobacterium tuberculosis (MTB) centers around lipid metabolism. To determine the lipid metabolism related proteins, a quantitative proteomic study was performed here to identify differential proteins in the cerebrospinal fluid (CSF) obtained from TBM patients (n = 12) and healthy controls (n = 12). CSF samples were desalted, concentrated, labelled with isobaric tags for relative and absolute quantitation (iTRAQ™), and analyzed by multi-dimensional liquid chromatography-tandem mass spectrometry (LC-MS/MS). Gene ontology and proteomic phenotyping analysis of the differential proteins were conducted using Database for Annotation, Visualization, and Integrated Discovery (DAVID) Bioinformatics Resources. ApoE and ApoB were selected for validation by ELISA. Proteomic phenotyping of the 4 differential proteins was invloved in the lipid metabolism. ELISA showed significantly increased ApoB levels in TBM subjects compared to healthy controls. Area under the receiver operating characteristic curve analysis demonstrated ApoB levels could distinguish TBM subjects from healthy controls and viral meningitis subjects with 89.3% sensitivity and 92% specificity. CSF lipid metabolism disregulation, especially elevated expression of ApoB, gives insights into the pathogenesis of TBM. Further evaluation of these findings in larger studies including anti-tuberculosis medicated and unmedicated patient cohorts with other center nervous system infectious diseases is required for successful clinical translation. Copyright © 2015 Elsevier Inc. All rights reserved.

An 8-month history of meningitis in an extremely low birth weight infant? - Long-lasting Infection with Ureaplasma parvum.

PubMed

Glaser, K; Wohlleben, M; Speer, C P

2015-02-01

Ureaplasma spp. have been implicated in the pathogenesis of both preterm labor and neonatal morbidity including pneumonia and sepsis and the development of chronic lung disease of prematurity. Data on Ureaplasma meningitis are limited and partly controversially discussed. We report the unique case of a 9-month-old infant with progressive internal hydrocephalus of unknown origin and developmental delay due to a history of>200 days of inflammation of the central nervous system. The female extremely low birth weight infant had been referred to our hospital for ventriculoperitoneal shunt implantation. She had been born at 26+3 weeks of gestation with a birth weight of 940 g. With the exception of a moderate respiratory distress syndrome, postnatal period had been reported uneventful. However, internal hydrocephalus had become manifest at 4 weeks of postnatal age. Intraventricular hemorrhage had not been documented by cranial ultrasound and magnetic resonance imaging. Cerebrospinal fluid (CSF) analysis had repetitively revealed pronounced inflammation reflected by pleocytosis (50-86 leukocytes/μL, 60% lymphocytes), CSF protein levels of 578-1,026 mg/dL and undetectable CSF glucose. Although suggesting bacterial meningitis, microbial diagnostics had not been indicative, and empirical antibiotics had not affected the CSF findings. On admission to our hospital, CSF analysis still documented significant inflammation (125 leukocytes/μL, CSF protein 565 mg/dL, CSF glucose<2 mg/dL). Due to a prenatal history of cerclage, we initiated microbial diagnostics on Ureaplasma spp. and Mycoplasma hominis. U. parvum was detected in CSF by culture and PCR, no other pathogens were isolated. On intravenous treatment with chloramphenicol, CSF profile continuously normalized, and cultures and PCR became negative. Treatment was continued for 3 weeks, and the infant was discharged after uncomplicated ventriculoperitoneal shunt placement. During a 12-month observation period she has shown encouraging recovery. In preterm infants, in particular, internal hydrocephalus of unknown origin and sustained CSF inflammation are highly suggestive of Ureaplasma meningitis. Our case highlights that infection may escape detection if not explicitly considered, since microbial diagnosis requires complex media and PCR. © Georg Thieme Verlag KG Stuttgart · New York.

Cerebrospinal fluid pressures resulting from experimental traumatic spinal cord injuries in a pig model.

PubMed

Jones, Claire F; Lee, Jae H T; Burstyn, Uri; Okon, Elena B; Kwon, Brian K; Cripton, Peter A

2013-10-01

Despite considerable effort over the last four decades, research has failed to translate into consistently effective treatment options for spinal cord injury (SCI). This is partly attributed to differences between the injury response of humans and rodent models. Some of this difference could be because the cerebrospinal fluid (CSF) layer of the human spine is relatively large, while that of the rodents is extremely thin. We sought to characterize the fluid impulse induced in the CSF by experimental SCIs of moderate and high human-like severity, and to compare this with previous studies in which fluid impulse has been associated with neural tissue injury. We used a new in vivo pig model (n = 6 per injury group, mean age 124.5 days, 20.9 kg) incorporating four miniature pressure transducers that were implanted in pairs in the subarachnoid space, cranial, and caudal to the injury at 30 mm and 100 mm. Tissue sparing was assessed with Eriochrome Cyanine and Neutral Red staining. The median peak pressures near the injury were 522.5 and 868.8 mmHg (range 96.7-1430.0) and far from the injury were 7.6 and 36.3 mmHg (range 3.8-83.7), for the moderate and high injury severities, respectively. Pressure impulse (mmHg.ms), apparent wave speed, and apparent attenuation factor were also evaluated. The data indicates that the fluid pressure wave may be sufficient to affect the severity and extent of primary tissue damage close to the injury site. However, the CSF pressure was close to normal physiologic values at 100 mm from the injury. The high injury severity animals had less tissue sparing than the moderate injury severity animals; this difference was statistically significant only within 1.6 mm of the epicenter. These results indicate that future research seeking to elucidate the mechanical origins of primary tissue damage in SCI should consider the effects of CSF. This pig model provides advantages for basic and preclinical SCI research due to its similarities to human scale, including the existence of a human-like CSF fluid layer.

Laboratory-based clinical audit as a tool for continual improvement: an example from CSF chemistry turnaround time audit in a South-African teaching hospital.

PubMed

Imoh, Lucius C; Mutale, Mubanga; Parker, Christopher T; Erasmus, Rajiv T; Zemlin, Annalise E

2016-01-01

Timeliness of laboratory results is crucial to patient care and outcome. Monitoring turnaround times (TAT), especially for emergency tests, is important to measure the effectiveness and efficiency of laboratory services. Laboratory-based clinical audits reveal opportunities for improving quality. Our aim was to identify the most critical steps causing a high TAT for cerebrospinal fluid (CSF) chemistry analysis in our laboratory. A 6-month retrospective audit was performed. The duration of each operational phase across the laboratory work flow was examined. A process-mapping audit trail of 60 randomly selected requests with a high TAT was conducted and reasons for high TAT were tested for significance. A total of 1505 CSF chemistry requests were analysed. Transport of samples to the laboratory was primarily responsible for the high average TAT (median TAT = 170 minutes). Labelling accounted for most delays within the laboratory (median TAT = 71 minutes) with most delays occurring after regular work hours (P < 0.05). CSF chemistry requests without the appropriate number of CSF sample tubes were significantly associated with delays in movement of samples from the labelling area to the technologist's work station (caused by a preference for microbiological testing prior to CSF chemistry). A laboratory-based clinical audit identified sample transportation, work shift periods and use of inappropriate CSF sample tubes as drivers of high TAT for CSF chemistry in our laboratory. The results of this audit will be used to change pre-analytical practices in our laboratory with the aim of improving TAT and customer satisfaction.

Utility of (1-3)-β-D-glucan testing for diagnostics and monitoring response to treatment during the multistate outbreak of fungal meningitis and other infections.

PubMed

Litvintseva, Anastasia P; Lindsley, Mark D; Gade, Lalitha; Smith, Rachel; Chiller, Tom; Lyons, Jennifer L; Thakur, Kiran T; Zhang, Sean X; Grgurich, Dale E; Kerkering, Thomas M; Brandt, Mary E; Park, Benjamin J

2014-03-01

 The 2012 outbreak of fungal meningitis associated with contaminated methylprednisolone produced by a compounding pharmacy has resulted in >750 infections. An important question facing patients and clinicians is the duration of antifungal therapy. We evaluated (1-3)-β-d-glucan (BDG) as a marker for monitoring response to treatment.  We determined sensitivity and specificity of BDG testing using the Fungitell assay, by testing 41 cerebrospinal fluid (CSF) specimens from confirmed cases of fungal meningitis and 66 negative control CSF specimens. We also assessed whether BDG levels correlate with clinical status by using incident samples from 108 case patients with meningitis and 20 patients with serially collected CSF.  A cutoff value of 138 pg/mL provided 100% sensitivity and 98% specificity for diagnosis of fungal meningitis in this outbreak. Patients with serially collected CSF were divided into 2 groups: those in whom BDG levels declined with treatment and those in whom BDG remained elevated. Whereas most patients with a decline in CSF BDG had clinical improvement, all 3 patients with continually elevated BDG had poor clinical outcomes (stroke, meningitis relapse, or development of new disease).  Our data suggest that measuring BDG in CSF is a highly sensitive test for diagnosis of fungal meningitis in this outbreak. Analysis of BDG levels in serially collected CSF demonstrated that BDG may correlate with clinical response. Routine measurement of BDG in CSF may provide useful adjunctive data for the clinical management of patients with outbreak-associated meningitis.

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

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

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.

Neutrophil-to-lymphocyte ratio in the differential diagnosis of acute bacterial meningitis.

PubMed

Mentis, A-F A; Kyprianou, M A; Xirogianni, A; Kesanopoulos, K; Tzanakaki, G

2016-03-01

The differential diagnosis of acute community-acquired meningitis is of paramount importance in both therapeutic and healthcare-related economic terms. Despite the routinely used markers, novel, easily calculated, and rapidly available biomarkers are needed particularly in resource-poor settings. A promising, exponentially studied inflammatory marker is the neutrophil-to-lymphocyte ratio (NLR), albeit not assessed in meningitis. The aim of this study was to investigate the utility of the NLR in the differential diagnosis of acute meningitis. Data on cerebrospinal fluid (CSF) and blood leukocyte parameters from more than 4,000 patients diagnosed with either bacterial or viral meningitis in Greece during the period 2006-2013 were retrospectively examined. The diagnostic accuracy of the NLR and neutrophil counts in CSF and blood were evaluated by receiver operating characteristic curves. The discrimination ability of both the NLR and neutrophil counts was significantly higher in CSF than in blood. The optimal cutoff values of the NLR and neutrophil counts were 2 in CSF vs 8 in blood, and 287 cells in CSF vs 12,100 cells in blood, respectively. For these values, sensitivity, negative predictive value, and odds ratio were statistically significantly higher in CSF than blood for both markers. Logistic regression analysis showed that the CSF NLR carries independent and additive information to neutrophil counts in the differential diagnosis of acute meningitis. This study is the first one to assess NLR in acute meningitis, providing promising results for its differential diagnosis.

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.

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.

Measurements of auto-antibodies to α-synuclein in the serum and cerebral spinal fluids of patients with Parkinson's disease.

PubMed

Akhtar, Rizwan S; Licata, Joseph P; Luk, Kelvin C; Shaw, Leslie M; Trojanowski, John Q; Lee, Virginia M-Y

2018-03-03

Biomarkers for α-synuclein are needed for diagnosis and prognosis in Parkinson's disease (PD). Endogenous auto-antibodies to α-synuclein could serve as biomarkers for underlying synucleinopathy, but previous assessments of auto-antibodies have shown variability and inconsistent clinical correlations. We hypothesized that auto-antibodies to α-synuclein could be diagnostic for PD and explain its clinical heterogeneity. To test this hypothesis, we developed an enzyme-linked immunosorbent assay for measuring α-synuclein auto-antibodies in human samples. We evaluated 69 serum samples (16 healthy controls (HC) and 53 PD patients) and 145 CSF samples (52 HC and 93 PD patients) from our Institution. Both serum and CSF were available for 24 participants. Males had higher auto-antibody levels than females in both fluids. CSF auto-antibody levels were significantly higher in PD patients as compared to HC, whereas serum levels were not significantly different. CSF auto-antibody levels did not associate with amyloid-β 1-42 , total tau, or phosphorylated tau. CSF auto-antibody levels correlated with performance on the Montreal Cognitive Assessment, even when controlled for CSF amyloidβ 1-42 . CSF hemoglobin levels, as a proxy for contamination of CSF by blood during lumbar puncture, did not influence these observations. Using recombinant α-synuclein with N- and C-terminal truncations, we found that CSF auto-antibodies target amino acids 100 through 120 of α-synuclein. We conclude that endogenous CSF auto-antibodies are significantly higher in PD patients as compared to HC, suggesting that they could indicate the presence of underlying synucleinopathy. These auto-antibodies associate with poor cognition, independently of CSF amyloidβ 1-42 ., and target a select C-terminal region of α-synuclein. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Population Pharmacokinetics and Dosing Regimen Optimization of Meropenem in Cerebrospinal Fluid and Plasma in Patients with Meningitis after Neurosurgery

PubMed Central

Lu, Cheng; Zhang, Yuyi; Chen, Mingyu; Zhong, Ping; Chen, Yuancheng; Yu, Jicheng; Wu, Xiaojie; Wu, Jufang

2016-01-01

Meropenem is used to manage postneurosurgical meningitis, but its population pharmacokinetics (PPK) in plasma and cerebrospinal fluid (CSF) in this patient group are not well-known. Our aims were to (i) characterize meropenem PPK in plasma and CSF and (ii) recommend favorable dosing regimens in postneurosurgical meningitis patients. Eighty-two patients were enrolled to receive meropenem infusions of 2 g every 8 h (q8h), 1 g q8h, or 1 g q6h for at least 3 days. Serial blood and CSF samples were collected, and concentrations were determined and analyzed via population modeling. Probabilities of target attainment (PTA) were predicted via Monte Carlo simulations, using the target of unbound meropenem concentrations above the MICs for at least 40% of dosing intervals in plasma and at least of 50% or 100% of dosing intervals in CSF. A two-compartment model plus another CSF compartment best described the data. The central, intercentral/peripheral, and intercentral/CSF compartment clearances were 22.2 liters/h, 1.79 liters/h, and 0.01 liter/h, respectively. Distribution volumes of the central and peripheral compartments were 17.9 liters and 3.84 liters, respectively. The CSF compartment volume was fixed at 0.13 liter, with its clearance calculated by the observed drainage amount. The multiplier for the transfer from the central to the CSF compartment was 0.172. Simulation results show that the PTAs increase as infusion is prolonged and as the daily CSF drainage volume decreases. A 4-hour infusion of 2 g q8h with CSF drainage of less than 150 ml/day, which provides a PTA of >90% for MICs of ≤8 mg/liter in blood and of ≤0.5 mg/liter or 0.25 mg/liter in CSF, is recommended. (This study has been registered at ClinicalTrials.gov under identifier NCT02506686.) PMID:27572392

Gadolinium Distribution in Cerebrospinal Fluid after Administration of a Gadolinium-based MR Contrast Agent in Humans.

PubMed

Berger, Florian; Kubik-Huch, Rahel A; Niemann, Tilo; Schmid, Hans Ruedi; Poetzsch, Michael; Froehlich, Johannes M; Beer, Jürg H; Thali, Michael J; Kraemer, Thomas

2018-05-08

Purpose To evaluate whether gadolinium penetrates human cerebrospinal fluid (CSF) after MR imaging (MRI) with a gadolinium-based contrast agent (GBCA). Materials and Methods For this retrospective study, the authors analyzed 60 CSF samples from 57 patients (median age, 50 years; range, 3-92 years) who underwent one contrast material-enhanced MRI examination with gadoterate meglumine within 60 days of CSF extraction between January and December 2016. CSF samples from patients who underwent MRI without contrast material administration (n = 22) or those who underwent contrast-enhanced MRI at least 1 year before extraction (n = 2) were analyzed and used as control samples. CSF measurements were performed with inductively coupled plasma mass spectrometry by monitoring the gadolinium 158 isotope. Statistical analyses were performed by using a preliminary Kruskal-Wallis test. Results Higher CSF gadolinium concentrations were detected within the first 8 hours after GBCA administration (mean concentration, 1152 ng/mL ± 734.6). Concentrations were lower between 8 and 48 hours (872 ng/mL ± 586). After 48 hours, gadolinium was almost completely cleared from CSF (121 ng/mL ± 296.3). All but two samples from the 24 control patients (median age, 60.5 years; range, 19-79 years) were negative for the presence of gadolinium. Those samples were from patients who had undergone GBCA-enhanced MRI examination more than a year before CSF extraction (0.1 and 0.2 ng/mL after 1 and 3 years, respectively). The concentrations in patients with chronic renal insufficiency (n = 3), cerebral toxoplasmosis (n = 1), and liver cirrhosis (n = 1) were higher than the mean concentrations. Conclusion Gadoterate meglumine can be detected in human CSF after intravenous administration. © RSNA, 2018.

Cerebrospinal fluid neuropeptide Y in combat veterans with and without posttraumatic stress disorder.

PubMed

Sah, Renu; Ekhator, Nosakhare N; Jefferson-Wilson, Lena; Horn, Paul S; Geracioti, Thomas D

2014-02-01

Accruing evidence indicates that neuropeptide Y (NPY), a peptide neurotransmitter, is a resilience-to-stress factor in humans. We previously reported reduced cerebrospinal fluid (CSF) NPY concentrations in combat-related posttraumatic stress disorder (PTSD) subjects as compared with healthy, non-combat-exposed volunteers. Here we report CSF NPY in combat-exposed veterans with and without PTSD. We quantified NPY concentrations in morning CSF from 11 male subjects with PTSD from combat in Iraq and/or Afghanistan and from 14 combat-exposed subjects without PTSD. NPY-like immunoreactivity (NPY-LI) was measured by EIA. The relationship between CSF NPY and clinical symptoms, as measured by the Clinician-Administered PTSD Scale (CAPS) and Beck Depression Inventory (BDI), was assessed, as was the relationship between combat exposure scale (CES) scores and CSF NPY. As compared with the combat-exposed comparison subjects without PTSD, individuals with PTSD had significantly lower concentrations of CSF NPY [mean CSF NPY was 258. 6 ± 21.64 pg/mL in the combat trauma-no PTSD group but only 180.5 ± 12.62 pg/mL in PTSD patients (p=0.008)]. After adjusting for CES and BDI scores the two groups were still significantly different with respect to NPY. Importantly, CSF NPY was negatively correlated with composite CAPS score and intrusive (re-experiencing) subscale scores, but did not significantly correlate with CES or BDI scores. Our current findings further suggest that NPY may regulate the manifestation of PTSD symptomatology, and extend previous observations of low CSF NPY concentrations in the disorder. Central nervous system NPY may be a clinically important pharmacotherapeutic target, and/or diagnostic measure, for PTSD. Published by Elsevier Ltd.

Impact of frequent cerebrospinal fluid sampling on Aβ levels: systematic approach to elucidate influencing factors.

PubMed

Van Broeck, Bianca; Timmers, Maarten; Ramael, Steven; Bogert, Jennifer; Shaw, Leslie M; Mercken, Marc; Slemmon, John; Van Nueten, Luc; Engelborghs, Sebastiaan; Streffer, Johannes Rolf

2016-05-19

Cerebrospinal fluid (CSF) amyloid-beta (Aβ) peptides are predictive biomarkers for Alzheimer's disease and are proposed as pharmacodynamic markers for amyloid-lowering therapies. However, frequent sampling results in fluctuating CSF Aβ levels that have a tendency to increase compared with baseline. The impact of sampling frequency, volume, catheterization procedure, and ibuprofen pretreatment on CSF Aβ levels using continuous sampling over 36 h was assessed. In this open-label biomarker study, healthy participants (n = 18; either sex, age 55-85 years) were randomized into one of three cohorts (n = 6/cohort; high-frequency sampling). In all cohorts except cohort 2 (sampling started 6 h post catheterization), sampling through lumbar catheterization started immediately post catheterization. Cohort 3 received ibuprofen (800 mg) before catheterization. Following interim data review, an additional cohort 4 (n = 6) with an optimized sampling scheme (low-frequency and lower volume) was included. CSF Aβ(1-37), Aβ(1-38), Aβ(1-40), and Aβ(1-42) levels were analyzed. Increases and fluctuations in mean CSF Aβ levels occurred in cohorts 1-3 at times of high-frequency sampling. Some outliers were observed (cohorts 2 and 3) with an extreme pronunciation of this effect. Cohort 4 demonstrated minimal fluctuation of CSF Aβ both on a group and an individual level. Intersubject variability in CSF Aβ profiles over time was observed in all cohorts. CSF Aβ level fluctuation upon catheterization primarily depends on the sampling frequency and volume, but not on the catheterization procedure or inflammatory reaction. An optimized low-frequency sampling protocol minimizes or eliminates fluctuation of CSF Aβ levels, which will improve the capability of accurately measuring the pharmacodynamic read-out for amyloid-lowering therapies. ClinicalTrials.gov NCT01436188 . Registered 15 September 2011.

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.

Plasma and cerebrospinal fluid pharmacokinetics of erlotinib and its active metabolite OSI-420.

PubMed

Broniscer, Alberto; Panetta, John C; O'Shaughnessy, Melinda; Fraga, Charles; Bai, Feng; Krasin, Matthew J; Gajjar, Amar; Stewart, Clinton F

2007-03-01

To report cerebrospinal fluid (CSF) penetration of erlotinib and its metabolite OSI-420. Pharmacokinetic measurements were done in plasma (days 1, 2, 3, and 8 of therapy) and, concurrently, in plasma and CSF (before and at 1, 2, 4, 8, and 24 h after dose on day 34 of therapy) in an 8-year-old patient diagnosed with glioblastoma who received local irradiation and oral erlotinib in a phase I protocol. CSF samples were collected from a ventriculoperitoneal shunt, which was externalized because of infection. Erlotinib concentrations were determined by liquid chromatography/mass spectrometry. CSF penetration of erlotinib and OSI-420 were estimated by a compartmental model and by calculating the ratio of CSF to plasma 24-h area under concentration-time curve (AUC(0-24)). This patient was assigned to receive erlotinib at a dose level of 70 mg/m(2), but the actual daily dose was 75 mg (78 mg/m(2)). Erlotinib and OSI-420 plasma pharmacokinetic variables on days 8 and 34 overlapped to suggest that steady state had been reached. Whereas erlotinib and OSI-420 AUC(0-24) in plasma on day 34 were 30,365 and 2,527 ng h/mL, respectively, the correspondent AUC(0-24) in the CSF were 2,129 and 240 ng h/mL, respectively. Erlotinib and OSI-420 CSF penetration were 7% and approximately 9%, respectively, using both estimate methods. The maximum steady-state CSF concentration of erlotinib was approximately 130 ng/mL (325 nmol/L). The plasma pharmacokinetics of erlotinib in this child overlapped with results described in adults. Oral administration of erlotinib achieves CSF concentrations comparable with those active against several cancer cell lines in preclinical models.

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.

Cerebrospinal fluid neopterin decay characteristics after initiation of antiretroviral therapy

PubMed Central

2013-01-01

Background Neopterin, a biomarker of macrophage activation, is elevated in the cerebrospinal fluid (CSF) of most HIV-infected individuals and decreases after initiation of antiretroviral therapy (ART). We studied decay characteristics of neopterin in CSF and blood after commencement of ART in HIV-infected subjects and estimated the set-point levels of CSF neopterin after ART-mediated viral suppression. Methods CSF and blood neopterin were longitudinally measured in 102 neurologically asymptomatic HIV-infected subjects who were treatment-naïve or had been off ART for ≥ 6 months. We used a non-linear model to estimate neopterin decay in response to ART and a stable neopterin set-point attained after prolonged ART. Seven subjects with HIV-associated dementia (HAD) who initiated ART were studied for comparison. Results Non-HAD patients were followed for a median 84.7 months. Though CSF neopterin concentrations decreased rapidly after ART initiation, it was estimated that set-point levels would be below normal CSF neopterin levels (<5.8 nmol/L) in only 60/102 (59%) of these patients. Pre-ART CSF neopterin was the primary predictor of set-point (P <0.001). HAD subjects had higher baseline median CSF neopterin levels than non-HAD subjects (P <0.0001). Based on the non-HAD model, only 14% of HAD patients were predicted to reach normal levels. Conclusions After virologically suppressive ART, abnormal CSF neopterin levels persisted in 41% of non-HAD and the majority of HAD patients. ART is not fully effective in ameliorating macrophage activation in CNS as well as blood, especially in subjects with higher pre-ART levels of immune activation. PMID:23664008

Soluble CD14 in cerebrospinal fluid is associated with markers of inflammation and axonal damage in untreated HIV-infected patients: a retrospective cross-sectional study.

PubMed

Jespersen, Sofie; Pedersen, Karin Kæreby; Anesten, Birgitta; Zetterberg, Henrik; Fuchs, Dietmar; Gisslén, Magnus; Hagberg, Lars; Trøseid, Marius; Nielsen, Susanne Dam

2016-04-21

HIV-associated cognitive impairment has declined since the introduction of combination antiretroviral treatment (cART). However, milder forms of cognitive impairment persist. Inflammation in the cerebrospinal fluid (CSF) has been associated with cognitive impairment, and CSF neurofilament light chain protein (NFL) and CSF neopterin concentrations are increased in those patients. Microbial translocation in HIV infection has been suggested to contribute to chronic inflammation, and lipopolysaccharide (LPS) and soluble CD14 (sCD14) are markers of microbial translocation and the resulting monocyte activation, respectively. We hypothesised that microbial translocation contributes to inflammation and axonal damage in the central nervous system (CNS) in untreated HIV infection. We analyzed paired samples of plasma and CSF from 62 HIV-infected, untreated patients without cognitive symptoms from Sahlgrenska University Hospital, Gothenburg, Sweden. Measurements of neopterin and NFL in CSF were available from previous studies. Plasma and CSF sCD14 was measured using ELISA (R&D, Minneapolis, MN), and plasma and CSF LPS was measured using LAL colorimetric assay (Lonza, Walkersville, MD, USA). Univariate and multivariate regression analyses were performed. LPS in plasma was associated with plasma sCD14 (r = 0.31, P = 0.015), and plasma sCD14 was associated with CSF sCD14 (r = 0.32, P = 0.012). Furthermore, CSF sCD14 was associated with NFL (r = 0.32, P = 0.031) and neopterin (r = 0.32, P = 0.012) in CSF. LPS was not detectable in CSF. In a multivariate regression model CSF sCD14 remained associated with NFL and neopterin after adjusting for age, CD4+ cell count, and HIV RNA in CSF. In a group of untreated, HIV-infected patients LPS was associated with sCD14 in plasma, and plasma sCD14 was associated CSF sCD14. CSF sCD14 were associated with markers of CNS inflammation and axonal damage. This suggest that microbial translocation might be a driver of systemic and CNS inflammation. However, LPS was not detectable in the CSF, and since sCD14 is a marker of monocyte activation sCD14 may be increased due to other causes than microbial translocation. Further studies regarding cognitive impairment and biomarkers are warranted to fully understand causality.

Preservation of the Myofascial Cuff During Posterior Fossa Surgery to Reduce the Rate of Pseudomeningocele Formation and Cerebrospinal Fluid Leak: A Technical Note

PubMed Central

Felbaum, Daniel R; Anaizi, Amjad; Mason, Robert B; Jean, Walter C; Voyadzis, Jean M

2016-01-01

Introduction: Suboccipital craniotomy is a workhorse neurosurgical operation for approaching the posterior fossa but carries a high risk of pseudomeningocele and cerebrospinal fluid (CSF) leak. We describe our experience with a simple T-shaped fascial opening that preserves the occipital myofascial cuff as compared to traditional methods to reduce this risk. Methods: A single institution, retrospective review of prospectively collected database was performed of patients that underwent a suboccipital craniectomy or craniotomy. Patient data was reviewed for craniotomy or craniectomy, dural graft, and/or sealant use as well as CSF complications. A pseudomeningocele was defined as a subcutaneous collection of cerebrospinal fluid palpable clinically and confirmed on imaging. A CSF leak was defined as a CSF-cutaneous fistula manifested by CSF leaking through the wound. All patients underwent regular postoperative visits of two weeks, one month, and three months. Results: Our retrospective review identified 33 patients matching the inclusion criteria. Overall, our cohort had a 21% (7/33) rate of clinical and radiographic pseudomeningocele formation with 9% (3/33) requiring surgical revision or a separate procedure. The rate of clinical and radiographic pseudomeningocele formation in the myofascial cuff preservation technique was less than standard techniques (12% and 31%, respectively). Revision or further surgical procedures were also reduced in the myofascial cuff preservation technique vs. the standard technique (6% vs 13%). Conclusions: Preservation of the myofascial cuff during posterior fossa surgery is a simple and adoptable technique that reduces the rate of pseudomeningocele formation and CSF leak as compared with standard techniques.   PMID:28133584

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