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Sample records for decreases cerebral amyloid

  1. Cerebral amyloid angiopathy.

    PubMed

    Yamada, Masahito; Naiki, Hironobu

    2012-01-01

    Cerebral amyloid angiopathy (CAA) is cerebrovascular amyloid deposition. It is classified into several types according to the cerebrovascular amyloid proteins involved [amyloid β-protein (Aβ), cystatin C (ACys), prion protein (APrP), transthyretin (ATTR), gelsolin (AGel), ABri/ADan, and AL]. Sporadic Aβ-type CAA is commonly found in elderly individuals and patients with Alzheimer's disease (AD). CAA-related disorders include hemorrhagic and ischemic brain lesions and dementia. It has been proposed that cerebrovascular Aβ originates mainly from the brain and is transported to the vascular wall through a perivascular drainage pathway, where it polymerizes into fibrils on vascular basement membrane through interactions with extracellular components. CAA would be promoted by overproduction of Aβ40 (a major molecular species of cerebrovascular Aβ), a decrease of Aβ degradation, or reduction of Aβ clearance due to impairment of perivascular drainage pathway. Further understanding of the molecular pathogenesis of CAA would lead to development of disease-modifying therapies for CAA and CAA-related disorders. Copyright © 2012 Elsevier Inc. All rights reserved.

  2. [Cerebral amyloid angiopathy].

    PubMed

    Sakai, Kenji; Yamada, Masahito

    2014-07-01

    Cerebral amyloid angiopathy (CAA) is a disorder characterized by the accumulation of amyloid proteins in the small and medium-sized blood vessels of the leptomeninges and central nervous system. Amyloid β protein (Aβ), immunoglobulin light chains, cystatin C, prion protein (PrP), ABri/ADan, transthyretin, and gelsoline, are all associated with CAA. While most CAA patients demonstrated sporadic Aβ-type amyloid deposition, a small number of patients present with familial forms, e.g. Dutch-type hereditary cerebral hemorrhage with amyloidosis (HCHWA-D), Icelandic-type HCHWA (HCHWA-I), familial British dementia (FBD), familial Danish dementia (FDD), and PrP-CAA. Deposited amyloid proteins damage smooth muscle cells in blood vessel walls leading to pathological appearances calling 'double-barreled' changes, fibrinoid necrosis, and microaneurysms. These structural abnormalities result in microinfarcts and hemorrhages in the central nervous system. Recurrent hemorrhage is a common clinical manifestation in patients with CAA; however, small multiple infarctions, progressive dementia, transient neurological symptoms, and CAA-related inflammation can also occur. The pathomechanisms of CAA remain unknown. Although improvements in imaging techniques have allowed us to identify patients with CAA more readily, pathological examination is still essential for a definite diagnosis. There have been no curative treatments for CAA so far.

  3. Cerebral Amyloid Angiopathy: Emerging Concepts

    PubMed Central

    2015-01-01

    Cerebral amyloid angiopathy (CAA) involves cerebrovascular amyloid deposition and is classified into several types according to the amyloid protein involved. Of these, sporadic amyloid β-protein (Aβ)-type CAA is most commonly found in older individuals and in patients with Alzheimer's disease (AD). Cerebrovascular Aβ deposits accompany functional and pathological changes in cerebral blood vessels (CAA-associated vasculopathies). CAA-associated vasculopathies lead to development of hemorrhagic lesions [lobar intracerebral macrohemorrhage, cortical microhemorrhage, and cortical superficial siderosis (cSS)/focal convexity subarachnoid hemorrhage (SAH)], ischemic lesions (cortical infarction and ischemic changes of the white matter), and encephalopathies that include subacute leukoencephalopathy caused by CAA-associated inflammation/angiitis. Thus, CAA is related to dementia, stroke, and encephalopathies. Recent advances in diagnostic procedures, particularly neuroimaging, have enabled us to establish a clinical diagnosis of CAA without brain biopsies. Sensitive magnetic resonance imaging (MRI) methods, such as gradient-echo T2* imaging and susceptibility-weighted imaging, are useful for detecting cortical microhemorrhages and cSS. Amyloid imaging with amyloid-binding positron emission tomography (PET) ligands, such as Pittsburgh Compound B, can detect CAA, although they cannot discriminate vascular from parenchymal amyloid deposits. In addition, cerebrospinal fluid markers may be useful, including levels of Aβ40 for CAA and anti-Aβ antibody for CAA-related inflammation. Moreover, cSS is closely associated with transient focal neurological episodes (TFNE). CAA-related inflammation/angiitis shares pathophysiology with amyloid-related imaging abnormalities (ARIA) induced by Aβ immunotherapies in AD patients. This article reviews CAA and CAA-related disorders with respect to their epidemiology, pathology, pathophysiology, clinical features, biomarkers, diagnosis

  4. Cerebral amyloid angiopathy

    MedlinePlus

    ... 911) if you have sudden loss of movement , sensation, vision, or speech. Alternative Names Amyloidosis - cerebral; CAA; Congophilic angiopathy Images Amyloidosis on the fingers Arteries of the brain References Kase CS, Shoamanesh A. Intracerebral hemorrhage. In: Daroff ...

  5. Genetics Home Reference: hereditary cerebral amyloid angiopathy

    MedlinePlus

    ... Testing Registry: Dementia, familial Danish Genetic Testing Registry: Hereditary cerebral amyloid angiopathy, Icelandic type Other Diagnosis and Management Resources (2 links) Johns Hopkins Medicine: ...

  6. [A subacute dementia: Inflammatory cerebral amyloid angiopathy].

    PubMed

    Charef, S; Leblanc, A; Guibourg, B; Quintin-Roue, I; Ben Salem, D; Zagnoli, F

    2015-12-01

    We report a case of inflammatory cerebral amyloid angiopathy (CAA) that led to rapid cognitive decline, seizures, visual hallucinations, hyperproteinorrachia and right hemispheric leukopathy. Brain biopsy gave the diagnosis of CAA. Although no inflammatory infiltrate was found in the biopsy sample, corticosteroids led to a regression of the radiological lesions without significant clinical improvement. CAA is a rare disease, defined by lesions of classical cerebral amyloid angiopathy and perivascular infiltrates in contact with the affected vessels. In cases of rapidly progressive dementia associated with leukopathy, inflammatory amyloid angiopathy should be considered as cognitive disorders may improve after immunosuppressive therapy. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  7. Cerebral amyloidosis: amyloid subunits, mutants and phenotypes

    PubMed Central

    Rostagno, A.; Holton, J. L.; Lashley, T.; Revesz, T.

    2010-01-01

    Cerebral amyloid diseases are part of a complex group of chronic and progressive entities bracketed together under the common denomination of protein folding disorders and characterized by the intra- and extracellular accumulation of fibrillar aggregates. Of the more than 25 unrelated proteins known to produce amyloidosis in humans only about a third of them are associated with cerebral deposits translating in cognitive deficits, dementia, stroke, cerebellar and extrapyramidal signs, or a combination thereof. The familial forms reviewed herein, although infrequent, provide unique paradigms to examine the role of amyloid in the mechanism of disease pathogenesis and to dissect the link between vascular and parenchymal amyloid deposition and their differential contribution to neurodegeneration. PMID:19898742

  8. Cerebral perfusion alterations and cerebral amyloid in autosomal dominant Alzheimer disease.

    PubMed

    McDade, Eric; Kim, Albert; James, Jeffrey; Sheu, Lei K; Kuan, Dora Chieh-Hsin; Minhas, Davneet; Gianaros, Peter J; Ikonomovic, Snezana; Lopez, Oscar; Snitz, Beth; Price, Julie; Becker, Jim; Mathis, Chet; Klunk, William

    2014-08-19

    To evaluate alterations in cerebral blood flow (CBF) using arterial spin-labeled MRI in autosomal dominant Alzheimer disease (ADAD) mutation carriers (MCs) in relation to cerebral amyloid and compared with age-matched healthy controls. Recent work has identified alterations in CBF in elderly subjects with mild cognitive impairment and Alzheimer dementia using MRI. However, similar studies are lacking in ADAD. Subjects with ADAD are generally free of significant vascular disease and offer the opportunity to measure CBF early in the pathologic process before significant symptom onset when unique markers might be identified. Fourteen MCs (presenilin-1 and amyloid beta precursor protein) (Clinical Dementia Rating [CDR] 0 = 9, CDR 0.5 = 4, CDR 1 = 1) and 50 controls underwent 3-tesla pulsed arterial spin-labeled MRI. SPM8 was used to test the effect of MC status at the voxel level on CBF before and after controlling for age and CDR. MCs had decreased perfusion in the caudate and inferior striatum bilaterally even after controlling for age and CDR. In MCs, separate areas of decreased CBF were associated with increasing cerebral amyloid and to decreased performance of attention and executive function. Early CBF changes were identified in asymptomatic and mildly symptomatic subjects with ADAD, particularly in the anterior striatum. Furthermore, amyloid deposition was associated with decreased CBF in a number of regions including anterior and posterior cortical areas. Both amyloid and decreased CBF were associated with declines primarily in executive cognitive function. © 2014 American Academy of Neurology.

  9. Cerebral perfusion alterations and cerebral amyloid in autosomal dominant Alzheimer disease

    PubMed Central

    Kim, Albert; James, Jeffrey; Sheu, Lei K.; Kuan, Dora Chieh-Hsin; Minhas, Davneet; Gianaros, Peter J.; Ikonomovic, Snezana; Lopez, Oscar; Snitz, Beth; Price, Julie; Becker, Jim; Mathis, Chet; Klunk, William

    2014-01-01

    Objective: To evaluate alterations in cerebral blood flow (CBF) using arterial spin-labeled MRI in autosomal dominant Alzheimer disease (ADAD) mutation carriers (MCs) in relation to cerebral amyloid and compared with age-matched healthy controls. Background: Recent work has identified alterations in CBF in elderly subjects with mild cognitive impairment and Alzheimer dementia using MRI. However, similar studies are lacking in ADAD. Subjects with ADAD are generally free of significant vascular disease and offer the opportunity to measure CBF early in the pathologic process before significant symptom onset when unique markers might be identified. Methods: Fourteen MCs (presenilin-1 and amyloid beta precursor protein) (Clinical Dementia Rating [CDR] 0 = 9, CDR 0.5 = 4, CDR 1 = 1) and 50 controls underwent 3-tesla pulsed arterial spin-labeled MRI. SPM8 was used to test the effect of MC status at the voxel level on CBF before and after controlling for age and CDR. Results: MCs had decreased perfusion in the caudate and inferior striatum bilaterally even after controlling for age and CDR. In MCs, separate areas of decreased CBF were associated with increasing cerebral amyloid and to decreased performance of attention and executive function. Conclusions: Early CBF changes were identified in asymptomatic and mildly symptomatic subjects with ADAD, particularly in the anterior striatum. Furthermore, amyloid deposition was associated with decreased CBF in a number of regions including anterior and posterior cortical areas. Both amyloid and decreased CBF were associated with declines primarily in executive cognitive function. PMID:25031286

  10. Imaging of amyloid burden and distribution in cerebral amyloid angiopathy.

    PubMed

    Johnson, Keith A; Gregas, Matt; Becker, John A; Kinnecom, Catherine; Salat, David H; Moran, Erin K; Smith, Erin E; Rosand, Jonathan; Rentz, Dorene M; Klunk, William E; Mathis, Chester A; Price, Julie C; Dekosky, Steven T; Fischman, Alan J; Greenberg, Steven M

    2007-09-01

    Cerebrovascular deposition of beta-amyloid (cerebral amyloid angiopathy [CAA]) is a major cause of hemorrhagic stroke and a likely contributor to vascular cognitive impairment. We evaluated positron emission tomographic imaging with the beta-amyloid-binding compound Pittsburgh Compound B (PiB) as a potential noninvasive method for detection of CAA. We hypothesized that amyloid deposition would be observed with PiB in CAA, and based on the occipital predilection of CAA pathology and associated hemorrhages, that specific PiB retention would be disproportionately greater in occipital lobes. We compared specific cortical PiB retention in 6 nondemented subjects diagnosed with probable CAA with 15 healthy control subjects and 9 patients with probable Alzheimer's disease (AD). All CAA and AD subjects were PiB-positive, both by distribution volume ratio measurements and by visual inspection of positron emission tomographic images. Global cortical PiB retention was significantly increased in CAA (distribution volume ratio 1.18 +/- 0.06) relative to healthy control subjects (1.04 +/- 0.10; p = 0.0009), but was lower in CAA than in AD subjects (1.41 +/- 0.17; p = 0.002). The occipital-to-global PiB ratio, however, was significantly greater in CAA than in AD subjects (0.99 +/- 0.07 vs 0.86 +/- 0.05; p = 0.003). We conclude that PiB-positron emission tomography can detect cerebrovascular beta-amyloid and may serve as a method for identifying the extent of CAA in living subjects.

  11. Cerebral Amyloid Angiopathy: A Systematic Review

    PubMed Central

    Greenberg, Steven M.

    2011-01-01

    Cerebral amyloid angiopathy (CAA) is a disorder characterized by amyloid deposition in the walls of leptomeningeal and cortical arteries, arterioles, and less often capillaries and veins of the central nervous system. CAA occurs mostly as a sporadic condition in the elderly, its incidence associating with advancing age. All sporadic CAA cases are due to deposition of amyloid-β, originating from proteolytic cleavage of the Amyloid Precursor Protein. Hereditary forms of CAA are generally familial (and therefore rare in the general population), more severe and earlier in onset. CAA-related lobar intracerebral hemorrhage is the most well-studied clinical condition associated with brain amyloid deposition. Despite ever increasing understanding of CAA pathogenesis and availability of reliable clinical and diagnostic tools, preventive and therapeutic options remain very limited. Further research efforts are required in order to identify biological targets for novel CAA treatment strategies. We present a systematic review of existing evidence regarding the epidemiology, genetics, pathogenesis, diagnosis and clinical management of CAA. PMID:21519520

  12. Taxifolin inhibits amyloid-β oligomer formation and fully restores vascular integrity and memory in cerebral amyloid angiopathy.

    PubMed

    Saito, Satoshi; Yamamoto, Yumi; Maki, Takakuni; Hattori, Yorito; Ito, Hideki; Mizuno, Katsuhiko; Harada-Shiba, Mariko; Kalaria, Raj N; Fukushima, Masanori; Takahashi, Ryosuke; Ihara, Masafumi

    2017-04-04

    Cerebral amyloid angiopathy (CAA) induces various forms of cerebral infarcts and hemorrhages from vascular amyloid-β accumulation, resulting in acceleration of cognitive impairment, which is currently untreatable. Soluble amyloid-β protein likely impairs cerebrovascular integrity as well as cognitive function in early stage Alzheimer's disease. Taxifolin, a flavonol with strong anti-oxidative and anti-glycation activities, has been reported to disassemble amyloid-β in vitro but the in vivo relevance remains unknown. Here, we investigated whether taxifolin has therapeutic potential in attenuating CAA, hypothesizing that inhibiting amyloid-β assembly may facilitate its clearance through several elimination pathways. Vehicle- or taxifolin-treated Tg-SwDI mice (commonly used to model CAA) were used in this investigation. Cognitive and cerebrovascular function, as well as the solubility and oligomerization of brain amyloid-β proteins, were investigated. Spatial reference memory was assessed by water maze test. Cerebral blood flow was measured with laser speckle flowmetry and cerebrovascular reactivity evaluated by monitoring cerebral blood flow changes in response to hypercapnia. Significantly reduced cerebrovascular pan-amyloid-β and amyloid-β1-40 accumulation was found in taxifolin-treated Tg-SwDI mice compared to vehicle-treated counterparts (n = 5). Spatial reference memory was severely impaired in vehicle-treated Tg-SwDI mice but normalized after taxifolin treatment, with scoring similar to wild type mice (n = 10-17). Furthermore, taxifolin completely restored decreased cerebral blood flow and cerebrovascular reactivity in Tg-SwDI mice (n = 4-6). An in vitro thioflavin-T assay showed taxifolin treatment resulted in efficient inhibition of amyloid-β1-40 assembly. In addition, a filter trap assay and ELISA showed Tg-SwDI mouse brain homogenates exhibited significantly reduced levels of amyloid-β oligomers in vivo after taxifolin treatment (n

  13. Ischemic brain injury in cerebral amyloid angiopathy

    PubMed Central

    van Veluw, Susanne J; Greenberg, Steven M

    2016-01-01

    Cerebral amyloid angiopathy (CAA) is a common form of cerebral small vessel disease and an important risk factor for intracerebral hemorrhage and cognitive impairment. While the majority of research has focused on the hemorrhagic manifestation of CAA, its ischemic manifestations appear to have substantial clinical relevance as well. Findings from imaging and pathologic studies indicate that ischemic lesions are common in CAA, including white-matter hyperintensities, microinfarcts, and microstructural tissue abnormalities as detected with diffusion tensor imaging. Furthermore, imaging markers of ischemic disease show a robust association with cognition, independent of age, hemorrhagic lesions, and traditional vascular risk factors. Widespread ischemic tissue injury may affect cognition by disrupting white-matter connectivity, thereby hampering communication between brain regions. Challenges are to identify imaging markers that are able to capture widespread microvascular lesion burden in vivo and to further unravel the etiology of ischemic tissue injury by linking structural magnetic resonance imaging (MRI) abnormalities to their underlying pathophysiology and histopathology. A better understanding of the underlying mechanisms of ischemic brain injury in CAA will be a key step toward new interventions to improve long-term cognitive outcomes for patients with CAA. PMID:25944592

  14. Longitudinal cerebral blood flow and amyloid deposition: an emerging pattern?

    PubMed Central

    Sojkova, Jitka; Beason-Held, Lori; Zhou, Yun; An, Yang; Kraut, Michael A; Ye, Weigo; Ferrucci, Luigi; Mathis, Chester A; Klunk, William E; Wong, Dean F; Resnick, Susan M

    2008-01-01

    Although cerebral amyloid deposition may precede cognitive impairment by decades, the relationship between amyloid deposition and longitudinal change in neuronal function has not been studied. The aim of this paper is to determine whether nondemented individuals with high and low amyloid burden show different patterns of longitudinal regional cerebral blood flow (rCBF) changes in the years preceding measurement of amyloid deposition. Methods Twenty-eight nondemented participants (mean (SD) age at [11C] PIB 82.5(4.8) yrs; 6 mildly impaired) from the Baltimore Longitudinal Study of Aging underwent yearly resting-state [15O]H2O PET scans for up to 8 years. [11C]PIB images of amyloid deposition were acquired on average 10.8(0.8) years after the first CBF scan. [11C]PIB distribution volume ratios (DVR) of regions of interest were estimated by fitting a reference tissue model to the measured time activity curves. Based on mean cortical DVR, participants were divided into high and low [11C]PIB retention groups. Differences in longitudinal rCBF changes between high and low [11C]PIB groups were investigated by voxel-based analysis. Results Longitudinal rCBF changes differed significantly between high (n=10) and low (n=18) [11C]PIB groups (p<=0.001). Greater longitudinal decreases in rCBF in the high [11C]PIB group were seen in right anterior/mid cingulate, right supramarginal gyrus, left thalamus and midbrain bilaterally relative to the low group. Greater increases in rCBF over time in the high [11C]PIB group were found in left medial and inferior frontal gyri, right precuneus, left inferior parietal lobule, and the left postcentral gyrus. Conclusion In this group of nondemented older adults, those with high [11C]PIB show greater longitudinal declines in rCBF in certain areas, representing regions with greater decrements in neuronal function. Greater longitudinal increases in rCBF are also observed in those with higher amyloid load and may represent an attempt to preserve

  15. APOE and Cerebral Amyloid Angiopathy in Community Dwelling Older Persons

    PubMed Central

    Yu, Lei; Boyle, Patricia A.; Nag, Sukriti; Leurgans, Sue; Buchman, Aron S.; Wilson, Robert S.; Arvanitakis, Zoe; Farfel, Jose M.; De Jager, Philip L.; Bennett, David A.; Schneider, Julie A.

    2015-01-01

    Both cerebral amyloid angiopathy and Alzheimer’s disease pathology involve abnormal β-amyloid processing. We aim to elucidate the relationship of the apolipoprotein E (APOE) genotypes with amyloid angiopathy in the presence of variable amounts of Alzheimer’s pathology. Data came from 1,062 autopsied subjects from two community-based studies of aging. Common neuropathologies including Alzheimer’s disease and amyloid angiopathy were assessed using uniform methods. APOE was genotyped by sequencing the two polymorphisms in codons 112 and 158 of exon 4. We examined the associations of APOE with amyloid angiopathy using ordinal logistic regression analyses, controlling for demographics and subsequently Alzheimer’s and other common pathologies. Moderate to severe amyloid angiopathy was identified in 35.2% (n=374) of the subjects. 15.3% (n=162) of the subjects were APOE ε2 carriers and 26.1% (n=277) ε4 carriers. Adjusting for demographics, the presence of ε4 allele, but not ε2, was associated with more severe amyloid angiopathy. After further adjustment for Alzheimer’s pathology, both ε2 (odds ratio 1.707, 95% confidence interval 1.236–2.358, p=0.001) and ε4 (odds ratio 2.284, 95% confidence interval 1.730–3.014, p<0.001) were independently associated with amyloid angiopathy. The results were confirmed by path analysis. Further, APOE ε4 carriers, but not ε2 carriers, were more likely to have capillary amyloid angiopathy. Accounting for capillary involvement did not alter the APOE associations with amyloid angiopathy. We conclude that both APOE ε2 and ε4 alleles are associated with more severe cerebral amyloid angiopathy, and the direct effect of ε2 is masked by the allele’s negative association with comorbid Alzheimer’s pathology. APOE ε4, but not ε2, is associated with capillary amyloid angiopathy. PMID:26341746

  16. Cerebrospinal Fluid Anti-Amyloid-β Autoantibodies and Amyloid PET in Cerebral Amyloid Angiopathy-Related Inflammation.

    PubMed

    Carmona-Iragui, María; Fernández-Arcos, Ana; Alcolea, Daniel; Piazza, Fabrizio; Morenas-Rodriguez, Estrella; Antón-Aguirre, Sofía; Sala, Isabel; Clarimon, Jordi; Dols-Icardo, Oriol; Camacho, Valle; Sampedro, Frederic; Munuera, Josep; Nuñez-Marin, Fidel; Lleó, Alberto; Fortea, Juan; Gómez-Ansón, Beatriz; Blesa, Rafael

    2016-01-01

    We report a biomarker and genetic evaluation of four patients with cerebral amyloid angiopathy-related inflammation (CAA-ri) treated with corticosteroids. Patients presented with focal symptomatology and cognitive impairment. MRI revealed cortical microbleeds and asymmetrical hyperintense white matter lesions (WML). Cerebrospinal fluid (CSF) biomarker analyses showed increased anti-Aβ autoantibodies, t-Tau, and p-Tau and decreased Aβ40 and Aβ42. After treatment, focal symptomatology disappeared, and WML and anti-Aβ autoantibodies decreased. The APOEɛ4 allele was overrepresented. Florbetapir-PET showed cortical deposition with lower retention in swollen areas. In the case of suspected CAA-ri, both CSF anti-Aβ autoantibodies levels and Florbetapir-PET could provide highly useful data to guide the correct diagnosis.

  17. Spontaneous upper limb monoplegia secondary to probable cerebral amyloid angiopathy.

    PubMed

    Sadek, Ahmed-Ramadan; Parmar, Nandita K; Sadek, Norah-Hager; Jaiganesh, Sanjana; Elkhodair, Samer; Jaiganesh, Thiagarajan

    2012-01-03

    Cerebral amyloid angiopathy is a clinicopathological disorder characterised by vascular amyloid deposition initially in leptomeningeal and neocortical vessels, and later affecting cortical and subcortical regions. The presence of amyloid within the walls of these vessels leads to a propensity for primary intracerebral haemorrhage. We report the unusual case of a 77-year-old female who presented to our emergency department with sudden onset isolated hypoaesthesia and right upper limb monoplegia. A CT scan demonstrated a peripheral acute haematoma involving the left perirolandic cortices. Subsequent magnetic resonance imaging demonstrated previous superficial haemorrhagic events. One week following discharge the patient re-attended with multiple short-lived episodes of aphasia and jerking of the right upper limb. Further imaging demonstrated oedematous changes around the previous haemorrhagic insult. Cerebral amyloid angiopathy is an overlooked cause of intracerebral haemorrhage; the isolated nature of the neurological deficit in this case illustrates the many guises in which it can present.

  18. Spontaneous upper limb monoplegia secondary to probable cerebral amyloid angiopathy

    PubMed Central

    2012-01-01

    Cerebral amyloid angiopathy is a clinicopathological disorder characterised by vascular amyloid deposition initially in leptomeningeal and neocortical vessels, and later affecting cortical and subcortical regions. The presence of amyloid within the walls of these vessels leads to a propensity for primary intracerebral haemorrhage. We report the unusual case of a 77-year-old female who presented to our emergency department with sudden onset isolated hypoaesthesia and right upper limb monoplegia. A CT scan demonstrated a peripheral acute haematoma involving the left perirolandic cortices. Subsequent magnetic resonance imaging demonstrated previous superficial haemorrhagic events. One week following discharge the patient re-attended with multiple short-lived episodes of aphasia and jerking of the right upper limb. Further imaging demonstrated oedematous changes around the previous haemorrhagic insult. Cerebral amyloid angiopathy is an overlooked cause of intracerebral haemorrhage; the isolated nature of the neurological deficit in this case illustrates the many guises in which it can present. PMID:22214197

  19. Magnetic Fluids Have Ability to Decrease Amyloid Aggregation Associated with Amyloid-Related Diseases

    NASA Astrophysics Data System (ADS)

    Antosova, Andrea; Koneracka, Martina; Siposova, Katarina; Zavisova, Vlasta; Daxnerova, Zuzana; Vavra, Ivo; Fabian, Martin; Kopcansky, Peter; Gazova, Zuzana

    2010-12-01

    At least twenty human proteins can fold abnormally to form pathological deposits that are associated with several amyloid-related diseases. We have investigated the effect of four magnetic fluids (MFs)—electrostatically stabilized Fe3O4 magnetic nanoparticles (MF1) and sterically stabilized Fe3O4 magnetic nanoparticles by sodium oleate (MF2, MF3 and MF4) with adsorbed BSA (MF2) or dextran (MF4)—on amyloid aggregation of two proteins, human insulin and chicken egg lysozyme. The morphology, particle size and size distribution of the prepared magnetic fluids were characterized. We have found that MFs are able to decrease amyloid aggregation of both studied proteins and the extent of depolymerization depended on the MF properties. The most effective reduction was observed for MF4 as 90% decrease of amyloids was detected for insulin and lysozyme amyloid aggregates. Our findings indicate that MFs have potential to be used for treatment of amyloid diseases.

  20. Recurrence of Lobar Hemorrhage: A Red Flag for Cerebral Amyloid Angiopathy-related Inflammation?

    PubMed Central

    Rastogi, Vaibhav; Donnangelo, Lauren L.; Asaithambi, Ganesh; Bidari, Sharatchandra; Khanna, Anna Y.

    2015-01-01

    Background. Recurrent lobar intracerebral hemorrhage is more commonly associated with cerebral amyloid angiopathy and less likely associated with hypertension. Cerebral amyloid angiopathy-related inflammation is a subgroup of cerebral amyloid angiopathy that can present with lobar intracerebral hemorrhage, encephalopathy, and seizures; wherein corticosteroids may facilitate favorable outcome. Whether recurrence of lobar intracerebral hemorrhage in cerebral amyloid angiopathy is related to cerebral amyloid angiopathy-related inflammation is unknown. Case presentation. A 68-year-old woman presented with an acute onset of confusion. She was known to have a history of recurrent lobar intracerebral hemorrhage related to cerebral amyloid angiopathy. Brain imaging revealed previous sequelae of cerebral amyloid angiopathy and a new lobar intracerebral hemorrhage. An empirical diagnosis of cerebral amyloid angiopathy-related inflammation was made given the patent’s clinical course of recurrence. Utilizing current evidence of criteria used to diagnose cerebral amyloid angiopathy-related inflammation, corticosteroid therapy was initiated with significant improvement in clinical and imaging characteristics. Discussion. Inflammatory pathways incited as a result of cerebrovascular amyloid deposition play a vital role in pathogenesis of cerebral amyloid angiopathy-related inflammation. We highlight the need to consider corticosteroid therapy in patients presenting with recurrent lobar intracerebral hemorrhage in the setting of cerebral amyloid angiopathy since inflammation may play a role in its pathophysiology. Evidence in the literature is sparse to suggest that cerebral amyloid angiopathy-related inflammation might be the root cause for the lobar intracerebral hemorrhage recurrence in cerebral amyloid angiopathy. Further studies are needed to identify mechanisms of recurrent hemorrhage, its correlations with cerebral amyloid angiopathy-related inflammation, and the potential

  1. Cerebral amyloid angiopathy increases susceptibility to infarction after focal cerebral ischemia in Tg2576 mice.

    PubMed

    Milner, Eric; Zhou, Meng-Liang; Johnson, Andrew W; Vellimana, Ananth K; Greenberg, Jacob K; Holtzman, David M; Han, Byung Hee; Zipfel, Gregory J

    2014-10-01

    We and others have shown that soluble amyloid β-peptide (Aβ) and cerebral amyloid angiopathy (CAA) cause significant cerebrovascular dysfunction in mutant amyloid precursor protein (APP) mice, and that these deficits are greater in aged APP mice having CAA compared with young APP mice lacking CAA. Amyloid β-peptide in young APP mice also increases infarction after focal cerebral ischemia, but the impact of CAA on ischemic brain injury is unknown. To determine this, we assessed cerebrovascular reactivity, cerebral blood flow (CBF), and extent of infarction and neurological deficits after transient middle cerebral artery occlusion in aged APP mice having extensive CAA versus young APP mice lacking CAA (and aged-matched littermate controls). We found that aged APP mice have more severe cerebrovascular dysfunction that is CAA dependent, have greater CBF compromise during and immediately after middle cerebral artery occlusion, and develop larger infarctions after middle cerebral artery occlusion. These data indicate CAA induces a more severe form of cerebrovascular dysfunction than amyloid β-peptide alone, leading to intra- and postischemic CBF deficits that ultimately exacerbate cerebral infarction. Our results shed mechanistic light on human studies identifying CAA as an independent risk factor for ischemic brain injury. © 2014 American Heart Association, Inc.

  2. Angiotensin type 1a receptor deficiency decreases amyloid β-protein generation and ameliorates brain amyloid pathology

    PubMed Central

    Liu, Junjun; Liu, Shuyu; Matsumoto, Yukino; Murakami, Saki; Sugakawa, Yusuke; Kami, Ayako; Tanabe, Chiaki; Maeda, Tomoji; Michikawa, Makoto; Komano, Hiroto; Zou, Kun

    2015-01-01

    Alzheimer’s disease is characterized by neuronal loss and cerebral accumulation of amyloid-β protein (Aβ) and lowering the generation of Aβ is a pivotal approach in the strategy of Alzheimer’s disease treatment. Midlife hypertension is a major risk factor for the future onset of sporadic Alzheimer’s disease and the use of some antihypertensive drugs may decrease the incidence of Alzheimer’s disease. However, it is largely unknown how the blood pressure regulation system is associated with the pathogenesis of Alzheimer’s disease. Here we found that the deficiency of angiotensin type 1a receptor (AT1a), a key receptor for regulating blood pressure, significantly decreased Aβ generation and amyloid plaque formation in a mouse model of Alzheimer’s disease. The lack of AT1a inhibited the endocleavage of presenilin-1 (PS1), which is essential for γ-secretase complex formation and Aβ generation. Notably, the ligand of AT1a, angiotensin II, enhanced Aβ generation, PS1 endocleavage and γ-secretase complex formation. Our results suggest that AT1a activation is closely associated with Aβ generation and brain amyloid accumulation by regulating γ-secretase complex formation. Thus, removal of life style factors or stresses that stimulate AT1a to elevate blood pressure may decrease Aβ generation and brain amyloid accumulation, thereby preventing the pathogenesis of Alzheimer’s disease. PMID:26154270

  3. β-amyloid deposits in veins in patients with cerebral amyloid angiopathy and intracerebral haemorrhage.

    PubMed

    Mendel, Tadeusz; Wierzba-Bobrowicz, Teresa; Stępień, Tomasz; Szpak, Grazyna Maria

    2013-01-01

    To review the incidence and grade of cerebral amyloid angiopathy (CAA) in veins in patients who died due to spontaneous intracerebral haemorrhage (ICH). Neuropathological examinations were performed in the study group of 189 patients. Cerebral amyloid angiopathy was diagnosed according to the Boston criteria and confirmed during an autopsy. The Vonsattel and Mountjoy scales were used to assess the grade and scores of CAA. In the study group composed of 189 ICH patients, 42 presented CAA. In the microscopic examination, of the 42 patients 33 (78%) showed β-amyloid deposits in veins, which makes 17% of the total group of patients with ICH. In this group, the age ranged from 54 to 97 (mean age 80.18 ± 8.15 years). A group of 33 (27 women and 6 men) patients comprised 15 (45%) patients with severe CAA, 13 (40%) with moderate and 5 (15%) with mild CAA classified according to the Vonsattel scale. According to the Mountjoy scale 28 (85%) patients had a score of 4, which indicated the total involvement of the vessel. β-amyloid deposits in veins were found in 78% of patients with CAA and ICH, which makes 17% of the total group of patients with ICH. Interestingly, β-amyloid deposits in veins are not so rare in patients with CAA who died due to intracerebral haemorrhage. Cerebral amyloid angiopathy localization in the veins of the brain was observed more frequently than previously suspected. Veins may play a role in the elimination of β-amyloid from the brain.

  4. The Cerebrovascular Basement Membrane: Role in the Clearance of β-amyloid and Cerebral Amyloid Angiopathy

    PubMed Central

    Morris, Alan W. J.; Carare, Roxana O.; Schreiber, Stefanie; Hawkes, Cheryl A.

    2014-01-01

    Cerebral amyloid angiopathy (CAA), the accumulation of β-amyloid (Aβ) peptides in the walls of cerebral blood vessels, is observed in the majority of Alzheimer’s disease (AD) brains and is thought to be due to a failure of the aging brain to clear Aβ. Perivascular drainage of Aβ along cerebrovascular basement membranes (CVBMs) is one of the mechanisms by which Aβ is removed from the brain. CVBMs are specialized sheets of extracellular matrix that provide structural and functional support for cerebral blood vessels. Changes in CVBM composition and structure are observed in the aged and AD brain and may contribute to the development and progression of CAA. This review summarizes the properties of the CVBM, its role in mediating clearance of interstitial fluids and solutes from the brain, and evidence supporting a role for CVBM in the etiology of CAA. PMID:25285078

  5. Prevalence of Cerebral Amyloid Pathology in Persons Without Dementia

    PubMed Central

    Jansen, Willemijn J.; Ossenkoppele, Rik; Knol, Dirk L.; Tijms, Betty M.; Scheltens, Philip; Verhey, Frans R. J.; Visser, Pieter Jelle

    2015-01-01

    IMPORTANCE Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies. OBJECTIVE To use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI). DATA SOURCES Relevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE and Web of Science databases and through personal communication with investigators. STUDY SELECTION Studies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity. DATA EXTRACTION AND SYNTHESIS Individual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies. MAIN OUTCOMES AND MEASURES Prevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations. RESULTS The prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95% CI, 8%-13%) to 44% (95% CI, 37%-51%) among participants with normal cognition; from 12% (95% CI, 8%-18%) to 43% (95% CI, 32%-55%) among patients with SCI; and from 27% (95% CI, 23%-32%) to 71% (95% CI, 66%-76%) among patients with MCI. APOE-ε4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOEε4ε4 carriers, 50 years for ε2ε4 carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 carriers, and

  6. Amyloid-Related Imaging Abnormalities in an Aged Squirrel Monkey with Cerebral Amyloid Angiopathy.

    PubMed

    Heuer, Eric; Jacobs, Jessica; Du, Rebecca; Wang, Silun; Keifer, Orion P; Cintron, Amarallys F; Dooyema, Jeromy; Meng, Yuguang; Zhang, Xiaodong; Walker, Lary C

    2017-01-01

    Amyloid-related imaging abnormalities (ARIA) in magnetic resonance imaging scans have emerged as indicators of potentially serious side effects in clinical trials of therapeutics for Alzheimer's disease. These anomalies include an edematous type (ARIA-E) that appears as hyperintense (bright) regions by T2-weighted MRI, and a type characterized by the deposition of hemosiderin (ARIA-H) that elicits a hypointense signal, especially in T2* susceptibility weighted images. ARIA in general has been linked to the presence of amyloid-β (Aβ)-type cerebral amyloid angiopathy, an accumulation of misfolded Aβ protein in the vascular wall that impairs the integrity of brain blood vessels. However, the pathobiology of ARIA remains poorly understood, in part due to the absence of an animal model of the disorder that would enable a contemporaneous analysis of tissue integrity in the affected region. Here we describe both ARIA-E and ARIA-H in an aged squirrel monkey (Saimiri sciureus), a nonhuman primate model of naturally occurring cerebral amyloid angiopathy. Histopathologic examination of the anomalous region revealed reactive astrocytosis and microgliosis, infiltration of systemic inflammatory/immune cells, damage to axons and myelin, and hemosiderin deposition. The disruption of axons in particular suggests that ARIA-E could have functional consequences for affected regions. The squirrel monkey model can be useful for studying the pathogenesis and long-term effects of ARIA, and for testing the safety and efficacy of emerging therapies for Alzheimer's disease.

  7. Mutation of the Alzheimer's Disease Amyloid Gene in Hereditary Cerebral Hemorrhage, Dutch Type

    NASA Astrophysics Data System (ADS)

    Levy, Efrat; Carman, Mark D.; Fernandez-Madrid, Ivan J.; Power, Michael D.; Lieberburg, Ivan; van Duinen, Sjoerd G.; Bots, Gerard Th. A. M.; Luyendijk, Willem; Frangione, Blas

    1990-06-01

    An amyloid protein that precipitates in the cerebral vessel walls of Dutch patients with hereditary cerebral hemorrhage with amyloidosis is similar to the amyloid protein in vessel walls and senile plaques in brains of patients with Alzheimer's disease, Down syndrome, and sporadic cerebral amyloid angiopathy. Cloning and sequencing of the two exons that encode the amyloid protein from two patients with this amyloidosis revealed a cytosine-to-guanine transversion, a mutation that caused a single amino acid substitution (glutamine instead of glutamic acid) at position 22 of the amyloid protein. The mutation may account for the deposition of this amyloid protein in the cerebral vessel walls of these patients, leading to cerebral hemorrhages and premature death.

  8. Recurrent craniospinal subarachnoid hemorrhage in cerebral amyloid angiopathy

    PubMed Central

    Alexander, Mathew; Patil, Anil Kumar B.; Mathew, Vivek; Sivadasan, Ajith; Chacko, Geeta; Mani, Sunithi E.

    2013-01-01

    Cerebral amyloid angiopathy (CAA) usually manifests as cerebral hemorrhage, especially as nontraumatic hemorrhages in normotensive elderly patients. Other manifestations are subarachnoid (SAH), subdural, intraventricular hemorrhage (IVH) and superficial hemosiderosis. A 52-year-old hypertensive woman presented with recurrent neurological deficits over a period of 2 years. Her serial brain magnetic resonance imaging and computed tomography scans showed recurrent SAH hemorrhage, and also intracerebral, IVH and spinal hemorrhage, with superficial siderosis. Cerebral angiograms were normal. Right frontal lobe biopsy showed features of CAA. CAA can present with unexplained recurrent SAH hemorrhage, and may be the initial and prominent finding in the course of disease in addition to superficial cortical siderosis and intracerebal and spinal hemorrhages. PMID:23661974

  9. Recurrent craniospinal subarachnoid hemorrhage in cerebral amyloid angiopathy.

    PubMed

    Alexander, Mathew; Patil, Anil Kumar B; Mathew, Vivek; Sivadasan, Ajith; Chacko, Geeta; Mani, Sunithi E

    2013-01-01

    Cerebral amyloid angiopathy (CAA) usually manifests as cerebral hemorrhage, especially as nontraumatic hemorrhages in normotensive elderly patients. Other manifestations are subarachnoid (SAH), subdural, intraventricular hemorrhage (IVH) and superficial hemosiderosis. A 52-year-old hypertensive woman presented with recurrent neurological deficits over a period of 2 years. Her serial brain magnetic resonance imaging and computed tomography scans showed recurrent SAH hemorrhage, and also intracerebral, IVH and spinal hemorrhage, with superficial siderosis. Cerebral angiograms were normal. Right frontal lobe biopsy showed features of CAA. CAA can present with unexplained recurrent SAH hemorrhage, and may be the initial and prominent finding in the course of disease in addition to superficial cortical siderosis and intracerebal and spinal hemorrhages.

  10. Cerebral amyloid angiopathy in the elderly: vessel walls changes and relationship with dementia.

    PubMed

    Zekry, Dina; Duyckaerts, Charles; Belmin, Joël; Geoffre, Caroline; Moulias, Robert; Hauw, Jean-Jacques

    2003-10-01

    Abeta peptide deposits are observed in brain cortical and leptomeningeal microvessels in a few families, in patients with Alzheimer's disease and in cognitively normal elderly subjects. These deposits, which cause Abeta amyloid angiopathy, are usually associated with other lesions induced by Abeta peptide and tau pathologies. To investigate the consequences of cerebral amyloid angiopathy on arterial morphology and search for correlations with the degree of cognitive impairment, we carried out a prospective clinicopathological and morphometric study in 29 institutionalized elderly patients cognitively normal or affected with sporadic dementia associated with Alzheimer-type lesions, cerebral infarcts or both. We measured the external and internal diameters of arteries 40-120 microm wide, containing moderate or severe Abeta deposits, and of unaffected arteries in the temporal and frontal lobes. We found no differences in the mean external diameters. In contrast, the mean internal diameters of vessels with moderate Abeta deposits were smaller than those of unaffected vessels. Conversely, the internal diameters of severely affected vessels were larger than those of unaffected vessels. This suggests that arterial walls become thicker during the early stages of amyloid angiopathy, and the diameter of the lumen decreases, whereas during advanced stages, the walls become thinner and the lumen becomes larger. In addition, we assessed the overall severity of amyloid angiopathy. This showed that thinner arterial walls and the severity of amyloid angiopathy were correlated to dementia. In a multivariate model that integrates the other macroscopic and microscopic lesions that may be implied in the mechanism of cognitive impairment, the severity of amyloid angiopathy per se explained 10% of the variability in the cognitive impairment.

  11. Tumoral Presentation of Homonymous Hemianopia and Prosopagnosia in Cerebral Amyloid Angiopathy-Related Inflammation.

    PubMed

    Hainline, Clotilde; Rucker, Janet C; Zagzag, David; Golfinos, John G; Lui, Yvonne W; Liechty, Benjamin; Warren, Floyd A; Balcer, Laura J; Galetta, Steven L

    2017-03-01

    While cerebral amyloid angiopathy is a common cause of lobar hemorrhage, rarely it may be associated with an inflammatory response, thought to be incited by amyloid deposits. We report a 73-year-old woman with an extensive cancer history who presented with tumor-like lesions and symptoms of homonymous hemianopia and prosopagnosia. Found to have cerebral amyloid angiopathy-related inflammation proven by brain biopsy, she was treated successfully with immunosuppression.

  12. Brain abscess associated with cerebral amyloid angiopathy and hemorrhage.

    PubMed

    Wee, Hsiao-Yue; Wang, Che-Chuan; Li, Chien-Feng; Kuo, Jinn-Rung

    2011-06-01

    We want to report an extremely rare condition, brain abscess associated with cerebral amylid angiopathy and hemorrhage. We report on a 64-year-old woman who presented initially with moderate fever and headache. She was initially misdiagnosed with a bleeding tumor or arteriovenous malformation rupture and treated without antibiotic therapy. The mass was surgically drained due to neurological deterioration on day 14 after admission. Streptococcus virdians was isolated from the pus culture. The pathology evaluation showed cerebral amyloid angiopathy. She received intravenous antibiotic therapy for 4 weeks. She was eventually discharged home with left quadrantanopia. This case reminds us early recognition of brain abscess formation at the site of intracerebral hemorrhage is very important for prompt and appropriate treatment to improve the overall prognosis.

  13. 18F-AV-1451 PET Imaging in Three Patients with Probable Cerebral Amyloid Angiopathy.

    PubMed

    Kim, Hee Jin; Cho, Hanna; Werring, David J; Jang, Young Kyoung; Kim, Yeo Jin; Lee, Jin San; Lee, Juyoun; Jun, Soomin; Park, Seongbeom; Ryu, Young Hoon; Choi, Jae Yong; Cho, Young Seok; Moon, Seung Hwan; Na, Duk L; Lyoo, Chul Hyoung; Seo, Sang Won

    2017-03-06

    Cerebrovascular deposition of amyloid-β, known as cerebral amyloid angiopathy (CAA), is associated with MRI findings of lobar hemorrhage, cerebral microbleeds, and cortical superficial siderosis. Although pathological studies suggest that tau may co-localize with vascular amyloid, this has not yet been investigated in CAA in vivo. Three patients with probable CAA underwent 11C-Pittsburgh Compound B (PiB) PET or 18F-florbetaben PET to evaluate amyloid burden, and 18F-AV-1451 PET to evaluate paired helical filament tau burden. Regions that had cerebral microbleeds or cortical superficial siderosis largely overlapped with those showing increased 18F-AV-1451 and increased 11C-PiB uptake. Our preliminary study raised the possibility that lobar cerebral microbleeds, and cortical superficial siderosis, which are characteristic markers of vascular amyloid, may be associated with local production of paired helical filament tau.

  14. Neurovascular decoupling is associated with severity of cerebral amyloid angiopathy.

    PubMed

    Peca, Stefano; McCreary, Cheryl R; Donaldson, Emily; Kumarpillai, Gopukumar; Shobha, Nandavar; Sanchez, Karla; Charlton, Anna; Steinback, Craig D; Beaudin, Andrew E; Flück, Daniela; Pillay, Neelan; Fick, Gordon H; Poulin, Marc J; Frayne, Richard; Goodyear, Bradley G; Smith, Eric E

    2013-11-05

    We used functional MRI (fMRI), transcranial Doppler ultrasound, and visual evoked potentials (VEPs) to determine the nature of blood flow responses to functional brain activity and carbon dioxide (CO2) inhalation in patients with cerebral amyloid angiopathy (CAA), and their association with markers of CAA severity. In a cross-sectional prospective cohort study, fMRI, transcranial Doppler ultrasound CO2 reactivity, and VEP data were compared between 18 patients with probable CAA (by Boston criteria) and 18 healthy controls, matched by sex and age. Functional MRI consisted of a visual task (viewing an alternating checkerboard pattern) and a motor task (tapping the fingers of the dominant hand). Patients with CAA had lower amplitude of the fMRI response in visual cortex compared with controls (p = 0.01), but not in motor cortex (p = 0.22). In patients with CAA, lower visual cortex fMRI amplitude correlated with higher white matter lesion volume (r = -0.66, p = 0.003) and more microbleeds (r = -0.78, p < 0.001). VEP P100 amplitudes, however, did not differ between CAA and controls (p = 0.45). There were trends toward reduced CO2 reactivity in the middle cerebral artery (p = 0.10) and posterior cerebral artery (p = 0.08). Impaired blood flow responses in CAA are more evident using a task to activate the occipital lobe than the frontal lobe, consistent with the gradient of increasing vascular amyloid severity from frontal to occipital lobe seen in pathologic studies. Reduced fMRI responses in CAA are caused, at least partly, by impaired vascular reactivity, and are strongly correlated with other neuroimaging markers of CAA severity.

  15. Reducing Available Soluble β-Amyloid Prevents Progression of Cerebral Amyloid Angiopathy in Transgenic Mice

    PubMed Central

    Gregory, Julia L.; Prada, Claudia M.; Fine, Sara J.; Garcia-Alloza, Monica; Betensky, Rebecca A.; Arbel-Ornath, Michal; Greenberg, Steven M.; Bacskai, Brian J.; Frosch, Matthew P.

    2012-01-01

    Cerebral amyloid angiopathy (CAA), the accumulation of β-amyloid (Aβ) in the walls of leptomeningeal and cortical blood vessels of the brain, is a major cause of intracerebral hemorrhage and cognitive impairment, and is commonly associated with Alzheimer disease (AD). CAA progression, as measured in transgenic mice by longitudinal imaging with multiphoton microscopy, occurs in a predictable linear manner. The dynamics of Aβ deposition in and clearance from vascular walls and their relationship to the concentration of Aβ in the brain is poorly understood. We manipulated Aβ levels in the brain using 2 approaches: peripheral clearance via administration of the amyloid binding “peripheral sink” protein gelsolin, and direct inhibition of its formation via administration of LY-411575, a small molecule γ-secretase inhibitor. We found that gelsolin and LY-411575 both reduced the rate of CAA progression in Tg2576 mice from untreated rates of 0.58 ± 0.15% and 0.52 ± 0.09% to 0.11 ± 0.18% (p = 0.04) and −0.17 ± 0.09% (p < 0.001) of affected vessel per day, respectively, in the absence of an immune response. CAA progression was also halted when gelsolin was combined with LY-411575 (−0.004 ± 0.10%, p < 0.003). These data suggest that CAA progression can be prevented with non-immune approaches that may reduce the availability of soluble Aβ, but without evidence of substantial amyloid clearance from vessels. PMID:23095848

  16. Transcutaneous β-amyloid immunization reduces cerebral β-amyloid deposits without T cell infiltration and microhemorrhage

    PubMed Central

    Nikolic, William V.; Bai, Yun; Obregon, Demian; Hou, Huayan; Mori, Takashi; Zeng, Jin; Ehrhart, Jared; Shytle, R. Douglas; Giunta, Brian; Morgan, Dave; Town, Terrence; Tan, Jun

    2007-01-01

    Alzheimer's disease (AD) immunotherapy accomplished by vaccination with β-amyloid (Aβ) peptide has proved efficacious in AD mouse models. However, “active” Aβ vaccination strategies for the treatment of cerebral amyloidosis without concurrent induction of detrimental side effects are lacking. We have developed a transcutaneous (t.c.) Aβ vaccination approach and evaluated efficacy and monitored for deleterious side effects, including meningoencephalitis and microhemorrhage, in WT mice and a transgenic mouse model of AD. We demonstrate that t.c. immunization of WT mice with aggregated Aβ1–42 plus the adjuvant cholera toxin (CT) results in high-titer Aβ antibodies (mainly of the Ig G1 class) and Aβ1–42-specific splenocyte immune responses. Confocal microscopy of the t.c. immunization site revealed Langerhans cells in areas of the skin containing the Aβ1–42 immunogen, suggesting that these unique innate immune cells participate in Aβ1–42 antigen processing. To evaluate the efficacy of t.c. immunization in reducing cerebral amyloidosis, transgenic PSAPP (APPsw, PSEN1dE9) mice were immunized with aggregated Aβ1–42 peptide plus CT. Similar to WT mice, PSAPP mice showed high Aβ antibody titers. Most importantly, t.c. immunization with Aβ1–42 plus CT resulted in significant decreases in cerebral Aβ1–40,42 levels coincident with increased circulating levels of Aβ1–40,42, suggesting brain-to-blood efflux of Aβ. Reduction in cerebral amyloidosis was not associated with deleterious side effects, including brain T cell infiltration or cerebral microhemorrhage. Together, these data suggest that t.c. immunization constitutes an effective and potentially safe treatment strategy for AD. PMID:17264212

  17. Cerebral vascular amyloid seeds drive amyloid β-protein fibril assembly with a distinct anti-parallel structure

    PubMed Central

    Xu, Feng; Fu, Ziao; Dass, Sharmila; Kotarba, AnnMarie E.; Davis, Judianne; Smith, Steven O.; Van Nostrand, William E.

    2016-01-01

    Cerebrovascular accumulation of amyloid β-protein (Aβ), a condition known as cerebral amyloid angiopathy (CAA), is a common pathological feature of patients with Alzheimer's disease. Familial Aβ mutations, such as Dutch-E22Q and Iowa-D23N, can cause severe cerebrovascular accumulation of amyloid that serves as a potent driver of vascular cognitive impairment and dementia. The distinctive features of vascular amyloid that underlie its unique pathological properties remain unknown. Here, we use transgenic mouse models producing CAA mutants (Tg-SwDI) or overproducing human wild-type Aβ (Tg2576) to demonstrate that CAA-mutant vascular amyloid influences wild-type Aβ deposition in brain. We also show isolated microvascular amyloid seeds from Tg-SwDI mice drive assembly of human wild-type Aβ into distinct anti-parallel β-sheet fibrils. These findings indicate that cerebrovascular amyloid can serve as an effective scaffold to promote rapid assembly and strong deposition of Aβ into a unique structure that likely contributes to its distinctive pathology. PMID:27869115

  18. Cerebral Amyloid Angiopathy Pathology and Cognitive Domains in Older Persons

    PubMed Central

    Arvanitakis, Zoe; Leurgans, Sue E.; Wang, Zhenxin; Wilson, Robert S.; Bennett, David A.; Schneider, Julie A.

    2011-01-01

    Objective To examine the relation of cerebral amyloid angiopathy (CAA) to cognitive domains in older community-dwelling persons with and without dementia. Methods Subjects were 404 persons in the Religious Orders Study, a cohort study of aging, who underwent annual clinical evaluations, including 19 neuropsychological tests from which 5 cognitive domain and global summary scores were derived, and brain autopsy at time-of-death (mean age-at-death 86). Using amyloid-β immunostaining, CAA severity was graded in 5 regions (midfrontal, inferior temporal, angular, calcarine, and hippocampal cortices), as 0 = none, 1 = mild, 2 = moderate, 3 = severe, and 4 = very severe. Because severity was related across regions (all rs > 0.63), and almost all persons had some CAA, we averaged regional CAA scores and created class variable predictors for no-to-minimal (<0.5), mild-to-moderate (0.5-2.5) and moderate-to-very severe CAA (>2.5). Results CAA was very common (84.9%; 94 had no-to-minimal, 233 mild-to-moderate, and 76 moderate-to-very severe disease) and was related to AD pathology (rs = 0.68). In linear regression analyses controlling for age, sex, education, AD pathology, infarcts, and Lewy bodies, moderate-to-very severe CAA was associated with lower perceptual speed (p = 0.012) and episodic memory (p = 0.047), but not semantic memory, working memory, visuospatial skills, or a composite of all cognitive measures. No associations of mild-to-moderate CAA with cognition were found. Dementia did not modify these findings. Interpretation CAA pathology is very common in older community-dwelling persons and is associated with AD pathology. Moderate-to-very severe CAA, but not mild-to-moderate CAA, is associated with lower performance in specific cognitive domains, most notably perceptual speed, separately from the effect of AD pathology. PMID:21387377

  19. Pseudotumoral presentation of cerebral amyloid angiopathy-related inflammation.

    PubMed

    Ronsin, Solène; Deiana, Gianluca; Geraldo, Ana Filipa; Durand-Dubief, Françoise; Thomas-Maisonneuve, Laure; Formaglio, Maïté; Desestret, Virginie; Meyronet, David; Nighoghossian, Norbert; Berthezène, Yves; Honnorat, Jérôme; Ducray, François

    2016-03-08

    To identify the clinical and radiologic features that should raise suspicion for the pseudotumoral presentation of cerebral amyloid angiopathy-related inflammation (CAA-I). We retrospectively reviewed the characteristics of 5 newly diagnosed and 23 previously reported patients in whom the CAA-I imaging findings were initially interpreted as CNS neoplasms. Most cases (85%) occurred in patients >60 years old. The clinical characteristics at presentation included subacute cognitive decline (50%), confusion (32%), focal deficits (32%), seizures (25%), and headaches (21%). Brain MRI demonstrated infiltrative white matter lesions that exhibited a loco-regional mass effect without parenchymal enhancement (93%). In general, these findings were interpreted as low-grade glioma or lymphoma. Eighteen patients (64%) underwent a biopsy, which was nondiagnostic in 4 patients (14%), and 6 patients (21%) underwent a surgical resection. The primary reason for the misinterpretation of the imaging findings was the absence of T2*-weighted gradient recalled echo (T2*-GRE) sequences on initial imaging (89%). When subsequently performed (39%), the T2*-GRE sequences demonstrated multiple characteristic cortical and subcortical microhemorrhages in all cases. Perfusion MRI and magnetic resonance spectroscopy (MRS), which were performed on a subset of patients, indicated markedly reduced relative cerebral blood flow and a normal metabolic ratio. The identification of one or several nonenhancing space-occupying lesions, especially in elderly patients presenting with cognitive impairment, should raise suspicion for the pseudotumoral presentation of CAA-I and lead to T2*-GRE sequences. Perfusion MRI and MRS appear to be useful techniques for the differential diagnosis of this entity. © 2016 American Academy of Neurology.

  20. Pseudotumoral presentation of cerebral amyloid angiopathy–related inflammation

    PubMed Central

    Ronsin, Solène; Deiana, Gianluca; Geraldo, Ana Filipa; Durand-Dubief, Françoise; Thomas-Maisonneuve, Laure; Formaglio, Maïté; Desestret, Virginie; Meyronet, David; Nighoghossian, Norbert; Berthezène, Yves; Ducray, François

    2016-01-01

    Objective: To identify the clinical and radiologic features that should raise suspicion for the pseudotumoral presentation of cerebral amyloid angiopathy–related inflammation (CAA-I). Methods: We retrospectively reviewed the characteristics of 5 newly diagnosed and 23 previously reported patients in whom the CAA-I imaging findings were initially interpreted as CNS neoplasms. Results: Most cases (85%) occurred in patients >60 years old. The clinical characteristics at presentation included subacute cognitive decline (50%), confusion (32%), focal deficits (32%), seizures (25%), and headaches (21%). Brain MRI demonstrated infiltrative white matter lesions that exhibited a loco-regional mass effect without parenchymal enhancement (93%). In general, these findings were interpreted as low-grade glioma or lymphoma. Eighteen patients (64%) underwent a biopsy, which was nondiagnostic in 4 patients (14%), and 6 patients (21%) underwent a surgical resection. The primary reason for the misinterpretation of the imaging findings was the absence of T2*-weighted gradient recalled echo (T2*-GRE) sequences on initial imaging (89%). When subsequently performed (39%), the T2*-GRE sequences demonstrated multiple characteristic cortical and subcortical microhemorrhages in all cases. Perfusion MRI and magnetic resonance spectroscopy (MRS), which were performed on a subset of patients, indicated markedly reduced relative cerebral blood flow and a normal metabolic ratio. Conclusion: The identification of one or several nonenhancing space-occupying lesions, especially in elderly patients presenting with cognitive impairment, should raise suspicion for the pseudotumoral presentation of CAA-I and lead to T2*-GRE sequences. Perfusion MRI and MRS appear to be useful techniques for the differential diagnosis of this entity. PMID:26850981

  1. Outcome Markers for Clinical Trials in Cerebral Amyloid Angiopathy

    PubMed Central

    Greenberg, Steven M.; Rustam Al-Shahi, Salman; Biessels, Geert Jan; van Buchem, Mark; Cordonnier, Charlotte; Lee, Jin-Moo; Montaner, Joan; Schneider, Julie A.; Smith, Eric E; Vernooij, Meike; Werring, David J.

    2014-01-01

    Efforts are underway for early-phase trials of candidate therapies for cerebral amyloid angiopathy (CAA), an untreatable cause of hemorrhagic stroke and vascular cognitive impairment. A major barrier to these trials is the lack of consensus on measuring treatment effectiveness. We review a range of potential outcome markers for CAA against the ideal criteria of being clinically meaningful, closely reflective of biological progression, efficient for smaller/shorter trials, reliably measurable, and cost effective. In practice, outcomes tend either to have high clinical salience but relatively low statistical efficiency and thus more applicability for later phase studies, or greater statistical efficiency but more limited clinical meaning. The most statistically efficient outcomes are those that are potentially reversible with treatment, though their clinical significance remains unproven. Many of the candidate outcomes for CAA trials are likely to be applicable to other small vessel brain diseases as well. Considerations emerging from this review outline a path towards rapid and efficient testing of emerging candidate therapies for CAA and other small vessel diseases. PMID:24581702

  2. Amyloid imaging as a biomarker for cerebral β-amyloidosis and risk prediction for Alzheimer dementia.

    PubMed

    Klunk, William E

    2011-12-01

    Since the introduction of amyloid imaging nearly 10 years ago, this technique has gained widespread use and acceptance. More recently, published reports have begun to appear in which amyloid imaging is used to detect the effects of antiamyloid therapies. This review will consider the issues involved in the use of amyloid imaging in the development and evaluation of drugs for the treatment of Alzheimer's disease. Current evidence regarding the postmortem correlates of in vivo amyloid imaging data are considered. The application of amyloid imaging to screening subjects for trials and use as an outcome measure is discussed in light of longitudinal changes in the in vivo amyloid signal. While the bulk of this review is directed at symptomatic patients with dementia, consideration is given to the use of amyloid imaging in nondemented subjects as well. Similarities and differences of cerebral amyloid assessment by amyloid imaging and cerebrospinal fluid (CSF) measurements are delineated and an agenda for further research to improve the applicability of amyloid positron emission tomography (PET) to clinical trials is proposed.

  3. Multiple medullary venous malformations decreasing cerebral blood flow: Case report

    SciTech Connect

    Tomura, N.; Inugami, A.; Uemura, K.; Hadeishi, H.; Yasui, N. )

    1991-02-01

    A rare case of multiple medullary venous malformations in the right cerebral hemisphere is reported. The literature review yielded only one case of multiple medullary venous malformations. Computed tomography scan showed multiple calcified lesions with linear contrast enhancement representing abnormal dilated vessels and mild atrophic change of the right cerebral hemisphere. Single-photon emission computed tomography using N-isopropyl-p-({sup 123}I) iodoamphetamine demonstrated decreased cerebral blood flow in the right cerebral hemisphere.

  4. Progression of Brain Network Alterations in Cerebral Amyloid Angiopathy

    PubMed Central

    Reijmer, Yael D.; Fotiadis, Panagiotis; Riley, Grace A.; Xiong, Li; Charidimou, Andreas; Boulouis, Gregoire; Ayres, Alison M.; Schwab, Kristin; Rosand, Jonathan; Gurol, M. Edip; Viswanathan, Anand; Greenberg, Steven M.

    2016-01-01

    Background and Purpose We recently showed that cerebral amyloid angiopathy (CAA) is associated with functionally relevant brain network impairments, in particular affecting posterior white matter connections. Here we examined how these brain network impairments progress over time. Methods Thirty-three patients with probable CAA underwent multimodal brain MRI at two time points (mean follow-up time: 1.3±0.4 years). Brain networks of the hemisphere free of intracerebral hemorrhages were reconstructed using fiber tractography and graph theory. The global efficiency of the network and mean fractional anisotropies (FA) of posterior-posterior, frontal-frontal, and posterior-frontal network connections were calculated. Patients with moderate vs. severe CAA were defined based on microbleed count, dichotomized at the median (median=35). Results Global efficiency of the ICH-free hemispheric network declined from baseline to follow up (−0.008 ± 0.003, p=0.029). The decline in global efficiency was most pronounced for patients with severe CAA (group × time interaction p=0.03). The decline in global network efficiency was associated with worse executive functioning (Beta=0.46, p=0.03). Examination of subgroups of network connections revealed a decline in FA of posterior-posterior connections at both levels of CAA severity (−0.006 ± 0.002, p=0.017; group × time interaction p=0.16). The FA of posterior-frontal and frontal-frontal connections declined in patients with severe but not moderate CAA (group × time interaction: p=0.007 and p=0.005). Associations were independent of change in white matter hyperintensity volume. Conclusions Brain network impairment in patients with CAA worsens measurably over just 1.3-year follow-up and appear to progress from posterior to frontal connections with increasing disease severity. PMID:27576378

  5. [Apolipoprotein E (APOE) gene polymorphism and risk and prognosis in cerebral amyloid angiopathy-related haemorrhage].

    PubMed

    Mendel, Tadeusz; Gromadzka, Grażyna

    2010-01-01

    The authors present current opinions about the role of APOE (apolipoprotein E gene) genotype as a factor modifying risk, course and prognosis in haemorrhagic stroke of cerebral amyloid origin. The search for the role of genetics in haemorrhagic stroke has been ongoing for more than 15 years. One of the most frequently investigated genotypes in the context of intracerebral haemorrhages is the APOE genotype. Alleles APOE e2 and e4 have been established as risk factors for cerebral amyloid angiopathy (CAA), as well as for cerebral amyloid angiopathy-related haemorrhage (CAAH). Moreover, APOE genotype seems to determine prognosis in CAAH in terms of early mortality, as well as risk of recurrence. Current findings related to the association between different isoforms of apoE and haemorrhagic stroke due to CAA do not allow us to formulate any clinical recommendations yet.

  6. Hemorrhagic stroke, cerebral amyloid angiopathy, Down syndrome and the Boston criteria.

    PubMed

    Jastrzębski, Karol; Kacperska, Magdalena Justyna; Majos, Agata; Grodzka, Magdalena; Głąbiński, Andrzej

    2015-01-01

    A stroke, or a cerebrovascular accident (CVA) is a life-threatening condition which often results in permanent or significant disability in the adult population. Several classifications of CVAs exist, one of them being based on the mechanism of injury of brain tissue: ischemic (85-90%) and hemorrhagic (10-15%). In a hemorrhagic stroke an intercranial bleeding occurs, leading to the formation of a focal hematoma typically located in the basal ganglia of the brain (approx. 45% of cases). A common yet underestimated cause of intracerebral hemorrhage is cerebral small vessel disease with microhemorrhages, including the cerebral amyloid angiopathy (CAA). This condition is associated with the deposition of amyloid-beta in arterial walls (in soft meninges, subcortical areas and the cerebral cortex). Research has shown that causes of hemorrhagic changes in the brain include genetic disorders, such as Down syndrome. The association is caused by the so-called 'gene dosage effect', as the gene for the precursor protein for amyloid-beta is located in chromosome 21. We wish to present the case of a 60 year old patient with Down syndrome who suffered a hemorrhagic stroke without antecedent hypertension. Based on the history taken, diagnostic imaging and the source literature, a diagnosis of cerebral amyloid angiopathy as the source of the bleeding was made (however it must be noted that without a full post-mortem examination, the Boston criteria allow only for a 'probable cerebral amyloid angiopathy' diagnosis to be made). The authors hereby also report the need to modify the Boston criteria for cerebral amyloid angiopathy.

  7. Cerebral Amyloid Angiopathy Burden Associated with Leukoaraiosis:a PET/MRI Study

    PubMed Central

    Gurol, M. Edip; Viswanathan, Anand; Gidicsin, Christopher; Hedden, Trey; Ramirez-Martinez, Sergi; Dumas, Andrew; Vashkevich, Anastasia; Ayres, Alison M.; Auriel, Eitan; van Etten, Ellis; Becker, Alex; Carmasin, Jeremy; Schwab, Kristin; Rosand, Jonathan; Johnson, Keith A.; Greenberg, Steven M.

    2013-01-01

    Objective We hypothesized that vascular amyloid contributes to chronic brain ischemia, therefore amyloid burden measured by Pittsburgh Compound B retention on PET (PiB-PET) would correlate with the extent of MRI white matter hyperintensities (WMHor leukoaraiosis) in patients with high vascular amyloid deposition (Cerebral Amyloid Angiopathy, CAA) but not high parenchymal amyloid deposition (Alzheimer’s Disease, AD; Mild Cognitive Impairment, MCI) or healthy elderly (HE). Methods Fourty-two non-demented CAA patients, 50 HE subjects and 43 AD/MCI patients had brain MRI and PiB-PET. Multivariate linear regression was used to assess the independent association between PiB retention and WMD volume controlling for age, gender, apolipoprotein E genotype, and vascular risk factors within each group. Results CAA patients were younger than HE and AD (68±10 vs 73.3±7 and 74±7.4, p<0.01) but had higher amounts of WMH (medians: 21ml vs 3.2ml and 10.8ml respectively, p<0.05 for both comparisons). Global PiB retention and WMH showed strong correlation (rho=0.52, p<0.001) in the CAA group but not in HE or AD. These associations did not change in the multivariate models. Lobar microbleed count, another marker of CAA severity also remained as an independent predictor of WMH volume. Interpretation Our results indicate that amyloid burden in CAA subjects (with primarily vascular amyloid) but not AD subjects (with primarily parenchymal amyloid) independently correlate with WMH volume. These findings support the idea that vascular amyloid burden directly contributes to chronic cerebral ischemia and highlights the possible utility of amyloid imaging as a marker of CAA severity. PMID:23424091

  8. Amyloid-β peptide absence in short term effects on kinase activity of energy metabolism in mice hippocampus and cerebral cortex.

    PubMed

    Ianiski, Francine R; Rech, Virginia C; Nishihira, Vivian S K; Alves, Catiane B; Baldissera, Matheus D; Wilhelm, Ethel A; Luchese, Cristiane

    2016-01-01

    Considering that Alzheimer's disease is a prevalent neurodegenerative disease worldwide, we investigated the activities of three key kinases: creatine kinase, pyruvate kinase and adenylate kinase in the hippocampus and cerebral cortex in Alzheimer's disease model. Male adult Swiss mice received amyloid-β or saline. One day after, mice were treated with blank nanocapsules (17 ml/kg) or meloxicam-loaded nanocapsules (5 mg/kg) or free meloxicam (5 mg/kg). Treatments were performed on alternating days, until the end of the experimental protocol. In the fourteenth day, kinases activities were performed. Amyloid-β did not change the kinases activity in the hippocampus and cerebral cortex of mice. However, free meloxicam decrease the creatine kinase activity in mitochondrial-rich fraction in the group induced by amyloid-β, but for the cytosolic fraction, it has raised in the activity of pyruvate kinase activity in cerebral cortex. Further, meloxicam-loaded nanocapsules administration reduced adenylate kinase activity in the hippocampus of mice injected by amyloid-β. In conclusion we observed absence in short-term effects in kinases activities of energy metabolism in mice hippocampus and cerebral cortex using amyloid-β peptide model. These findings established the foundation to further study the kinases in phosphoryltransfer network changes observed in the brains of patients post-mortem with Alzheimer's disease.

  9. Cerebrospinal fluid analysis detects cerebral amyloid-β accumulation earlier than positron emission tomography.

    PubMed

    Palmqvist, Sebastian; Mattsson, Niklas; Hansson, Oskar

    2016-04-01

    Cerebral accumulation of amyloid-β is thought to be the starting mechanism in Alzheimer's disease. Amyloid-β can be detected by analysis of cerebrospinal fluid amyloid-β42 or amyloid positron emission tomography, but it is unknown if any of the methods can identify an abnormal amyloid accumulation prior to the other. Our aim was to determine whether cerebrospinal fluid amyloid-β42 change before amyloid PET during preclinical stages of Alzheimer's disease. We included 437 non-demented subjects from the prospective, longitudinal Alzheimer's Disease Neuroimaging Initiative (ADNI) study. All underwent (18)F-florbetapir positron emission tomography and cerebrospinal fluid amyloid-β42 analysis at baseline and at least one additional positron emission tomography after a mean follow-up of 2.1 years (range 1.1-4.4 years). Group classifications were based on normal and abnormal cerebrospinal fluid and positron emission tomography results at baseline. We found that cases with isolated abnormal cerebrospinal fluid amyloid-β and normal positron emission tomography at baseline accumulated amyloid with a mean rate of 1.2%/year, which was similar to the rate in cases with both abnormal cerebrospinal fluid and positron emission tomography (1.2%/year, P = 0.86). The mean accumulation rate of those with isolated abnormal cerebrospinal fluid was more than three times that of those with both normal cerebrospinal fluid and positron emission tomography (0.35%/year, P = 0.018). The group differences were similar when analysing yearly change in standardized uptake value ratio of florbetapir instead of percentage change. Those with both abnormal cerebrospinal fluid and positron emission tomography deteriorated more in memory and hippocampal volume compared with the other groups (P < 0.001), indicating that they were closer to Alzheimer's disease dementia. The results were replicated after adjustments of different factors and when using different cut-offs for amyloid-β abnormality

  10. Cerebrospinal Fluid Alzheimer's Disease Biomarkers in Cerebral Amyloid Angiopathy-Related Inflammation.

    PubMed

    Renard, Dimitri; Wacongne, Anne; Ayrignac, Xavier; Charif, Mahmoud; Fourcade, Genevieve; Azakri, Souhayla; Le Floch, Anne; Bouly, Stephane; Marelli, Cecilia; Arquizan, Caroline; Hirtz, Christophe; Gabelle, Audrey; Thouvenot, Eric; Lehmann, Sylvain

    2016-01-01

    Decreased cerebrospinal fluid (CSF) amyloid-β 1-40 (Aβ40) and amyloid-β 1-42 (Aβ42) and increased total and phosphorylated tau (t-tau, p-tau) concentrations have been described in cerebral amyloid angiopathy (CAA). Our aim was to analyze these biomarkers in patients with CAA-related inflammation (CAA-I). We prospectively recruited nine patients with acute phase CAA-I fulfilling Chung criteria. CSF was analyzed for t-tau, p-tau, Aβ42, and Aβ40. Data were compared to controls (n = 14), patients with Alzheimer's disease (AD, n = 42), CAA (n = 10), and primary angiitis of the central nervous system (PACNS, n = 3). For the CAA-I group, statistically significant differences were: lower Aβ42 (p = 0.00053) compared to the control group; lower t-tau (p = 0.018), p-tau (p <  0.001), and Aβ40 (p <  0.001) compared to AD; lower Aβ42 (p = 0.027) compared to CAA; lower Aβ42 (p = 0.012) compared to PACNS. Nearly significantly lower Aβ40 (p = 0.051) and higher t-tau (p = 0.051) were seen in CAA-I compared to controls. CSF biomarkers profile similar to that of CAA was observed in CAA-I (with even lower levels of Aβ42 compared to CAA). Based on our findings, high p-tau seems more specific for AD, whereas low Aβ42 differentiates CAA-I from CAA, PACNS, and controls, and low Aβ40 differentiates CAA-I from AD.

  11. The hemorrhage caused by sporadic-type cerebral amyloid angiopathy occurs primarily in the cerebral sulci.

    PubMed

    Takeda, Shigeki; Hinokuma, Kaoru; Yamazaki, Kazunori; Onda, Kiyoshi; Miyakawa, Teruo; Ikuta, Fusahiro; Arai, Hiroyuki

    2012-02-01

    We examined a solitary hematoma in a patient with sporadic cerebral amyloid angiopathy (CAA). The hematoma affected the middle frontal sulcus, cerebral cortex (CC) and subcortical frontal white matter (sfWM). We embedded the hematoma in four paraffin blocks, each of which was cut serially into 6-µm-thick sections. The first section and every 18th section from each block were subjected to Elastica-Goldner (E-G) staining, and the distribution and diameter of the ruptured blood vessels (rBVs) were examined. The rBVs were then marked on diagrams representing each E-G-stained section. The present study yielded the following important findings: (i), early- and recently ruptured Aβ-positive arteries were present mainly in the intrasulcal hematoma (ISH), rather than in the CC; (ii) many early-ruptured arteries in the ISH were larger in diameter than those in the CC; and (iii) ruptures of the cortical arteries, even near the cortical surface, did not occur so frequently and the ruptured vessels were small in size. We concluded that in patients with subcortical hematoma caused by sporadic-type CAA, successive rupturse of the meningeal vessels, mainly arteries, occur in the cerebral sulcus initially, followed by formation of an ISH and development of a fresh hemorrhagic or anemic infarct in the CC surrounding the ISH, the latter in most cases then extending into the brain parenchyma through the necrotic CC at the depth of the sulcus, finally creating a secondary hematoma in the subcortical white matter. © 2011 Japanese Society of Neuropathology.

  12. Visualization of microhemorrhages with optical histology in mouse model of cerebral amyloid angiopathy (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Lo, Patrick; Crouzet, Christian; Vasilevko, Vitaly; Choi, Bernard

    2016-03-01

    Cerebral amyloid angiopathy (CAA) is a neurovascular disease that is strongly associated with an increase in the number and size of spontaneous microhemorrhages. Conventional methods, such as magnetic resonance imaging (MRI), can detect microhemorrhages while positron emission tomography (PET) with Pittsburgh Compound B can detect amyloid deposits. MRI and PET can separately demonstrate the presence of microhemorrhages and CAA in affected brains in vivo; however, there is still a lack of strong evidence for the direct involvement of CAA in the presence of microhemorrhage formation. In this study, we use optical histology, a method which combines histochemical staining, chemical optical clearing, and optical imaging, in a Tg2576 mouse model of Alzheimer's disease to enable simultaneous, co-registered three-dimensional visualization of cerebral microvasculature, microhemorrhages, and amyloid deposits. Our data strongly suggest that microhemorrhages are localized within the brain regions affected by amyloid deposits. All but two observed microhemorrhages (n=18) were closely localized with vessels affected by CAA whereas no microhemorrhages or amyloid deposits were observed in wild type mouse brain sections. Our data also suggest that the predominant type of CAA-related microhemorrhage is associated with leaky or ruptured hemorrhagic microvasculature within the hippocampus and cerebral cortex rather than occluded ischemic microvasculature. The proposed optical histology method will allow future studies about the relationship between CAA and microhemorrhages during disease development and in response to treatment strategies.

  13. Correlation of Cerebral Microbleed Distribution to Amyloid Burden in Patients with Primary Intracerebral Hemorrhage

    PubMed Central

    Tsai, Hsin-Hsi; Tsai, Li-Kai; Chen, Ya-Fang; Tang, Sung-Chun; Lee, Bo-Ching; Yen, Ruoh-Fang; Jeng, Jiann-Shing

    2017-01-01

    The underlying pathology of cerebral microbleeds (CMBs) with mixed lobar and deep distribution remains contentious. The aim of this study was to correlate CMBs distribution to β-amyloid burden in patients with primary intracerebral hemorrhage (ICH). Fourty-seven ICH patients underwent magnetic resonance susceptibility-weighted imaging and 11C-Pittsburgh Compound B positron emission tomography. The amyloid burden was expressed as standardized uptake value ratio with reference to cerebellum, and presented as median (interquartile range). Patients were categorized into the lobar, mixed (both lobar and deep regions), and deep types of CMB. Comparing the lobar (17%), mixed (59.6%) and deep (23.4%) CMB types, the global amyloid burden was significantly higher in the mixed type than the deep type (1.10 [1.03–1.25] vs 1.00 [0.97–1.09], p = 0.011), but lower than in the lobar type (1.48 [1.18–1.50], p = 0.048). On multivariable analysis, the ratio of lobar to deep CMB number was positively correlated with global (p = 0.028) and occipital (p = 0.031) amyloid burden. In primary ICH, patients with lobar and mixed CMB types are associated with increased amyloid burden than patients with deep type. The ratio of lobar to deep CMB number is an independent indicator of cerebral β-amyloid deposition. PMID:28303922

  14. Aging and cerebrovascular dysfunction: contribution of hypertension, cerebral amyloid angiopathy, and immunotherapy.

    PubMed

    Vasilevko, Vitaly; Passos, Giselle F; Quiring, Daniel; Head, Elizabeth; Kim, Richard C; Fisher, Mark; Cribbs, David H

    2010-10-01

    Age-related cerebrovascular dysfunction contributes to ischemic stroke, intracerebral hemorrhages (ICHs), microbleeds, cerebral amyloid angiopathy (CAA), and cognitive decline. Importantly, there is increasing recognition that this dysfunction plays a critical secondary role in many neurodegenerative diseases, including Alzheimer's disease (AD). Atherosclerosis, hypertension, and CAA are the most common causes of blood-brain barrier (BBB) lesions. The accumulation of amyloid beta (Aβ) in the cerebrovascular system is a significant risk factor for ICH and has been linked to endothelial transport failure and blockage of perivascular drainage. Moreover, recent anti-Aβ immunotherapy clinical trials demonstrated efficient clearance of parenchymal amyloid deposits but have been plagued by CAA-associated adverse events. Although management of hypertension and atherosclerosis can reduce the incidence of ICH, there are currently no approved therapies for attenuating CAA. Thus, there is a critical need for new strategies that improve BBB function and limit the development of β-amyloidosis in the cerebral vasculature.

  15. Cerebral Amyloid Angiopathy: Diagnosis, Clinical Implications, and Management Strategies in Atrial Fibrillation.

    PubMed

    DeSimone, Christopher V; Graff-Radford, Jonathan; El-Harasis, Majd A; Rabinstein, Alejandro A; Asirvatham, Samuel J; Holmes, David R

    2017-08-29

    With an aging population, clinicians are more frequently encountering patients with atrial fibrillation who are also at risk of intracerebral hemorrhage due to cerebral amyloid angiopathy, the result of β-amyloid deposition in cerebral vessels. Cerebral amyloid angiopathy is common among elderly patients, and is associated with an increased risk of intracerebral bleeding, especially with the use of anticoagulation. Despite this association, this entity is absent in current risk-benefit analysis models, which may result in underestimation of the chance of bleeding in the subset of patients with this disease. Determining the presence and burden of cerebral amyloid angiopathy is particularly important when planning to start or restart anticoagulation after an intracerebral hemorrhage. Given the lack of randomized trial data to guide management strategies, we discuss a heart-brain team approach that includes clinician-patient shared decision making for the use of pharmacologic and nonpharmacologic approaches to diminish stroke risk. Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  16. Preliminary Investigation of Cerebral Blood Flow and Amyloid Burden in Veterans With and Without Combat-Related Traumatic Brain Injury.

    PubMed

    Ponto, Laura L Boles; Brashers-Krug, Thomas M; Pierson, Ronald K; Menda, Yusuf; Acion, Laura; Watkins, G Leonard; Sunderland, John J; Koeppel, Julie A; Jorge, Ricardo E

    2016-01-01

    This study aimed to examine global and regional cerebral blood flow and amyloid burden in combat veterans with and without traumatic brain injury (TBI). Cerebral blood flow (in milliliters per minute per 100 mL) was measured by quantitative [(15)O]water, and amyloid burden was measured by [(11)C]PIB imaging. Mean global cerebral blood flow was significantly lower in veterans with TBI compared with non-TBI veterans. There were essentially no differences between groups for globally normalized regional cerebral blood flow. Amyloid burden did not differ between TBI and non-TBI veterans. Veterans who have suffered a TBI have significantly lower cerebral blood flow than non-TBI controls but did not manifest increased levels of amyloid, globally or regionally.

  17. Deposition of amyloid β in the walls of human leptomeningeal arteries in relation to perivascular drainage pathways in cerebral amyloid angiopathy☆

    PubMed Central

    Keable, Abby; Fenna, Kate; Yuen, Ho Ming; Johnston, David A.; Smyth, Neil R.; Smith, Colin; Salman, Rustam Al-Shahi; Samarasekera, Neshika; Nicoll, James A.R.; Attems, Johannes; Kalaria, Rajesh N.; Weller, Roy O.; Carare, Roxana O.

    2016-01-01

    Deposition of amyloid β (Aβ) in the walls of cerebral arteries as cerebral amyloid angiopathy (CAA) suggests an age-related failure of perivascular drainage of soluble Aβ from the brain. As CAA is associated with Alzheimer's disease and with intracerebral haemorrhage, the present study determines the unique sequence of changes that occur as Aβ accumulates in artery walls. Paraffin sections of post-mortem human occipital cortex were immunostained for collagen IV, fibronectin, nidogen 2, Aβ and smooth muscle actin and the immunostaining was analysed using Image J and confocal microscopy. Results showed that nidogen 2 (entactin) increases with age and decreases in CAA. Confocal microscopy revealed stages in the progression of CAA: Aβ initially deposits in basement membranes in the tunica media, replaces first the smooth muscle cells and then the connective tissue elements to leave artery walls completely or focally replaced by Aβ. The pattern of development of CAA in the human brain suggests expansion of Aβ from the basement membranes to progressively replace all tissue elements in the artery wall. Establishing this full picture of the development of CAA is pivotal in understanding the clinical presentation of CAA and for developing therapies to prevent accumulation of Aβ in artery walls. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. PMID:26327684

  18. Amyloid deposition after cerebral hypoperfusion: evidenced on [(18)F]AV-45 positron emission tomography.

    PubMed

    Huang, Kuo-Lun; Lin, Kun-Ju; Ho, Meng-Yang; Chang, Yeu-Jhy; Chang, Chien-Hung; Wey, Shiaw-Pyng; Hsieh, Chia-Ju; Yen, Tzu-Chen; Hsiao, Ing-Tsung; Lee, Tsong-Hai

    2012-08-15

    Animal studies have shown that cerebral hypoperfusion may be associated with amyloid plaque accumulation. Amyloid plaque is known to be associated with dementia and [(18)F]AV-45 is a positron emission tomography (PET) ligand that binds to extracelluar plaques. We hypothesized that demented patients with cerebral hypoperfusion may have increased [(18)F]AV-45 uptake. Five demented patients with cerebral hypoperfusion due to unilateral carotid artery stenosis (CAS) were examined with [(18)F]AV-45 PET, and the results were compared with six elderly controls. The standard uptake value ratio (SUVR) of each region of interest (ROI) was created using whole cerebellum as the reference region. All subjects underwent magnetic resonance imaging (MRI) for obtaining structural information. Patients with dementia and unilateral CAS had a higher global [(18)F]AV-45 SUVR (1.34 ± 0.06) as compared with controls (1.10 ± 0.04, p=0.0043), especially over the frontal, temporal, precuneus, anterior cingulate and occipital regions. The statistical distribution maps revealed a significantly increased [(18)F]AV-45 SUVR in the medial frontal, caudate, thalamus, posterior cingulate, occipital and middle and superior temporal regions ipsilateral to the side of CAS (p<0.01). The present study found that cerebral [(18)F]AV-45 binding is increased in demented patients with CAS, and its distribution is lateralized to the CAS side, suggesting that amyloid-related dementia may occur under cerebral hypoperfusion.

  19. Centella asiatica extract selectively decreases amyloid beta levels in hippocampus of Alzheimer's disease animal model.

    PubMed

    Dhanasekaran, Muralikrishnan; Holcomb, Leigh A; Hitt, Angie R; Tharakan, Binu; Porter, Jami W; Young, Keith A; Manyam, Bala V

    2009-01-01

    PSAPP mice expressing the 'Swedish' amyloid precursor protein and the M146L presenilin 1 mutations are a well-characterized model for spontaneous amyloid beta plaque formation. Centella asiatica has a long history of use in India as a memory enhancing drug in Ayurvedic literature. The study investigated whether Centella asiatica extract (CaE) can alter the amyloid pathology in PSAPP mice by administering CaE (2.5 or 5.0 g/kg/day) starting at 2 months of age prior to the onset of detectable amyloid deposition and continued for either 2 months or 8 months. A significant decrease in amyloid beta 1-40 and 1-42 was detectable by ELISA following an 8 month treatment with 2.5 mg/kg of CaE. A reduction in Congo Red stained fibrillar amyloid plaques was detected with the 5.0 mg/kg CaE dose and long-term treatment regimen. It was also confirmed that CaE functions as an antioxidant in vitro, scavenging free radicals, reducing lipid peroxidation and protecting against DNA damage. The data indicate that CaE can impact the amyloid cascade altering amyloid beta pathology in the brains of PSAPP mice and modulating components of the oxidative stress response that has been implicated in the neurodegenerative changes that occur with Alzheimer's disease. Copyright 2008 John Wiley & Sons, Ltd.

  20. Association of brain amyloid-β with cerebral perfusion and structure in Alzheimer's disease and mild cognitive impairment.

    PubMed

    Mattsson, Niklas; Tosun, Duygu; Insel, Philip S; Simonson, Alix; Jack, Clifford R; Beckett, Laurel A; Donohue, Michael; Jagust, William; Schuff, Norbert; Weiner, Michael W

    2014-05-01

    Patients with Alzheimer's disease have reduced cerebral blood flow measured by arterial spin labelling magnetic resonance imaging, but it is unclear how this is related to amyloid-β pathology. Using 182 subjects from the Alzheimer's Disease Neuroimaging Initiative we tested associations of amyloid-β with regional cerebral blood flow in healthy controls (n = 51), early (n = 66) and late (n = 41) mild cognitive impairment, and Alzheimer's disease with dementia (n = 24). Based on the theory that Alzheimer's disease starts with amyloid-β accumulation and progresses with symptoms and secondary pathologies in different trajectories, we tested if cerebral blood flow differed between amyloid-β-negative controls and -positive subjects in different diagnostic groups, and if amyloid-β had different associations with cerebral blood flow and grey matter volume. Global amyloid-β load was measured by florbetapir positron emission tomography, and regional blood flow and volume were measured in eight a priori defined regions of interest. Cerebral blood flow was reduced in patients with dementia in most brain regions. Higher amyloid-β load was related to lower cerebral blood flow in several regions, independent of diagnostic group. When comparing amyloid-β-positive subjects with -negative controls, we found reductions of cerebral blood flow in several diagnostic groups, including in precuneus, entorhinal cortex and hippocampus (dementia), inferior parietal cortex (late mild cognitive impairment and dementia), and inferior temporal cortex (early and late mild cognitive impairment and dementia). The associations of amyloid-β with cerebral blood flow and volume differed across the disease spectrum, with high amyloid-β being associated with greater cerebral blood flow reduction in controls and greater volume reduction in late mild cognitive impairment and dementia. In addition to disease stage, amyloid-β pathology affects cerebral blood flow across the span from controls to

  1. Imaging of Cerebral Amyloid Angiopathy with Bivalent 99mTc-Hydroxamamide Complexes

    NASA Astrophysics Data System (ADS)

    Iikuni, Shimpei; Ono, Masahiro; Watanabe, Hiroyuki; Matsumura, Kenji; Yoshimura, Masashi; Kimura, Hiroyuki; Ishibashi-Ueda, Hatsue; Okamoto, Yoko; Ihara, Masafumi; Saji, Hideo

    2016-05-01

    Cerebral amyloid angiopathy (CAA), characterized by the deposition of amyloid aggregates in the walls of cerebral vasculature, is a major factor in intracerebral hemorrhage and vascular cognitive impairment and is also associated closely with Alzheimer’s disease (AD). We previously reported 99mTc-hydroxamamide (99mTc-Ham) complexes with a bivalent amyloid ligand showing high binding affinity for β-amyloid peptide (Aβ(1-42)) aggregates present frequently in the form in AD. In this article, we applied them to CAA-specific imaging probes, and evaluated their utility for CAA-specific imaging. In vitro inhibition assay using Aβ(1-40) aggregates deposited mainly in CAA and a brain uptake study were performed for 99mTc-Ham complexes, and all 99mTc-Ham complexes with an amyloid ligand showed binding affinity for Aβ(1-40) aggregates and very low brain uptake. In vitro autoradiography of human CAA brain sections and ex vivo autoradiography of Tg2576 mice were carried out for bivalent 99mTc-Ham complexes ([99mTc]SB2A and [99mTc]BT2B), and they displayed excellent labeling of Aβ depositions in human CAA brain sections and high affinity and selectivity to CAA in transgenic mice. These results may offer new possibilities for the development of clinically useful CAA-specific imaging probes based on the 99mTc-Ham complex.

  2. Cerebral amyloid angiopathy in a 95+ cohort: complement activation and apolipoprotein E (ApoE) genotype.

    PubMed

    Tanskanen, M; Lindsberg, P J; Tienari, P J; Polvikoski, T; Sulkava, R; Verkkoniemi, A; Rastas, S; Paetau, A; Kiuru-Enari, S

    2005-12-01

    There is growing evidence that in Alzheimer's disease (AD) amyloid beta-protein (Abeta) triggers a chronic inflammatory reaction in cerebral amyloid plaques, including complement proteins. Abeta also accumulates cerebrovascularly in age- and AD-associated cerebral amyloid angiopathy (CAA). We investigated complement proteins in CAA in a population-based series using histological and immunohistochemical staining methods. The 74 subjects, aged 95 years or more, had undergone clinical neurological examination and apolipoprotein E (ApoE) genotyping. The brains had been studied for AD post-mortem, allowing us to relate the histopathological findings to clinical and genetic conditions. CAA with congophilic amyloid was found in 36/74 individuals (48.6%). The vascular amyloid deposits immunoreacted with antibodies to Abeta and complements 3d (C3d) and 9 (C9). The positivity in complement stains increased with growing severity of CAA (P = 0.001). The presence of CAA associated with ApoE epsilon4 (P = 0.0005) and overrepresentation of epsilon4 among those with moderate or severe vs. mild CAA (P = 0.03) was demonstrated. The presence of CAA associated with dementia (P = 0.01), which was contributed by both epsilon4+ (P = 0.02) and epsilon4- (P = 0.06) subjects. Our study shows that complement proteins are deposited in the affected vessels in Abeta-associated CAA. They may solely represent the cerebral Abeta- burden associated to inflammatory stimuli, or signal a contribution in the clearance of cerebral Abeta, thereby contributing to the events associated with evolution of clinical dementia. Our results demonstrate a strong association between CAA and ApoE epsilon4 as well as dementia and suggest that the contribution of CAA to dementia is largely independent of ApoE epsilon4.

  3. Platelets in the Alzheimer's disease brain: do they play a role in cerebral amyloid angiopathy?

    PubMed

    Kniewallner, Kathrin M; Ehrlich, Daniela; Kiefer, Andreas; Marksteiner, Josef; Humpel, Christian

    2015-01-01

    Alzheimer's disease (AD) is characterized by extracellular beta-amyloid plaques and intracellular tau tangles. AD-related pathology is often accompanied by vascular changes. The predominant vascular lesions in AD are cerebral amyloid angiopathy (CAA) and arteriosclerosis. Platelets circulate along the vessel wall responding immediately to vascular injury. The aim of the present study was to explore the presence and migration of platelets (thrombocytes) to sites of small vascular bleedings and/or to beta-amyloid plaques in the brain. We infused fluorescently labeled red PKH26 mouse platelets into transgenic Alzheimer mice overexpressing APP with Swedish/Dutch/Iowa mutations (APP_SDI) and explored if platelets migrate into the brain. Further we studied whether platelets accumulate in the vicinity of β-amyloid plaques. Our animal data shows that infused platelets are found in the liver and partly in the lung, while in the brain platelets were visible to a minor degree. In mice, we did not observe a significant association of platelets with beta-amyloid plaques or vessels. In the brain of Alzheimer postmortem patients platelets could be detected by immunohistochemistry for CD41 and CD62P, but the majority was found in vessels with or without beta-amyloid load, and only a few single platelets migrated deeper into the brain. Our findings suggest that platelets do not migrate into the brains of Alzheimer disease but are concentrated in brain vessels.

  4. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis.

    PubMed

    Jansen, Willemijn J; Ossenkoppele, Rik; Knol, Dirk L; Tijms, Betty M; Scheltens, Philip; Verhey, Frans R J; Visser, Pieter Jelle; Aalten, Pauline; Aarsland, Dag; Alcolea, Daniel; Alexander, Myriam; Almdahl, Ina S; Arnold, Steven E; Baldeiras, Inês; Barthel, Henryk; van Berckel, Bart N M; Bibeau, Kristen; Blennow, Kaj; Brooks, David J; van Buchem, Mark A; Camus, Vincent; Cavedo, Enrica; Chen, Kewei; Chetelat, Gael; Cohen, Ann D; Drzezga, Alexander; Engelborghs, Sebastiaan; Fagan, Anne M; Fladby, Tormod; Fleisher, Adam S; van der Flier, Wiesje M; Ford, Lisa; Förster, Stefan; Fortea, Juan; Foskett, Nadia; Frederiksen, Kristian S; Freund-Levi, Yvonne; Frisoni, Giovanni B; Froelich, Lutz; Gabryelewicz, Tomasz; Gill, Kiran Dip; Gkatzima, Olymbia; Gómez-Tortosa, Estrella; Gordon, Mark Forrest; Grimmer, Timo; Hampel, Harald; Hausner, Lucrezia; Hellwig, Sabine; Herukka, Sanna-Kaisa; Hildebrandt, Helmut; Ishihara, Lianna; Ivanoiu, Adrian; Jagust, William J; Johannsen, Peter; Kandimalla, Ramesh; Kapaki, Elisabeth; Klimkowicz-Mrowiec, Aleksandra; Klunk, William E; Köhler, Sebastian; Koglin, Norman; Kornhuber, Johannes; Kramberger, Milica G; Van Laere, Koen; Landau, Susan M; Lee, Dong Young; de Leon, Mony; Lisetti, Viviana; Lleó, Alberto; Madsen, Karine; Maier, Wolfgang; Marcusson, Jan; Mattsson, Niklas; de Mendonça, Alexandre; Meulenbroek, Olga; Meyer, Philipp T; Mintun, Mark A; Mok, Vincent; Molinuevo, José Luis; Møllergård, Hanne M; Morris, John C; Mroczko, Barbara; Van der Mussele, Stefan; Na, Duk L; Newberg, Andrew; Nordberg, Agneta; Nordlund, Arto; Novak, Gerald P; Paraskevas, George P; Parnetti, Lucilla; Perera, Gayan; Peters, Oliver; Popp, Julius; Prabhakar, Sudesh; Rabinovici, Gil D; Ramakers, Inez H G B; Rami, Lorena; Resende de Oliveira, Catarina; Rinne, Juha O; Rodrigue, Karen M; Rodríguez-Rodríguez, Eloy; Roe, Catherine M; Rot, Uros; Rowe, Christopher C; Rüther, Eckart; Sabri, Osama; Sanchez-Juan, Páscual; Santana, Isabel; Sarazin, Marie; Schröder, Johannes; Schütte, Christin; Seo, Sang W; Soetewey, Femke; Soininen, Hilkka; Spiru, Luiza; Struyfs, Hanne; Teunissen, Charlotte E; Tsolaki, Magda; Vandenberghe, Rik; Verbeek, Marcel M; Villemagne, Victor L; Vos, Stephanie J B; van Waalwijk van Doorn, Linda J C; Waldemar, Gunhild; Wallin, Anders; Wallin, Åsa K; Wiltfang, Jens; Wolk, David A; Zboch, Marzena; Zetterberg, Henrik

    2015-05-19

    Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies. To use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI). Relevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE and Web of Science databases and through personal communication with investigators. Studies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity. Individual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies. Prevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations. The prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95% CI, 8%-13%) to 44% (95% CI, 37%-51%) among participants with normal cognition; from 12% (95% CI, 8%-18%) to 43% (95% CI, 32%-55%) among patients with SCI; and from 27% (95% CI, 23%-32%) to 71% (95% CI, 66%-76%) among patients with MCI. APOE-ε4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE ε4ε4 carriers, 50 years for ε2ε4 carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 carriers, and 95 years for ε2ε3 carriers. Amyloid positivity was more common in highly educated participants but not associated

  5. Induced dimerization of the amyloid precursor protein leads to decreased amyloid-beta protein production.

    PubMed

    Eggert, Simone; Midthune, Brea; Cottrell, Barbara; Koo, Edward H

    2009-10-16

    The amyloid precursor protein (APP) plays a central role in Alzheimer disease (AD) pathogenesis because sequential cleavages by beta- and gamma-secretase lead to the generation of the amyloid-beta (Abeta) peptide, a key constituent in the amyloid plaques present in brains of AD individuals. In several studies APP has recently been shown to form homodimers, and this event appears to influence Abeta generation. However, these studies have relied on APP mutations within the Abeta sequence itself that may affect APP processing by interfering with secretase cleavages independent of dimerization. Therefore, the impact of APP dimerization on Abeta production remains unclear. To address this question, we compared the approach of constitutive cysteine-induced APP dimerization with a regulatable dimerization system that does not require the introduction of mutations within the Abeta sequence. To this end we generated an APP chimeric molecule by fusing a domain of the FK506-binding protein (FKBP) to the C terminus of APP. The addition of the synthetic membrane-permeant drug AP20187 induces rapid dimerization of the APP-FKBP chimera. Using this system we were able to induce up to 70% APP dimers. Our results showed that controlled homodimerization of APP-FKBP leads to a 50% reduction in total Abeta levels in transfected N2a cells. Similar results were obtained with the direct precursor of beta-secretase cleavage, C99/SPA4CT-FKBP. Furthermore, there was no modulation of different Abeta peptide species after APP dimerization in this system. Taken together, our results suggest that APP dimerization can directly affect gamma-secretase processing and that dimerization is not required for Abeta production.

  6. Association between Cerebral Amyloid Deposition and Clinical Factors Including Cognitive Function in Geriatric Depression: Pilot Study Using Amyloid Positron Emission Tomography

    PubMed Central

    Kim, Hye-Geum; Kong, Eun-Jung; Cheon, Eun-Jin; Kim, Hae-Won; Koo, Bon-Hoon

    2016-01-01

    The purpose of this study was to explore the relationship between cerebral amyloid deposition and overall clinical factors including cognitive functions in geriatric depression by using 18F-florbetaben positron emission tomography. Thirteen subjects aged over 60 years who had a history of major depressive disorder and also had subjective memory complaint were included. Of all subjects, 3 subjects judged as amyloid positive, and the others judged as amyloid negative. Their memory, visuospatial functions and attention abilities were negatively correlated with amyloid deposition in specific brain regions, but their language and recognition abilities were not correlated with any region. The amyloid deposition of the whole brain region was significantly negatively correlated with immediate memory. PMID:27776391

  7. Cerebrospinal fluid analysis detects cerebral amyloid-β accumulation earlier than positron emission tomography

    PubMed Central

    Mattsson, Niklas

    2016-01-01

    See Rabinovici (doi:10.1093/brain/aww025) for a scientific commentary on this article. Cerebral accumulation of amyloid-β is thought to be the starting mechanism in Alzheimer’s disease. Amyloid-β can be detected by analysis of cerebrospinal fluid amyloid-β42 or amyloid positron emission tomography, but it is unknown if any of the methods can identify an abnormal amyloid accumulation prior to the other. Our aim was to determine whether cerebrospinal fluid amyloid-β42 change before amyloid PET during preclinical stages of Alzheimer’s disease. We included 437 non-demented subjects from the prospective, longitudinal Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. All underwent 18F-florbetapir positron emission tomography and cerebrospinal fluid amyloid-β42 analysis at baseline and at least one additional positron emission tomography after a mean follow-up of 2.1 years (range 1.1–4.4 years). Group classifications were based on normal and abnormal cerebrospinal fluid and positron emission tomography results at baseline. We found that cases with isolated abnormal cerebrospinal fluid amyloid-β and normal positron emission tomography at baseline accumulated amyloid with a mean rate of 1.2%/year, which was similar to the rate in cases with both abnormal cerebrospinal fluid and positron emission tomography (1.2%/year, P = 0.86). The mean accumulation rate of those with isolated abnormal cerebrospinal fluid was more than three times that of those with both normal cerebrospinal fluid and positron emission tomography (0.35%/year, P = 0.018). The group differences were similar when analysing yearly change in standardized uptake value ratio of florbetapir instead of percentage change. Those with both abnormal cerebrospinal fluid and positron emission tomography deteriorated more in memory and hippocampal volume compared with the other groups (P < 0.001), indicating that they were closer to Alzheimer’s disease dementia. The results were replicated after

  8. Multiple intracranial hemorrhages in a normotensive demented patient: A probable cerebral amyloid angiopathy.

    PubMed

    Chitsaz, Ahmad; Norouzi, Rasul; Marashi, Seyed Mohammad Javad; Salimianfard, Marzieh; Fard, Salman Abbasi

    2012-01-01

    Cerebral amyloid angiopathy (CAA) is the most common cause of lobar intracerebral hemorrhage. Repeated bleeding may be presented with vascular dementia. We have reported a 68-year-old normotensive demented patient with probable CAA presented with hemiparesia, headache and vomiting. According to the experience of this case, it is recommended to consider CAA for normotensive elderly patients presented with multiple and superficial intracerebral hemorrhage.

  9. Multiple intracranial hemorrhages in a normotensive demented patient: A probable cerebral amyloid angiopathy

    PubMed Central

    Chitsaz, Ahmad; Norouzi, Rasul; Marashi, Seyed Mohammad Javad; Salimianfard, Marzieh; Fard, Salman Abbasi

    2012-01-01

    Cerebral amyloid angiopathy (CAA) is the most common cause of lobar intracerebral hemorrhage. Repeated bleeding may be presented with vascular dementia. We have reported a 68-year-old normotensive demented patient with probable CAA presented with hemiparesia, headache and vomiting. According to the experience of this case, it is recommended to consider CAA for normotensive elderly patients presented with multiple and superficial intracerebral hemorrhage. PMID:23248664

  10. Rapidly Sequential and Fatal Hemorrhaging in a Case of Cerebral Amyloid Angiopathy

    PubMed Central

    Bulwa, Zachary B.; Ward, G. Carter; Kramer, Owen N.; Rao, Birju; Wichter, Melvin

    2016-01-01

    Patient: Female, 63 Final Diagnosis: Cerebral amyloid angiopathy Symptoms: Altered mental state • aphasia • hemiplegia Medication: — Clinical Procedure: — Specialty: Neurology Objective: Unusual clinical course Background: Cerebral amyloid angiopathy (CAA) is an increasingly recognized cause of lobar intracerebral hemorrhage (ICH) and cognitive impairment in the aging population. Magnetic resonance imaging (MRI) of cerebral microbleeds is the most reliable option for clinical diagnosis of suspected CAA. The pathophysiology of microbleeds and ICH in CAA is not well understood, but it is thought to be the result of vessel weakening and rupture secondary to amyloid deposition. Little evidence has been established pertaining to the time course of recurrent CAA-related microbleeds or larger hemorrhages. Although several risk factors have been associated with an increased risk of ICH in CAA, there are no current treatment guidelines for recurrent hemorrhaging in CAA. Case Report: We present a rare case of rapidly sequential and fatal lobar hemorrhaging in the setting of suspected CAA, diagnosed by numerous microbleeds on MRI, compounded by the use of subcutaneous heparin in a 63-year-old female patient. Conclusions: This case broadens our understanding of a rarely identified progression of CAA and illustrates the need for further investigation of the use of subcutaneous heparin in the setting of probable CAA. PMID:27853131

  11. The association between cerebral amyloid angiopathy and atherosclerosis in patients with intracerebral hemorrhages.

    PubMed

    Mendel, Tadeusz Andrzej; Wierzba-Bobrowicz, Teresa; Stępień, Tomasz; Szpak, Grażyna Maria

    2013-01-01

    aim of the study: To analyze the incidence and grade of cerebral amyloid angiopathy (CAA) and atherosclerosis (AS) in cerebral vessels in patients who died from spontaneous intracerebral hemorrhage. The clinical diagnosis, based on CT scans of the brain, was made and immunohistochemic neuropathological examinations were performed in patients with intracerebral hemorrhages due to CAA. Cerebral amyloid angiopathy was diagnosed according to the Boston criteria. The Vonsattel and Mountoy scales were used to assess the grade and score of CAA. Atherosclerosis was assessed according to a four-grade scale presented in the Coding Guide from Collaborative Study of Epidemiological Factors in Cerebral Vascular Disease. Of the 189 patients who died due to intracerebral hemorrhages 42 (22%) presented CAA. According to the Vonsattel scale this group comprised 32 (76%) patients who showed severe, 6 (14%) moderate and 4 (10%) mild CAA. Atherosclerosis was diagnosed in the CAA group of patients as follows: 6 (14%) with grade 1; 20 (49%) with grade 2; 9 (20%) with grade 3; and 7 (17%) patients with grade 4. There was no correlation between CAA and AS. The CAA was probably the direct cause of death in part of cases with advanced CAA. The different mechanisms presumably can cause CAA and AS.

  12. Neprilysin protects against cerebral amyloid angiopathy and Aβ-induced degeneration of cerebrovascular smooth muscle cells.

    PubMed

    Miners, James Scott; Kehoe, Patrick; Love, Seth

    2011-09-01

    Neprilysin (NEP), which degrades amyloid-β (Aβ), is expressed by neurons and cerebrovascular smooth muscle cells (CVSMCs). NEP immunolabeling is reduced within cerebral blood vessels of Alzheimer's disease (AD) patients with cerebral amyloid angiopathy (CAA). We have now measured NEP enzyme activity in leptomeningeal and purified cerebral cortical blood vessel preparations from control and AD patients with and without CAA. Measurements were adjusted for smooth muscle actin (SMA) to control for variations in CVSMC content. NEP activity was reduced in CAA, in both controls and AD. In leptomeningeal vessels, NEP activity was related to APOE genotype, being highest in ε2-positive and lowest in ε4-positive brains. To assess the role of NEP in protecting CVSMCs from Aβ toxicity, we measured cell death in primary human adult CVSMCs exposed to Aβ(1-40) , Aβ(1-42) or Aβ(1-40(Dutch variant)) . Aβ(1-42) was most cytotoxic to CVSMCs. Aβ(1-42) -mediated cell death was increased following siRNA-mediated knockdown or thiorphan-mediated inhibition of NEP activity; conversely Aβ(1-42) -mediated cytotoxicity was reduced by the addition of somatostatin and NEP over-expression following transfection with NEP cDNA. Our findings suggest that NEP protects CVSMCs from Aβ toxicity and protects cerebral blood vessels from the development and complications of CAA.

  13. Curcumin Reduces Amyloid Fibrillation of Prion Protein and Decreases Reactive Oxidative Stress

    PubMed Central

    Lin, Chi-Fen; Yu, Kun-Hua; Jheng, Cheng-Ping; Chung, Raymond; Lee, Cheng-I

    2013-01-01

    Misfolding and aggregation into amyloids of the prion protein (PrP) is responsible for the development of fatal transmissible neurodegenerative diseases. Various studies on curcumin demonstrate promise for the prevention of Alzheimer’s disease and inhibition of PrPres accumulation. To evaluate the effect of curcumin on amyloid fibrillation of prion protein, we first investigated the effect of curcumin on mouse prion protein (mPrP) in a cell-free system. Curcumin reduced the prion fibril formation significantly. Furthermore, we monitored the change in apoptosis and reactive oxygen species (ROS) level upon curcumin treatment in mouse neuroblastoma cells (N2a). Curcumin effectively rescues the cells from apoptosis and decreases the ROS level caused by subsequent co-incubation with prion amyloid fibrils. The assays in cell-free mPrP and in N2a cells of this work verified the promising effect of curcumin on the prevention of transmissible neurodegenerative diseases. PMID:25437204

  14. Cortical Amyloid Beta in Cognitively Normal Elderly Adults is Associated with Decreased Network Efficiency within the Cerebro-Cerebellar System

    PubMed Central

    Steininger, Stefanie C.; Liu, Xinyang; Gietl, Anton; Wyss, Michael; Schreiner, Simon; Gruber, Esmeralda; Treyer, Valerie; Kälin, Andrea; Leh, Sandra; Buck, Alfred; Nitsch, Roger M.; Prüssmann, Klaas P.; Hock, Christoph; Unschuld, Paul G.

    2014-01-01

    Background: Deposition of cortical amyloid beta (Aβ) is a correlate of aging and a risk factor for Alzheimer disease (AD). While several higher order cognitive processes involve functional interactions between cortex and cerebellum, this study aims to investigate effects of cortical Aβ deposition on coupling within the cerebro-cerebellar system. Methods: We included 15 healthy elderly subjects with normal cognitive performance as assessed by neuropsychological testing. Cortical Aβ was quantified using (11)carbon-labeled Pittsburgh compound B positron-emission-tomography late frame signals. Volumes of brain structures were assessed by applying an automated parcelation algorithm to three dimensional magnetization-prepared rapid gradient-echo T1-weighted images. Basal functional network activity within the cerebro-cerebellar system was assessed using blood-oxygen-level dependent resting state functional magnetic resonance imaging at the high field strength of 7 T for measuring coupling between cerebellar seeds and cerebral gray matter. A bivariate regression approach was applied for identification of brain regions with significant effects of individual cortical Aβ load on coupling. Results: Consistent with earlier reports, a significant degree of positive and negative coupling could be observed between cerebellar seeds and cerebral voxels. Significant positive effects of cortical Aβ load on cerebro-cerebellar coupling resulted for cerebral brain regions located in inferior temporal lobe, prefrontal cortex, hippocampus, parahippocampal gyrus, and thalamus. Conclusion: Our findings indicate that brain amyloidosis in cognitively normal elderly subjects is associated with decreased network efficiency within the cerebro-cerebellar system. While the identified cerebral regions are consistent with established patterns of increased sensitivity for Aβ-associated neurodegeneration, additional studies are needed to elucidate the relationship between dysfunction of the

  15. Cortical Amyloid Beta in Cognitively Normal Elderly Adults is Associated with Decreased Network Efficiency within the Cerebro-Cerebellar System.

    PubMed

    Steininger, Stefanie C; Liu, Xinyang; Gietl, Anton; Wyss, Michael; Schreiner, Simon; Gruber, Esmeralda; Treyer, Valerie; Kälin, Andrea; Leh, Sandra; Buck, Alfred; Nitsch, Roger M; Prüssmann, Klaas P; Hock, Christoph; Unschuld, Paul G

    2014-01-01

    Deposition of cortical amyloid beta (Aβ) is a correlate of aging and a risk factor for Alzheimer disease (AD). While several higher order cognitive processes involve functional interactions between cortex and cerebellum, this study aims to investigate effects of cortical Aβ deposition on coupling within the cerebro-cerebellar system. We included 15 healthy elderly subjects with normal cognitive performance as assessed by neuropsychological testing. Cortical Aβ was quantified using (11)carbon-labeled Pittsburgh compound B positron-emission-tomography late frame signals. Volumes of brain structures were assessed by applying an automated parcelation algorithm to three dimensional magnetization-prepared rapid gradient-echo T1-weighted images. Basal functional network activity within the cerebro-cerebellar system was assessed using blood-oxygen-level dependent resting state functional magnetic resonance imaging at the high field strength of 7 T for measuring coupling between cerebellar seeds and cerebral gray matter. A bivariate regression approach was applied for identification of brain regions with significant effects of individual cortical Aβ load on coupling. Consistent with earlier reports, a significant degree of positive and negative coupling could be observed between cerebellar seeds and cerebral voxels. Significant positive effects of cortical Aβ load on cerebro-cerebellar coupling resulted for cerebral brain regions located in inferior temporal lobe, prefrontal cortex, hippocampus, parahippocampal gyrus, and thalamus. Our findings indicate that brain amyloidosis in cognitively normal elderly subjects is associated with decreased network efficiency within the cerebro-cerebellar system. While the identified cerebral regions are consistent with established patterns of increased sensitivity for Aβ-associated neurodegeneration, additional studies are needed to elucidate the relationship between dysfunction of the cerebro-cerebellar system and risk for AD.

  16. Chemically treated plasma Aβ is a potential blood-based biomarker for screening cerebral amyloid deposition.

    PubMed

    Park, Jong-Chan; Han, Sun-Ho; Cho, Hyun Jin; Byun, Min Soo; Yi, Dahyun; Choe, Young Min; Kang, Seokjo; Jung, Eun Sun; Won, Su Jin; Kim, Eun Hye; Kim, Yu Kyeong; Lee, Dong Young; Mook-Jung, Inhee

    2017-03-22

    Plasma β-amyloid (Aβ) is a potential candidate for an Alzheimer's disease (AD) biomarker because blood is an easily accessible bio-fluid, which can be collected routinely, and Aβ is one of the major hallmarks of AD pathogenesis in the brain. However, the association between plasma Aβ levels and AD diagnosis is still unclear due to the instability and inaccurate measurements of plasma Aβ levels in the blood of patients with AD. If a consistent value of plasma Aβ from the blood can be obtained, this might help determine whether plasma Aβ is a potential biomarker for AD diagnosis. We predicted the brain amyloid deposit by measuring the plasma Aβ levels. This cross-sectional study included 353 participants (215 cognitively normal, 79 with mild cognitive impairment, and 59 with AD dementia) who underwent Pittsburgh-compound B positron emission tomography (PiB-PET) scans. We treated a mixture of protease inhibitors and phosphatase inhibitors (MPP) and detected plasma Aβ42 and Aβ40 (MPP-Aβ42 and MPP-Aβ40) in a stable manner using xMAP technology. MPP-Aβ40 and MPP-Aβ42/40 (MPP-Aβs) were significantly different between subjects with positive amyloid deposition (PiB+) and those with negative amyloid deposition (PiB-) (P < 0.0001). Furthermore, MPP-Aβ40 (P < 0.0001, r = 0.23) and MPP-Aβ42/40 ratio (P < 0.0001, r = -0.23) showed significant correlation with global PiB deposition (standardized uptake value ratio). In addition, our integrated multivariable (MPP-Aβ42/40, gender, age, and apolipoprotein E genotypes) logistic regression model proposes a new standard for the prediction of cerebral amyloid deposition. MPP-Aβ might be one of the potential blood biomarkers for the prediction of PiB-PET positivity in the brain.

  17. Partial eNOS deficiency causes spontaneous thrombotic cerebral infarction, amyloid angiopathy and cognitive impairment.

    PubMed

    Tan, Xing-Lin; Xue, Yue-Qiang; Ma, Tao; Wang, Xiaofang; Li, Jing Jing; Lan, Lubin; Malik, Kafait U; McDonald, Michael P; Dopico, Alejandro M; Liao, Francesca-Fang

    2015-06-24

    Cerebral infarction due to thrombosis leads to the most common type of stroke and a likely cause of age-related cognitive decline and dementia. Endothelial nitric oxide synthase (eNOS) generates NO, which plays a crucial role in maintaining vascular function and exerting an antithrombotic action. Reduced eNOS expression and eNOS polymorphisms have been associated with stroke and Alzheimer's disease (AD), the most common type of dementia associated with neurovascular dysfunction. However, direct proof of such association is lacking. Since there are no reports of complete eNOS deficiency in humans, we used heterozygous eNOS(+/-) mice to mimic partial deficiency of eNOS, and determine its impact on cerebrovascular pathology and perfusion of cerebral vessels. Combining cerebral angiography with immunohistochemistry, we found thrombotic cerebral infarctions in eNOS(+/-) mice as early as 3-6 months of age but not in eNOS(+/+) mice at any age. Remarkably, vascular occlusions in eNOS(+/-) mice were found almost exclusively in three areas: temporoparietal and retrosplenial granular cortexes, and hippocampus this distribution precisely matching the hypoperfused areas identified in preclinical AD patients. Moreover, progressive cerebral amyloid angiopaphy (CAA), blood brain barrier (BBB) breakdown, and cognitive impairment were also detected in aged eNOS(+/-) mice. These data provide for the first time the evidence that partial eNOS deficiency results in spontaneous thrombotic cerebral infarctions that increase with age, leading to progressive CAA and cognitive impairments. We thus conclude that eNOS(+/-) mouse may represent an ideal model of ischemic stroke to address early and progressive damage in spontaneously-evolving chronic cerebral ischemia and thus, study vascular mechanisms contributing to vascular dementia and AD.

  18. Cerebral β-amyloid deposition predicts HIV-associated neurocognitive disorders in APOE ε4 carriers

    PubMed Central

    Soontornniyomkij, Virawudh; Moore, David J.; Gouaux, Ben; Soontornniyomkij, Benchawanna; Tatro, Erick T.; Umlauf, Anya; Masliah, Eliezer; Levine, Andrew J.; Singer, Elyse J.; Vinters, Harry V.; Gelman, Benjamin B.; Morgello, Susan; Cherner, Mariana; Grant, Igor; Achim, Cristian L.

    2013-01-01

    Objective The apolipoprotein E (APOE) ε4 allele enhances cerebral accumulation of β-amyloid (Aβ) and is a major risk factor for sporadic Alzheimer’s disease (AD). We hypothesized that HIV-associated neurocognitive disorders (HAND) would be associated with the APOE ε4 genotype and cerebral Aβ deposition. Design Clinico-pathological study of HIV-infected adults from four prospective cohorts in the U.S. National NeuroAIDS Tissue Consortium. Methods We used multivariable logistic regressions to model outcomes (Aβ plaques [immunohistochemistry] and HAND [standard criteria]) on predictors (APOE ε4 [allelic discrimination assay], older age [≥ 50 years], Aβ plaques, and their two-way interactions) and co-morbid factors. Results Isocortical Aβ deposits generally occurred as diffuse plaques and mild to moderate amyloid angiopathy. Isocortical phospho-Tau-immunoreactive neurofibrillary lesions were sparse. The APOE ε4 and older age were independently associated with the presence of Aβ plaques (adjusted odds ratio [OR] 10.16 and 5.77 [95% confidence interval (CI) 2.89–35.76 and 1.91–17.48], P=0.0003 and 0.0019, respectively, n=96). The probability of HAND was increased in the presence of Aβ plaques among APOE ε4 carriers (adjusted OR 30.00 [95% CI 1.41–638.63], P=0.029, n=15), but not in non-ε4 carriers (n=57). Conclusion The APOE ε4 and older age increased the likelihood of cerebral Aβ plaque deposition in HIV-infected adults. Generally Aβ plaques in HIV brains were immunohistologically different from those in symptomatic AD brains. Nonetheless, Aβ plaques were associated with HAND among APOE ε4 carriers. The detection of APOE ε4 genotype and cerebral Aβ deposition biomarkers may be useful in identifying living HAND subjects who could benefit from Aβ-targeted therapies. PMID:23018443

  19. Labetalol decreases cerebral perfusion pressure without negatively affecting cerebral blood flow in hypertensive gravidas.

    PubMed

    Belfort, Michael A; Tooke-Miller, Cathy; Allen, John C; Dizon-Townson, Donna; Varner, Michael A

    2002-01-01

    To research the cerebral hemodynamic effects of labetalol in pregnant women with hypertension. Prospective observational study. Tertiary Care Medical Center. Pregnant patients with hypertension. Transcranial Doppler (TCD) ultrasound was used to measure the blood velocity in the middle cerebral arteries (MCA) of eight pregnant patients with hypertension, before and after the administration of a 200 mg oral dose of labetalol. Five patients had severe preeclampsia, and three had chronic hypertension with superimposed preeclampsia. MCA blood velocity and systemic blood pressure were measured simultaneously at the baseline, and at 60 and 180 min after labetalol. Selected cerebral hemodynamic parameters were compared with normative curves. Values outside of the 5th and 95th percentiles were regarded as abnormal. Cerebral perfusion pressure (CPP), resistance area product (RAP), and cerebral flow index (CFI). Patient age, gestational age, and parity were similar to those of the normal women from whom the normative data were obtained. Women with hypertension had higher baseline CPP, MAP, and RAP than normal pregnant women, but their CFI was within the normal range. Labetalol reduced the CPP, as well as the systolic, diastolic, and mean BP significantly at 60 and 180 min without significantly affecting the heart rate, MCA velocities, RAP, or CFI. Labetalol effectively reduces CPP, without affecting cerebral perfusion, primarily by a decrease in systemic blood pressure. This makes it an ideal agent for blood pressure control in severely hypertensive pregnant women.

  20. Senile systemic amyloidosis, cerebral amyloid angiopathy, and dementia in a very old Finnish population.

    PubMed

    Tanskanen, Maarit; Kiuru-Enari, Sari; Tienari, Pentti; Polvikoski, Tuomo; Verkkoniemi, Auli; Rastas, Sari; Sulkava, Raimo; Paetau, Anders

    2006-09-01

    Senile systemic amyloidosis (SSA) and cerebral amyloid angiopathy (CAA) are amyloid disorders, which typically manifest with old age. The aim of our study was to examine the possible association of these disorders in very old Finns. We performed a prospective, population-based post mortem study and used histological and immunohistochemical staining methods to verify the presence of these types of amyloid. All 63 subjects (59% of the 107 individuals 95 years of age or more, who died during the 10-year follow-up study), 53 women and 10 men), had been neurologically examined. The prevalence of SSA and its association with CAA, dementia, and neuropathologically verified AD was analyzed. Overall SSA occurred in 23 (37%) and CAA in 28 (44%) of the 63 subjects. At clinical examination 41 individuals (65%) were demented; 24 (38%) had Alzheimer's disease. SSA showed no association with the presence of CAA (P = 0.45), clinical dementia (P = 0.09), or Alzheimer's disease (P = 0.21), or sex (P = 0.53). Our prospective population based study shows that SSA and CAA are frequent in very old Finns, but they do not associate.

  1. Late onset aura may herald cerebral amyloid angiopathy: A case report.

    PubMed

    Samanci, Bedia; Coban, Oguzhan; Baykan, Betul

    2016-09-01

    Although migraine usually begins in the early decades of life, late onset of migraine with aura is occasionally observed and can occur without headache, causing confusion in the differential diagnosis. A 72-year-old man presented with recurrent episodes of visual aura lasting for 20 minutes. These episodes had started at 57 years of age and were only once accompanied by a severe headache. Magnetic resonance imaging revealed changes in the periventricular white matter, left occipital haemorrhage and subcortical haemosiderin deposits, compatible with cerebral amyloid angiopathy. Previous treatment with antiplatelet drugs was discontinued. His episodes of visual aura stopped on treatment with lamotrigine and add-on treatment with verapamil. In patients with a late onset of migraine aura, doctors must consider other under-recognized causes of transient neurological symptoms, such as cerebral amyloid angiopathy. Blood-sensitive magnetic resonance imaging sequences are the best tool for the early detection of an underlying pathology and therefore treatment with antiplatelet/anticoagulant drugs should be avoided as this may increase the risk of haemorrhage. © International Headache Society 2015.

  2. p75NTR antagonistic cyclic peptide decreases the size of beta amyloid-induced brain inflammation.

    PubMed

    Yaar, Mina; Arble, Bennet L; Stewart, Kenneth B; Qureshi, Nazer H; Kowall, Neil W; Gilchrest, Barbara A

    2008-12-01

    Amyloid beta (Abeta) was shown to bind the 75 kD neurotrophin receptor (p75(NTR)) to induce neuronal death. We synthesized a p75(NTR) antagonistic peptide (CATDIKGAEC) that contains the KGA motif that is present in the toxic part of Abeta and closely resembles the binding site of NGF for p75(NTR). In vivo injections of Abeta into the cerebral cortex of B57BL/6 mice together with the peptide produced significantly less inflammation than simultaneous injections of Abeta and a control (CKETIADGAC, scrambled) peptide injected into the contralateral cortex. These data suggest that blocking the binding of Abeta to p75(NTR) may reduce neuronal loss in Alzheimer's disease.

  3. p75NTR Antagonistic Cyclic Peptide Decreases the Size of β Amyloid-Induced Brain Inflammation

    PubMed Central

    Yaar, Mina; Arble, Bennet L.; Stewart, Kenneth B.; Qureshi, Nazer H.; Kowall, Neil W.

    2010-01-01

    Amyloid beta (Aβ) was shown to bind the 75 kD neurotrophin receptor (p75NTR) to induce neuronal death. We synthesized a p75NTR antagonistic peptide (CATDIKGAEC) that contains the KGA motif that is present in the toxic part of Aβ and closely resembles the binding site of NGF for p75NTR. In vivo injections of Aβ into the cerebral cortex of B57BL/6 mice together with the peptide produced significantly less inflammation than simultaneous injections of Aβ and a control (CKETIADGAC, scrambled) peptide injected into the contralateral cortex. These data suggest that blocking the binding of Aβ to p75NTR may reduce neuronal loss in Alzheimer’s disease. PMID:18807174

  4. Magnesium sulfate decreases cerebral perfusion pressure in preeclampsia.

    PubMed

    Belfort, Michael; Allred, Janalee; Dildy, Gary

    2008-01-01

    To determine the cerebral hemodynamic effect of magnesium sulfate (MgSO4) in preeclampsia. Prospective observational study. Tertiary Care Medical Center. Preeclamptic patients (systolic < 160, diastolic < 110 mmHg). Transcranial Doppler (TCD) of the middle cerebral arteries (MCA) of 15 preeclamptics, before and after IV MgSO4. No vasoactive drugs other than MgSO4 were given. 11 patients with mild range BP (140/90-160/110 mmHg) had measurements at baseline, 30 and 120 minutes after MgSO4, and 7 patients with elevated CPP had baseline and 30 minute measurements. Hemodynamic parameters were compared with normative curves. Mean arterial pressure (MAP), heart rate (HR), cerebral perfusion pressure (CPP), resistance index (RI), resistance area product (RAP), and cerebral flow index (CFI). Eight women had normal baseline CPP, and 11 had normal CFI. 11 had mild preeclampsia range blood pressure and MgSO4 had no significant effect on CPP, CFI, HR, MCA velocities, or RAP but did decrease the MAP in the first 30 minutes (107 +/- 8 to 100 +/- 9 mmHg; p = 0.035), mainly due to a drop in diastolic pressure (87 +/- 10 to 82 +/- 9 mmHg; p = 0.004). 7 patients with elevated baseline CPP had a significant reduction in CPP, but no change in CFI, after MgSO4. MgSO4 does not significantly effect CPP or CFI in preeclamptics with baseline blood pressure in the mild range, but does significantly reduce CPP in those with high baseline CPP. This may be important in the prevention of hypertensive encephalopathy.

  5. New Therapeutic Approaches for Alzheimer’s Disease and Cerebral Amyloid Angiopathy

    PubMed Central

    Saito, Satoshi; Ihara, Masafumi

    2014-01-01

    Accumulating evidence has shown a strong relationship between Alzheimer’s disease (AD), cerebral amyloid angiopathy (CAA), and cerebrovascular disease. Cognitive impairment in AD patients can result from cortical microinfarcts associated with CAA, as well as the synaptic and neuronal disturbances caused by cerebral accumulations of β-amyloid (Aβ) and tau proteins. The pathophysiology of AD may lead to a toxic chain of events consisting of Aβ overproduction, impaired Aβ clearance, and brain ischemia. Insufficient removal of Aβ leads to development of CAA and plays a crucial role in sporadic AD cases, implicating promotion of Aβ clearance as an important therapeutic strategy. Aβ is mainly eliminated by three mechanisms: (1) enzymatic/glial degradation, (2) transcytotic delivery, and (3) perivascular drainage (3-“d” mechanisms). Enzymatic degradation may be facilitated by activation of Aβ-degrading enzymes such as neprilysin, angiotensin-converting enzyme, and insulin-degrading enzyme. Transcytotic delivery can be promoted by inhibition of the receptor for advanced glycation end products (RAGE), which mediates transcytotic influx of circulating Aβ into brain. Successful use of the RAGE inhibitor TTP488 in Phase II testing has led to a Phase III clinical trial for AD patients. The perivascular drainage system seems to be driven by motive force generated by cerebral arterial pulsations, suggesting that vasoactive drugs can facilitate Aβ clearance. One of the drugs promoting this system is cilostazol, a selective inhibitor of type 3 phosphodiesterase. The clearance of fluorescent soluble Aβ tracers was significantly enhanced in cilostazol-treated CAA model mice. Given that the balance between Aβ synthesis and clearance determines brain Aβ accumulation, and that Aβ is cleared by several pathways stated above, multi-drugs combination therapy could provide a mainstream cure for sporadic AD. PMID:25368578

  6. Decreased cerebellar-cerebral connectivity contributes to complex task performance

    PubMed Central

    Knops, André

    2016-01-01

    The cerebellum's role in nonmotor processes is now well accepted, but cerebellar interaction with cerebral targets is not well understood. Complex cognitive tasks activate cerebellar, parietal, and frontal regions, but the effective connectivity between these regions has never been tested. To this end, we used psycho-physiological interactions (PPI) analysis to test connectivity changes of cerebellar and parietal seed regions in complex (2-digit by 1-digit multiplication, e.g., 12 × 3) vs. simple (1-digit by 1-digit multiplication, e.g., 4 × 3) task conditions (“complex − simple”). For cerebellar seed regions (lobule VI, hemisphere and vermis), we found significantly decreased cerebellar-parietal, cerebellar-cingulate, and cerebellar-frontal connectivity in complex multiplication. For parietal seed regions (PFcm, PFop, PFm) we found significantly increased parietal-parietal and parietal-frontal connectivity in complex multiplication. These results suggest that decreased cerebellar-cerebral connectivity contributes to complex task performance. Interestingly, BOLD activity contrasts revealed partially overlapping parietal areas of increased BOLD activity but decreased cerebellar-parietal PPI connectivity. PMID:27334957

  7. Magnetic Resonance Q Mapping Reveals a Decrease in Microvessel Density in the arcAβ Mouse Model of Cerebral Amyloidosis.

    PubMed

    Ielacqua, Giovanna D; Schlegel, Felix; Füchtemeier, Martina; Xandry, Jael; Rudin, Markus; Klohs, Jan

    2015-01-01

    reduction of microvessel density in the old arcAβ mice. We further demonstrated a region-specific association between parenchymal and vascular deposition of β-amyloid and decreased vascular density, without a correlation with the amount of Aβ deposition. We found that Q mapping was more suitable than the hemodynamic read-outs to detect amyloid-related degeneration of the cerebral microvasculature.

  8. Magnetic Resonance Q Mapping Reveals a Decrease in Microvessel Density in the arcAβ Mouse Model of Cerebral Amyloidosis

    PubMed Central

    Ielacqua, Giovanna D.; Schlegel, Felix; Füchtemeier, Martina; Xandry, Jael; Rudin, Markus; Klohs, Jan

    2016-01-01

    . We further demonstrated a region-specific association between parenchymal and vascular deposition of β-amyloid and decreased vascular density, without a correlation with the amount of Aβ deposition. We found that Q mapping was more suitable than the hemodynamic read-outs to detect amyloid-related degeneration of the cerebral microvasculature. PMID:26834622

  9. The amyloid-β₄₂ proxy, amyloid-β(25-35), induces normal human cerebral astrocytes to produce amyloid-β₄₂.

    PubMed

    Dal Prà, Ilaria; Whitfileld, James F; Pacchiana, Raffaella; Bonafini, Clara; Talacchi, Andrea; Chakravarthy, Balu; Armato, Ubaldo; Chiarini, Anna

    2011-01-01

    Astrocytes in amyloid-β (Aβ)₄₂-accumulating human brains afflicted with Alzheimer's disease (AD) upregulate vascular endothelial growth factor (VEGF)-A synthesis and also become loaded with Aβ₄₂. We have already shown that Aβ(25-35) (surrogate of Aβ₄₂)-induced VEGF-A production in 'normoxic' cultures of early passage normal human cerebral astrocytes (NAHAs) is mediated by the stabilization of VEGF gene-stimulating hypoxia-inducible factor (HIF)-1α and nuclear translocation of HIF-1α•HIF-1β complexes. We have now found that treating these NAHAs with Aβ(25-35) also stimulates them to make Aβ₄₂ (appearing in immunoblots as several bands with M(r)'s from 8 kDa upwards), whose levels peak at 48 h (2.8-fold versus 0 h, p < 0.001) and then start falling slowly. This rise of Aβ₄₂ peptide production coincides with a transiently increased flow of HIF-1α (therefore HIF-1α•HIF-1β complexes; at 24 h, 1.5-fold versus 0 h, p < 0.001) into the nucleus and transient surges first of β-secretase (BACE-1/β-S) mRNA expression (1.2-fold versus 0 h, p = 0.013) and activity peaking at 24-h (1.4-fold versus 0 h, p = 0.001), and then of γ-secretase (γ-S) activity cresting at 48 h (1.6-fold versus 0 h, p < 0.001) that cleave the Aβ₄₂ peptides from amyloid-β protein precursor. Since the genes encoding components of these two secretases have the same HIF-1α•HIF-1β-responsive elements in their promoters as the VEGF gene, these observations suggest that the Aβ₄₂ released from neurons in the AD brain can recruit associated astrocytes via HIF-1α•HIF-1β signaling into the pool of Aβ₄₂-producing cells. In other words, Aβ₄₂ begets Aβ₄₂ in NAHAs.

  10. Minocycline Reduces Spontaneous Hemorrhage in Mouse Models of Cerebral Amyloid Angiopathy

    PubMed Central

    Liao, Fan; Xiao, Qingli; Kraft, Andrew; Gonzales, Ernie; Perez, Ron; Greenberg, Steven M.; Holtzman, David; Lee, Jin-Moo

    2015-01-01

    Background and Purpose Cerebral Amyloid Angiopathy (CAA) is a common cause of recurrent intracerebral hemorrhage (ICH) in the elderly. Previous studies have shown that CAA induces inflammation and expression of matrix metalloproteinase-2 and -9 (gelatinases) in amyloid-laden vessels. Here, we inhibited both using minocycline in CAA mouse models to determine if spontaneous ICH could be reduced. Methods Tg2576 (n=16) and 5×FAD/ApoE4 knock-in mice (n=16), aged to 17 and 12 months, respectively, were treated with minocycline (50 mg/kg, i.p.) or saline every other day for two months. Brains were extracted and stained with X-34 (to quantify amyloid), Perl’s blue (to quantify hemorrhage), and immunostained to examined Aβ load, gliosis (GFAP, Iba-1), and vascular markers of blood-brain-barrier integrity (ZO-1 and collagen IV). Brain extracts were used to quantify mRNA for a variety of inflammatory genes. Results Minocycline treatment significantly reduced hemorrhage frequency in the brains of Tg2576 and 5×FAD/ApoE4 mice relative to the saline-treated mice, without affecting CAA load. Gliosis (GFAP and Iba-1 immunostaining), gelatinase activity, and expression of a variety of inflammatory genes (MMP-9, Nox4, CD45, S-100b, Iba-1) were also significantly reduced. Higher levels of microvascular tight junction and basal lamina proteins were found in the brains of minocycline-treated Tg2576 mice relative to saline-treated controls. Conclusions Minocycline reduced gliosis, inflammatory gene expression, gelatinase activity, and spontaneous hemorrhage in two different mouse models of CAA, supporting the importance of MMP-related and inflammatory pathways in ICH pathogenesis. As an FDA-approved drug, minocycline might be considered for clinical trials to test efficacy in preventing CAA-related ICH. PMID:25944329

  11. Iron transport across the blood-brain barrier; Development, neurovascular regulation and cerebral amyloid angiopathy

    PubMed Central

    McCarthy, Ryan C; Kosman, Daniel J

    2014-01-01

    There are two barriers for iron entry into the brain: 1) the brain-cerebrospinal fluid (CSF) barrier and 2) the blood-brain barrier (BBB). Here, we review the literature on developmental iron accumulation by the brain, focusing on the transport of iron through the brain microvascular endothelial cells (BMVEC) of the BBB. We review the iron trafficking proteins which may be involved in the iron flux across BMVEC and discuss the plausible mechanisms of BMVEC iron uptake and efflux. We suggest a model for how BMVEC iron uptake and efflux are regulated and a mechanism by which the majority of iron is trafficked across the developing BBB under the direct guidance of neighboring astrocytes. Thus, we place brain iron uptake in the context of the neurovascular unit of the adult brain. Last, we propose that BMVEC iron is involved in the aggregation of amyloid-β peptides leading to the progression of cerebral amyloid angiopathy which often occurs prior to dementia and the onset of Alzheimer's disease. PMID:25355056

  12. Oligomerization of beta-amyloid of the Alzheimer's and the Dutch-cerebral-haemorrhage types.

    PubMed Central

    Sian, A K; Frears, E R; El-Agnaf, O M; Patel, B P; Manca, M F; Siligardi, G; Hussain, R; Austen, B M

    2000-01-01

    A novel ELISA has been developed which detects oligomerization of beta-amyloid (A beta). Oligomerization, fibrillization and neurotoxicity of native A beta associated with Alzheimer's disease (AD) type has been compared with E22Q A beta (amyloid beta-protein containing residues 1--40 with the native Glu at residue 22 changed to Gln) implicated in Dutch cerebral haemorrhage disease. Solutions of A beta rapidly yield soluble oligomers in a concentration-dependent manner, which are detected by the ELISA, and by size-exclusion gel chromatography. Conformational changes from disordered to beta-sheet occur more slowly than oligomerization, and fibrils are produced after prolonged incubation. The E22Q A beta oligomerizes, changes conformation and fibrillizes more rapidly than the native form and produces shorter stubbier fibrils. Aged fibrillar preparations of E22Q A beta are more potent than aged fibrils of native A beta in inducing apoptotic changes and toxic responses in human neuroblastoma cell lines, whereas low-molecular-mass oligomers in briefly incubated solutions are much less potent. The differences in the rates of oligomerization of the two A beta forms, their conformational behaviour over a range of pH values, and NMR data reported elsewhere, are consistent with a molecular model of oligomerization in which strands of A beta monomers initially overcome charge repulsion to form dimers in parallel beta-sheet arrangement, stabilized by intramolecular hydrophobic interactions, with amino acids of adjacent chains in register. PMID:10861242

  13. Matrix metalloproteinase inhibition reduces oxidative stress associated with cerebral amyloid angiopathy in vivo in transgenic mice.

    PubMed

    Garcia-Alloza, Monica; Prada, Claudia; Lattarulo, Carli; Fine, Sara; Borrelli, Laura A; Betensky, Rebecca; Greenberg, Steven M; Frosch, Matthew P; Bacskai, Brian J

    2009-06-01

    Cerebral amyloid angiopathy (CAA), characterized by extracellular beta-amyloid peptide (Abeta) deposits in vessel walls, is present in the majority of cases of Alzheimer's disease and is a major cause of hemorrhagic stroke. Although the molecular pathways activated by vascular Abeta are poorly understood, extracellular matrix metalloproteinases (MMP) and Abeta-induced oxidative stress appear to play important roles. We adapted fluorogenic assays for MMP activity and reactive oxygen species generation for use in vivo. Using multiphoton microscopy in APPswe/PS1dE9 and Tg-2576 transgenic mice, we observed strong associations between MMP activation, oxidative stress, and CAA deposition in leptomeningeal vessels. Antioxidant treatment with alpha-phenyl-N-tert-butyl-nitrone reduced oxidative stress associated with CAA (approximately 50% reduction) without affecting MMP activation. Conversely, a selection of agents that inhibit MMP by different mechanisms of action, including minocycline, simvastatin, and GM6001, reduced not only CAA-associated MMP activation (approximately 30-40% reduction) but also oxidative stress (approximately 40% reduction). The inhibitors of MMP did not have direct antioxidant effects. Treatment of animals with alpha-phenyl-N-tert-butyl-nitrone or minocycline did not have a significant effect on CAA progression rates. These data suggest a close association between Abeta-related MMP activation and oxidative stress in vivo and raise the possibility that treatment with MMP inhibitors may have beneficial effects by indirectly reducing the oxidative stress associated with CAA.

  14. Cerebral amyloid angiopathy in Down syndrome and sporadic and autosomal-dominant Alzheimer's disease.

    PubMed

    Carmona-Iragui, María; Balasa, Mircea; Benejam, Bessy; Alcolea, Daniel; Fernández, Susana; Videla, Laura; Sala, Isabel; Sánchez-Saudinós, María Belén; Morenas-Rodriguez, Estrella; Ribosa-Nogué, Roser; Illán-Gala, Ignacio; Gonzalez-Ortiz, Sofía; Clarimón, Jordi; Schmitt, Frederick; Powell, David K; Bosch, Beatriz; Lladó, Albert; Rafii, Michael S; Head, Elizabeth; Molinuevo, José Luis; Blesa, Rafael; Videla, Sebastián; Lleó, Alberto; Sánchez-Valle, Raquel; Fortea, Juan

    2017-04-29

    We aimed to investigate if cerebral amyloid angiopathy (CAA) is more frequent in genetically determined than in sporadic early-onset forms of Alzheimer's disease (AD) (early-onset AD [EOAD]). Neuroimaging features of CAA, apolipoprotein (APOE), and cerebrospinal fluid amyloid β (Aβ) 40 levels were studied in subjects with Down syndrome (DS, n = 117), autosomal-dominant AD (ADAD, n = 29), sporadic EOAD (n = 42), and healthy controls (n = 68). CAA was present in 31%, 38%, and 12% of cognitively impaired DS, symptomatic ADAD, and sporadic EOAD subjects and in 13% and 4% of cognitively unimpaired DS individuals and healthy controls, respectively. APOE ε4 genotype was borderline significantly associated with CAA in sporadic EOAD (P = .06) but not with DS or ADAD. There were no differences in Aβ040 levels between groups or between subjects with and without CAA. CAA is more frequently found in genetically determined AD than in sporadic EOAD. Cerebrospinal fluid Aβ40 levels are not a useful biomarker for CAA in AD. Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  15. Iron transport across the blood-brain barrier: development, neurovascular regulation and cerebral amyloid angiopathy.

    PubMed

    McCarthy, Ryan C; Kosman, Daniel J

    2015-02-01

    There are two barriers for iron entry into the brain: (1) the brain-cerebrospinal fluid (CSF) barrier and (2) the blood-brain barrier (BBB). Here, we review the literature on developmental iron accumulation by the brain, focusing on the transport of iron through the brain microvascular endothelial cells (BMVEC) of the BBB. We review the iron trafficking proteins which may be involved in the iron flux across BMVEC and discuss the plausible mechanisms of BMVEC iron uptake and efflux. We suggest a model for how BMVEC iron uptake and efflux are regulated and a mechanism by which the majority of iron is trafficked across the developing BBB under the direct guidance of neighboring astrocytes. Thus, we place brain iron uptake in the context of the neurovascular unit of the adult brain. Last, we propose that BMVEC iron is involved in the aggregation of amyloid-β peptides leading to the progression of cerebral amyloid angiopathy which often occurs prior to dementia and the onset of Alzheimer's disease.

  16. High levels of homocysteine results in cerebral amyloid angiopathy in mice.

    PubMed

    Li, Jian-Guo; Praticò, Domenico

    2015-01-01

    High levels of homocysteine is a risk factor for developing Alzheimer's disease (AD), and the effect that this amino acid has on amyloid-β (Aβ) protein precursor metabolism is considered one of the potential mechanism(s) involved in this effect. However, despite consistent literature indicating that this condition results in brain parenchyma amyloidosis, no data are available on whether it may also influence the amount of Aβ deposited in the vasculature. To test this hypothesis, we implemented a model of diet-inducing high homocysteinemia in AD transgenic mice, 3xTg, and assessed them for the development of cerebral amyloid angiopathy (CAA). Compared with controls, mice with high homocysteine showed a significant increase in the amount of Aβ deposited in the brain vasculature, which was not associated with histological evidence of microhemorrhage occurrence. Mice with high homocysteine had a significant reduction in steady state level of the apolipoprotein E, which is a main Aβ chaperon protein, but no changes in its receptor, the low-density-lipoprotein-receptor-1. Our data demonstrate that a diet-induced high homocysteine level favors the development of CAA via a reduction of Aβ clearance and transport within the brain. Therapeutic approaches aimed at restoring brain apolipoprotein E levels should be considered in individuals carrying this environmental risk factor in order to reduce the incidence of homocysteine-dependent CAA.

  17. Development of a Smart Nano-vehicle to Target Cerebrovascular Amyloid Deposits and Brain Parenchymal Plaques Observed in Alzheimer's Disease and Cerebral Amyloid Angiopathy

    PubMed Central

    Agyare, Edward K.; Curran, Geoffry L.; Ramakrishnan, Muthu; Yu, Caroline C.; Poduslo, Joseph F.; Kandimalla, Karunya K.

    2013-01-01

    Purpose To design a smart nano-vehicle (SNV) capable of permeating the blood-brain barrier (BBB) to target cerebrovascular amyloid formed in both Alzheimer's disease (AD) and cerebrovascular amyloid angiopathy (CAA). Methods SNV consists of a chitosan polymeric core prepared through ionic gelation with tripolyphosphate. A polyamine modified F(ab') portion of IgG4.1, an anti-amyloid antibody, was coated as a biosensor on the SNV surface. A similar polymeric core coated with bovine serum albumin (BSA) served as a control nano-vehicle (CNV). The BBB uptake of 125I-SNVs and 125I-CNVs was evaluated in mice. The uptake and transcytosis of SNVs and CNVs across bovine brain microvascular endothelial cells (BBMECs) was evaluated using flow cytometry and confocal microscopy. Results Plasma clearance of 125I-SNVs was nine times higher than that of the 125I-CNVs. However, the uptake of 125I-SNVs in various brain regions was about 8 to 11 times higher than that of 125I-CNVs. The uptake of FITC-BSA loaded SNVs in BBMECs was twice the uptake of FITC-BSA loaded CNVs. Confocal micrographs demonstrated the uptake and transcytosis of Alexa Fluor 647 labeled SNVs, but not CNVs, across the BBMEC monolayer. Conclusions SNVs are capable of carrying a payload of model protein across the BBB to target cerebral amyloid. PMID:18712585

  18. Role of prostacyclin signaling in endothelial production of soluble amyloid precursor protein-α in cerebral microvessels.

    PubMed

    He, Tongrong; Santhanam, Anantha Vijay R; Lu, Tong; d'Uscio, Livius V; Katusic, Zvonimir S

    2017-01-01

    We tested hypothesis that activation of the prostacyclin (PGI2) receptor (IP receptor) signaling pathway in cerebral microvessels plays an important role in the metabolism of amyloid precursor protein (APP). In human brain microvascular endothelial cells activation of IP receptor with the stable analogue of PGI2, iloprost, stimulated expression of amyloid precursor protein and a disintegrin and metalloprotease 10 (ADAM10), resulting in an increased production of the neuroprotective and anticoagulant molecule, soluble APPα (sAPPα). Selective agonist of IP receptor, cicaprost, and adenylyl cyclase activator, forskolin, also enhanced expression of amyloid precursor protein and ADAM10. Notably, in cerebral microvessels of IP receptor knockout mice, protein levels of APP and ADAM10 were reduced. In addition, iloprost increased protein levels of peroxisome proliferator-activated receptor δ (PPARδ) in human brain microvascular endothelial cells. PPARδ-siRNA abolished iloprost-augmented protein expression of ADAM10. In contrast, GW501516 (a selective agonist of PPARδ) upregulated ADAM10 and increased production of sAPPα. Genetic deletion of endothelial PPARδ (ePPARδ(-/-)) in mice significantly reduced cerebral microvascular expression of ADAM10 and production of sAPPα. In vivo treatment with GW501516 increased sAPPα content in hippocampus of wild type mice but not in hippocampus of ePPARδ(-/-) mice. Our findings identified previously unrecognized role of IP-PPARδ signal transduction pathway in the production of sAPPα in cerebral microvasculature. © The Author(s) 2015.

  19. Aura attacks from acute convexity subarachnoid haemorrhage not due to cerebral amyloid angiopathy.

    PubMed

    Field, D K; Kleinig, T J

    2011-02-01

    Convexity subarachnoid haemorrhage (cSAH) has recently been recognised as a cause of recurrent aura-like symptoms, mimicking transient ischaemic attacks (TIAs). Subarachnoid haemorrhage and recurrent aura-like episodes can occur in patients with cerebral amyloid angiopathy (CAA), which has been the presumed cause in the majority of reported cases. However, this syndrome can occur following cSAH secondary to other conditions, and it is important for clinicians to investigate and manage such patients appropriately. Case series. We describe two patients who presented with recurrent stereotyped transient neurological symptoms in the setting of acute cSAH identified on MRI. In one patient, SAH occurred secondary to cerebral venous sinus thrombosis. In the other, SAH was due to extension of a traumatic subdural haematoma. Conditions other than CAA can cause the clinicoradiological syndrome of cSAH with recurrent TIA-like events. Gradient echo or susceptibility-weighted imaging should be included in the diagnostic work-up of patients presenting with such events. When cSAH is detected, the full differential diagnosis for this should be considered. Aetiologies other than CAA can cause this syndrome and management can vary greatly depending on the underlying cause.

  20. Identification of neurovascular changes associated with cerebral amyloid angiopathy from subject-specific hemodynamic response functions.

    PubMed

    Williams, Rebecca J; Goodyear, Bradley G; Peca, Stefano; McCreary, Cheryl R; Frayne, Richard; Smith, Eric E; Pike, G Bruce

    2017-01-01

    Cerebral amyloid angiopathy (CAA) is a small-vessel disease preferentially affecting posterior brain regions. Recent evidence has demonstrated the efficacy of functional MRI in detecting CAA-related neurovascular injury, however, it is unknown whether such perturbations are associated with changes in the hemodynamic response function (HRF). Here we estimated HRFs from two different brain regions from block design activation data, in light of recent findings demonstrating how block designs can accurately reflect HRF parameter estimates while maximizing signal detection. Patients with a diagnosis of probable CAA and healthy controls performed motor and visual stimulation tasks. Time-to-peak (TTP), full-width at half-maximum (FWHM), and area under the curve (AUC) of the estimated HRFs were compared between groups and to MRI features associated with CAA including cerebral microbleed (CMB) count. Motor HRFs in CAA patients showed significantly wider FWHM ( P = 0.006) and delayed TTP ( P = 0.03) compared to controls. In the patient group, visual HRF FWHM was positively associated with CMB count ( P = 0.03). These findings indicate that hemodynamic abnormalities in patients with CAA may be reflected in HRFs estimated from block designs across different brain regions. Moreover, visual FWHM may be linked to structural MR indications associated with CAA.

  1. Schisandrin B protects PC12 cells by decreasing the expression of amyloid precursor protein and vacuolar protein sorting 35★

    PubMed Central

    Yan, Mingmin; Mao, Shanping; Dong, Huimin; Liu, Baohui; Zhang, Qian; Pan, Gaofeng; Fu, Zhiping

    2012-01-01

    PC12 cell injury was induced using 20 μM amyloid β-protein 25–35 to establish a model of Alzheimer's disease. The cells were then treated with 5, 10, and 25 μM Schisandrin B. Methylthiazolyldiphenyl-tetrazolium bromide assays and Hoechst 33342 staining results showed that with increasing Schisandrin B concentration, the survival rate of PC12 cells injured by amyloid β-protein 25–35 gradually increased and the rate of apoptosis gradually decreased. Reverse transcription-PCR, immunocytochemical staining and western blot results showed that with increasing Schisandrin B concentration, the mRNA and protein expression of vacuolar protein sorting 35 and amyloid precursor protein were gradually decreased. Vacuolar protein sorting 35 and amyloid precursor protein showed a consistent trend for change. These findings suggest that 5, 10, and 25 μM Schisandrin B antagonizes the cellular injury induced by amyloid β-protein 25–35 in a dose-dependent manner. This may be caused by decreasing the expression of vacuolar protein sorting 35 and amyloid precursor protein. PMID:25745458

  2. Statins Decrease Neuroinflammation and Prevent Cognitive Impairment after Cerebral Malaria

    PubMed Central

    Reis, Patricia A.; Estato, Vanessa; da Silva, Tathiany I.; d'Avila, Joana C.; Siqueira, Luciana D.; Assis, Edson F.; Bozza, Patricia T.; Bozza, Fernando A.; Tibiriça, Eduardo V.; Zimmerman, Guy A.; Castro-Faria-Neto, Hugo C.

    2012-01-01

    Cerebral malaria (CM) is the most severe manifestation of Plasmodium falciparum infection in children and non-immune adults. Previous work has documented a persistent cognitive impairment in children who survive an episode of CM that is mimicked in animal models of the disease. Potential therapeutic interventions for this complication have not been investigated, and are urgently needed. HMG-CoA reductase inhibitors (statins) are widely prescribed for cardiovascular diseases. In addition to their effects on the inhibition of cholesterol synthesis, statins have pleiotropic immunomodulatory activities. Here we tested if statins would prevent cognitive impairment in a murine model of cerebral malaria. Six days after infection with Plasmodium berghei ANKA (PbA) mice displayed clear signs of CM and were treated with chloroquine, or chloroquine and lovastatin. Intravital examination of pial vessels of infected animals demonstrated a decrease in functional capillary density and an increase in rolling and adhesion of leukocytes to inflamed endothelium that were reversed by treatment with lovastatin. In addition, oedema, ICAM-1, and CD11b mRNA levels were reduced in lovastatin-treated PbA-infected mice brains. Moreover, HMOX-1 mRNA levels are enhanced in lovastatin-treated healthy and infected brains. Oxidative stress and key inflammatory chemokines and cytokines were reduced to non-infected control levels in animals treated with lovastatin. Fifteen days post-infection cognitive dysfunction was detected by a battery of cognition tests in animals rescued from CM by chloroquine treatment. In contrast, it was absent in animals treated with lovastatin and chloroquine. The outcome was similar in experimental bacterial sepsis, suggesting that statins have neuroprotective effects in severe infectious syndromes in addition to CM. Statin treatment prevents neuroinflammation and blood brain barrier dysfunction in experimental CM and related conditions that are associated with

  3. Endothelium-specific amyloid precursor protein deficiency causes endothelial dysfunction in cerebral arteries.

    PubMed

    d'Uscio, Livius V; He, Tongrong; Santhanam, Anantha V; Katusic, Zvonimir S

    2017-01-01

    The exact physiological function of amyloid-β precursor protein (APP) in endothelial cells is unknown. Endothelium-specific APP-deficient (eAPP(-/-)) mice were created to gain new insights into the role of APP in the control of vascular endothelial function. Endothelium-dependent relaxations to acetylcholine were significantly impaired in basilar arteries of global APP knockout (APP(-/-)) and eAPP(-/-) mice ( P < 0.05). In contrast, endothelium-independent relaxations to nitric oxide (NO)-donor diethylamine-NONOate were unchanged. Western blot analysis revealed that protein expression of endothelial nitric oxide synthase (eNOS) was significantly downregulated in large cerebral arteries of APP(-/-) mice and eAPP(-/-) mice as compared to respective wild-type littermates ( P < 0.05). Furthermore, basal levels of cyclic guanosine monophosphate (cGMP) were also significantly reduced in large cerebral arteries of APP-deficient mice ( P < 0.05). In contrast, protein expression of prostacyclin synthase as well as levels of cyclic adenosine monophosphate (cAMP) was not affected by genetic inactivation of APP in endothelial cells. By using siRNA to knockdown APP in cultured human brain microvascular endothelial cells we also found a significant downregulation of eNOS mRNA and protein expressions in APP-deficient endothelium ( P < 0.05). These findings indicate that under physiological conditions, expression of APP in cerebral vascular endothelium plays an important protective function by maintaining constitutive expression of eNOS .

  4. Alzheimer-related decrease in CYFIP2 links amyloid production to tau hyperphosphorylation and memory loss

    PubMed Central

    Tiwari, Sachin Suresh; Mizuno, Keiko; Ghosh, Anshua; Aziz, Wajeeha; Troakes, Claire; Daoud, Jason; Golash, Vidushi; Noble, Wendy; Hortobágyi, Tibor

    2016-01-01

    Characteristic features of Alzheimer’s disease are memory loss, plaques resulting from abnormal processing of amyloid precursor protein (APP), and presence of neurofibrillary tangles and dystrophic neurites containing hyperphosphorylated tau. Currently, it is not known what links these abnormalities together. Cytoplasmic FMR1 interacting protein 2 (CYFIP2) has been suggested to regulate mRNA translation at synapses and this may include local synthesis of APP and alpha-calcium/calmodulin-dependent kinase II, a kinase that can phosphorylate tau. Further, CYFIP2 is part of the Wiskott-Aldrich syndrome protein-family verprolin-homologous protein complex, which has been implicated in actin polymerization at synapses, a process thought to be required for memory formation. Our previous studies on p25 dysregulation put forward the hypothesis that CYFIP2 expression is reduced in Alzheimer’s disease and that this contributes to memory impairment, abnormal APP processing and tau hyperphosphorylation. Here, we tested this hypothesis. First, in post-mortem tissue CYFIP2 expression was reduced by ∼50% in severe Alzheimer’s hippocampus and superior temporal gyrus when normalized to expression of a neuronal or synaptic marker protein. Interestingly, there was also a trend for decreased expression in mild Alzheimer’s disease hippocampus. Second, CYFIP2 expression was reduced in old but not in young Tg2576 mice, a model of familial Alzheimer’s disease. Finally, we tested the direct impact of reduced CYFIP2 expression in heterozygous null mutant mice. We found that in hippocampus this reduced expression causes an increase in APP and β-site amyloid precursor protein cleaving enzyme 1 (BACE1) protein, but not mRNA expression, and elevates production of amyloid-β42. Reduced CYFIP2 expression also increases alpha-calcium/calmodulin-dependent kinase II protein expression, and this is associated with hyperphosphorylation of tau at serine-214. The reduced expression also

  5. Acat1 knockdown gene therapy decreases amyloid-β in a mouse model of Alzheimer's disease.

    PubMed

    Murphy, Stephanie R; Chang, Catherine Cy; Dogbevia, Godwin; Bryleva, Elena Y; Bowen, Zachary; Hasan, Mazahir T; Chang, Ta-Yuan

    2013-08-01

    Both genetic inactivation and pharmacological inhibition of the cholesteryl ester synthetic enzyme acyl-CoA:cholesterol acyltransferase 1 (ACAT1) have shown benefit in mouse models of Alzheimer's disease (AD). In this study, we aimed to test the potential therapeutic applications of adeno-associated virus (AAV)-mediated Acat1 gene knockdown in AD mice. We constructed recombinant AAVs expressing artificial microRNA (miRNA) sequences, which targeted Acat1 for knockdown. We demonstrated that our AAVs could infect cultured mouse neurons and glia and effectively knockdown ACAT activity in vitro. We next delivered the AAVs to mouse brains neurosurgically, and demonstrated that Acat1-targeting AAVs could express viral proteins and effectively diminish ACAT activity in vivo, without inducing appreciable inflammation. We delivered the AAVs to the brains of 10-month-old AD mice and analyzed the effects on the AD phenotype at 12 months of age. Acat1-targeting AAV delivered to the brains of AD mice decreased the levels of brain amyloid-β and full-length human amyloid precursor protein (hAPP), to levels similar to complete genetic ablation of Acat1. This study provides support for the potential therapeutic use of Acat1 knockdown gene therapy in AD.

  6. Induction of ketosis may improve mitochondrial function and decrease steady-state amyloid-beta precursor protein (APP) levels in the aged dog.

    PubMed

    Studzinski, Christa M; MacKay, William A; Beckett, Tina L; Henderson, Samuel T; Murphy, M Paul; Sullivan, Patrick G; Burnham, W McIntyre

    2008-08-21

    Region specific declines in the cerebral glucose metabolism are an early and progressive feature of Alzheimer's disease (AD). Such declines occur pre-symptomatically and offer a potential point of intervention in developing AD therapeutics. Medium chain triglycerides (MCTs), which are rapidly converted to ketone bodies, were tested for their ability to provide an alternate energy source to neurons suffering from compromised glucose metabolism. The present study determined the short-term effects of ketosis in aged dogs, a natural model of amyloidosis. The animals were administered a 2 g/kg/day dose of MCTs for 2 months. Mitochondrial function and oxidative damage assays were then conducted on the frontal and parietal lobes. Amyloid-beta (Abeta), amyloid precursor protein (APP) processing and beta-site APP cleaving enzyme (BACE1) assays were conducted on the frontal, parietal and occipital lobes. Aged dogs receiving MCTs, as compared to age-matched controls, showed dramatically improved mitochondrial function, as evidenced by increased active respiration rates. This effect was most prominent in the parietal lobe. The improved mitochondrial function may have been due to a decrease in oxidative damage, which was limited to the mitochondrial fraction. Steady-state APP levels were also decreased in the parietal lobe after short-term MCT administration. Finally, there was a trend towards a decrease in total Abeta levels in the parietal lobe. BACE1 levels remained unchanged. Combined, these findings suggest that short-term MCT administration improves energy metabolism and decreases APP levels in the aged dog brain.

  7. Spontaneous convexity subarachnoid haemorrhage: Clinical series of 3 patients with associated cerebral amyloid angiopathy.

    PubMed

    García Estévez, D A; García-Dorrego, R M; Nieto-Baltar, B; Marey-Garrido, M; Hierro-Torner, T

    2017-05-01

    Convexity subarachnoid haemorrhage (cSAH) is a rare type of spontaneous, non-traumatic, and nonaneurysmal SAH characterised by blood collections in one or more cortical sulci in the convexity of the brain; the aetiology varies. We report a clinical case series of 3 patients with cSAH associated with probable cerebral amyloid angiopathy (CAA) who presented with focal sensory seizures and responded well to corticosteroid treatment. Case 1 was a 67-year-old man reporting right-sided paroxysmal sensory episodes with Jacksonian progression, cheiro-oral symptoms, and motor dysphasia. Case 2 was a 79-year-old man reporting left-sided paroxysmal episodes with cheiro-oral signs and dysarthria. Case 3 was a 71-year-old woman also reporting recurrent left cheiro-oral signs and dysarthria. None of the patients had headache or clinical dementia. Aneurysms were ruled out using MR angiography. Brain CT scan detected an isolated hyperintensity in a sulcus of the frontal convexity; brain gradient echo T2-weighted MRI sequences showed meningeal haemosiderosis and microbleeds. However, no atrophy was identified in medial temporal lobes including the hippocampal formation. All patients had low levels of beta-amyloid in CSF, low values on the Hulstaert index and high levels of phosphorylated tau protein. Patients were initially treated with prednisone and levetiracetam, but symptoms recurred in 2 patients after prednisone was discontinued. We present a series of 3 patients with cSAH associated with CAA, characterised by a stereotypical syndrome responding well to corticoid treatment; there were no cases of headache or clinical dementia. Copyright © 2015 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

  8. Amyloid-β Peptide on Sialyl-LewisX-Selectin-Mediated Membrane Tether Mechanics at the Cerebral Endothelial Cell Surface

    PubMed Central

    Askarova, Sholpan; Sun, Zhe; Sun, Grace Y.; Meininger, Gerald A.; Lee, James C-M.

    2013-01-01

    Increased deposition of amyloid-β peptide (Aβ) at the cerebral endothelial cell (CEC) surface has been implicated in enhancement of transmigration of monocytes across the brain blood barrier (BBB) in Alzheimer's disease (AD). In this study, quantitative immunofluorescence microscopy (QIM) and atomic force microscopy (AFM) with cantilevers biofunctionalized by sialyl-Lewisx (sLex) were employed to investigate Aβ-altered mechanics of membrane tethers formed by bonding between sLex and p-selectin at the CEC surface, the initial mechanical step governing the transmigration of monocytes. QIM results indicated the ability for Aβ to increase p-selectin expression at the cell surface and promote actin polymerization in both bEND3 cells (immortalized mouse CECs) and human primary CECs. AFM data also showed the ability for Aβ to increase cell stiffness and adhesion probability in bEND3 cells. On the contrary, Aβ lowered the overall force of membrane tether formation (Fmtf), and produced a bimodal population of Fmtf, suggesting subcellular mechanical alterations in membrane tethering. The lower Fmtf population was similar to the results obtained from cells treated with an F-actin-disrupting drug, latrunculin A. Indeed, AFM results also showed that both Aβ and latrunculin A decreased membrane stiffness, suggesting a lower membrane-cytoskeleton adhesion, a factor resulting in lower Fmtf. In addition, these cerebral endothelial alterations induced by Aβ were abrogated by lovastatin, consistent with its anti-inflammatory effects. In sum, these results demonstrated the ability for Aβ to enhance p-selectin expression at the CEC surface and induce cytoskeleton reorganization, which in turn, resulted in changes in membrane-cytoskeleton adhesion and membrane tethering, mechanical factors important in transmigration of monocytes through the BBB. PMID:23593361

  9. Amyloid-β peptide on sialyl-Lewis(X)-selectin-mediated membrane tether mechanics at the cerebral endothelial cell surface.

    PubMed

    Askarova, Sholpan; Sun, Zhe; Sun, Grace Y; Meininger, Gerald A; Lee, James C-M

    2013-01-01

    Increased deposition of amyloid-β peptide (Aβ) at the cerebral endothelial cell (CEC) surface has been implicated in enhancement of transmigration of monocytes across the brain blood barrier (BBB) in Alzheimer's disease (AD). In this study, quantitative immunofluorescence microscopy (QIM) and atomic force microscopy (AFM) with cantilevers biofunctionalized by sialyl-Lewis(x) (sLe(x)) were employed to investigate Aβ-altered mechanics of membrane tethers formed by bonding between sLe(x) and p-selectin at the CEC surface, the initial mechanical step governing the transmigration of monocytes. QIM results indicated the ability for Aβ to increase p-selectin expression at the cell surface and promote actin polymerization in both bEND3 cells (immortalized mouse CECs) and human primary CECs. AFM data also showed the ability for Aβ to increase cell stiffness and adhesion probability in bEND3 cells. On the contrary, Aβ lowered the overall force of membrane tether formation (Fmtf ), and produced a bimodal population of Fmtf , suggesting subcellular mechanical alterations in membrane tethering. The lower Fmtf population was similar to the results obtained from cells treated with an F-actin-disrupting drug, latrunculin A. Indeed, AFM results also showed that both Aβ and latrunculin A decreased membrane stiffness, suggesting a lower membrane-cytoskeleton adhesion, a factor resulting in lower Fmtf . In addition, these cerebral endothelial alterations induced by Aβ were abrogated by lovastatin, consistent with its anti-inflammatory effects. In sum, these results demonstrated the ability for Aβ to enhance p-selectin expression at the CEC surface and induce cytoskeleton reorganization, which in turn, resulted in changes in membrane-cytoskeleton adhesion and membrane tethering, mechanical factors important in transmigration of monocytes through the BBB.

  10. Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer's disease.

    PubMed

    Adlard, Paul A; Perreau, Victoria M; Pop, Viorela; Cotman, Carl W

    2005-04-27

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there are few therapeutics that affect the underlying disease mechanism. Recent epidemiological studies, however, suggest that lifestyle changes may slow the onset/progression of AD. Here we have used TgCRND8 mice to examine directly the interaction between exercise and the AD cascade. Five months of voluntary exercise resulted in a decrease in extracellular amyloid-beta (Abeta) plaques in the frontal cortex (38%; p = 0.018), the cortex at the level of the hippocampus (53%; p = 0.0003), and the hippocampus (40%; p = 0.06). This was associated with decreased cortical Abeta1-40 (35%; p = 0.005) and Abeta1-42 (22%; p = 0.04) (ELISA). The mechanism appears to be mediated by a change in the processing of the amyloid precursor protein (APP) after short-term exercise, because 1 month of activity decreased the proteolytic fragments of APP [for alpha-C-terminal fragment (alpha-CTF), 54% and p = 0.04; for beta-CTF, 35% and p = 0.03]. This effect was independent of mRNA/protein changes in neprilysin and insulin-degrading enzyme and, instead, may involve neuronal metabolism changes that are known to affect APP processing and to be regulated by exercise. Long-term exercise also enhanced the rate of learning of TgCRND8 animals in the Morris water maze, with significant (p < 0.02) reductions in escape latencies over the first 3 (of 6) trial days. In support of existing epidemiological studies, this investigation demonstrates that exercise is a simple behavioral intervention sufficient to inhibit the normal progression of AD-like neuropathology in the TgCRND8 mouse model.

  11. Regional cerebral blood flow estimated by early PiB uptake is reduced in mild cognitive impairment and associated with age in an amyloid-dependent manner.

    PubMed

    Gietl, Anton F; Warnock, Geoffrey; Riese, Florian; Kälin, Andrea M; Saake, Antje; Gruber, Esmeralda; Leh, Sandra E; Unschuld, Paul G; Kuhn, Felix P; Burger, Cyrill; Mu, Linjing; Seifert, Burkhardt; Nitsch, Roger M; Schibli, Roger; Ametamey, Simon M; Buck, Alfred; Hock, Christoph

    2015-04-01

    Early uptake of [(11)C]-Pittsburgh Compound B (ePiB, 0-6 minutes) estimates cerebral blood flow. We studied ePiB in 13 PiB-negative and 10 PiB-positive subjects with mild cognitive impairment (MCI, n = 23) and 11 PiB-positive and 74 PiB-negative cognitively healthy elderly control subjects (HCS, n = 85) in 6 bilateral volumes of interest: posterior cingulate cortex (PCC), hippocampus (hipp), temporoparietal region, superior parietal gyrus, parahippocampal gyrus (parahipp), and inferior frontal gyrus (IFG) for the associations with cognitive status, age, amyloid deposition, and apolipoprotein E ε4-allele. We observed no difference in ePiB between PiB-positive and -negative subjects and carriers and noncarriers. EPiB decreased with age in PiB-positive subjects in bilateral superior parietal gyrus, bilateral temporoparietal region, right IFG, right PCC, and left parahippocampal gyrus but not in PiB-negative subjects. MCI had lower ePiB than HCS (left PCC, left IFG, and left and right hipp). Lowest ePiB values were found in MCI of 70 years and older, who also displayed high cortical PiB binding. This suggests that lowered regional cerebral blood flow indicated by ePiB is associated with age in the presence but not in the absence of amyloid pathology.

  12. Convexity subarachnoid haemorrhage has a high risk of intracerebral haemorrhage in suspected cerebral amyloid angiopathy.

    PubMed

    Wilson, D; Hostettler, I C; Ambler, G; Banerjee, G; Jäger, H R; Werring, D J

    2017-04-01

    The risk of future symptomatic intracerebral haemorrhage (sICH) remains uncertain in patients with acute convexity subarachnoid haemorrhage (cSAH) associated with suspected cerebral amyloid angiopathy (CAA). We assessed the risk of future sICH in patients presenting to our comprehensive stroke service with acute non-traumatic cSAH due to suspected CAA, between 2011 and 2016. We conducted a systematic search and pooled analysis including our cohort and other published studies including similar cohorts. Our hospital cohort included 20 patients (mean age 69 years; 60% male); 12 (60%) had probable CAA, and 6 (30%) had possible CAA according to the modified Boston criteria; two did not meet CAA criteria because of age <55 years, but were judged likely to be due to CAA. Fourteen patients (70%) had cortical superficial siderosis; 12 (60%) had cerebral microbleeds. Over a mean follow-up period of 19 months, 2 patients (9%) suffered sICH, both with probable CAA (annual sICH risk for probable CAA 8%). In a pooled analysis including our cohort and eight other studies (n = 172), the overall sICH rate per patient-year was 16% (95% CI 11-24%). In those with probable CAA (n = 104), the sICH rate per patient-year was 19% (95% CI 13-27%), compared to 7% (95% CI 3-15%) for those without probable CAA (n = 72). Patients with acute cSAH associated with suspected CAA are at high risk of future sICH (16% per patient-year); probable CAA might carry the highest risk.

  13. Mapping the landscape of cerebral amyloid angiopathy research: an informetric analysis perspective.

    PubMed

    Charidimou, Andreas; Fox, Zoe; Werring, David J; Song, Min

    2016-03-01

    To quantitatively analyse the research output and major trends in the field of cerebral amyloid angiopathy (CAA) over six decades, from 1954 to 2014, using advanced informetrics methods, we systematically identified CAA-related articles from PubMed, collected metadata and performed productivity analysis, copublication analysis, and network and content analysis over defined time periods. Linear regression was used to investigate these relationships. Changes in CAA research themes (2000-2014) were defined using a topic modelling technique. A total of 2340 CAA papers were published between 1954 and 2014. The mean number (3.03; 95% CI 2.62 to 3.45; p<0.0001) and mean rate (0.13%; 95% CI 0.11% to 0.15%; p<0.0001) of CAA publications increased yearly. Analysis of copublication networks over 5-year periods from 1990 to 2014, revealed a great increase in the total number of connected investigators publishing on CAA (coefficient 16.74; 95% CI 14 to 19.49; p<0.0001) as well as the interactions between them (coefficient 73.53; 95% CI 52.03 to 89.03; p<0.0001). Further analysis of the network characteristics showed that in the past 15 years, copublication networks became not only larger, but also more connected and coherent. Content analysis identified 16 major CAA research themes and their differential evolution in the past 15 years, with the following main trends: (A) limited focus on vascular cognitive impairment; (B) a shift in emphasis towards neuroimaging, cerebral microbleeds and diagnostic aspects and away from pathological aspects; and (3) a reduced emphasis on basic biology apart from an increased focus on mouse models and perivascular drainage. Our study reveals the rapidly developing nature of the CAA research landscape, providing a novel quantitative and objective basis for identifying unmet needs and new directions. Our findings support the idea of a collaborative culture in the field, encouraging international research initiatives.

  14. Caffeine reverses cognitive impairment and decreases brain amyloid-beta levels in aged Alzheimer's disease mice.

    PubMed

    Arendash, Gary W; Mori, Takashi; Cao, Chuanhai; Mamcarz, Malgorzata; Runfeldt, Melissa; Dickson, Alexander; Rezai-Zadeh, Kavon; Tane, Jun; Citron, Bruce A; Lin, Xiaoyang; Echeverria, Valentina; Potter, Huntington

    2009-01-01

    We have recently shown that Alzheimer's disease (AD) transgenic mice given a moderate level of caffeine intake (the human equivalent of 5 cups of coffee per day) are protected from development of otherwise certain cognitive impairment and have decreased hippocampal amyloid-beta (Abeta) levels due to suppression of both beta-secretase (BACE1) and presenilin 1 (PS1)/gamma-secretase expression. To determine if caffeine intake can have beneficial effects in "aged" APPsw mice already demonstrating cognitive impairment, we administered caffeine in the drinking water of 18-19 month old APPsw mice that were impaired in working memory. At 4-5 weeks into caffeine treatment, those impaired transgenic mice given caffeine (Tg/Caff) exhibited vastly superior working memory compared to the continuing impairment of control transgenic mice. In addition, Tg/Caff mice had substantially reduced Abeta deposition in hippocampus (decrease 40%) and entorhinal cortex (decrease 46%), as well as correlated decreases in brain soluble Abeta levels. Mechanistically, evidence is provided that caffeine suppression of BACE1 involves the cRaf-1/NFkappaB pathway. We also determined that caffeine concentrations within human physiological range effectively reduce active and total glycogen synthase kinase 3 levels in SweAPP N2a cells. Even with pre-existing and substantial Abeta burden, aged APPsw mice exhibited memory restoration and reversal of AD pathology, suggesting a treatment potential of caffeine in cases of established AD.

  15. Colocalization of cerebral iron with Amyloid beta in Mild Cognitive Impairment.

    PubMed

    van Bergen, J M G; Li, X; Hua, J; Schreiner, S J; Steininger, S C; Quevenco, F C; Wyss, M; Gietl, A F; Treyer, V; Leh, S E; Buck, F; Nitsch, R M; Pruessmann, K P; van Zijl, P C M; Hock, C; Unschuld, P G

    2016-10-17

    Quantitative Susceptibility Mapping (QSM) MRI at 7 Tesla and 11-Carbon Pittsburgh-Compound-B PET were used for investigating the relationship between brain iron and Amyloid beta (Aβ) plaque-load in a context of increased risk for Alzheimer's disease (AD), as reflected by the Apolipoprotein E ε4 (APOE-e4) allele and mild cognitive impairment (MCI) in elderly subjects. Carriers of APOE-e4 with normal cognition had higher cortical Aβ-plaque-load than non-carriers. In MCI an association between APOE-e4 and higher Aβ-plaque-load was observable both for cortical and subcortical brain-regions. APOE-e4 and MCI was also associated with higher cortical iron. Moreover, cerebral iron significantly affected functional coupling, and was furthermore associated with increased Aβ-plaque-load (R(2)-adjusted = 0.80, p < 0.001) and APOE-e4 carrier status (p < 0.001) in MCI. This study confirms earlier reports on an association between increased brain iron-burden and risk for neurocognitive dysfunction due to AD, and indicates that disease-progression is conferred by spatial colocalization of brain iron deposits with Aβ-plaques.

  16. Cerebral amyloid angiopathy-related atraumatic convexal subarachnoid hemorrhage: an ARIA before the tsunami

    PubMed Central

    Martínez-Lizana, Eva; Carmona-Iragui, María; Alcolea, Daniel; Gómez-Choco, Manuel; Vilaplana, Eduard; Sánchez-Saudinós, María B; Clarimón, Jordi; Hernández-Guillamon, Mar; Munuera, Josep; Gelpi, Ellen; Gómez-Anson, Beatriz; de Juan-Delago, Manel; Delgado-Mederos, Raquel; Montaner, Joan; Ois, Angel; Amaro, Sergi; Blesa, Rafael; Martí-Fàbregas, Joan; Lleó, Alberto; Fortea, Juan

    2015-01-01

    Atraumatic convexal subarachnoid hemorrhage (cSAH) in elderly patients is a rare entity that has been associated with cerebral amyloid angiopathy (CAA) and intracerebral hematomas (ICH). To characterize this entity and to study these associations, 22 patients over 60 with cSAH were included in a multicenter ambispective cohort study. Clinical data, magnetic resonance imaging (MRI) studies, APOE genotyping, and cerebrospinal fluid (CSF) biomarkers were evaluated. Results were compared with data from healthy controls (HC), non-cSAH CAA patients (CAAo), and Alzheimer disease patients. Convexal subarachnoid hemorrhage presented with transient sensory or motor symptoms. At follow-up (median 30.7 months), 5 patients had died, 6 survivors showed functional disability (modified Rankins Scale (mRS)>2), and 12 cognitive impairment. Four patients had prior ICH and six had an ICH during follow-up. CSF-Aß40 and Aß42 levels were lower in cSAH and CAAo compared with HC. Convexal subarachnoid hemorrhage presented an APOE-ɛ2 overrepresentation and CAAo had an APOE-ɛ4 overrepresentation. On MRI, all patients fulfilled CAA-modified Boston criteria and 9 showed cortical ischemia in the surrounding cortex or the vicinity of superficial siderosis. The neuropathologic study, available in one patient, showed severe CAA and advanced Alzheimer-type pathology. Convexal subarachnoid hemorrhage in the elderly is associated with cognitive impairment and lobar ICH occurrence. Our findings support the existence of an underlying CAA pathology. PMID:25735919

  17. Colocalization of cerebral iron with Amyloid beta in Mild Cognitive Impairment

    PubMed Central

    van Bergen, J. M. G.; Li, X.; Hua, J.; Schreiner, S. J.; Steininger, S. C.; Quevenco, F. C.; Wyss, M.; Gietl, A. F.; Treyer, V.; Leh, S. E.; Buck, F.; Nitsch, R. M.; Pruessmann, K. P.; van Zijl, P. C. M.; Hock, C.; Unschuld, P. G.

    2016-01-01

    Quantitative Susceptibility Mapping (QSM) MRI at 7 Tesla and 11-Carbon Pittsburgh-Compound-B PET were used for investigating the relationship between brain iron and Amyloid beta (Aβ) plaque-load in a context of increased risk for Alzheimer's disease (AD), as reflected by the Apolipoprotein E ε4 (APOE-e4) allele and mild cognitive impairment (MCI) in elderly subjects. Carriers of APOE-e4 with normal cognition had higher cortical Aβ-plaque-load than non-carriers. In MCI an association between APOE-e4 and higher Aβ-plaque-load was observable both for cortical and subcortical brain-regions. APOE-e4 and MCI was also associated with higher cortical iron. Moreover, cerebral iron significantly affected functional coupling, and was furthermore associated with increased Aβ-plaque-load (R2-adjusted = 0.80, p < 0.001) and APOE-e4 carrier status (p < 0.001) in MCI. This study confirms earlier reports on an association between increased brain iron-burden and risk for neurocognitive dysfunction due to AD, and indicates that disease-progression is conferred by spatial colocalization of brain iron deposits with Aβ-plaques. PMID:27748454

  18. Mitofusin-2 knockdown increases ER-mitochondria contact and decreases amyloid β-peptide production.

    PubMed

    Leal, Nuno Santos; Schreiner, Bernadette; Pinho, Catarina Moreira; Filadi, Riccardo; Wiehager, Birgitta; Karlström, Helena; Pizzo, Paola; Ankarcrona, Maria

    2016-09-01

    Mitochondria are physically and biochemically in contact with other organelles including the endoplasmic reticulum (ER). Such contacts are formed between mitochondria-associated ER membranes (MAM), specialized subregions of ER, and the outer mitochondrial membrane (OMM). We have previously shown increased expression of MAM-associated proteins and enhanced ER to mitochondria Ca(2+) transfer from ER to mitochondria in Alzheimer's disease (AD) and amyloid β-peptide (Aβ)-related neuronal models. Here, we report that siRNA knockdown of mitofusin-2 (Mfn2), a protein that is involved in the tethering of ER and mitochondria, leads to increased contact between the two organelles. Cells depleted in Mfn2 showed increased Ca(2+) transfer from ER to mitchondria and longer stretches of ER forming contacts with OMM. Interestingly, increased contact resulted in decreased concentrations of intra- and extracellular Aβ40 and Aβ42 . Analysis of γ-secretase protein expression, maturation and activity revealed that the low Aβ concentrations were a result of impaired γ-secretase complex function. Amyloid-β precursor protein (APP), β-site APP-cleaving enzyme 1 and neprilysin expression as well as neprilysin activity were not affected by Mfn2 siRNA treatment. In summary, our data shows that modulation of ER-mitochondria contact affects γ-secretase activity and Aβ generation. Increased ER-mitochondria contact results in lower γ-secretase activity suggesting a new mechanism by which Aβ generation can be controlled. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  19. Docosahexaenoic acid-induced amelioration on impairment of memory learning in amyloid beta-infused rats relates to the decreases of amyloid beta and cholesterol levels in detergent-insoluble membrane fractions.

    PubMed

    Hashimoto, Michio; Hossain, Shahdat; Agdul, Haqu; Shido, Osamu

    2005-12-30

    We investigated the effects of dietary administration of docosahexaenoic acid (DHA; C22:6n-3) on the levels of amyloid beta (A beta) peptide (1-40) and cholesterol in the nonionic detergent Triton 100 x-insoluble membrane fractions (DIFs) of the cerebral cortex and, also, on learning-related memory in an animal model of Alzheimer's disease (AD) rats infused with A beta peptide (1-40) into the cerebral ventricle. The infusion increased the levels of A beta peptide and cholesterol in the DIFs concurrently with a significant increase in reference memory errors (measured by eight-arm radial-maze tasks) compared with those of vehicle rats. Conversely, the dietary administration of DHA to AD-model rats decreased the levels of A beta peptide and cholesterol in the DIFs, with the decrease being more prominent in the DHA-administered rats. Regression analysis revealed a significant positive correlation between A beta peptide and each of cholesterol, palmitic acid and stearic acid, and between the number of reference memory errors and each of cholesterol, palmitic, stearic and oleic acid; moreover, a significant negative correlation was observed between the number of reference memory errors and the molar ratio of DHA to palmitic plus stearic acid. These results suggest that DHA-induced protection of memory deficits in AD-model rats is related to the interactions of cholesterol, palmitic acid or stearic acid with A beta peptides in DIFs where DHA ameliorates these interactions.

  20. Cerebral Palsy Symptoms in Children Decreased Following Massage Therapy

    ERIC Educational Resources Information Center

    Hernandez-Reif, Maria; Field, Tiffany; Largie, Shay; Diego, Miguel; Manigat, Natasha; Seoanes, Jacqueline; Bornstein, Joan

    2005-01-01

    Twenty young children (mean age = 32 months) with cerebral palsy (CP) recruited from early intervention programs received 30 minutes of massage or reading twice weekly for 12 weeks. The children receiving massage therapy showed fewer physical symptoms including reduced spasticity, less rigid muscle tone overall and in the arms, and improved fine…

  1. Cerebral Palsy Symptoms in Children Decreased Following Massage Therapy

    ERIC Educational Resources Information Center

    Hernandez-Reif, Maria; Field, Tiffany; Largie, Shay; Diego, Miguel; Manigat, Natasha; Seoanes, Jacqueline; Bornstein, Joan

    2005-01-01

    Twenty young children (mean age = 32 months) with cerebral palsy (CP) recruited from early intervention programs received 30 minutes of massage or reading twice weekly for 12 weeks. The children receiving massage therapy showed fewer physical symptoms including reduced spasticity, less rigid muscle tone overall and in the arms, and improved fine…

  2. Possible involvement of NO/NOS signaling in hippocampal amyloid-beta production induced by transient focal cerebral ischemia in aged rats.

    PubMed

    Li, Song; Wang, Wei; Wang, Che; Tang, Yi-Yuan

    2010-02-12

    In the present study, to define the roles of nitric oxide (NO) signaling in amyloid-beta (A beta) production after transient cerebral ischemia, extracellular levels of NO and A beta were monitored by intracerebral microdialysis in the hippocampus of aged rats exposed to transient middle cerebral artery occlusion and reperfusion (MCAO/R). The results indicated that 1-h MCAO significantly upregulated hippocampal NO and A beta levels. In addition, the NO elevation preceded the A beta changes. The Western blotting suggested that acute hypoperfusion could increase the expression of beta-secretase 1 (BACE1) but not BACE2. The enhanced NO concentration in acute stage of MCAO/R was coincident with increased eNOS expression, while in subacute stage was coincident with increased iNOS and nNOS. Our results also indicated that pretreatment of L-NAME, one non-selective NOS inhibitor could decrease the BACE1 expression, reverse both NO and A beta changes and rescue the delayed neuronal death. These preliminary findings indicated that activation of NOS/NO signaling system could trigger A beta production through BACE1 pathway during acute ischemic episode. The present data may be important in understanding, at least in part, the pathological role of NO/NOS system involved in hippocampal A beta production and neuronal damage induced by transient cerebral ischemia.

  3. Cerebral amyloid angiopathy-related cognitive impairment: The search for a specific neuropsychological pattern.

    PubMed

    Planton, M; Raposo, N; Albucher, J-F; Pariente, J

    2017-10-06

    Cerebral amyloid angiopathy is diagnosed in stroke units after lobar intracerebral hemorrhage. CAA can also be diagnosed in memory clinics when patients are referred for cognitive impairment assessment, and may be a reason for admission to emergency or neurology departments because of rapidly progressive cognitive or neurological decline, or a transient focal neurological episode. CAA may even be observed in older community-dwelling individuals. Neuropsychological impairment in CAA has been described over the past 20 years. The symptoms most commonly reported are perceptual speed, episodic memory, semantic memory, attention and executive function, and global cognitive impairments. Psychiatric symptoms, such as personality changes, behavioral disturbances and depression, have been more recently described. CAA is also a risk factor for the development of dementia, and its relationship with Alzheimer's disease has been demonstrated in post-mortem studies. Yet, despite the increase in literature on CAA-related cognitive and psychiatric symptoms, the specific characteristics of symptoms in CAA are difficult to assess because of the substantial prevalence of comorbidities such as small vessel disease due to high blood pressure, Lewy body disease and, of course, AD, all of which act as important confounding factors. Also, within the entity of CAA itself, the additive and perhaps synergistic effects of each lesion on cognition remain to be assessed. In the present paper, the focus is on the latest evidence of neuropsychological impairment observed in CAA patients, and the emergence of a possible specific neuropsychological profile due to CAA is also discussed. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  4. Acute Convexity Subarachnoid Hemorrhage Related to Cerebral Amyloid Angiopathy: Clinicoradiological Features and Outcome.

    PubMed

    Calviere, Lionel; Cuvinciuc, Victor; Raposo, Nicolas; Faury, Alexandre; Cognard, Christophe; Larrue, Vincent; Viguier, Alain; Bonneville, Fabrice

    2016-05-01

    The specificities of acute convexity subarachnoid hemorrhage (cSAH) related to cerebral amyloid angiopathy (CAA) and its evolution are not well known. We aimed to describe the clinicoradiological pattern, the magnetic resonance imaging (MRI) evolution, and the risk of recurrent bleeding in such patients. Among consecutive patients with an acute nontraumatic cSAH, subjects with available MRI who meet the modified Boston criteria for probable CAA were included. Review of medical records, MRI findings, and follow-up data was performed. Twenty-three patients (14 women; mean age ± standard deviation: 75.9 ± 7.3 years) were included. cSAH was revealed by transient focal neurological episodes (TFNEs) in 18 of 23 (78.3%) patients. In all patients, acute cSAH appeared as a sulcal fluid-attenuated inversion recovery hyperintensity and GRE T2 hypointensity. Cortical superficial siderosis and cortical microbleeds, respectively, were observed in 21 (91.3%) and 20 (86.9%) patients. Twenty patients (87%) had available follow-up data with a mean duration of 29.8 ± 20.2 months. Recurrent TFNEs occurred in 40% of patients. Acute cSAH evolved into cortical superficial siderosis in all patients. New subarachnoid bleedings defined by recurrent acute cSAH (n = 8) or extension of siderosis (n = 14) were detected in 83.3% of the patients. Lobar intracerebral hemorrhage (ICH) occurred in 7 patients (35%). CAA-related cSAH has a specific pattern defined by a high prevalence of TFNEs and cortical superficial siderosis, with a high risk of recurrent bleeding, either cSAH or lobar ICH. The systematic evolution from cSAH to focal cortical superficial siderosis reveals data on siderosis physiopathology. Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  5. Imaging features of intracerebral hemorrhage with cerebral amyloid angiopathy: Systematic review and meta-analysis.

    PubMed

    Samarasekera, Neshika; Rodrigues, Mark Alexander; Toh, Pheng Shiew; Salman, Rustam Al-Shahi

    2017-01-01

    We sought to summarize Computed Tomography (CT)/Magnetic Resonance Imaging (MRI) features of intracerebral hemorrhage (ICH) associated with cerebral amyloid angiopathy (CAA) in published observational radio-pathological studies. In November 2016, two authors searched OVID Medline (1946-), Embase (1974-) and relevant bibliographies for studies of imaging features of lobar or cerebellar ICH with pathologically proven CAA ("CAA-associated ICH"). Two authors assessed studies' diagnostic test accuracy methodology and independently extracted data. We identified 22 studies (21 cases series and one cross-sectional study with controls) of CT features in 297 adults, two cross-sectional studies of MRI features in 81 adults and one study which reported both CT and MRI features in 22 adults. Methods of CAA assessment varied, and rating of imaging features was not masked to pathology. The most frequently reported CT features of CAA-associated ICH in 21 case series were: subarachnoid extension (pooled proportion 82%, 95% CI 69-93%, I2 = 51%, 12 studies) and an irregular ICH border (64%, 95% CI 32-91%, I2 = 85%, five studies). CAA-associated ICH was more likely to be multiple on CT than non-CAA ICH in one cross-sectional study (CAA-associated ICH 7/41 vs. non-CAA ICH 0/42; χ2 = 7.8, p = 0.005). Superficial siderosis on MRI was present in 52% of CAA-associated ICH (95% CI 39-65%, I2 = 35%, 3 studies). Subarachnoid extension and an irregular ICH border are common imaging features of CAA-associated ICH, but methodologically rigorous diagnostic test accuracy studies are required to determine the sensitivity and specificity of these features.

  6. Vascular and parenchymal amyloid pathology in an Alzheimer disease knock-in mouse model: interplay with cerebral blood flow

    PubMed Central

    2014-01-01

    Background Accumulation and deposition of β-amyloid peptides (Aβ) in the brain is a central event in the pathogenesis of Alzheimer’s disease (AD). Besides the parenchymal pathology, Aβ is known to undergo active transport across the blood–brain barrier and cerebral amyloid angiopathy (CAA) is a prominent feature in the majority of AD. Although impaired cerebral blood flow (CBF) has been implicated in faulty Aβ transport and clearance, and cerebral hypoperfusion can exist in the pre-clinical phase of Alzheimer’s disease (AD), it is still unclear whether it is one of the causal factors for AD pathogenesis, or an early consequence of a multi-factor condition that would lead to AD at late stage. To study the potential interaction between faulty CBF and amyloid accumulation in clinical-relevant situation, we generated a new amyloid precursor protein (APP) knock-in allele that expresses humanized Aβ and a Dutch mutation in addition to Swedish/London mutations and compared this line with an equivalent knock-in line but in the absence of the Dutch mutation, both crossed onto the PS1M146V knock-in background. Results Introduction of the Dutch mutation results in robust CAA and parenchymal Aβ pathology, age-dependent reduction of spatial learning and memory deficits, and CBF reduction as detected by fMRI. Direct manipulation of CBF by transverse aortic constriction surgery on the left common carotid artery caused differential changes in CBF in the anterior and middle region of the cortex, where it is reduced on the left side and increased on the right side. However these perturbations in CBF resulted in the same effect: both significantly exacerbate CAA and amyloid pathology. Conclusions Our study reveals a direct and positive link between vascular and parenchymal Aβ; both can be modulated by CBF. The new APP knock-in mouse model recapitulates many symptoms of AD including progressive vascular and parenchymal Aβ pathology and behavioral deficits in the absence

  7. 99mTc(CO)3-Labeled Benzothiazole Derivatives Preferentially Bind Cerebrovascular Amyloid: Potential Use as Imaging Agents for Cerebral Amyloid Angiopathy.

    PubMed

    Jia, Jianhua; Cui, Mengchao; Dai, Jiapei; Liu, Boli

    2015-08-03

    Cerebral amyloid angiopathy (CAA) is a disorder affecting the elderly that is characterized by amyloid-β (Aβ) deposition in blood vessel walls of the brain. A series of 99mTc(CO)3-labeled benzothiazole derivatives as potential SPECT imaging probes for cerebrovascular Aβ deposition is reported. Rhenium surrogate displayed high affinities to Aβ aggregates with Ki values ranging from 106 to 42 nM, and they strongly stained Aβ deposits in transgenic mice (Tg) and Alzheimer's disease (AD) patients. In vitro autoradiography on brain sections of Tg and AD patients confirmed that [99mTc]24 possessed sufficient affinity for Aβ plaques, and [99mTc]24 could only label Aβ deposition in blood vessels but not Aβ plaques in the parenchyma of the brain of AD patients. Moreover, [99mTc]24 possessed favorable initial uptake (1.21% ID/g) and fast blood washout (blood2 min/blood60 min=23) in normal mice. These preliminary results suggest that [99mTc]24 may be used as an Aβ imaging probe for the detection of CAA.

  8. Elongation of the C-terminal domain of an anti-amyloid β single-chain variable fragment increases its thermodynamic stability and decreases its aggregation tendency

    PubMed Central

    Rivera-Hernández, Geovanny; Marín-Argany, Marta; Blasco-Moreno, Bernat; Bonet, Jaume; Oliva, Baldomero; Villegas, Sandra

    2013-01-01

    Amyloid β (Aβ) immunotherapy is considered a promising approach to Alzheimer disease treatment. In contrast to the use of complete antibodies, administration of single-chain variable fragments (scFv) has not been associated with either meningoencephalitis or cerebral hemorrhage. ScFv-h3D6 is known to preclude cytotoxicity of the Aβ1–42 peptide by removing its oligomers from the amyloid pathway. As is the case for other scFv molecules, the recombinant production of scFv-h3D6 is limited by its folding and stability properties. Here, we show that its urea-induced unfolding pathway is characterized by the presence of an intermediate state composed of the unfolded VL domain and the folded VH domain, which suggests the VL domain as a target for thermodynamic stability redesign. The modeling of the 3D structure revealed that the VL domain, located at the C-terminal of the molecule, was ending before its latest β-strand was completed. Three elongation mutants, beyond VL-K107, showed increased thermodynamic stability and lower aggregation tendency, as determined from urea denaturation experiments and Fourier-transform infrared spectroscopy, respectively. Because the mutants maintained the capability of removing Aβ-oligomers from the amyloid pathway, we expect these traits to increase the half-life of scFv-h3D6 in vivo and, consequently, to decrease the effective doses. Our results led to the improvement of a potential Alzheimer disease treatment and may be extrapolated to other class-I scFv molecules of therapeutic interest. PMID:23924802

  9. Elongation of the C-terminal domain of an anti-amyloid β single-chain variable fragment increases its thermodynamic stability and decreases its aggregation tendency.

    PubMed

    Rivera-Hernández, Geovanny; Marin-Argany, Marta; Blasco-Moreno, Bernat; Bonet, Jaume; Oliva, Baldo; Villegas, Sandra

    2013-01-01

    Amyloid β (Aβ) immunotherapy is considered a promising approach to Alzheimer disease treatment. In contrast to the use of complete antibodies, administration of single-chain variable fragments (scFv) has not been associated with either meningoencephalitis or cerebral hemorrhage. ScFv-h3D6 is known to preclude cytotoxicity of the Aβ 1-42 peptide by removing its oligomers from the amyloid pathway. As is the case for other scFv molecules, the recombinant production of scFv-h3D6 is limited by its folding and stability properties. Here, we show that its urea-induced unfolding pathway is characterized by the presence of an intermediate state composed of the unfolded VL domain and the folded VH domain, which suggests the VL domain as a target for thermodynamic stability redesign. The modeling of the 3D structure revealed that the VL domain, located at the C-terminal of the molecule, was ending before its latest β-strand was completed. Three elongation mutants, beyond VL-K107, showed increased thermodynamic stability and lower aggregation tendency, as determined from urea denaturation experiments and Fourier-transform infrared spectroscopy, respectively. Because the mutants maintained the capability of removing Aβ-oligomers from the amyloid pathway, we expect these traits to increase the half-life of scFv-h3D6 in vivo and, consequently, to decrease the effective doses. Our results led to the improvement of a potential Alzheimer disease treatment and may be extrapolated to other class-I scFv molecules of therapeutic interest.

  10. Early-Phase 11C-PiB PET in Amyloid Angiopathy-Related Symptomatic Cerebral Hemorrhage: Potential Diagnostic Value?

    PubMed

    Farid, Karim; Hong, Young T; Aigbirhio, Franklin I; Fryer, Tim D; Menon, David K; Warburton, Elizabeth A; Baron, Jean-Claude

    2015-01-01

    Although late-phase (>35min post-administration) 11C-PiB-PET has good sensitivity in cerebral amyloid angiopathy (CAA), its specificity is poor due to frequently high uptake in healthy aged subjects. By detecting perfusion-like abnormalities, early-phase 11C-PiB-PET might add diagnostic value. Early-frame (1-6min) 11C-PiB-PET was obtained in 11 non-demented patients with probable CAA-related symptomatic lobar intracerebral haemorrhage (70±7yrs), 9 age-matched healthy controls (HCs) and 10 HCs <55yrs. There was a significant decrease in early-phase atrophy-corrected whole-cortex SUV relative to cerebellar vermis (SUVR) in the CAA vs age-matched HC group. None of the age-matched controls fell below the lower 95% confidence limit derived from the young HCs, while 6/11 CAA patients did (sensitivity = 55%, specificity = 100%). Combining both early- and late-phase 11C-PiB data did not change the sensitivity and specificity of late-phase PiB, but combined early- and late-phase positivity entails a very high suspicion of underlying Aβ-related clinical disorder, i.e., CAA or Alzheimer disease (AD). In order to clarify this ambiguity, we then show that the occipital/posterior cingulate ratio is markedly lower in CAA than in AD (N = 7). These pilot data suggest that early-phase 11C-PiB-PET may not only add to late-phase PiB-PET with respect to the unclear situation of late-phase positivity, but also help differentiate CAA from AD.

  11. Early-Phase 11C-PiB PET in Amyloid Angiopathy-Related Symptomatic Cerebral Hemorrhage: Potential Diagnostic Value?

    PubMed Central

    Aigbirhio, Franklin I.; Fryer, Tim D.; Menon, David K.; Warburton, Elizabeth A.; Baron, Jean-Claude

    2015-01-01

    Although late-phase (>35min post-administration) 11C-PiB-PET has good sensitivity in cerebral amyloid angiopathy (CAA), its specificity is poor due to frequently high uptake in healthy aged subjects. By detecting perfusion-like abnormalities, early-phase 11C-PiB-PET might add diagnostic value. Early-frame (1–6min) 11C-PiB-PET was obtained in 11 non-demented patients with probable CAA-related symptomatic lobar intracerebral haemorrhage (70±7yrs), 9 age-matched healthy controls (HCs) and 10 HCs <55yrs. There was a significant decrease in early-phase atrophy-corrected whole-cortex SUV relative to cerebellar vermis (SUVR) in the CAA vs age-matched HC group. None of the age-matched controls fell below the lower 95% confidence limit derived from the young HCs, while 6/11 CAA patients did (sensitivity = 55%, specificity = 100%). Combining both early- and late-phase 11C-PiB data did not change the sensitivity and specificity of late-phase PiB, but combined early- and late-phase positivity entails a very high suspicion of underlying Aβ-related clinical disorder, i.e., CAA or Alzheimer disease (AD). In order to clarify this ambiguity, we then show that the occipital/posterior cingulate ratio is markedly lower in CAA than in AD (N = 7). These pilot data suggest that early-phase 11C-PiB-PET may not only add to late-phase PiB-PET with respect to the unclear situation of late-phase positivity, but also help differentiate CAA from AD. PMID:26439113

  12. Posterior reversible encephalopathy syndrome (PRES) with immune system activation, VEGF up-regulation, and cerebral amyloid angiopathy.

    PubMed

    Kofler, Julia; Bartynski, Walter S; Reynolds, Thomas Q; Lieberman, Frank S; Murdoch, Geoffrey H; Hamilton, Ronald L

    2011-01-01

    The case of a 75-year-old man with a history of lymphoma, recent upper respiratory tract infection, and a protracted course of encephalopathy is presented. Radiologically, findings were consistent with posterior reversible encephalopathy syndrome. A brain biopsy revealed evidence of endothelial activation, T-cell trafficking, and vascular endothelial growth factor expression, suggesting that systemic immune system activation may be involved with triggering posterior reversible encephalopathy syndrome. In addition, underlying cerebral amyloid angiopathy may have contributed to the initial nonclassical edema distribution by compromising autoregulatory blood flow mechanisms.

  13. Subcortical hematoma caused by cerebral amyloid angiopathy: does the first evidence of hemorrhage occur in the subarachnoid space?

    PubMed

    Takeda, Shigeki; Yamazaki, Kazunori; Miyakawa, Teruo; Onda, Kiyoshi; Hinokuma, Kaoru; Ikuta, Fusahiro; Arai, Hiroyuki

    2003-12-01

    Six autopsy cases of subcortical hematoma caused by CAA were examined to elucidate the primary site of hemorrhage. Immunohistochemistry for amyloid beta-protein (A beta) revealed extensive CAA in the intrasulcal meningeal vessels rather than in the cerebral cortical vessels. All of the examined cases had multiple hematomas in the subarachnoid space, mainly in the cerebral sulci, as well as intracerebral hematomas. Each intracerebral hematoma was connected to the subarachnoid hematomas at the depth of cerebral sulci or through the lateral side of the cortex. There was no debris of the cerebral cortical tissue in the subarachnoid hematomas. In case 2, another solitary subarachnoid hematoma, which was not connected to any intracerebral hematoma, was seen. In all of these subarachnoid hematomas, many ruptured A beta-immunopositive arteries were observed. These ruptured arteries did not accompany any debris of the brain tissue, some of them were large in diameter (250-300 microm), and several of them were far from the cerebral cortex. Therefore, it was considered that they were not cortical arteries but meningeal arteries. Within the cerebral cortex, there were only a few ruptured arteries associated with small hemorrhages. There were no ruptured vessels within the intracerebral hematomas. There was a strong suggestion that all of the subarachnoid hematomas, including the solitary one in case 2, originated from the rupture of the meningeal arteries. The present study indicates that in some cases of subcortical hematoma caused by CAA, the primary hemorrhage occurs in the subarachnoid space, in particular the cerebral sulci, because of rupture of multiple meningeal arteries. Infarction occurs subsequently in the cortex around the hematoma, the hematoma penetrates into the brain parenchyma, and finally, a subcortical hematoma is formed.

  14. Distribution of precursor amyloid-. beta. -protein messenger RNA in human cerebral cortex: relationship to neurofibrillary tangles and neuritic plaques

    SciTech Connect

    Lewis, D.A.; Higgins, G.A.; Young, W.G.; Goldgaber, D.; Gajdusek, D.C.; Wilson, M.C.; Morrison, J.H.

    1988-03-01

    Neurofibrillary tangles (NFT) and neuritic plaques (NP), two neuropathological markers of Alzheimer disease, may both contain peptide fragments derived from the human amyloid ..beta.. protein. However, the nature of the relationship between NFT and NP and the source of the amyloid ..beta.. proteins found in each have remained unclear. The authors used in situ hybridization techniques to map the anatomical distribution of precursor amyloid-..beta..-protein mRNA in the neocortex of brains from three subjects with no known neurologic disease and from five patients with Alzheimer disease. In brains from control subjects, positively hybridizing neurons were present in cortical regions and layers that contain a high density of neuropathological markers in Alzheimer disease, as well as in those loci that contain NP but few NFT. Quantitative analyses of in situ hybridization patterns within layers III and V of the superior frontal cortex revealed that the presence of high numbers of NFT in Alzheimer-diseased brains was associated with a decrease in the number of positively hybridizing neurons compared to controls and Alzheimer-diseased brains with few NFT. These findings suggest that the expression of precursor amyloid-..beta..-protein mRNA may be a necessary but is clearly not a sufficient prerequisite for NFT formation. In addition, these results may indicate that the amyloid ..beta.. protein, present in NP in a given region or layer of cortex, is not derived from the resident neuronal cell bodies that express the mRNA for the precursor protein.

  15. Detection of cerebral amyloid angiopathy by 3-T magnetic resonance imaging and amyloid positron emission tomography in a patient with subcortical ischaemic vascular dementia.

    PubMed

    Kida, Hirotaka; Satoh, Masayuki; Ii, Yuichiro; Fukuyama, Hidenao; Maeda, Masayuki; Tomimoto, Hidekazu

    2017-01-01

    The patient was an 81-year-old man who had been treated for hypertension for several decades. In 2012, he developed gait disturbance and mild amnesia. One year later, his gait disturbance worsened, and he developed urinary incontinence. Conventional brain magnetic resonance imaging using T 2 -weighted images and fluid-attenuated inversion recovery showed multiple lacunar infarctions. These findings fulfilled the diagnostic criteria for subcortical ischaemic vascular dementia. However, susceptibility weighted imaging showed multiple lobar microbleeds in the bilateral occipitoparietal lobes, and double inversion recovery and 3-D fluid-attenuated inversion recovery images on 3-T magnetic resonance imaging revealed cortical microinfarctions in the left parietal-temporo-occipito region. Pittsburgh compound B-positron emission tomography revealed diffuse uptake in the cerebral cortex. Therefore, we diagnosed the patient with subcortical ischaemic vascular dementia associated with Alzheimer's disease. The use of the double inversion recovery and susceptibility weighted imaging on 3-T magnetic resonance imaging may be a supplemental strategy for diagnosing cerebral amyloid angiopathy, which is closely associated with Alzheimer's disease.

  16. Development of Cerebral Microbleeds in the APP23-Transgenic Mouse Model of Cerebral Amyloid Angiopathy—A 9.4 Tesla MRI Study

    PubMed Central

    Reuter, Björn; Venus, Alexander; Heiler, Patrick; Schad, Lothar; Ebert, Anne; Hennerici, Michael G.; Grudzenski, Saskia; Fatar, Marc

    2016-01-01

    Background: Cerebral amyloid angiopathy (CAA) is characterized by extracellular deposition of amyloid β (Aβ) around cerebral arteries and capillaries and leads to an increased risk for vascular dementia, spontaneous lobar hemorrhage, convexal subarachnoid hemorrhage, and transient focal neurological episodes, which might be an indicator of imminent spontaneous intracerebral hemorrhage. In CAA cerebral microbleeds (cMBs) with a cortical/juxtacortical distribution are frequently observed in standard magnetic resonance imaging (MRI). In vivo MRI of transgenic mouse models of CAA may serve as a useful tool to investigate translational aspects of the disease. Materials and Methods: APP23-transgenic mice demonstrate cerebrovascular Aβ deposition with subsequent neuropathological changes characteristic for CAA. We performed a 9.4 Tesla high field MRI study using T2, T2* and time of flight-magnetic resonance angiograpy (TOF-MRA) sequences in APP23-transgenic mice and wildtype (wt) littermates at the age of 8, 12, 16, 20 and 24 months, respectively. Numbers, size, and location of cMBs are reported. Results: T2* imaging demonstrated cMBs (diameter 50–300 μm) located in the neocortex and, to a lesser degree, in the thalamus. cMBs were detected at the earliest at 16 months of age. Numbers increased exponentially with age, with 2.5 ± 2 (median ± interquartilrange) at 16 months, 15 ± 6 at 20 months, and 31.5 ± 17 at 24 months of age, respectively. Conclusion: We report the temporal and spatial development of cMBs in the aging APP23-transgenic mouse model which develops characteristic pathological patterns known from human CAA. We expect this mouse model to serve as a useful tool to non-invasively monitor mid- and longterm translational aspects of CAA and to investigate experimental therapeutic strategies in longitudinal studies. PMID:27458375

  17. Habitual exercise levels are associated with cerebral amyloid load in presymptomatic autosomal dominant Alzheimer's disease.

    PubMed

    Brown, Belinda M; Sohrabi, Hamid R; Taddei, Kevin; Gardener, Samantha L; Rainey-Smith, Stephanie R; Peiffer, Jeremiah J; Xiong, Chengjie; Fagan, Anne M; Benzinger, Tammie; Buckles, Virginia; Erickson, Kirk I; Clarnette, Roger; Shah, Tejal; Masters, Colin L; Weiner, Michael; Cairns, Nigel; Rossor, Martin; Graff-Radford, Neill R; Salloway, Stephen; Vöglein, Jonathan; Laske, Christoph; Noble, James; Schofield, Peter R; Bateman, Randall J; Morris, John C; Martins, Ralph N

    2017-05-11

    The objective of this study was to evaluate the relationship between self-reported exercise levels and Alzheimer's disease (AD) biomarkers, in a cohort of autosomal dominant AD mutation carriers. In 139 presymptomatic mutation carriers from the Dominantly Inherited Alzheimer Network, the relationship between self-reported exercise levels and brain amyloid load, cerebrospinal fluid (CSF) Aβ42, and CSF tau levels was evaluated using linear regression. No differences in brain amyloid load, CSF Aβ42, or CSF tau were observed between low and high exercise groups. Nevertheless, when examining only those already accumulating AD pathology (i.e., amyloid positive), low exercisers had higher mean levels of brain amyloid than high exercisers. Furthermore, the interaction between exercise and estimated years from expected symptom onset was a significant predictor of brain amyloid levels. Our findings indicate a relationship exists between self-reported exercise levels and brain amyloid in autosomal dominant AD mutation carriers. Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  18. The blood clotting Factor XIIIa forms unique complexes with amyloid-beta (Aβ) and colocalizes with deposited Aβ in cerebral amyloid angiopathy.

    PubMed

    de Jager, M; Boot, M V; Bol, J G J M; Brevé, J J P; Jongenelen, C A M; Drukarch, B; Wilhelmus, M M M

    2016-04-01

    Cerebral amyloid angiopathy (CAA) is a key pathological hallmark of Alzheimer's disease (AD) characterized by accumulation of amyloid-beta (Aβ) protein in blood vessel walls. CAA impairs vessel functioning, affects blood brain barrier integrity and accelerates cognitive decline of AD patients. Unfortunately, mechanisms underlying Aβ deposition in the vessel wall remain largely unknown. Factor XIIIa (FXIIIa) is a blood-derived transglutaminase crucial in blood coagulation by cross-linking fibrin molecules. Evidence is mounting that blood-derived factors are present in CAA and may play a role in protein deposition in the vessel wall. We therefore investigated whether FXIIIa is present in CAA and if FXIIIa cross-link activity affects Aβ aggregation. Using immunohistochemistry, we investigated the distribution of FXIIIa, its activator thrombin and in situ FXIIIa activity in CAA in post-mortem AD tissue. We used surface plasmon resonance and Western blot analysis to study binding of FXIIIa to Aβ and the formation of FXIIIa-Aβ complexes, respectively. In addition, we studied cytotoxicity of FXIIIa-Aβ complexes to cerebrovascular cells. FXIIIa, thrombin and in situ FXIIIa activity colocalize with the Aβ deposition in CAA. Furthermore, FXIIIa binds to Aβ with a higher binding affinity for Aβ1-42 compared with Aβ1-40 . Moreover, highly stable FXIIIa-Aβ complexes are formed independently of FXIIIa cross-linking activity that protected cerebrovascular cells from Aβ-induced toxicity in vitro. Our data showed that FXIIIa colocalizes with Aβ in CAA and that FXIIIa forms unique protein complexes with Aβ that might play an important role in Aβ deposition and persistence in the vessel wall. © 2015 British Neuropathological Society.

  19. A Stepwise Approach: Decreasing Infection in Deep Brain Stimulation for Childhood Dystonic Cerebral Palsy.

    PubMed

    Johans, Stephen J; Swong, Kevin N; Hofler, Ryan C; Anderson, Douglas E

    2017-09-01

    Dystonia is a movement disorder characterized by involuntary muscle contractions, which cause twisting movements or abnormal postures. Deep brain stimulation has been used to improve the quality of life for secondary dystonia caused by cerebral palsy. Despite being a viable treatment option for childhood dystonic cerebral palsy, deep brain stimulation is associated with a high rate of infection in children. The authors present a small series of patients with dystonic cerebral palsy who underwent a stepwise approach for bilateral globus pallidus interna deep brain stimulation placement in order to decrease the rate of infection. Four children with dystonic cerebral palsy who underwent a total of 13 surgical procedures (electrode and battery placement) were identified via a retrospective review. There were zero postoperative infections. Using a multistaged surgical plan for pediatric patients with dystonic cerebral palsy undergoing deep brain stimulation may help to reduce the risk of infection.

  20. Role of hypotension in decreasing cerebral blood flow in porcine endotoxemia

    SciTech Connect

    Miller, C.F.; Breslow, M.J.; Shapiro, R.M.; Traystman, R.J. )

    1987-10-01

    The role of reduced arterial blood pressure (MAP) in decreasing cerebral blood flow (CBF) during endotoxemia was studied in pentobarbital-anesthetized pigs. Microspheres were used to measure regional CBF changes during MAP manipulations in animals with and without endotoxin. Endotoxin decreased MAP to 50 mmHg and decreased blood flow to the cortex and cerebellum without affecting cerebral cortical oxygen consumption (CMRo{sub 2}). Elevating MAP from 50 to 70 mmHg during endotoxemia with norepinephrine did not change cortical blood flow or CMRo{sub 2} but increased cerebellar blood flow. Brain stem blood flow was not affected by endotoxin or norepinephrine. When MAP was decreased to 50 mmHg by hemorrhage without endotoxin, no change in blood flow to cortex, cerebellum, or brain stem was observed from base-line levels. These results suggest that decreased MAP below a lower limit for cerebral autoregulation does not account for the decreased CBF observed after endotoxin.

  1. Decreased kidney function relates to progression of cerebral microbleeds in lacunar stroke patients.

    PubMed

    van Overbeek, Ellen C; Staals, Julie; van Oostenbrugge, Robert J

    2016-08-01

    It is hypothesized that impaired kidney function and cerebral microbleeds represent microvascular damage in different organs. Several cross-sectional studies found impaired kidney function to be associated with the presence of cerebral microbleeds. To further confirm the association between both small vessel diseases, we aimed to determine whether kidney function is related to progression of cerebral microbleeds in a longitudinal study design. In 89 lacunar stroke patients, baseline brain magnetic resonance imaging (including gradient-echo images), baseline estimated glomerular filtration rate (eGFR), blood pressure measurements, and follow-up brain magnetic resonance imaging after two years were available. Presence of cerebral microbleeds on baseline and follow-up magnetic resonance imaging was scored visually. Cerebral microbleeds progression was defined as the presence of any new microbleed on follow-up magnetic resonance imaging. The association between cerebral microbleeds progression (dependent variable) and eGFR (independent variable) was assessed by logistic regression analysis. Cerebral microbleeds progression was present in 17 patients (19.1%). Lower eGFR was associated with cerebral microbleeds progression (OR 1.55 per 10 ml/min/1.73 m(2) decrease, 95% CI 1.05-2.30, with correction for sex and age). After additional correction for baseline presence of cerebral microbleeds or correction for cardiovascular risk factors, including blood pressure, this result remained significant. In this longitudinal study, we found an independent association between lower eGFR and cerebral microbleeds progression. Cerebral microbleeds and impaired kidney function are both seen as manifestations of microvascular organ damage and our findings further strengthen the association between both small vessel pathologies and also the assumption that small vessel disease could be considered a multisystem disorder. © 2016 World Stroke Organization.

  2. beta-amyloid protein of Alzheimer's disease is found in cerebral and spinal cord vascular malformations.

    PubMed Central

    Hart, M. N.; Merz, P.; Bennett-Gray, J.; Menezes, A. H.; Goeken, J. A.; Schelper, R. L.; Wisniewski, H. M.

    1988-01-01

    Congo/Red deposition with birefringence to polarized light was demonstrated focally in cerebrovascular malformations removed surgically from 4 older patients (ages 85, 74, 74, and 63), and in a spinal cord vascular malformation in a 76-year-old patient. Lesser degrees of Congophilic change were observed in cerebrovascular malformations screened from 4 of 10 patients between the ages of 30 and 59. No Congophilic change was seen in 10 cerebrovascular malformations removed from patients under 30 years of age. Congophilic areas in all cases decorated with W-2 and 85/45 polyclonal antibodies raised to peptide sequences of cerebrovascular beta-amyloid and beta-amyloid of senile plaques from patients with Alzheimer's disease. Thus, the amyloid in these vascular malformations is immunologically related to beta-amyloid protein. This finding provides another indication that vascular beta-amyloid deposition is not specific for Alzheimer's disease and suggests that an existing abnormality of vessels may be a predisposing factor. Images Figure 1 Figure 2A Figure 2B Figure 3 Figure 4 PMID:3293463

  3. Coaccumulation of calcium and beta-amyloid in the thalamus after transient middle cerebral artery occlusion in rats.

    PubMed

    Mäkinen, Susanna; van Groen, Thomas; Clarke, Jared; Thornell, Anders; Corbett, Dale; Hiltunen, Mikko; Soininen, Hilkka; Jolkkonen, Jukka

    2008-02-01

    Transient occlusion of the middle cerebral artery (MCAO) in rats leads to abnormal accumulation of beta-amyloid (Abeta) peptides in the thalamus. This study investigated the chemical composition of these deposits. Adult male human beta-amyloid precursor protein (APP) overexpressing (hAPP695) rats and their wild-type littermates were subjected to transient MCAO for 2 h or sham operation. After 26-week survival time, histological examination revealed an overlapping distribution pattern for rodent and human Abeta in the thalamus of hAPP695 rats subjected to MCAO. X-ray microanalysis showed that the deposits did not contain significant amount of iron, zinc, or copper typical to senile plaques. In contrast, the deposit both in hAPP695 and non-transgenic rats contained calcium and phosphorus in a ratio (1.28+/-0.15) characteristic to hydroxyapatites. Alizarin red staining confirmed that calcium coaccumulated in these Abeta deposits. It is suggested that APP expression is induced by ischemic insult in cortical neurons adjacent to infarct, which in turn is reflected as increased release of Abeta peptides by their corticothalamic axon endings. This together with insufficient clearance or atypical degradation of Abeta peptides lead to dysregulation of calcium homeostatis and coaccumulation in the thalamus.

  4. Reduced nitric oxide bioavailability mediates cerebroarterial dysfunction independent of cerebral amyloid angiopathy in a mouse model of Alzheimer's disease.

    PubMed

    Merlini, Mario; Shi, Yi; Keller, Stephan; Savarese, Gianluigi; Akhmedov, Alexander; Derungs, Rebecca; Spescha, Remo D; Kulic, Luka; Nitsch, Roger M; Lüscher, Thomas F; Camici, Giovanni G

    2017-02-01

    In Alzheimer's disease (AD), cerebral arteries, in contrast to cerebral microvessels, show both cerebral amyloid angiopathy (CAA) -dependent and -independent vessel wall pathology. However, it remains unclear whether CAA-independent vessel wall pathology affects arterial function, thereby chronically reducing cerebral perfusion, and, if so, which mechanisms mediate this effect. To this end, we assessed the ex vivo vascular function of the basilar artery and a similar-sized peripheral artery (femoral artery) in the Swedish-Arctic (SweArc) transgenic AD mouse model at different disease stages. Furthermore, we used quantitative immunohistochemistry to analyze CAA, endothelial morphology, and molecular pathways pertinent to vascular relaxation. We found that endothelium-dependent, but not smooth muscle-dependent, vasorelaxation was significantly impaired in basilar and femoral arteries of 15-mo-old SweArc mice compared with that of age-matched wild-type and 6-mo-old SweArc mice. This impairment was accompanied by significantly reduced levels of cyclic GMP, indicating a reduced nitric oxide (NO) bioavailability. However, no age- and genotype-related differences in oxidative stress as measured by lipid peroxidation were observed. Although parenchymal capillaries, arterioles, and arteries showed abundant CAA in the 15-mo-old SweArc mice, no CAA or changes in endothelial morphology were detected histologically in the basilar and femoral artery. Thus our results suggest that, in this AD mouse model, dysfunction of large intracranial, extracerebral arteries important for brain perfusion is mediated by reduced NO bioavailability rather than by CAA. This finding supports the growing body of evidence highlighting the therapeutic importance of targeting the cerebrovasculature in AD.

  5. The plasma membrane redox system is impaired by amyloid β-peptide and in the hippocampus and cerebral cortex of 3xTgAD mice.

    PubMed

    Hyun, Dong-Hoon; Mughal, Mohamed R; Yang, Hyunwon; Lee, Ji Hyun; Ko, Eun Joo; Hunt, Nicole D; de Cabo, Rafael; Mattson, Mark P

    2010-10-01

    Membrane-associated oxidative stress has been implicated in the synaptic dysfunction and neuronal degeneration that occurs in Alzheimer's disease (AD), but the underlying mechanisms are unknown. Enzymes of the plasma membrane redox system (PMRS) provide electrons for energy metabolism and recycling of antioxidants. Here, we show that activities of several PMRS enzymes are selectively decreased in plasma membranes from the hippocampus and cerebral cortex of 3xTgAD mice, an animal model of AD. Our results that indicate the decreased PMRS enzyme activities are associated with decreased levels of coenzyme Q(10) and increased levels of oxidative stress markers. Neurons overexpressing the PMRS enzymes (NQO1 or cytochrome b5 reductase) exhibit increased resistance to amyloid β-peptide (Aβ). If and to what extent Aβ is the cause of the impaired PMRS enzymes in the 3xTgAD mice is unknown. Because these mice also express mutant tau and presenilin-1, it is possible that one or more of the PMRS could be adversely affected by these mutations. Nevertheless, the results of our cell culture studies clearly show that exposure of neurons to Aβ1-42 is sufficient to impair PMRS enzymes. The impairment of the PMRS in an animal model of AD, and the ability of PMRS enzyme activities to protect neurons against Aβ-toxicity, suggest enhancement PMRS function as a novel approach for protecting neurons against oxidative damage in AD and related disorders. Copyright © 2010 Elsevier Inc. All rights reserved.

  6. Dietary supplementation with apple juice decreases endogenous amyloid-beta levels in murine brain.

    PubMed

    Chan, Amy; Shea, Thomas B

    2009-01-01

    Folate deficiency has been associated with age-related neurodegeneration. We demonstrate herein that dietary deficiency in folate and vitamin E, coupled pro-oxidant stress induced by dietary iron, increased amyloid-beta (Abeta) levels in normal adult mice. This increase was potentiated by apolipoprotein E (ApoE) deficiency as shown by treatment of transgenic mice homozygously lacking murine ApoE. Dietary supplementation with apple juice concentrate in drinking water alleviated the increase in Abeta for both mouse genotypes. These findings provide further evidence linking nutritional and genetic risk factors for age-related neurodegeneration, and underscore that dietary supplementation may be useful to augment therapeutic approaches.

  7. Angiotensin II Moderately Decreases Plasmodium Infection and Experimental Cerebral Malaria in Mice.

    PubMed

    Gallego-Delgado, Julio; Baravian, Charlotte; Edagha, Innocent; Ty, Maureen C; Ruiz-Ortega, Marta; Xu, Wenyue; Rodriguez, Ana

    2015-01-01

    Angiotensin II, a peptide hormone that regulates blood pressure, has been proposed as a protective factor against cerebral malaria based on a genetic analysis. In vitro studies have documented an inhibitory effect of angiotensin II on Plasmodium growth, while studies using chemical inhibitors of angiotensin II in mice showed protection against experimental cerebral malaria but not major effects on parasite growth. To determine whether the level of angiotensin II affects Plasmodium growth and/or disease outcome in malaria, elevated levels of angiotensin II were induced in mice by intradermal implantation of osmotic mini-pumps providing constant release of this hormone. Mice were then infected with P. berghei and monitored for parasitemia and incidence of cerebral malaria. Mice infused with angiotensin II showed decreased parasitemia seven days after infection. The development of experimental cerebral malaria was delayed and a moderate increase in survival was observed in mice with elevated angiotensin II, as confirmed by decreased number of cerebral hemorrhages compared to controls. The results presented here show for the first time the effect of elevated levels of angiotensin II in an in vivo model of malaria. The decreased pathogenesis observed in mice complements a previous human genetic study, reinforcing the hypothesis of a beneficial effect of angiotensin II in malaria.

  8. Angiotensin II Moderately Decreases Plasmodium Infection and Experimental Cerebral Malaria in Mice

    PubMed Central

    Gallego-Delgado, Julio; Baravian, Charlotte; Edagha, Innocent; Ty, Maureen C.; Ruiz-Ortega, Marta; Xu, Wenyue; Rodriguez, Ana

    2015-01-01

    Angiotensin II, a peptide hormone that regulates blood pressure, has been proposed as a protective factor against cerebral malaria based on a genetic analysis. In vitro studies have documented an inhibitory effect of angiotensin II on Plasmodium growth, while studies using chemical inhibitors of angiotensin II in mice showed protection against experimental cerebral malaria but not major effects on parasite growth. To determine whether the level of angiotensin II affects Plasmodium growth and/or disease outcome in malaria, elevated levels of angiotensin II were induced in mice by intradermal implantation of osmotic mini-pumps providing constant release of this hormone. Mice were then infected with P. berghei and monitored for parasitemia and incidence of cerebral malaria. Mice infused with angiotensin II showed decreased parasitemia seven days after infection. The development of experimental cerebral malaria was delayed and a moderate increase in survival was observed in mice with elevated angiotensin II, as confirmed by decreased number of cerebral hemorrhages compared to controls. The results presented here show for the first time the effect of elevated levels of angiotensin II in an in vivo model of malaria. The decreased pathogenesis observed in mice complements a previous human genetic study, reinforcing the hypothesis of a beneficial effect of angiotensin II in malaria. PMID:26376293

  9. Midlife adiposity predicts earlier onset of Alzheimer's dementia, neuropathology and presymptomatic cerebral amyloid accumulation.

    PubMed

    Chuang, Y-F; An, Y; Bilgel, M; Wong, D F; Troncoso, J C; O'Brien, R J; Breitner, J C; Ferruci, L; Resnick, S M; Thambisetty, M

    2016-07-01

    Understanding how midlife risk factors influence age at onset (AAO) of Alzheimer's disease (AD) may provide clues to delay disease expression. Although midlife adiposity predicts increased incidence of AD, it is unclear whether it affects AAO and severity of Alzheimer's neuropathology. Using a prospective population-based cohort, Baltimore Longitudinal Study of Aging (BLSA), this study aims to examine the relationships between midlife body mass index (BMI) and (1) AAO of AD (2) severity of Alzheimer's neuropathology and (3) fibrillar brain amyloid deposition during aging. We analyzed data on 1394 cognitively normal individuals at baseline (8643 visits; average follow-up interval 13.9 years), among whom 142 participants developed incident AD. In two subsamples of BLSA, 191 participants underwent autopsy and neuropathological assessment, and 75 non-demented individuals underwent brain amyloid imaging. Midlife adiposity was derived from BMI data at 50 years of age. We find that each unit increase in midlife BMI predicts earlier onset of AD by 6.7 months (P=0.013). Higher midlife BMI was associated with greater Braak neurofibrillary but not CERAD (Consortium to Establish a Registry for Alzheimer's Disease) neuritic plaque scores at autopsy overall. Associations between midlife BMI and brain amyloid burden approached statistical significance. Thus, higher midlife BMI was also associated with greater fibrillar amyloid measured by global mean cortical distribution volume ratio (P=0.075) and within the precuneus (left, P=0.061; right, P=0.079). In conclusion, midlife overweight predicts earlier onset of AD and greater burden of Alzheimer's neuropathology. A healthy BMI at midlife may delay the onset of AD.

  10. Malignant infarction in cats after prolonged middle cerebral artery occlusion: glutamate elevation related to decrease of cerebral perfusion pressure.

    PubMed

    Toyota, Shingo; Graf, Rudolf; Valentino, Mario; Yoshimine, Toshiki; Heiss, Wolf-Dieter

    2002-05-01

    To study the putative role and predictive significance of glutamate elevation in space-occupying ischemic stroke, we investigated the correlation between perfusional disturbances and glutamate alterations in a transient ischemia model in cats that is susceptible to secondary deterioration after reperfusion. In 10 halothane-anesthetized cats, the left middle cerebral artery was occluded for 3 hours, followed by 6 hours of reperfusion. Laser-Doppler flowmetry (LDF) probes, microdialysis/high-performance liquid chromatography, and pressure sensors measured simultaneously regional cerebral blood flow (CBF), extracellular amino acids, mean arterial blood pressure, and intracranial pressure, respectively. Cerebral perfusion pressure (CPP) was calculated. In complementary experiments (n=2), regional CBF was assessed by sequential positron emission tomography. Middle cerebral artery occlusion reduced LDF-measured CBF in all animals to <25% of control. In 5 of 10 cats, glutamate rose approximately 30-fold during ischemia. LDF-measured CBF and glutamate primarily recovered after reperfusion. Glutamate rose again in the late reperfusion phase, when CPP decreased to <60 mm Hg, and symptoms of transtentorial herniation were recognized. Positron emission tomography revealed ischemic thresholds of 15 to 20 mL/100 g per minute for secondary deterioration. In the other 5 cats, ischemic elevation of glutamate was significantly smaller, and signs of secondary deterioration were not recognized. Glutamate determinations during ischemia predict fatal outcome, as do intracranial pressure and CPP measurements during early reperfusion. Secondary amino acid elevation during reperfusion is presumably caused by a drastic decrease of CPP to <50 mm Hg in the final stage of space-occupying, malignant focal ischemia. At this stage, a further progression of injury due to increased glutamate may be irrelevant with respect to fatal outcome.

  11. Novel Bivalent 99mTc-Complex with N-Methyl-Substituted Hydroxamamide as Probe for Imaging of Cerebral Amyloid Angiopathy

    PubMed Central

    Iikuni, Shimpei; Ono, Masahiro; Watanabe, Hiroyuki; Yoshimura, Masashi; Ishibashi-Ueda, Hatsue; Ihara, Masafumi; Saji, Hideo

    2016-01-01

    Cerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid aggregates in the walls of the cerebral vasculature. Recently, the development of molecular imaging probes targeting CAA has been attracting much attention. We previously reported the 99mTc-hydroxamamide (99mTc-Ham) complex with a bivalent benzothiazole scaffold as a binding moiety for amyloid aggregates ([99mTc]BT2) and its utility for CAA-specific imaging. However, the simultaneous generation of two radiolabeled complexes derived from the geometric isomers was observed in the 99mTc-labeling reaction. It was recently reported that the complexation reaction of 99Tc with N-methyl-substituted Ham provided a single 99Tc-Ham complex consisting of two N-methylated Ham ligands with marked stability. In this article, we designed and synthesized a novel N-methylated bivalent 99mTc-Ham complex ([99mTc]MBT2) and evaluated its utility for CAA-specific imaging. N-Methyl substitution of [99mTc]BT2 prevented the generation of its isomer in the 99mTc-labeling reaction. Enhanced in vitro stability of [99mTc]MBT2 as compared with [99mTc]BT2 was observed. [99mTc]MBT2 showed very low brain uptake, which is favorable for CAA-specific imaging. An in vitro inhibition assay using β-amyloid aggregates and in vitro autoradiographic examination of brain sections from a Tg2576 mouse and a CAA patient showed a decline in the binding affinity for amyloid aggregates due to N-methylation of the 99mTc-Ham complex. These results suggest that the scaffold of the 99mTc-Ham complex may play important roles in the in vitro stability and the binding affinity for amyloid aggregates. PMID:27689870

  12. Pathogenesis of cerebral microbleeds: In vivo imaging of amyloid and subcortical ischemic small vessel disease in 226 individuals with cognitive impairment.

    PubMed

    Park, Jae-Hyun; Seo, Sang Won; Kim, Changsoo; Kim, Geon Ha; Noh, Hyun Jin; Kim, Sung Tae; Kwak, Ki-Chang; Yoon, Uicheul; Lee, Jong Min; Lee, Jong Weon; Shin, Ji Soo; Kim, Chi Hun; Noh, Young; Cho, Hanna; Kim, Hee Jin; Yoon, Cindy W; Oh, Seung Jun; Kim, Jae Seung; Choe, Yearn Seong; Lee, Kyung-Han; Lee, Jae-Hong; Ewers, Michael; Weiner, Michael W; Werring, David J; Na, Duk L

    2013-05-01

    Cerebral microbleeds (CMBs) are a neuroimaging marker of small vessel disease (SVD) with relevance for understanding disease mechanisms in cerebrovascular disease, cognitive impairment, and normal aging. It is hypothesized that lobar CMBs are due to cerebral amyloid angiopathy (CAA) and deep CMBs are due to subcortical ischemic SVD. We tested this hypothesis using structural magnetic resonance imaging (MRI) markers of subcortical SVD and in vivo imaging of amyloid in patients with cognitive impairment. We included 226 patients: 89 with Alzheimer disease-related cognitive impairment (ADCI) and 137 with subcortical vascular cognitive impairment (SVCI). All subjects underwent amyloid imaging with [(11) C] Pittsburgh compound B (PiB) positron emission tomography, and MRI to detect CMBs and markers of subcortical SVD, including the volume of white matter hyperintensities (WMH) and the number of lacunes. Parietal and occipital lobar CMBs counts were higher in PiB(+) ADCI with moderate WMH than PiB(+) ADCI with minimal WMH, whereas PiB(-) patients with SVCI (ie, "pure" SVCI) showed both lobar and deep CMBs. In multivariate analyses of the whole cohort, WMH volume and lacuna counts were positively associated with both lobar and deep CMBs, whereas amyloid burden (PiB) was only associated with lobar CMBs. There was an interaction between lacuna burden and PiB retention on lobar (but not deep) CMBs (p<0.001). Our findings suggest that although deep CMBs are mainly linked to subcortical SVD, both subcortical SVD and amyloid-related pathologies (eg, CAA) contribute to the pathogenesis of lobar CMBs, at least in subjects with mixed lobar and deep CMBs. Furthermore, subcortical SVD and amyloid-related pathologies interact to increase the risk of lobar CMBs. Copyright © 2012 American Neurological Association.

  13. β-amyloid decreases detectable endothelial nitric oxide synthase in human erythrocytes: a role for membrane acetylcholinesterase.

    PubMed

    Misiti, Francesco; Carelli-Alinovi, Cristiana; Sampaolese, Beatrice; Giardina, Bruno

    2012-08-01

    Until few years ago, many studies of Alzheimer's disease investigated the effects of this syndrome in the central nervous system. Only recently, the detection of amyloid beta peptide (Aβ) in the blood has evidenced the necessity to extend studies on extraneuronal cells, particularly on erythrocytes. Aβ is also present in brain capillaries, where it interacts with the erythrocytes, inducing several metabolic and functional alterations. Recently, functionally active endothelial type nitric oxide synthase (eNOS) was discovered in human erythrocytes. The goal of the present study was to evidence the effect of Aβ on erythrocyte eNOS. We found that Aβ following to 24-h exposure causes a decrease in the immune staining of erythrocyte eNOS. Concurrently, Aβ alters erythrocyte cell morphology, decreases nitrites and nitrates levels, and affects membrane acetylcholinesterase activity. Propidium, an acetylcholinesterase inhibitor, was able to reverse the effects elicited by Aβ. These events could contribute to the vascular alterations associated with Alzheimer's disease disease.

  14. Cerebral blood flow decreases with time whereas cerebral oxygen consumption remains stable during hypothermic cardiopulmonary bypass in humans

    SciTech Connect

    Prough, D.S.; Rogers, A.T.; Stump, D.A.; Roy, R.C.; Cordell, A.R.; Phipps, J.; Taylor, C.L. )

    1991-02-01

    Recent investigations demonstrate that cerebral blood flow (CBF) progressively declines during hypothermic, nonpulsatile cardiopulmonary bypass (CPB). If CBF declines because of brain cooling, the cerebral metabolic rate for oxygen (CMRO2) should decline in parallel with the reduction in CBF. Therefore we studied the response of CBF, the cerebral arteriovenous oxygen content difference (A-VDcereO2) and CMRO2 as a function of the duration of CPB in humans. To do this, we compared the cerebrovascular response to changes in the PaCO2. Because sequential CBF measurements using xenon 133 (133Xe) clearance must be separated by 15-25 min, we hypothesized that a time-dependent decline in CBF would accentuate the CBF reduction caused by a decrease in PaCO2, but would blunt the CBF increase associated with a rise in PaCO2. We measured CBF in 25 patients and calculated the cerebral arteriovenous oxygen content difference using radial arterial and jugular venous bulb blood samples. Patients were randomly assigned to management within either a lower (32-48 mm Hg) or higher (50-71 mm Hg) range of PaCO2 uncorrected for temperature. Each patient underwent two randomly ordered sets of measurements, one at a lower PaCO2 and the other at a higher PaCO2 within the respective ranges. Cerebrovascular responsiveness to changes in PaCO2 was calculated as specific reactivity (SR), the change in CBF divided by the change in PaCO2, expressed in mL.100 g-1.min-1.mm Hg-1.

  15. Organoselenium (Sel-Plex diet) decreases amyloid burden and RNA and DNA oxidative damage in APP/PS1 mice.

    PubMed

    Lovell, Mark A; Xiong, Shuling; Lyubartseva, Ganna; Markesbery, William R

    2009-06-01

    To evaluate potential antioxidant characteristics of organic selenium (Se), double knock-in transgenic mice expressing human mutations in the amyloid precursor protein (APP) and human presenilin-1 (PS1) were provided a Se-deficient diet, a Se-enriched diet (Sel-Plex), or a control diet from 4 to 9 months of age followed by a control diet until 12 months of age. Levels of DNA, RNA, and protein oxidation as well as lipid peroxidation markers were determined in all mice and amyloid beta-peptide (Abeta) plaques were quantified. APP/PS1 mice provided Sel-Plex showed significantly (P<0.05) lower levels of Abeta plaque deposition and significantly decreased levels of DNA and RNA oxidation. Sel-Plex-treated mice showed no significant differences in levels of lipid peroxidation or protein oxidation compared to APP/PS1 mice on a control diet. To determine if diminished oxidative damage was associated with increased antioxidant enzyme activities, brain glutathione peroxidase (GSH-Px), glutathione reductase, and glutathione transferase activities were measured. Sel-Plex-treated mice showed a modest but significant increase in GSH-Px activity compared to mice on a normal diet (P<0.5). Overall, these data suggest that organic Se can reduce Abeta burden and minimize DNA and RNA oxidation and support a role for it as a potential therapeutic agent in neurologic disorders with increased oxidative stress.

  16. Pomegranate juice decreases amyloid load and improves behavior in a mouse model of Alzheimer's disease.

    PubMed

    Hartman, Richard E; Shah, Aartie; Fagan, Anne M; Schwetye, Katherine E; Parsadanian, Maia; Schulman, Risa N; Finn, Mary Beth; Holtzman, David M

    2006-12-01

    Although there are no proven ways to delay onset or slow progression of Alzheimer's disease (AD), studies suggest that diet can affect risk. Pomegranates contain very high levels of antioxidant polyphenolic substances as compared to other fruits and vegetables. Polyphenols have been shown to be neuroprotective in different model systems. We asked whether dietary supplementation with pomegranate juice (PJ) would influence behavior and AD-like pathology in a transgenic mouse model. Transgenic mice (APP(sw)/Tg2576) received either PJ or sugar water control from 6 to 12.5 months of age. PJ-treated mice learned water maze tasks more quickly and swam faster than controls. Mice treated with PJ had significantly less (approximately 50%) accumulation of soluble Abeta42 and amyloid deposition in the hippocampus as compared to control mice. These results suggest that further studies to validate and determine the mechanism of these effects, as well as whether substances in PJ may be useful in AD, should be considered.

  17. Cerebral white matter lesions – associations with Aβ isoforms and amyloid PET

    PubMed Central

    van Westen, Danielle; Lindqvist, Daniel; Blennow, Kaj; Minthon, Lennart; Nägga, Katarina; Stomrud, Erik; Zetterberg, Henrik; Hansson, Oskar

    2016-01-01

    Small vessel disease (SVD) and amyloid deposition may promote each other, with a potential association between SVD and altered production or clearance of β-amyloid (Aβ) affecting its cleavage products. We investigated the relationship between SVD, multiple isoforms of Aβ in cerebrospinal fluid (CSF) and cortical Aβ in 831 subjects with cognitive performance ranging from normal to Alzheimer’s disease (AD) (the Swedish BioFINDER study). SVD was estimated as white matter lesions (WML) and lacunes. 18F-flutemetamol PET was performed in 321 subjects. Lower CSF levels of Aβ38 and Aβ40 were consistently associated with increased WML in all subgroups, while lower levels of CSF Aβ42 were associated with WML mainly in AD. CSF Aβ38 and Aβ40 were associated with regional WML in all regions, while CSF Aβ42 was associated with temporal WML only. A composite measure of 18F-flutemetamol uptake was not associated with WML, and regional 18F-flutemetamol uptake only with temporal WML. Lacunes were not associated with Aβ isoforms nor 18F-flutemetamol uptake. Our results suggest that WML may be associated with alterations in the production or clearance of Aβ species, particularly of Aβ38 and Aβ40. However, in AD cases, Aβ42 pathology might be associated with WML, especially in the temporal lobe. PMID:26856756

  18. Hyperglycemia aggravates decreases of PEA-15 and its two phosphorylated forms in cerebral ischemia

    PubMed Central

    SUNG, Jin-Hee; KOH, Phil-Ok

    2017-01-01

    Diabetes is a metabolic health disorder and an important risk factor for stroke. Phosphoprotein enriched in astrocytes 15 (PEA-15) is a multifunctional protein modulating cell proliferation, survival, apoptosis and glucose metabolism. This study investigated whether diabetes modulates the expression of PEA-15 and two phosphorylated forms (Ser 104 and Ser 116) in middle cerebral artery occlusion (MCAO)-induced brain injury. Male Sprague-Dawley rats were administrated with streptozotocin (40 mg/kg) and were underwent right middle cerebral artery occlusion (MCAO) 4 weeks after streptozotocin injection. Brain tissues were collected 24 hr after MCAO and stained using triphenyltetrazolium chloride. Western blot analysis was performed to elucidate the expression of PEA-15 and two phosphorylated forms (Ser 104 and Ser 116) in right cerebral cortex. Infarct volume during MCAO injury was severely increased in diabetic animals compared to non-diabetic animals. We identified the decrease in PEA-15 in animals that underwent MCAO using proteomic approach. PEA-15 expression during MCAO was strongly decreased in diabetic animals compared to non-diabetic animals. Western blots analysis confirmed that diabetes exacerbated the decrease in PEA-15 expression after MCAO. Moreover, decrease in expression of phospho-PEA-15 (Ser 104 and Ser 116) was greater in diabetic than in non-diabetic animals. These results suggested that a diabetic condition may aggravate brain damage through decreasing expression of PEA-15 and phospho-PEA-15 (Ser 104 and Ser 116) in ischemic brain injury. PMID:28216548

  19. Review: cerebral amyloid angiopathy, prion angiopathy, CADASIL and the spectrum of protein elimination failure angiopathies (PEFA) in neurodegenerative disease with a focus on therapy.

    PubMed

    Carare, R O; Hawkes, C A; Jeffrey, M; Kalaria, R N; Weller, R O

    2013-10-01

    Failure of elimination of proteins from the brain is a major feature in many neurodegenerative diseases. Insoluble proteins accumulate in brain parenchyma and in walls of cerebral capillaries and arteries. Cerebral amyloid angiopathy (CAA) is a descriptive term for amyloid in vessel walls. Here, we adopt the term protein elimination failure angiopathy (PEFA) to focus on mechanisms involved in the pathogenesis of a spectrum of disorders that exhibit both unique and common features of protein accumulation in blood vessel walls. We review (a) normal pathways and mechanisms by which proteins and other soluble metabolites are eliminated from the brain along 100- to 150-nm-thick basement membranes in walls of cerebral capillaries and arteries that serve as routes for lymphatic drainage of the brain; (b) a spectrum of proteins involved in PEFA; and (c) changes that occur in artery walls and contribute to failure of protein elimination. We use accumulation of amyloid beta (Aβ), prion protein and granular osmiophilic material (GOM) in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) as examples of different factors involved in the aetiology and pathogenesis of PEFA. Finally, we discuss how knowledge of factors involved in PEFA may help to focus on new therapies for neurodegenerative diseases. When Aβ (following immunotherapy) and prion protein are released from brain parenchyma they deposit in walls of cerebral capillaries and arteries; GOM in CADASIL accumulates primarily in artery walls. Therefore, the focus of therapy for protein clearance in neurodegenerative disease should perhaps be on facilitating perivascular elimination of proteins and reducing PEFA.

  20. Decreased physical activity predicts cognitive dysfunction and reduced cerebral blood flow in heart failure.

    PubMed

    Alosco, Michael L; Spitznagel, Mary Beth; Cohen, Ronald; Raz, Naftali; Sweet, Lawrence H; Josephson, Richard; Hughes, Joel; Rosneck, Jim; Gunstad, John

    2014-04-15

    Cognitive impairment in heart failure (HF) is believed to result from brain hypoperfusion subsequent to cardiac dysfunction. Physical inactivity is prevalent in HF and correlated with reduced cardiac and cognitive function. Yet, no longitudinal studies have examined the neurocognitive effects of physical inactivity in HF. The current study examined whether reduced physical activity increases risk for cognitive impairment and brain hypoperfusion over time in HF. At baseline and 12 months later, 65 HF patients underwent neuropsychological testing, transcranial Doppler ultrasonography, and were asked to wear an accelerometer for seven days. Lower baseline step count and less time spent in moderate free-living activity best predicted worse attention/executive function and decreased cerebral perfusion at the 12-month follow-up. Decreased baseline cerebral perfusion also emerged as a strong predictor of poorer 12-month attention/executive function. Lower physical activity predicted worse cognition and cerebral perfusion 12 months later in HF. Physical inactivity in HF may contribute to cognitive impairment and exacerbate risk for conditions such as Alzheimer's disease. Larger studies are needed to elucidate the mechanisms by which physical inactivity leads to cognitive dysfunction in HF, including clarification of the role of cerebral hypoperfusion. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Electromagnetic treatment to old Alzheimer's mice reverses β-amyloid deposition, modifies cerebral blood flow, and provides selected cognitive benefit.

    PubMed

    Arendash, Gary W; Mori, Takashi; Dorsey, Maggie; Gonzalez, Rich; Tajiri, Naoki; Borlongan, Cesar

    2012-01-01

    Few studies have investigated physiologic and cognitive effects of "long-term" electromagnetic field (EMF) exposure in humans or animals. Our recent studies have provided initial insight into the long-term impact of adulthood EMF exposure (GSM, pulsed/modulated, 918 MHz, 0.25-1.05 W/kg) by showing 6+ months of daily EMF treatment protects against or reverses cognitive impairment in Alzheimer's transgenic (Tg) mice, while even having cognitive benefit to normal mice. Mechanistically, EMF-induced cognitive benefits involve suppression of brain β-amyloid (Aβ) aggregation/deposition in Tg mice and brain mitochondrial enhancement in both Tg and normal mice. The present study extends this work by showing that daily EMF treatment given to very old (21-27 month) Tg mice over a 2-month period reverses their very advanced brain Aβ aggregation/deposition. These very old Tg mice and their normal littermates together showed an increase in general memory function in the Y-maze task, although not in more complex tasks. Measurement of both body and brain temperature at intervals during the 2-month EMF treatment, as well as in a separate group of Tg mice during a 12-day treatment period, revealed no appreciable increases in brain temperature (and no/slight increases in body temperature) during EMF "ON" periods. Thus, the neuropathologic/cognitive benefits of EMF treatment occur without brain hyperthermia. Finally, regional cerebral blood flow in cerebral cortex was determined to be reduced in both Tg and normal mice after 2 months of EMF treatment, most probably through cerebrovascular constriction induced by freed/disaggregated Aβ (Tg mice) and slight body hyperthermia during "ON" periods. These results demonstrate that long-term EMF treatment can provide general cognitive benefit to very old Alzheimer's Tg mice and normal mice, as well as reversal of advanced Aβ neuropathology in Tg mice without brain heating. Results further underscore the potential for EMF treatment

  2. Decreased IDE and IGF2 expression but increased Aβ40 in the cerebral cortex of mouse pups by early life lead exposure.

    PubMed

    Li, Ning; Yang, Guojun; Wang, Yueying; Qiao, Mingwu; Zhang, Pingan; Shao, Jianfeng; Yang, Guoyu

    2016-03-01

    As the abbreviation of plumbum and a chemical symbol for lead, Pb produces neurotoxic effects, which result into an impairment of learning and memory and other neurological dysfunctions. However, the mechanism of neurotoxicity of Pb exposure is unclear. The present study was undertaken to investigate the effects of maternal lead exposure on expression of insulin-degrading enzyme (IDE),insulin-like growth factor 2 (IGF2) and beta amyloid protein 40 (Aβ40) in the cerebral cortex of mice offspring. Lead exposure initiated from beginning of gestation to weaning. Lead acetate administered in drinking solutions was dissolved in distilled deionized water at the concentrations of 0.1%, 0.2% and 0.5% groups respectively. On the 21st postnatal day, On the PND21, the learning and memory ability were tested by water maze test and the Pb levels were also determined by graphite furnace atomic absorption spectrometry. The expression of IDE, IGF2 and Aβ40 in cerebral cortex was examined by immunohistochemistry, immunofluorescence and western blotting. The lead levels in blood and cerebral cortex of all lead exposure groups were significantly higher than that of the control group (P<0.05). In water maze test, the performances of 0.5% and 1% lead exposure groups were worse than that of the control group (P<0.05).The expression of IDE and IGF2 was decreased, but Aβ40 was increased in lead exposed groups than that of the control group (P<0.05). The decreased expression of IDE and IGF2 and increased expression of Aβ40 in the cerebral cortex of pups may contribute to the neurotoxicity associated with maternal Pb exposure.

  3. Sleep apnea termination decreases cerebral blood volume: a near-infrared spectroscopy case study

    NASA Astrophysics Data System (ADS)

    Virtanen, Jaakko; Noponen, Tommi; Salmi, Tapani; Toppila, Jussi; Meriläinen, Pekka

    2009-07-01

    Medical near-infrared spectroscopy (NIRS) can be used to estimate cerebral haemodynamic changes non-invasively. Sleep apnea is a common sleep disorder where repetitive pauses in breathing decrease the quality of sleep and exposes the individual to various health problems. We have measured oxygenated and deoxygenated haemoglobin concentration changes during apneic events in sleep from the forehead of one subject using NIRS and used principal component analysis to extract extracerebral and cortical haemodynamic changes from NIRS signals. Comparison of NIRS signals with EEG, bioimpedance, and pulse oximetry data suggests that termination of apnea leads to decreases in cerebral blood volume and flow that may be related to neurological arousal via neurovascular coupling.

  4. Anaphylactic shock decreases cerebral blood flow more than what would be expected from severe arterial hypotension.

    PubMed

    Davidson, Julien; Zheng, Feng; Tajima, Keiko; Barthel, Grégoire; Alb, Ionel; Tabarna, Adriana; Thornton, Simon N; Lambert, Maud; Longrois, Dan; Audibert, Gérard; Malinovsky, Jean-Marc; Mertes, Paul-Michel

    2012-10-01

    The effects of acute reduction in arterial blood pressure in severe anaphylactic shock (AS) on cerebral blood flow are of paramount importance to be investigated. We studied cerebral circulation and oxygenation in a model of severe AS and compared it with a pharmacologically induced arterial hypotension of similar magnitude. Anaphylactic shock was induced by 1 mg intravenous ovalbumin (OVA) in sensitized rats. Rats were randomized to three groups: (i) no resuscitation (OVA; n = 10) (ii) intravenous volume expansion (10 mL in 10 min after OVA injection) (OVA + VE; n = 10); (iii) control hypotension (100 μg of nicardipine followed by continuous infusion of 1 mg · 100 g · h intravenously; NICAR; n = 10). Mean arterial pressure (MAP), carotid blood flow (CBF), cardiac output, cerebral cortical blood flow (CCBF; estimated by laser Doppler technique), and cerebral tissue oxygen pressure (PtiO2) were recorded over the 15 min following AS induction in all three groups. Results are expressed as mean (SD). One minute after OVA or nicardipine injection, there was a rapid and significant 50% decrease in MAP from basal values. In the OVA group, AS severely altered systemic and cerebral hemodynamics in 5 min: 93% (SD, 4%) decrease in CBF, 66% (SD, 8%) in CCBF, and 44% (SD, 8%) in PtiO2; the decrease in CBF was significantly (P < 0.05) attenuated in the OVA + VE group; however, CCBF and PtiO2 were not statistically different in the OVA versus OVA + VE groups. On the contrary, nicardipine-induced hypotension had only a limited impact on CBF, cardiac output, CCBF, and PtiO2 for a similar MAP decrease. There was a linear relation between CCBF and blood pressure in the OVA (regression slope: 0.87 [SD, 0.06]; median r = 0.81) but not in the NICAR group (regression slope: 0.23 [SD, 0.32]; median r = 0.33). Anaphylactic shock resulted in severe impairment of cerebral blood flow and oxygenation, beyond what could be expected from the level of arterial hypotension.

  5. Nicotinamide attenuates the decrease of astrocytic phosphoprotein PEA-15 in focal cerebral ischemic injury.

    PubMed

    Koh, Phil-Ok

    2012-03-01

    Nicotinamide exerts neuroprotective effects against focal cerebral ischemic injury. Phosphoprotein enriched in astrocytes 15 (PEA-15) is prominently expressed in astrocytes that exert broad anti-apoptotic functions. This study investigated whether nicotinamide modulates PEA-15 and levels of two phosphorylated PEA-15 (Serine 104 and 116) in an animal model of middle cerebral artery occlusion (MCAO)-induced injury. Adult male rats were treated with vehicle or nicotinamide (500 mg/kg) 2 hr after the onset of MCAO and cerebral cortices were collected at 24 hr after MCAO. In a proteomic approach, MCAO induced decreases of PEA-15 levels, while nicotinamide treatment attenuated the injury-induced decrease in PEA-15. The results of Western blot analysis suggest that nicotinamide prevented injury-induced reduction in phospho-PEA-15 (Serine 104) and phospho-PEA-15 (Serine 116) levels. The phosphorylation of PEA-15 exerts anti-apoptotic functions, and reduction of PEA-15 phosphorylation leads to apoptotic cell death. These results suggest that nicotinamide exerts a neuroprotective effect by attenuating the injury-induced decreases of PEA-15 and phospho-PEA-15 (Ser 104 and Ser 116) proteins.

  6. The load of amyloid-β oligomers is decreased in the cerebrospinal fluid of Alzheimer's disease patients.

    PubMed

    Sancesario, Giulia M; Cencioni, Maria T; Esposito, Zaira; Borsellino, Giovanna; Nuccetelli, Marzia; Martorana, Alessandro; Battistini, Luca; Sorge, Roberto; Spalletta, Gianfranco; Ferrazzoli, Davide; Bernardi, Giorgio; Bernardini, Sergio; Sancesario, Giuseppe

    2012-01-01

    Amyloid-β (Aβ) oligomers are heterogeneous and instable compounds of variable molecular weight. Flow cytometry and fluorescence resonance energy transfer (FRET)-based methods allow the simultaneous detection of Aβ oligomers with low and high molecular weight in their native form. We evaluated whether an estimate of different species of Aβ oligomers in the cerebrospinal fluid (CSF) with or without dilution with RIPA buffer could be more useful in the diagnosis of Alzheimer's disease (AD) than the measurement of Aβ42 monomers, total tau (t-tau), and phosphorylated tau (p-tau). Increased t-tau (p < 0.01) and p-tau (p < 0.01), and decreased Aβ42 (p < 0.01), were detected in the CSF of patients with AD (n = 46), compared to patients with other dementia (OD) (n = 35) or with other neurological disorders (OND) (n = 56). In native CSF (n = 137), the levels of Aβ oligomers were lower (p < 0.05) in AD than in OD and OND patients; in addition, the ratio Aβ oligomers/p-tau was lower in AD than in OD (p < 0.01) and OND (p < 0.05) patients, yielding a sensitivity of 75% and a specificity of 64%. However, in CSF diluted with RIPA (n = 30), Aβ oligomers appeared higher (p < 0.05) in AD than in OND patients, suggesting they become partially disaggregated and more easily detectable after RIPA. In conclusion, FRET analysis in native CSF is essential to correctly determine the composition of Aβ oligomers. In this experimental setting, the simultaneous estimate of low and high molecular weight Aβ oligomers is as useful as the other biomarkers in the diagnosis of AD. The low amount of Aβ oligomers detected in native CSF of AD may be inversely related to their levels in the brain, as occurs for Aβ monomers, representing a biomarker for the amyloid pathogenic cascade.

  7. Replacement of brain-resident myeloid cells does not alter cerebral amyloid-β deposition in mouse models of Alzheimer’s disease

    PubMed Central

    Varvel, Nicholas H.; Grathwohl, Stefan A.; Degenhardt, Karoline; Resch, Claudia; Bosch, Andrea; Jucker, Mathias

    2015-01-01

    Immune cells of myeloid lineage are encountered in the Alzheimer’s disease (AD) brain, where they cluster around amyloid-β plaques. However, assigning functional roles to myeloid cell subtypes has been problematic, and the potential for peripheral myeloid cells to alleviate AD pathology remains unclear. Therefore, we asked whether replacement of brain-resident myeloid cells with peripheral monocytes alters amyloid deposition in two mouse models of cerebral β-amyloidosis (APP23 and APPPS1). Interestingly, early after repopulation, infiltrating monocytes neither clustered around plaques nor showed Trem2 expression. However, with increasing time in the brain, infiltrating monocytes became plaque associated and also Trem2 positive. Strikingly, however, monocyte repopulation for up to 6 mo did not modify amyloid load in either model, independent of the stage of pathology at the time of repopulation. Our results argue against a long-term role of peripheral monocytes that is sufficiently distinct from microglial function to modify cerebral β-amyloidosis. Therefore, myeloid replacement by itself is not likely to be effective as a therapeutic approach for AD. PMID:26458770

  8. Binding of curcumin to senile plaques and cerebral amyloid angiopathy in the aged brain of various animals and to neurofibrillary tangles in Alzheimer's brain.

    PubMed

    Mutsuga, Mayu; Chambers, James Kenn; Uchida, Kazuyuki; Tei, Meina; Makibuchi, Takao; Mizorogi, Tatsuya; Takashima, Akihiko; Nakayama, Hiroyuki

    2012-01-01

    The binding of curcumin to senile plaques (SPs) and cerebral amyloid angiopathy (CAA) was examined in the aged brain of various animal species and a human patient with Alzheimer's disease (AD), together with its binding to neurofibrillary tangles (NFTs). Brain sections were immunostained with anti-amyloid β protein 1-42 (Aβ42) and anti-amyloid β protein 1-40 (Aβ40) antibodies. These sections were also stained with alkaline Congo red, periodic acid-methenamine silver (PAM), and curcumin (0.009% curcumin solution) with or without formic acid pretreatment. The sections from the AD brain were also immunostained for anti-paired helical filament-tau (PHF-tau), and were stained with Gallyas silver for NFTs. Some SPs in the AD, monkey, dog, bear, and amyloid precursor protein transgenic mouse (APP Tg-mouse) brains contained congophilic materials, and were intensely positive for curcumin. In addition, curcumin labeled some diffuse SPs negative for Congo red in the AD, monkey, bear, and APP Tg-mouse brains. In all animals, CAA was intensely positive for both Congo red and curcumin. The specific curcumin staining activity was lost by formic acid pretreatment. In the AD brain, NFTs positive for PHF-tau and Gallyas silver were moderately stained with curcumin. These findings indicate that curcumin specifically binds to the aggregated Aβ molecules in various animals, and further to phosphorylated tau protein, probably according to its conformational nature.

  9. Voxel-wise relationships between distribution volume ratio and cerebral blood flow: implications for analysis of β-amyloid images

    PubMed Central

    Sojkova, Jitka; Goh, Joshua; Bilgel, Murat; Landman, Bennett; Yang, Xue; Zhou, Yun; An, Yang; Beason-Held, Lori L.; Kraut, Michael A.; Wong, Dean F.; Resnick, Susan M.

    2017-01-01

    Quantification of β-amyloid (Aβ) in vivo is often accomplished using the distribution volume ratio (DVR), based on a simplified reference tissue model. We investigated the local relationships between DVR and cerebral blood flow (CBF), as well as relative blood flow (R1), in nondemented older adults. Methods Fifty-five nondemented participants (mean age 78.5 years) in the Baltimore Longitudinal Study of Aging underwent 15O-H2O PET CBF and dynamic 11C-PiB-PET. 15O-H2O PET images were normalized and smoothed using SPM. A simplified reference tissue model with linear regression and spatial constraints was used to generate parametric DVR images. The DVR images were regressed on CBF images on a voxel-by-voxel basis using robust Biological Parametric Mapping, adjusting for age and sex (FDR p=0.05, k=50). DVR images were also regressed on R1 images, a measure of the transport rate constant from vascular space to tissue. All analyses were performed in the entire sample, and in high and low tertiles of mean cortical DVR. Results Voxel-based analyses showed that increased DVR is associated with increased CBF in frontal, parietal, temporal, and occipital cortices. However, this association appears to spare regions that typically show early β-amyloid (Aβ) deposition. A more robust relationship between DVR and CBF was observed in the lowest tertile of DVR, i.e., negligible cortical Aβ load, compared to the highest tertile of cortical DVR and Aβ load. Spatial distributions of the DVR-CBF and DVR-R1 correlations showed similar patterns. No reliable negative voxel-wise relationships between DVR and CBF or R1 were observed. Conclusion Robust associations between DVR and CBF at negligible Aβ levels, together with similar spatial distributions of DVR-CBF and DVR-R1 correlations, suggest that regional distribution of DVR reflects blood flow and tracer influx rather than pattern of Aβ deposition in those with minimal Aβ load. DVR-CBF associations in individuals with higher DVR

  10. ApoA1, ApoJ and ApoE Plasma Levels and Genotype Frequencies in Cerebral Amyloid Angiopathy.

    PubMed

    Montañola, Alex; de Retana, Sofía Fernández; López-Rueda, Antonio; Merino-Zamorano, Cristina; Penalba, Anna; Fernández-Álvarez, Paula; Rodríguez-Luna, David; Malagelada, Ana; Pujadas, Francesc; Montaner, Joan; Hernández-Guillamon, Mar

    2016-03-01

    The involvement of apolipoproteins, such as the ApoE4 isoform, in Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) highlights the fact that certain lipid carriers may participate in soluble β-amyloid (Aβ) transport. Our general aim was to characterize the soluble levels of the apolipoproteins apoE, apoA1 and apoJ/clusterin and their genotype status in patients with CAA. We analyzed the genotypes frequency of APOA1 (rs5069, rs670), CLU (rs11136000, rs1532278, rs7012010, rs9331888) and APOE (rs429358, rs7412) in a cohort of patients with CAA-associated intracerebral hemorrhage (ICH) (n = 59) and compared the results with those from hypertension-associated ICH (n = 42), AD patients (n = 73) and controls (n = 88). In a subgroup of patients, we also determined the plasma concentrations of apoE, apoA1 and apoJ/clusterin. We found increased plasma apoJ/clusterin levels in CAA patients compared to AD patients or controls after adjusting for sex and age (CAA vs. controls, p = 0.033; CAA vs. AD, p = 0.013). ApoA1 levels were not altered between groups, although a strong correlation was observed between plasma Aβ(1-40) and apoA1 among CAA patients (r = 0.583, p = 0.007). Regarding plasma apoE concentration, a robust association between circulating levels and genotype status was confirmed (p < 0.001). Whereas the APOE4 frequency was higher in AD (p < 0.001) and CAA (p = 0.013), the APOA1 and CLU genotypes were not different among groups. In the CAA cohort, the risk-linked CLU variant (C) rs11136000 was associated with white matter hyperintensities (p = 0.045) and the presence of lobar microbleeds (p = 0.023) on MRI. In summary, our findings suggest that apoA1 may act as a physiological transporter of Aβ(1-40) and that apoJ/clusterin appears to be a chaperone related to distinctive lesions in CAA brains.

  11. PiB Fails to Map Amyloid Deposits in Cerebral Cortex of Aged Dogs with Canine Cognitive Dysfunction.

    PubMed

    Fast, Rikke; Rodell, Anders; Gjedde, Albert; Mouridsen, Kim; Alstrup, Aage K; Bjarkam, Carsten R; West, Mark J; Berendt, Mette; Møller, Arne

    2013-01-01

    Dogs with Canine Cognitive Dysfunction (CCD) accumulate amyloid beta (Aβ) in the brain. As the cognitive decline and neuropathology of these old dogs share features with Alzheimer's disease (AD), the relation between Aβ and cognitive decline in animal models of cognitive decline is of interest to the understanding of AD. However, the sensitivity of the biomarker Pittsburgh Compound B (PiB) to the presence of Aβ in humans and in other mammalian species is in doubt. To test the sensitivity and assess the distribution of Aβ in dog brain, we mapped the brains of dogs with signs of CCD (n = 16) and a control group (n = 4) of healthy dogs with radioactively labeled PiB ([(11)C]PiB). Structural magnetic resonance imaging brain scans were obtained from each dog. Tracer washout analysis yielded parametric maps of PiB retention in brain. In the CCD group, dogs had significant retention of [(11)C]PiB in the cerebellum, compared to the cerebral cortex. Retention in the cerebellum is at variance with evidence from brains of humans with AD. To confirm the lack of sensitivity, we stained two dog brains with the immunohistochemical marker 6E10, which is sensitive to the presence of both Aβ and Aβ precursor protein (AβPP). The 6E10 stain revealed intracellular material positive for Aβ or AβPP, or both, in Purkinje cells. The brains of the two groups of dogs did not have significantly different patterns of [(11)C]PiB binding, suggesting that the material detected with 6E10 is AβPP rather than Aβ. As the comparison with the histological images revealed no correlation between the [(11)C]PiB and Aβ and AβPP deposits in post-mortem brain, the marked intracellular staining implies intracellular involvement of amyloid processing in the dog brain. We conclude that PET maps of [(11)C]PiB retention in brain of dogs with CCD fundamentally differ from the images obtained in most humans with AD.

  12. Vascular pathology in Alzheimer disease: correlation of cerebral amyloid angiopathy and arteriosclerosis/lipohyalinosis with cognitive decline.

    PubMed

    Thal, Dietmar Rudolf; Ghebremedhin, Estifanos; Orantes, Mario; Wiestler, Otmar D

    2003-12-01

    Sporadic, late-onset Alzheimer disease (AD) constitutes the most frequent cause of dementia in the elderly population. AD-related pathology is often accompanied by vascular changes. The predominant vascular lesions in AD are cerebral amyloid angiopathy (CAA) and arteriosclerosis/lipohyalinosis (AS/LH). The present study was carried out to examine the coincidence of these small vessel pathologies during the development of cognitive deficits, amyloid beta-protein (A beta) deposition, and neurofibrillary tangle (NFT) formation in sporadic late-onset AD. We correlated the clinical dementia rating (CDR) score, the sequential extension of AD-related A beta deposition into different parts of the brain, and the extension of NFTs to involve more brain regions with the distribution of CAA and AS/LH in 52 human autopsy brains. The extension of CAA and AS/LH to involve different areas of the brain was associated with a rise of CDR scores and an increase in the extension of A beta deposition and NFT generation. AD cases showed a higher number of regions with CAA and AS/LH compared to nondemented patients with AD-related pathology and controls. Moreover, we demonstrated a hierarchical sequence in which the different regions of the brain exhibited CAA and AS/LH-affected vessels, allowing the distinction of 3 stages in the development of CAA and AS/LH. The first stage of CAA involved leptomeningeal and neocortical vessels. The second stage was characterized by additional A beta deposition in allocortical and midbrain vessels. Finally, in a third stage, CAA was observed in the basal ganglia, the thalamus, and in the lower brainstem. In contrast, AS/LH initially affected the basal ganglia in stage A. In stage B this pathology made inroads into the deep white matter, the leptomeningeal arteries of the cortex, the cerebellum, and into the thalamus. Stage C was characterized by AS/LH in brainstem vessels. Our results demonstrate widespread CAA and AS/LH to be associated with the

  13. Absence of PIttsburgh Compound B Detection of CerebralAmyloid Beta in a Patient With Clinical, Cognitive, and Cerebrospinal FluidMarkers of Alzheimer Disease

    PubMed Central

    Cairns, Nigel J.; Ikonomovic, Milos D.; Benzinger, Tammie; Storandt, Martha; Fagan, Anne M; Shah, Arti; Schmidt, Robert E.; Perry, Arie; Reinwald, Lisa Taylor; Carter, Deborah; Felton, Angela; Holtzman, David M.; Mintun, Mark A.; Klunk, William E.; Morris, John C.

    2009-01-01

    Objective To determine the temporal relationships of clinical, cognitive, Pittsburgh Compound-B (PiB) amyloid imaging, and cerebrospinal fluid (CSF) markers of Alzheimer’s disease (AD). Design A case report of a longitudinally assessed participant in a memory and aging study who had serial clinical and psychometric assessments over 6 years, in addition to PiB imaging and CSF biomarker assays, prior to coming to autopsy. Setting Alzheimer’s Disease Research Center Findings An 85-year old individual was cognitively normal at his initial and next 3 annual assessments. Decline in measures of episodic memory and, to a lesser degree, working memory began at about age 88 years. PiB-PET amyloid imaging was negative at age 88.5 years, but at age 89.5 years there was reduced amyloid-beta 42 (Aβ42) and elevated levels of tau in the CSF. At his 6th assessment, when he was 90 years old, he was diagnosed with very mild dementia of the Alzheimer type. After death at age 91 years, the autopsy revealed foci of frequent neocortical diffuse Aβ plaques, sufficient to fulfill Khachaturian neuropathologic criteria for AD, but neuritic plaques and neurofibrillary tangles were sparse. Postmortem biochemical analysis of the cerebral tissue confirmed that PiB-PET-binding was below the level needed for in vivo detection. Conclusion Clinical, cognitive, and CSF markers consistent with AD may precede detection of cerebral Aβ with amyloid imaging agents such as PiB, which primarily label fibrillar Aβ plaques. PMID:20008664

  14. MR microscopy of human amyloid-β deposits: characterization of parenchymal amyloid, diffuse plaques, and vascular amyloid.

    PubMed

    Nabuurs, Rob J A; Natté, Remco; de Ronde, Fenna M; Hegeman-Kleinn, Ingrid; Dijkstra, Jouke; van Duinen, Sjoerd G; Webb, Andrew G; Rozemuller, Annemieke J; van Buchem, Mark A; van der Weerd, Louise

    2013-01-01

    Cerebral deposits of amyloid-β peptides (Aβ) form the neuropathological hallmarks of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). In the brain, Aβ can aggregate as insoluble fibrils present in amyloid plaques and vascular amyloid, or as diffuse plaques consisting of mainly non-fibrillar Aβ. Previously, magnetic resonance imaging (MRI) has been shown to be capable of detecting individual amyloid plaques, not only via the associated iron, but also Aβ itself has been suggested to be responsible for a decrease in the image intensity. In this current study we aim to investigate the MRI properties of the different cerebral Aβ deposits including diffuse plaques and vascular amyloid. Postmortem 60-μm-thick brain sections of AD, CAA, and Down's syndrome patients, known to contain Aβ, were studied. High resolution T2*- and T2-weighted MRI scans and quantitative relaxation maps were acquired using a microcoil on a Bruker 9.4T MRI system. Specific MRI characteristics of each type of Aβ deposit were examined by co-registration of the MRI with Congo Red and Aβ-immunostainings of the same sections. Our results show that only fibrillar Aβ, present in both vascular and parenchymal amyloid, induced a significant change in T2* and T2 values. However, signal changes were not as consistent for all of the vessels affected by CAA, irrespective of possible dyshoric changes. In contrast, the non-fibrillar diffuse plaques did not create any detectable MRI signal changes. These findings are relevant for the interpretation and further development of (quantitative) MRI methods for the detection and follow-up of AD and CAA.

  15. Relative increase in Alzheimer's disease of soluble forms of cerebral Abeta amyloid protein precursor containing the Kunitz protease inhibitory domain.

    PubMed

    Moir, R D; Lynch, T; Bush, A I; Whyte, S; Henry, A; Portbury, S; Multhaup, G; Small, D H; Tanzi, R E; Beyreuther, K; Masters, C L

    1998-02-27

    Although a number of studies have examined amyloid precursor protein (APP) mRNA levels in Alzheimer's disease (AD), no clear consensus has emerged as to whether the levels of transcripts for isoforms containing a Kunitz protease inhibitory (KPI)-encoded region are increased or decreased in AD. Here we compare AD and control brain for the relative amounts of APP protein containing KPI to APP protein lacking this domain. APP protein was purified from the soluble subcellular fraction and Triton X-100 membrane pellet extract of one hemisphere of AD (n = 10), normal (n = 7), and neurological control (n = 5) brains. The amount of KPI-containing APP in the purified protein samples was determined using two independent assay methods. The first assay exploited the inhibitory action of KPI-containing APP on trypsin. The second assay employed reflectance analysis of Western blots. The proportion of KPI-containing forms of APP in the soluble subcellular fraction of AD brains is significantly elevated (p < 0.01) compared with controls. Species containing a KPI domain comprise 32-41 and 76-77% of purified soluble APP from control and AD brains, respectively. For purified membrane-associated APP, 72-77 and 65-82% of control and AD samples, respectively, contain a KPI domain. Since KPI-containing species of APP may be more amyloidogenic (Ho, L., Fukuchi, K., and Yonkin, S. G. (1996) J. Biol. Chem. 271, 30929-30934), our findings support an imbalance of isoforms as one possible mechanism for amyloid deposition in sporadic AD.

  16. Decreased brain-derived neurotrophic factor depends on amyloid aggregation state in transgenic mouse models of Alzheimer's disease.

    PubMed

    Peng, Shiyong; Garzon, Diego J; Marchese, Monica; Klein, William; Ginsberg, Stephen D; Francis, Beverly M; Mount, Howard T J; Mufson, Elliott J; Salehi, Ahmad; Fahnestock, Margaret

    2009-07-22

    Downregulation of brain-derived neurotrophic factor (BDNF) in the cortex occurs early in the progression of Alzheimer's disease (AD). Since BDNF plays a critical role in neuronal survival, synaptic plasticity, and memory, BDNF reduction may contribute to synaptic and cellular loss and memory deficits characteristic of AD. In vitro evidence suggests that amyloid-beta (A beta) contributes to BDNF downregulation in AD, but the specific A beta aggregation state responsible for this downregulation in vivo is unknown. In the present study, we examined cortical levels of BDNF mRNA in three different transgenic AD mouse models harboring mutations in APP resulting in A beta overproduction, and in a genetic mouse model of Down syndrome. Two of the three A beta transgenic strains (APP(NLh) and TgCRND8) exhibited significantly decreased cortical BDNF mRNA levels compared with wild-type mice, whereas neither the other strain (APP(swe)/PS-1) nor the Down syndrome mouse model (Ts65Dn) was affected. Only APP(NLh) and TgCRND8 mice expressed high A beta(42)/A beta(40) ratios and larger SDS-stable A beta oligomers (approximately 115 kDa). TgCRND8 mice exhibited downregulation of BDNF transcripts III and IV; transcript IV is also downregulated in AD. Furthermore, in all transgenic mouse strains, there was a correlation between levels of large oligomers, A beta(42)/A beta(40), and severity of BDNF decrease. These data show that the amount and species of A beta vary among transgenic mouse models of AD and are negatively correlated with BDNF levels. These findings also suggest that the effect of A beta on decreased BDNF expression is specific to the aggregation state of A beta and is dependent on large oligomers.

  17. [Hereditary Alzheimer's disease with amyloid angiopathy caused by amyloid precursor protein locus].

    PubMed

    Axer, H; Hüge, S; Wilhelm, C; Axer, M; Kunze, A; Reichenbach, J R; Freesmeyer, M; Kohlhase, J; Sauer, H; Bär, K-J

    2009-01-01

    We report a patient with early-onset autosomal dominant dementia. The CSF showed increased levels of tau protein and decreased amyloid beta (ratio 42:40) typical for Alzheimer's disease. Cerebral MRI revealed vascular lesions and white-matter changes around the posterior horns of the ventricles with only moderate atrophy of the brain. Susceptibility-weighted imaging detected multiple small hemorrhagic changes. Gene analysis revealed amyloid precursor protein (APP) locus duplication as the cause of hereditary Alzheimer's dementia. The co-occurrence of CSF changes typical for Alzheimer's disease and MRI findings of cerebral amyloid angiopathy is remarkable, as it is also described for APP locus duplication. In conjunction with a family history suggestive of hereditary dementia, such a constellation should lead to enhanced gene analysis.

  18. Cerebral microbleeds topography and cerebrospinal fluid biomarkers in cognitive impairment.

    PubMed

    Shams, Sara; Granberg, Tobias; Martola, Juha; Charidimou, Andreas; Li, Xiaozhen; Shams, Mana; Fereshtehnejad, Seyed-Mohammad; Cavallin, Lena; Aspelin, Peter; Wiberg-Kristoffersen, Maria; Wahlund, Lars-Olof

    2017-03-01

    Cerebral microbleeds, a marker of small vessel disease, are thought to be of importance in cognitive impairment. We aimed to study topographical distribution of cerebral microbleeds, and their involvement in disease pathophysiology, reflected by cerebrospinal fluid biomarkers; 1039 patients undergoing memory investigation underwent lumbar puncture and a brain magnetic resonance imaging scan. Cerebrospinal fluid samples were analyzed for amyloid β(Aβ)42, total tau(T-tau), tau phosphorylated at threonine 18(P-tau) and cerebrospinal fluid/serum albumin ratios. Magnetic resonance imaging sequences were evaluated for small vessel disease markers, including cerebral microbleeds, white matter hyperintensities and lacunes. Low Aβ42 levels were associated with lobar cerebral microbleeds in the whole cohort and Alzheimer's disease ( P < 0.001). High cerebrospinal fluid/serum albumin ratios were seen with increased number of cerebral microbleeds in the brainstem ( P < 0.001). There were tendencies for increased Aβ42 levels and decreased Tau levels with deep and infratentorial cerebral microbleeds ( P < 0.05). Lobar cerebral microbleeds were associated with white matter hyperintensities and lacunes ( P < 0.001). Probable cerebral amyloid angiopathy-related cerebral microbleeds were associated with low Aβ42 levels and lacunes, whereas probable cerebral amyloid angiopathy-unrelated cerebral microbleeds were associated with white matter hyperintensities ( P < 0.001). Our findings show that cerebral microbleed distribution is associated with different patterns of cerebrospinal fluid biomarkers, supporting different pathogenesis of deep/infratentorial and lobar cerebral microbleeds.

  19. Neurotensin decreases high affinity [3H]-ouabain binding to cerebral cortex membranes.

    PubMed

    Rosin, Carina; Ordieres, María Graciela López; Arnaiz, Georgina Rodríguez de Lores

    2011-12-10

    Previous work from this laboratory showed the ability of neurotensin to inhibit synaptosomal membrane Na(+), K(+)-ATPase activity, the effect being blocked by SR 48692, a non-peptidic antagonist for high affinity neurotensin receptor (NTS1) [López Ordieres and Rodríguez de Lores Arnaiz 2000; 2001]. To further study neurotensin interaction with Na(+), K(+)-ATPase, peptide effect on high affinity [(3)H]-ouabain binding was studied in cerebral cortex membranes. It was observed that neurotensin modified binding in a dose-dependent manner, leading to 80% decrease with 1 × 10(-4)M concentration. On the other hand, the single addition of 1 × 10(-6)M, 1 × 10(-5)M and 1 × 10(-4)M SR 48692 (Sanofi-Aventis, U.S., Inc.) decreased [(3)H]-ouabain binding (in %) to 87 ± 16; 74 ± 16 and 34 ± 17, respectively. Simultaneous addition of neurotensin and SR 48692 led to additive or synergic effects. Partial NTS2 agonist levocabastine inhibited [(3)H]-ouabain binding likewise. Saturation assays followed by Scatchard analyses showed that neurotensin increased K(d) value whereas failed to modify B(max) value, indicating a competitive type interaction of the peptide at Na(+), K(+)-ATPase ouabain site. At variance, SR 48692 decreased B(max) value whereas it did not modify K(d) value. [(3)H]-ouabain binding was also studied in cerebral cortex membranes obtained from rats injected i. p. 30 min earlier with 100 μg and 250 μg/kg SR 48692. It was observed that the 250 μg/kg SR 48692 dose led to 19% decrease in basal [(3)H]-ouabain binding. After SR 48692 treatments, addition of 1 × 10(-6)M led to additive or synergic effect. Results suggested that [(3)H]-ouabain binding inhibition by neurotensin hardly involves NTS1 receptor.

  20. Cerebral Blood Flow and Aβ-Amyloid Estimates by WARM Analysis of [(11)C]PiB Uptake Distinguish among and between Neurodegenerative Disorders and Aging.

    PubMed

    Rodell, Anders B; O'Keefe, Graeme; Rowe, Christopher C; Villemagne, Victor L; Gjedde, Albert

    2016-01-01

    Background: We report results of the novel Washout Allometric Reference Method (WARM) that uses estimates of cerebral blood flow and amyloid load from the same [(11)C]Pittsburgh Compound B ([(11)C]PiB) retention maps in brain to distinguish between patients with different forms dementia, including Alzheimer's disease, and healthy volunteers. The method introduces two approaches to the identification of brain pathology related to amyloid accumulation, (1) a novel analysis of amyloid binding based on the late washout of the tracer from brain tissue, and (2) the simultaneous estimation of absolute cerebral blood flow indices (sCBF) from the early accumulation of the tracer in brain tissue. Objective: We tested the hypothesis that a change of cerebral blood flow is correlated with the degree of tracer [(11)C]PiB retention, reflecting dendritic spine pathology and consequent inhibition of brain energy metabolism and reduction of blood flow by neurovascular coupling in neurodegenerative disorders, including Alzheimer's disease. Methods: Previously reported images of [(11)C]PiB retention in brain of 29 subjects with cognitive impairment or dementia [16 Alzheimer's Disease (AD), eight subjects with dementia with Lewy bodies (DLB), five patients with frontotemporal lobar degeneration (FTLD), five patients with mild cognitive impairment, and 29 age-matched healthy control subjects (HC)], underwent analysis of PiB delivery and retention by means of WARM for quantitation of [(11)C]PiB's binding potentials (BPND) and correlated surrogate cerebral blood flow (sCBF) estimates, based on the [(11)C]PiB images, compared to estimates by conventional Standard Uptake Value Ratio (SUVR) of [(11)C]PiB retention with cerebellum gray matter as reference. Receiver Operating Characteristics (ROC) revealed the power of discrimination among estimates. Results: For AD, the discriminatory power of [(11)C]PiB binding potential (BPND) by WARM exceeded the power of SUVR that in turn exceeded the

  1. Cerebral Blood Flow and Aβ-Amyloid Estimates by WARM Analysis of [11C]PiB Uptake Distinguish among and between Neurodegenerative Disorders and Aging

    PubMed Central

    Rodell, Anders B.; O’Keefe, Graeme; Rowe, Christopher C.; Villemagne, Victor L.; Gjedde, Albert

    2017-01-01

    Background: We report results of the novel Washout Allometric Reference Method (WARM) that uses estimates of cerebral blood flow and amyloid load from the same [11C]Pittsburgh Compound B ([11C]PiB) retention maps in brain to distinguish between patients with different forms dementia, including Alzheimer’s disease, and healthy volunteers. The method introduces two approaches to the identification of brain pathology related to amyloid accumulation, (1) a novel analysis of amyloid binding based on the late washout of the tracer from brain tissue, and (2) the simultaneous estimation of absolute cerebral blood flow indices (sCBF) from the early accumulation of the tracer in brain tissue. Objective: We tested the hypothesis that a change of cerebral blood flow is correlated with the degree of tracer [11C]PiB retention, reflecting dendritic spine pathology and consequent inhibition of brain energy metabolism and reduction of blood flow by neurovascular coupling in neurodegenerative disorders, including Alzheimer’s disease. Methods: Previously reported images of [11C]PiB retention in brain of 29 subjects with cognitive impairment or dementia [16 Alzheimer’s Disease (AD), eight subjects with dementia with Lewy bodies (DLB), five patients with frontotemporal lobar degeneration (FTLD), five patients with mild cognitive impairment, and 29 age-matched healthy control subjects (HC)], underwent analysis of PiB delivery and retention by means of WARM for quantitation of [11C]PiB’s binding potentials (BPND) and correlated surrogate cerebral blood flow (sCBF) estimates, based on the [11C]PiB images, compared to estimates by conventional Standard Uptake Value Ratio (SUVR) of [11C]PiB retention with cerebellum gray matter as reference. Receiver Operating Characteristics (ROC) revealed the power of discrimination among estimates. Results: For AD, the discriminatory power of [11C]PiB binding potential (BPND) by WARM exceeded the power of SUVR that in turn exceeded the power of s

  2. Decreased proteolytic activity of the mitochondrial amyloid-β degrading enzyme, PreP peptidasome, in Alzheimer's disease brain mitochondria.

    PubMed

    Alikhani, Nyosha; Guo, Lan; Yan, Shiqiang; Du, Heng; Pinho, Catarina Moreira; Chen, John Xi; Glaser, Elzbieta; Yan, Shirley ShiDu

    2011-01-01

    Accumulation of amyloid-β peptide (Aβ), the neurotoxic peptide implicated in the pathogenesis of Alzheimer's disease (AD), has been shown in brain mitochondria of AD patients and of AD transgenic mouse models. The presence of Aβ in mitochondria leads to free radical generation and neuronal stress. Recently, we identified the presequence protease, PreP, localized in the mitochondrial matrix in mammalian mitochondria as the novel mitochondrial Aβ-degrading enzyme. In the present study, we examined PreP activity in the mitochondrial matrix of the human brain's temporal lobe, an area of the brain highly susceptible to Aβ accumulation and reactive oxygen species (ROS) production. We found significantly lower hPreP activity in AD brains compared with non-AD age-matched controls. By contrast, in the cerebellum, a brain region typically spared from Aβ accumulation, there was no significant difference in hPreP activity when comparing AD samples to non-AD controls. We also found significantly reduced PreP activity in the mitochondrial matrix of AD transgenic mouse brains (Tg mAβPP and Tg mAβPP/ABAD) when compared to non-transgenic aged-matched mice. Furthermore, mitochondrial fractions isolated from AD brains and Tg mAβPP mice had higher levels of 4-hydroxynonenal, an oxidative product, as compared with those from non-AD and nonTg mice. Accordingly, activity of cytochrome c oxidase was significantly reduced in the AD mitochondria. These findings suggest that decreased PreP proteolytic activity, possibly due to enhanced ROS production, contributes to Aβ accumulation in mitochondria leading to the mitochondrial toxicity and neuronal death that is exacerbated in AD. Clearance of mitochondrial Aβ by PreP may thus be of importance in the pathology of AD.

  3. Anxiety symptoms, cerebral amyloid burden and memory decline in healthy older adults without dementia: 3-year prospective cohort study.

    PubMed

    Pietrzak, Robert H; Scott, J Cobb; Neumeister, Alexander; Lim, Yen Ying; Ames, David; Ellis, Kathryn A; Harrington, Karra; Lautenschlager, Nicola T; Szoeke, Cassandra; Martins, Ralph N; Masters, Colin L; Villemagne, Victor L; Rowe, Christopher C; Maruff, Paul

    2014-01-01

    Although beta-amyloid, anxiety and depression have linked cross-sectionally to reduced memory function in healthy older adults without dementia, prospective data evaluating these associations are lacking. Using data an observational cohort study of 178 healthy older adults without dementia followed for 3 years, we found that anxiety symptoms significantly moderated the relationship between beta-amyloid level and decline in verbal (Cohen's d = 0.65) and episodic (Cohen's d = 0.38) memory. Anxiety symptoms were additionally linked to greater decline in executive function, irrespective of beta-amyloid and other risk factors. These findings suggest that interventions to mitigate anxiety symptoms may help delay memory decline in otherwise healthy older adults with elevated beta-amyloid.

  4. Cerebral blood flow velocity and cranial fluid volume decrease during +Gz acceleration

    NASA Technical Reports Server (NTRS)

    Kawai, Y.; Puma, S. C.; Hargens, A. R.; Murthy, G.; Warkander, D.; Lundgren, C. E.

    1997-01-01

    Cerebral blood flow (CBF) velocity and cranial fluid volume, which is defined as the total volume of intra- and extracranial fluid, were measured using transcranial Doppler ultrasonography and rheoencephalography, respectively, in humans during graded increase of +Gz acceleration (onset rate: 0.1 G/s) without straining maneuvers. Gz acceleration was terminated when subjects' vision decreased to an angle of less than or equal to 60 degrees, which was defined as the physiological end point. In five subjects, mean CBF velocity decreased 48% from a baseline value of 59.4 +/- 11.2 cm/s to 31.0 +/- 5.6 cm/s (p<0.01) with initial loss of peripheral vision at 5.7 +/- 0.9 Gz. On the other hand, systolic CBF velocity did not change significantly during increasing +Gz acceleration. Cranial impedance, which is proportional to loss of cranial fluid volume, increased by 2.0 +/- 0.8% above the baseline value at the physiological end point (p<0.05). Both the decrease of CBF velocity and the increase of cranial impedance correlated significantly with Gz. These results suggest that +Gz acceleration without straining maneuvers decreases CBF velocity to half normal and probably causes a caudal fluid shift from both intra- and extracranial tissues.

  5. Cerebral blood flow velocity and cranial fluid volume decrease during +Gz acceleration

    NASA Technical Reports Server (NTRS)

    Kawai, Y.; Puma, S. C.; Hargens, A. R.; Murthy, G.; Warkander, D.; Lundgren, C. E.

    1997-01-01

    Cerebral blood flow (CBF) velocity and cranial fluid volume, which is defined as the total volume of intra- and extracranial fluid, were measured using transcranial Doppler ultrasonography and rheoencephalography, respectively, in humans during graded increase of +Gz acceleration (onset rate: 0.1 G/s) without straining maneuvers. Gz acceleration was terminated when subjects' vision decreased to an angle of less than or equal to 60 degrees, which was defined as the physiological end point. In five subjects, mean CBF velocity decreased 48% from a baseline value of 59.4 +/- 11.2 cm/s to 31.0 +/- 5.6 cm/s (p<0.01) with initial loss of peripheral vision at 5.7 +/- 0.9 Gz. On the other hand, systolic CBF velocity did not change significantly during increasing +Gz acceleration. Cranial impedance, which is proportional to loss of cranial fluid volume, increased by 2.0 +/- 0.8% above the baseline value at the physiological end point (p<0.05). Both the decrease of CBF velocity and the increase of cranial impedance correlated significantly with Gz. These results suggest that +Gz acceleration without straining maneuvers decreases CBF velocity to half normal and probably causes a caudal fluid shift from both intra- and extracranial tissues.

  6. RBC volume deficiency in patients with excessive orthostatic decrease in cerebral blood flow velocity.

    PubMed

    Lin, Chun-Jen; Chu, Yum-Kung; Chern, Chang-Ming

    2014-04-01

    Orthostatic intolerance (OI) is common but heterogeneous. There is a subgroup of OI patients who have excessive decrease in cerebral blood flow velocity (CBFV) of bilateral middle cerebral arteries (MCAs) during head-up tilt without systemic blood pressure change. This study evaluated the role of blood volume reduction in such patients. Patients with idiopathic OI who had excessive orthostatic decrease (>20% of the supine level) in mean CBFV of bilateral MCAs and who also received blood volume determination were collected. The chromium (⁵¹Cr) dilution method was used for red blood cell (RBC) volume determination in these patients. The blood volume was expressed as a percentage of the expected volume. These patients were further divided into two groups, those with postural tachycardia syndrome (POTS group) and those without (non-POTS group). The data of RBC volume were compared between the two groups. Besides, we used multivariate linear regression to evaluate the factors that predict RBC volume. Twenty-five patients (13 females, median age = 28 years) were enrolled in this study. Nine of these patients had POTS (5 females, median age = 26 years) and 16 did not (8 females, median age = 29.5 years). Compared with the expected volume, the RBC volume was significantly reduced in all patients (median = 82% of the expected volume). Moreover, the RBC volume was significantly lower in the POTS group than that in the non-POTS group (78% vs. 85% of the expected volume, p = 0.013). The orthostatic decrease of MCA flow velocity was 28.3% in the POTS group and 32.5% in the non-POTS group (p = 0.140). The orthostatic pulsatility index increment was 15.4% in the POTS group and 20.5% in the non-POTS group (p = 0.438). Moreover, basic demography and hemoglobin levels were not different between the two groups. After multivariate linear regression (dependent variables including age, sex, body surface, and groups), only the presence of POTS significantly predicted the RBC volume (p

  7. Decreased oxygen saturation in asymmetrically prominent cortical veins in patients with cerebral ischemic stroke.

    PubMed

    Xia, Shuang; Utriainen, David; Tang, Jin; Kou, Zhifeng; Zheng, Gang; Wang, Xuesong; Shen, Wen; Haacke, E Mark; Lu, Guangming

    2014-12-01

    Decreased oxygen saturation in asymmetrically prominent cortical veins (APCV) seen in ischemic stroke has been hypothesized to correlate with an increase of de-oxygenated hemoglobin. Our goal is to quantify magnetic susceptibility to define APCV by establishing a cutoff above which the deoxyhemoglobin levels are considered abnormal. A retrospective study was conducted on 26 patients with acute ischemic stroke in one cerebral hemisphere that exhibited APCV with 30 age- and sex-matched healthy controls. Quantitative susceptibility mapping (QSM) was used to calculate the magnetic susceptibility of the cortical veins. A paired t-test was used to compare the susceptibility of the cortical veins in the left and right hemispheres for healthy controls as well as in the contralateral hemisphere for stroke patients with APCV. The change in oxygen saturation in the APCV relative to the contralateral side was calculated after thresholding the susceptibility using the mean plus two standard deviations of the contralateral side for each individual. The thresholded susceptibility value of the APCVs in the stroke hemisphere was 254±48 ppb which was significantly higher (p<0.05) than that in the contralateral hemisphere (123±12 ppb) and in healthy controls (125±8 ppb). There was a decrease of oxygen saturation in the APCV ranging from 16% to 44% relative to the veins of the contralateral hemisphere. In conclusion, APCV seen in SWI correspond to reduced levels of oxygen saturation and these abnormal veins can be identified using a susceptibility threshold on the QSM data.

  8. Methanolic extract of Piper nigrum fruits improves memory impairment by decreasing brain oxidative stress in amyloid beta(1-42) rat model of Alzheimer's disease.

    PubMed

    Hritcu, Lucian; Noumedem, Jaurès A; Cioanca, Oana; Hancianu, Monica; Kuete, Victor; Mihasan, Marius

    2014-04-01

    The present study analyzed the possible memory-enhancing and antioxidant proprieties of the methanolic extract of Piper nigrum L. fruits (50 and 100 mg/kg, orally, for 21 days) in amyloid beta(1-42) rat model of Alzheimer's disease. The memory-enhancing effects of the plant extract were studied by means of in vivo (Y-maze and radial arm-maze tasks) approaches. Also, the antioxidant activity in the hippocampus was assessed using superoxide dismutase-, catalase-, glutathione peroxidase-specific activities and the total content of reduced glutathione, malondialdehyde, and protein carbonyl levels. The amyloid beta(1-42)-treated rats exhibited the following: decrease of spontaneous alternations percentage within Y-maze task and increase of working memory and reference memory errors within radial arm-maze task. Administration of the plant extract significantly improved memory performance and exhibited antioxidant potential. Our results suggest that the plant extract ameliorates amyloid beta(1-42)-induced spatial memory impairment by attenuation of the oxidative stress in the rat hippocampus.

  9. COPS5 protein overexpression increases amyloid plaque burden, decreases spinophilin-immunoreactive puncta, and exacerbates learning and memory deficits in the mouse brain.

    PubMed

    Wang, Ruizhi; Wang, Hongjie; Carrera, Ivan; Xu, Shaohua; Lakshmana, Madepalli K

    2015-04-03

    Brain accumulation of neurotoxic amyloid β (Aβ) peptide because of increased processing of amyloid precursor protein (APP), resulting in loss of synapses and neurodegeneration, is central to the pathogenesis of Alzheimer disease (AD). Therefore, the identification of molecules that regulate Aβ generation and those that cause synaptic damage is crucial for future therapeutic approaches for AD. We demonstrated previously that COPS5 regulates Aβ generation in neuronal cell lines in a RanBP9-dependent manner. Consistent with the data from cell lines, even by 6 months, COPS5 overexpression in APΔE9 mice (APΔE9/COPS5-Tg) significantly increased Aβ40 levels by 32% (p < 0.01) in the cortex and by 28% (p < 0.01) in the hippocampus, whereas the increases for Aβ42 were 37% (p < 0.05) and 34% (p < 0.05), respectively. By 12 months, the increase was even more robust. Aβ40 levels increased by 63% (p < 0.001) in the cortex and by 65% (p < 0.001) in the hippocampus. Similarly, Aβ42 levels were increased by 69% (p < 0.001) in the cortex and by 71% (p < 0.011) in the hippocampus. Increased Aβ levels were translated into an increased amyloid plaque burden both in the cortex (54%, p < 0.01) and hippocampus (64%, p < 0.01). Interestingly, COPS5 overexpression increased RanBP9 levels in the brain, which, in turn, led to increased amyloidogenic processing of APP, as reflected by increased levels of sAPPβ and decreased levels of sAPPα. Furthermore, COPS5 overexpression reduced spinophilin in both the cortex (19%, p < 0.05) and the hippocampus (20%, p < 0.05), leading to significant deficits in learning and memory skills. Therefore, like RanBP9, COPS5 also plays a pivotal role in amyloid pathology in vivo. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  10. Folic acid deficiency enhances abeta accumulation in APP/PS1 mice brain and decreases amyloid-associated miRNAs expression.

    PubMed

    Liu, Huan; Tian, Tian; Qin, Shanchun; Li, Wen; Zhang, Xumei; Wang, Xuan; Gao, Yuxia; Huang, Guowei

    2015-12-01

    Recent efforts have revealed the microRNA (miRNA) pathways in the pathogenesis of Alzheimer's disease (AD). Epidemiological studies have revealed an association between folic acid deficiency and AD risk. However, the effects of folic acid deficiency on miRNA expression in AD animals have not been observed. We aimed to find if folic acid deficiency may enhance amyloid-β (Aβ) peptide deposition and regulate amyloid-associated miRNAs and their target genes expression in APP/PS1 mice. APP/PS1 mice and N2a cells were treated with folic acid-deficient diet or medium. Cognitive function of mice was assessed using the Morris water maze. miRNA profile was tested by polymerase chain reaction (PCR) array. Different expressional miRNAs were validated by real-time PCR. The deposition of Aβ plaques was evaluated by immunohistochemistry and enzyme-linked immunosorbent assay. APP and BACE1 proteins in mice brain and N2a cells were determined by Western blot. Folic acid deficiency aggravated amyloid pathology in AD mice. The AD+FD group showed shorter time spent in the target zone during the probe test. Analysis of miRNAs predicted to target these genes revealed several miRNA candidates that were differentially modulated by folic acid deficiency. In APP/PS1 mice brains and N2a cells with folic acid-deficient treatment, miR-106a-5p, miR-200b-3p and miR-339-5p were down-regulated, and their target genes APP and BACE1 were up-regulated. In conclusion, folic acid deficiency can enhance Aβ accumulation in APP/PS1 mice brain and decrease amyloid-associated miRNAs expression.

  11. Tetrahydrohyperforin decreases cholinergic markers associated with amyloid-β plaques, 4-hydroxynonenal formation, and caspase-3 activation in AβPP/PS1 mice.

    PubMed

    Carvajal, Francisco J; Zolezzi, Juan M; Tapia-Rojas, Cheril; Godoy, Juan A; Inestrosa, Nibaldo C

    2013-01-01

    Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, amyloid-β peptide (Aβ) accumulation, neurofibrillary tangle deposition, synaptic alterations, and oxidative injury. In AD patients, acetylcholinesterase (AChE) activity is low in most regions of the brain, but increased within and around amyloid plaques, where it accelerates the Aβ assembly into oligomers and fibrils, increasing its neurotoxicity. Tetrahydrohyperforin (THH), a semi-synthetic derivative of hyperforin, reduces tau phosphorylation and Aβ accumulation in AD mouse models. In the present study, we examined the effects of THH on Aβ-AChE complexes, α7-nicotinic acetylcholine receptors (α7-nAChR), 4-hydroxynonenal (4-HNE) adducts, caspase-3 activation, and spatial memory in young AβPPSwe/PSEN1ΔE9 (AβPP/PS1) transgenic mice, in order to evaluate its potential preventive effects on the development of the disease. We report here that treatment with THH prevents the association of AChE to different types of amyloid plaques; partially restores the brain distribution of AChE molecular forms; increases α7-nAChR levels in the hippocampus of treated mice; decreases the amount of these receptors in amyloid plaques; and reduces the oxidative damage, evidenced by 4-HNE adduct formation and caspase-3 activation on AβPP/PS1 mice brain; demonstrating the neuroprotective properties of THH. Finally, we found that the acute treatment of hippocampal neurons with THH, in the presence of Aβ-AChE complexes, prevents 4-HNE adduct formation and caspase-3 activation. Our data support a therapeutic potential of THH for the treatment of AD.

  12. The Effect of Decreasing Flow Rate on Cerebral Hemodynamics During Veno-Arterial Extracorporeal Membrane Oxygenation in Piglets.

    PubMed

    Gerrits, Luella C; van Heijst, Arno F J; Hopman, Jeroen C W; de Haan, Anton F J; Liem, Kian D

    2015-01-01

    To explore the influence of decreasing flow rate on cerebral hemodynamics during veno-arterial extracorporeal membrane oxygenation (va-ECMO), six normoxemic and six hypoxemic piglets were put on va-ECMO. The ECMO flow rate was decreased from the maximal achievable level to 50 mL min1 with steps of 50 mL min1 every 2 minutes. Changes in mean arterial blood pressure (MABP), left common carotid artery blood flow (Qcar), and other physiologic variables were continuously measured. Changes in concentrations of oxyhemoglobin and deoxyhemoglobin were measured using near infrared spectrophotometry (NIRS). Changes in difference between cerebral oxygen hemoglobin and deoxyhemoglobin concentration (ΔcHbD) and total hemoglobin concentration (ΔctHb) were calculated. ΔcHbD represents changes in cerebral blood flow (CBF), and ΔctHb reflects changes in cerebral blood volume (CBV). Data analysis was performed using mixed models and demonstrated a significant positive correlation between ECMO flow and, respectively, MABP (r = 0.7, p < 0.001), Qcar (r = 0.7, p < 0.001), cHbD (r = 0.8, p < 0.001), and ctHb (r = 0.7, p < 0.001). There was no significant relation between oxygenation state preceding ECMO and Qcar, cHbD, and ctHb during decreasing ECMO flow rate. We conclude that decreasing ECMO flow rate ultimately leads to concurrent decrease in MABP, CBF, and CBV.

  13. A 3'-UTR polymorphism in the oxidized LDL receptor 1 gene increases Abeta40 load as cerebral amyloid angiopathy in Alzheimer's disease.

    PubMed

    Shi, Jing; Tian, Jinzhou; Pritchard, Antonia; Lendon, Corinne; Lambert, Jean-Charles; Iwatsubo, Takeshi; Mann, David M A

    2006-01-01

    It is presently unclear whether polymorphic variations in the oxidized low-density lipoprotein receptor 1 (OLR1), or low-density lipoprotein receptor-related protein 1 (LRP1), genes act as risk factors for Alzheimer's disease (AD). In the present study, we have investigated the extent of amyloid beta protein (Abeta) deposition as cerebral amyloid angiopathy (CAA) or senile plaques (SP) in relationship to OLR1 +1071 and +1073 polymorphisms and LRP1 C766T polymorphism in patients with AD There was an increased Abeta40 load as CAA, but not as SP, in frontal cortex of AD patients carrying OLR1+1073 CC genotype, compared to those with CT, TT or CT+TT genotypes, but only in those individuals without apolipoprotein (APOE) epsilon4 allele. No differences in total Abeta or Abeta42 load as CAA or SP between OLR1+1073 genotypes was seen, nor were there any differences between OLR1+1071 and LRP1 genotypes for any measure of Abeta. Present data suggests that homozygosity for the C allele for OLR1+1073 polymorphism, selectively in individuals without APOE epsilon4 allele, may impair clearance of Abeta, and particularly Abeta40, from the brain across the blood-brain barrier, leading to its 'diversion' into perivascular drainage channels, thereby increasing the severity of CAA in such persons.

  14. Decreased and Increased Anisotropy along Major Cerebral White Matter Tracts in Preterm Children and Adolescents

    PubMed Central

    Ben-Shachar, Michal; Feldman, Heidi M.

    2015-01-01

    Premature birth is highly prevalent and associated with neurodevelopmental delays and disorders. Adverse outcomes, particularly in children born before 32 weeks of gestation, have been attributed in large part to white matter injuries, often found in periventricular regions using conventional imaging. To date, tractography studies of white matter pathways in children and adolescents born preterm have evaluated only a limited number of tracts simultaneously. The current study compares diffusion properties along 18 major cerebral white matter pathways in children and adolescents born preterm (n = 27) and full term (n = 19), using diffusion magnetic resonance imaging and tractography. We found that compared to the full term group, the preterm group had significantly decreased FA in segments of the bilateral uncinate fasciculus and anterior segments of the right inferior fronto-occipital fasciculus. Additionally, the preterm group had significantly increased FA in segments of the right and left anterior thalamic radiations, posterior segments of the right inferior fronto-occipital fasciculus, and the right and left inferior longitudinal fasciculus. Increased FA in the preterm group was generally associated with decreased radial diffusivity. These findings indicate that prematurity-related white matter differences in later childhood and adolescence do not affect all tracts in the periventricular zone and can involve both decreased and increased FA. Differences in the patterns of radial diffusivity and axial diffusivity suggest that the tissue properties underlying group FA differences may vary within and across white matter tracts. Distinctive diffusion properties may relate to variations in the timing of injury in the neonatal period, extent of white matter dysmaturity and/or compensatory processes in childhood. PMID:26560745

  15. High flow rates during modified ultrafiltration decrease cerebral blood flow velocity and venous oxygen saturation in infants.

    PubMed

    Rodriguez, Rosendo A; Ruel, Marc; Broecker, Lothar; Cornel, Garry

    2005-07-01

    The intracranial hemodynamic effects of modified ultrafiltration in children are unknown. We investigated the effects of different blood flow rates during modified ultrafiltration on the cerebral hemodynamics of children with weights above and below 10 kg. Thirty-one children (weights: < or = 10 kg, n = 21; > 10 kg, n = 10) undergoing cardiopulmonary bypass were studied. Middle-cerebral artery blood flow velocities and cerebral mixed venous oxygen saturations were measured before, five minutes from the beginning, and at the end of ultrafiltration. Patients were classified according to their blood flow rates during ultrafiltration in three groups: high (> or = 20 mL/kg/min), moderate (10-19 mL/kg/min), and low flow rates (< 10 mL/kg/min). During modified ultrafiltration, blood pressures and hematocrit increased (p < 0.001), but cerebral blood flow velocities and mixed venous oxygen saturations decreased (p < 0.001). A significant correlation was found between blood flow rates of ultrafiltration and the decline in mean cerebral blood flow velocity (r = - 0.48; p = 0.005) and cerebral oxygen saturation (r = - 0.49; p = 0.005) or hematocrit increase (r = 0.59; p = 0.001). Infants exposed to high flow rates had greater reduction of cerebral blood flow velocity and regional mixed venous saturation and higher hematocrit at the end of ultrafiltration compared with those subjected to moderate and low flow rates (p < 0.04). No significant difference was found between moderate and low flow groups. The flow rate of ultrafiltration was the only independent predictor of the changes in cerebral mixed venous oxygen saturation (p = 0.033). High blood flow rates through the ultrafilter during modified ultrafiltration transiently decrease the cerebral circulation in young infants compared with lower blood flow rates. These effects may be related to an increased diastolic runoff from the aorta into the ultrafiltration circuit that leads to a "stealing" effect from the intracranial

  16. Fasudil Decreases Lesion Burden in a Murine Model of Cerebral Cavernous Malformation Disease

    PubMed Central

    McDonald, David A.; Shi, Changbin; Shenkar, Robert; Stockton, Rebecca A.; Liu, Feifei; Ginsberg, Mark H.; Marchuk, Douglas A.; Awad, Issam A.

    2011-01-01

    Background and Purpose Cerebral cavernous malformations (CCMs) are characterized by grossly dilated capillaries, associated with vascular leak and hemorrhage, and occur in sporadic or inherited (autosomal dominant) forms with mutations in one of three gene loci (CCM 1, 2 or 3). We previously reported that the CCM1 protein (KRIT1) localizes to endothelial cell-cell junctions and loss of KRIT1 leads to junctional instability associated with activation of RhoA and its effector Rho kinase (ROCK). Although ROCK inhibition has been proposed as potential therapy for CCM, there has been no demonstration of a therapeutic effect on CCM lesion genesis in vivo. Methods Our recently generated a model of CCM1 disease (Ccm1+/−Msh2−/−) was treated with ROCK inhibitor fasudil (100 mg/kg/day administered in drinking water from weaning to 5 months of age), or placebo, and blindly assessed CCM lesion burden by systematic survey of animals’ brains. For comparison, we also assessed therapeutic effect in previously described Ccm2+/−Trp53−/− mice, treated with the same dose and duration of fasudil and placebo. Results Fasudil treated Ccm1+/−Msh2−/− mice had a significantly decreased prevalence of CCM lesions compared to placebo controls. Lesions in treated animals were smaller and less likely associated with hemorrhage, inflammation and endothelial proliferation, and exhibited decreased expression of ROCK activation biomarkers. A therapeutic effect was also documented in Ccm2+/−Trp53−/− mice. Conclusion This represents the first report of therapeutic benefit of pharmacological therapy in development and progression of CCMs, and indicates that ROCK activation is a critical step in CCM lesion genesis and maturation. PMID:22034008

  17. Mechanisms of stroke in sickle cell disease: sickle erythrocytes decrease cerebral blood flow in rats after nitric oxide synthase inhibition.

    PubMed

    French, J A; Kenny, D; Scott, J P; Hoffmann, R G; Wood, J D; Hudetz, A G; Hillery, C A

    1997-06-15

    The etiology of stroke in sickle cell disease is unclear, but may involve abnormal red blood cell (RBC) adhesion to the vascular endothelium and altered vasomotor tone regulation. Therefore, we examined both the adhesion of sickle (SS)-RBCs to cerebral microvessels and the effect of SS-RBCs on cerebral blood flow when the nitric oxide (NO) pathway was inhibited. The effect of SS-RBCs was studied in the rat cerebral microcirculation using either a cranial window for direct visualization of infused RBCs or laser Doppler flowmetry (LDF) to measure RBC flow. When fluorescently labeled human RBCs were infused into rats, SS-RBCs had increased adhesion to rat cerebral microvessels compared with control AA-RBCs (P = .01). Next, washed SS-RBCs or AA-RBCs were infused into rats prepared with LDF probes after pretreatment (40 mg/kg intravenously) with the NO synthase inhibitor, N-omega-nitro-L-arginine methyl ester (L-NAME), or the control isomer, D-NAME. In 9 rats treated with systemic L-NAME and SS-RBCs, 5 of 9 experienced a significant decrease in LDF and died within 30 minutes after the RBC infusion (P = .0012). In contrast, all control groups completed the experiment with stable LDF and hemodynamics. Four rats received a localized superfusion of L-NAME (1 mmol/L) through the cranial window followed by infusion of SS-RBCs. Total cessation of flow in all observed cerebral microvessels occurred in 3 of 4 rats within 15 minutes after infusion of SS-RBCs. We conclude that the NO pathway is critical in maintaining cerebral blood flow in the presence of SS-RBCs in this rat model. In addition, the enhanced adhesion of SS-RBCs to rat brain microvessels may contribute to cerebral vaso-occlusion either directly, by disrupting blood flow, or indirectly, by disturbing the vascular endothelium.

  18. Inhalation of coriander volatile oil increased anxiolytic-antidepressant-like behaviors and decreased oxidative status in beta-amyloid (1-42) rat model of Alzheimer's disease.

    PubMed

    Cioanca, Oana; Hritcu, Lucian; Mihasan, Marius; Trifan, Adriana; Hancianu, Monica

    2014-05-28

    The present study analyzed the possible anxiolytic, antidepressant and antioxidant proprieties of inhaled coriander volatile oil extracted from Coriandrum sativum var. microcarpum in beta-amyloid (1-42) rat model of Alzheimer's disease. The anxiolytic- and antidepressant-like effects of inhaled coriander volatile oil were studied by means of in vivo (elevated plus-maze and forced swimming tests) approaches. Also, the antioxidant activity in the hippocampus was assessed using catalase specific activity and the total content of the reduced glutathione. The beta-amyloid (1-42)-treated rats exhibited the following: decrease of the locomotor activity, the percentage of the time spent and the number of entries in the open arm within elevated plus-maze test and decrease of swimming and immobility times within forced swimming test. Exposure to coriander volatile oil significantly improved these parameters, suggesting anxiolytic- and antidepressant-like effects. Moreover, coriander volatile oil decreased catalase activity and increased glutathione level in the hippocampus. Our results suggest that multiple exposures to coriander volatile oil can be useful as a mean to counteract anxiety, depression and oxidative stress in Alzheimer's disease conditions. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. Topography of Cortical Microbleeds in Alzheimer's Disease with and without Cerebral Amyloid Angiopathy: A Post-Mortem 7.0-Tesla MRI Study.

    PubMed

    De Reuck, J; Auger, F; Durieux, N; Deramecourt, V; Cordonnier, C; Pasquier, F; Maurage, C A; Leys, D; Bordet, R

    2015-11-01

    Cortical microbleeds (CMBs) detected on T2*-weighted gradient-echo (GRE) magnetic resonance imaging (MRI) are considered as a possible hallmark of cerebral amyloid angiopathy (CAA). The present post-mortem 7.0-tesla MRI study investigates whether topographic differences exist in Alzheimer's brains without (AD) and with CAA (AD-CAA). The distribution of CMBs in thirty-two post-mortem brains, consisting of 12 AD, 8 AD-CAA and 12 controls, was mutually compared on T2*-GRE MRI of six coronal sections of a cerebral hemisphere. The mean numbers of CMBs were determined in twenty-two different gyri. As a whole there was a trend of more CMBs on GRE MRI in the prefrontal section of the AD, the AD-CAA as well as of the control brains. Compared to controls AD brains had significantly more CMBs in the superior frontal, the inferior temporal, the rectus and the cinguli gyrus, and in the insular cortex. In AD-CAA brains CMBs were increased in all gyri with exception of the medial parietal gyrus and the hippocampus. AD-CAA brains showed a highly significant increase of CMBs in the inferior parietal gyrus (p value: 0.001) and a significant increase in the precuneus and the cuneus (p value: 0.01) compared to the AD brains. The differences in topographic distribution of CMBs between AD and AD-CAA brains should be further investigated on MRI in clinically suspected patients.

  20. Decreased GABA receptor in the cerebral cortex of epileptic rats: effect of Bacopa monnieri and Bacoside-A

    PubMed Central

    2012-01-01

    Abstact Background Gamma amino butyric acid (GABA), the principal inhibitory neurotransmitter in the cerebral cortex, maintains the inhibitory tones that counter balances neuronal excitation. When this balance is perturbed, seizures may ensue. Methods In the present study, alterations of the general GABA, GABAA and GABAB receptors in the cerebral cortex of the epileptic rat and the therapeutic application of Bacopa monnieri were investigated. Results Scatchard analysis of [3H]GABA, [3H]bicuculline and [3H]baclofen in the cerebral cortex of the epileptic rat showed significant decrease in Bmax (P < 0.001) compared to control. Real Time PCR amplification of GABA receptor subunits such as GABAAά1, GABAAγ, GABAAδ, GABAB and GAD where down regulated (P < 0.001) in epileptic rats. GABAAά5 subunit and Cyclic AMP responsible element binding protein were up regulated. Confocal imaging study confirmed the decreased GABA receptors in epileptic rats. Epileptic rats have deficit in radial arm and Y maze performance. Conclusions Bacopa monnieri and Bacoside-A treatment reverses epilepsy associated changes to near control suggesting that decreased GABA receptors in the cerebral cortex have an important role in epileptic occurrence; Bacopa monnieri and Bacoside-A have therapeutic application in epilepsy management. PMID:22364254

  1. FLZ Alleviates the Memory Deficits in Transgenic Mouse Model of Alzheimer’s Disease via Decreasing Beta-Amyloid Production and Tau Hyperphosphorylation

    PubMed Central

    Wang, Tao; Kong, Xiang-Chen; Tai, Wen-Jiao; Sun, Hua; Zhang, Dan

    2013-01-01

    Alzheimer’s disease (AD) is the most common cause of dementia worldwide and mainly characterized by the aggregated β-amyloid (Aβ) and hyperphosphorylated tau. FLZ is a novel synthetic derivative of natural squamosamide and has been proved to improve memory deficits in dementia animal models. In this study, we aimed to investigate the mechanisms of FLZ’s neuroprotective effect in APP/PS1 double transgenic mice and SH-SY5Y (APPwt/swe) cells. The results showed that treatment with FLZ significantly improved the memory deficits of APP/PS1 transgenic mice and decreased apoptosis of SH-SY5Y (APPwt/swe) cells. FLZ markedly attenuated Aβ accumulation and tau phosphorylation both in vivo and in vitro. Mechanistic study showed that FLZ interfered APP processing, i.e., FLZ decreased β-amyloid precursor protein (APP) phosphorylation, APP-carboxy-terminal fragment (APP-CTF) production and β-amyloid precursor protein cleaving enzyme 1 (BACE1) expression. These results indicated that FLZ reduced Aβ production through inhibiting amyloidogenic pathway. The mechanistic study about FLZ’s inhibitory effect on tau phosphorylation revealed t the involvement of Akt/glycogen synthase kinase 3β (GSK3β) pathway. FLZ treatment increased Akt activity and inhibited GSK3β activity both in vivo and in vitro. The inhibitory effect of FLZ on GSK3β activity and tau phosphorylation was suppressed by inhibiting Akt activity, indicating that Akt/GSK3β pathway might be the possible mechanism involved in the inhibitory effect of FLZ on tau hyperphosphorylation. These results suggested FLZ might be a potential anti-AD drug as it not only reduced Aβ production via inhibition amyloidogenic APP processing pathway, but also attenuated tau hyperphosphoylation mediated by Akt/GSK3β. PMID:24223757

  2. Amyloid Precursor Protein in the Cerebral Cortex is Rapidly and Persistently Induced by Loss of Subcortical Innervation

    DTIC Science & Technology

    1993-09-01

    IS. NUMBER OF PAGES Amyloid precursor protein; nucleus basalis of Meynert; 5 Alzheimer disease , Acetylcholine 16. PRICE’CODE 17. SECURITY...observed in Alzheimer disease . Dawley rats (-225-250 g) purchased from Charles River Breeding Laboratories were subcortically lesioned at the Among...the most prominent features of Alzheimer disease following sites: (i) unilateral lesions of the nbM with (AD) are profound deficits in cortical

  3. Rhein lysinate decreases the generation of β-amyloid in the brain tissues of Alzheimer's disease model mice by inhibiting inflammatory response and oxidative stress.

    PubMed

    Liu, Jiang; Hu, Gang; Xu, Rong; Qiao, Yue; Wu, He-Ping; Ding, Xun; Duan, Peng; Tu, Ping; Lin, Ya-Jun

    2013-07-01

    The protective effect of rhein lysinate (RHL) on Alzheimer's disease (AD) was explored in senescence-accelerated mouse prone-8 (SAMP8) mice. SAMP8 mice without treatment were used as the AD-positive control, and senescence-accelerated-resistant mice were used as the AD-negative control. In this study, 4-month-old male SAMP8 mice were orally administered 25 and 50 mg/kg RHL in drinking water for 6 months. The results of brain tissue enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, and Western blot were demonstrated that compared with SAMP8 group, β-amyloid1-40 and β-amyloid1-42 were reduced; the levels of tumor necrosis factor-α and interleukin 6 of brain tissues were also significantly decreased; however, the level of sirtuin 1 (SIRT1) was increased in the RHL-treated group. Compared with SAMP8 group, the ROS levels and malondialdehyde levels were decreased; however, superoxide dismutase and glutathione peroxidase levels were increased in the brain tissues of SAMP8 25 and 50 mg/kg RHL-treated groups. In conclusion, the reduction of Aβ induced by RHL was related to the increase of SIRT1 and the inhibition of the inflammatory response and oxidative stress in SAMP8 mice. It might be a promising biological therapeutic drug for AD.

  4. Decreased rhythmic GABAergic septal activity and memory-associated theta oscillations after hippocampal amyloid-beta pathology in the rat.

    PubMed

    Villette, Vincent; Poindessous-Jazat, Frédérique; Simon, Axelle; Léna, Clément; Roullot, Elodie; Bellessort, Brice; Epelbaum, Jacques; Dutar, Patrick; Stéphan, Aline

    2010-08-18

    The memory deficits associated with Alzheimer's disease result to a great extent from hippocampal network dysfunction. The coordination of this network relies on theta (symbol) oscillations generated in the medial septum. Here, we investigated in rats the impact of hippocampal amyloid beta (Abeta) injections on the physiological and cognitive functions that depend on the septohippocampal system. Hippocampal Abeta injections progressively impaired behavioral performances, the associated hippocampal theta power, and theta frequency response in a visuospatial recognition test. These alterations were associated with a specific reduction in the firing of the identified rhythmic bursting GABAergic neurons responsible for the propagation of the theta rhythm to the hippocampus, but without loss of medial septal neurons. Such results indicate that hippocampal Abeta treatment leads to a specific functional depression of inhibitory projection neurons of the medial septum, resulting in the functional impairment of the temporal network.

  5. Targeted suppression of claudin-5 decreases cerebral oedema and improves cognitive outcome following traumatic brain injury.

    PubMed

    Campbell, Matthew; Hanrahan, Finnian; Gobbo, Oliviero L; Kelly, Michael E; Kiang, Anna-Sophia; Humphries, Marian M; Nguyen, Anh T H; Ozaki, Ema; Keaney, James; Blau, Christoph W; Kerskens, Christian M; Cahalan, Stephen D; Callanan, John J; Wallace, Eugene; Grant, Gerald A; Doherty, Colin P; Humphries, Peter

    2012-05-22

    Traumatic brain injury is the leading cause of death in children and young adults globally. Malignant cerebral oedema has a major role in the pathophysiology that evolves after severe traumatic brain injury. Added to this is the significant morbidity and mortality from cerebral oedema associated with acute stroke, hypoxic ischemic coma, neurological cancers and brain infection. Therapeutic strategies to prevent cerebral oedema are limited and, if brain swelling persists, the risks of permanent brain damage or mortality are greatly exacerbated. Here we show that a temporary and size-selective modulation of the blood-brain barrier allows enhanced movement of water from the brain to the blood and significantly impacts on brain swelling. We also show cognitive improvement in mice with focal cerebral oedema following administration in these animals of short interfering RNA directed against claudin-5. These observations may have profound consequences for early intervention in cases of traumatic brain injury, or indeed any neurological condition where cerebral oedema is the hallmark pathology.

  6. Significance of decreased serum interleukin-10 levels in the progression of cerebral infarction.

    PubMed

    Diao, Zeng-Yan; Wang, Cui-Lan; Qi, Hong-Shun; Jia, Guo-Yong; Yan, Chuan-Zhu

    2016-05-01

    Anti-inflammatory cytokine and its serological detection may have an important role in the process of cardiovascular and cerebrovascular diseases. We investigated whether serum interleukin-10 (IL-10) is associated with cerebral infarction or not in the general population. Identified comprehensive searching was performed covering PubMed, EMBASE, Web of Science, Cochrane Library, CISCOM, CINAHL, Google Scholar, China BioMedicine, and China National Knowledge Infrastructure databases. Two reviewers extracted data and assessed studies independently. Information was extracted separately and classed into Asians and Caucasians. Summary standardized mean differences (SMDs) with 95 % confidence intervals (CI) were used with the utilization of Z test. Nine studies ranged from 2003 to 2014 were collected for meta-analysis. Results identified a negative association between serum IL-10 levels and cerebral infarction (SMD = 1.80, 95 % CI 0.79-2.81, P < 0.001). Country-subgroup analysis showed that low IL-10 level may be the main risk factor for cerebral infarction in India (SMD = 1.44, 95 % CI 1.13-1.75, P < 0.001) and Croatia (SMD = 2.96, 95 % CI 2.48-3.44, P < 0.001). In the ethnicity-stratified subgroup analysis, serum IL-10 levels were negatively correlated with cerebral infarction in Asians (SMD = 2.52, 95 % CI 0.47-4.57, P = 0.016), while not in Caucasians (P > 0.05). The lower serum IL-10 concentration was significantly associated with an increased likelihood of cerebral infarction in this meta-analysis. More prospective studies should be conducted to provide stronger evidence justifying the use of IL-10 as new biomarker to identify a predisposition toward cerebral infarction.

  7. Prolonged diet induced obesity has minimal effects towards brain pathology in mouse model of cerebral amyloid angiopathy: implications for studying obesity-brain interactions in mice.

    PubMed

    Zhang, Le; Dasuri, Kalavathi; Fernandez-Kim, Sun-Ok; Bruce-Keller, Annadora J; Freeman, Linnea R; Pepping, Jennifer K; Beckett, Tina L; Murphy, M Paul; Keller, Jeffrey N

    2013-09-01

    Cerebral amyloid angiopathy (CAA) occurs in nearly every individual with Alzheimer's disease (AD) and Down's syndrome, and is the second largest cause of intracerebral hemorrhage. Mouse models of CAA have demonstrated evidence for increased gliosis contributing to CAA pathology. Nearly two thirds of Americans are overweight or obese, with little known about the effects of obesity on the brain, although increasingly the vasculature appears to be a principle target of obesity effects on the brain. In the current study we describe for the first time whether diet induced obesity (DIO) modulates glial reactivity, amyloid levels, and inflammatory signaling in a mouse model of CAA. In these studies we identify surprisingly that DIO does not significantly increase Aβ levels, astrocyte (GFAP) or microglial (IBA-1) gliosis in the CAA mice. However, within the hippocampal gyri a localized increase in reactive microglia were increased in the CA1 and stratum oriens relative to CAA mice on a control diet. DIO was observed to selectively increase IL-6 in CAA mice, with IL-1β and TNF-α not increased in CAA mice in response to DIO. Taken together, these data show that prolonged DIO has only modest effects towards Aβ in a mouse model of CAA, but appears to elevate some localized microglial reactivity within the hippocampal gyri and selective markers of inflammatory signaling. These data are consistent with the majority of the existing literature in other models of Aβ pathology, which surprisingly show a mixed profile of DIO effects towards pathological processes in mouse models of neurodegenerative disease. The importance for considering the potential impact of ceiling effects in pathology within mouse models of Aβ pathogenesis, and the current experimental limitations for DIO in mice to fully replicate metabolic dysfunction present in human obesity, are discussed. This article is part of a Special Issue entitled: Animal Models of Disease.

  8. No Decrease in Muscle Strength after Botulinum Neurotoxin-A Injection in Children with Cerebral Palsy.

    PubMed

    Eek, Meta N; Himmelmann, Kate

    2016-01-01

    Spasticity and muscle weakness is common in children with cerebral palsy (CP). Spasticity can be treated with botulinum neurotoxin-A (BoNT-A), but this drug has also been reported to induce muscle weakness. Our purpose was to describe the effect on muscle strength in the lower extremities after BoNT-A injections in children with CP. A secondary aim was to relate the effect of BoNT-A to gait pattern and range of motion. Twenty children with spastic CP were included in the study, 8 girls and 12 boys (mean age 7.7 years). All were able to walk without support, but with increased muscle tone interfering with motor function and gait pattern. Sixteen children had unilateral spastic CP and four bilateral spastic CP. Twenty-four legs received injections with BoNT-A in the plantar flexor muscles. The children were tested before treatment, around 6 weeks after at the peak effect of BoNT-A, and at 6 months after treatment, with measurement of muscle strength, gait analysis, and range of motion. There were no differences in muscle strength in plantar flexors of treated legs at peak effect compared to baseline. Six months after treatment, there was still no change in untreated plantar flexor muscles, but an increasing trend in plantar flexor strength in legs treated with BoNT-A. Parents reported positive effects in all children, graded as: small in three children, moderate in eight, and large in nine children. The gait analysis showed a small improvement in knee extension at initial contact, and there was a small increase in passive range of motion for ankle dorsiflexion. Two children had a period with transient weakness and pain. We found that voluntary force production in plantar flexor muscles did not decrease after BoNT-A, instead there was a trend to increased muscle strength at follow-up. The increase may be explained as an effect of the blocking of involuntary nerve impulses, leading to an opportunity to using and training the muscles with voluntary control. Adequate

  9. No Decrease in Muscle Strength after Botulinum Neurotoxin-A Injection in Children with Cerebral Palsy

    PubMed Central

    Eek, Meta N.; Himmelmann, Kate

    2016-01-01

    Spasticity and muscle weakness is common in children with cerebral palsy (CP). Spasticity can be treated with botulinum neurotoxin-A (BoNT-A), but this drug has also been reported to induce muscle weakness. Our purpose was to describe the effect on muscle strength in the lower extremities after BoNT-A injections in children with CP. A secondary aim was to relate the effect of BoNT-A to gait pattern and range of motion. Twenty children with spastic CP were included in the study, 8 girls and 12 boys (mean age 7.7 years). All were able to walk without support, but with increased muscle tone interfering with motor function and gait pattern. Sixteen children had unilateral spastic CP and four bilateral spastic CP. Twenty-four legs received injections with BoNT-A in the plantar flexor muscles. The children were tested before treatment, around 6 weeks after at the peak effect of BoNT-A, and at 6 months after treatment, with measurement of muscle strength, gait analysis, and range of motion. There were no differences in muscle strength in plantar flexors of treated legs at peak effect compared to baseline. Six months after treatment, there was still no change in untreated plantar flexor muscles, but an increasing trend in plantar flexor strength in legs treated with BoNT-A. Parents reported positive effects in all children, graded as: small in three children, moderate in eight, and large in nine children. The gait analysis showed a small improvement in knee extension at initial contact, and there was a small increase in passive range of motion for ankle dorsiflexion. Two children had a period with transient weakness and pain. We found that voluntary force production in plantar flexor muscles did not decrease after BoNT-A, instead there was a trend to increased muscle strength at follow-up. The increase may be explained as an effect of the blocking of involuntary nerve impulses, leading to an opportunity to using and training the muscles with voluntary control. Adequate

  10. Decreased Cerebral Blood Flow in Chronic Pediatric Mild TBI: An MRI Perfusion Study

    PubMed Central

    Wang, Yang; West, John D.; Bailey, Jessica N.; Westfall, Daniel R.; Xiao, Hui; Arnold, Todd W.; Kersey, Patrick A.; Saykin, Andrew J.; McDonald, Brenna C.

    2015-01-01

    We evaluated cerebral blood flow (CBF) in chronic pediatric mild traumatic brain injury (mTBI) using arterial spin labeling (ASL) magnetic resonance imaging perfusion. mTBI patients showed lower CBF than controls in bilateral frontotemporal regions, with no between-group cognitive differences. Findings suggest ASL may be useful to assess functional abnormalities in pediatric mTBI. PMID:25649779

  11. Clinical predictors of severe cerebral amyloid angiopathy and influence of APOE genotype in persons with pathologically-verified Alzheimer’s disease

    PubMed Central

    Ringman, John M.; Sachs, Michael C.; Zhou, Yan; Monsell, Sarah E.; Saver, Jeffrey L.; Vinters, Harry V.

    2014-01-01

    Importance Though cerebral amyloid angiopathy (CAA) has important clinical implications, our understanding of it and ability to diagnose it is limited. Objective We sought to determine pathological correlates and clinical factors identifiable during life that predict the presence of severe CAA in persons with pathologically-confirmed Alzheimer’s disease (AD). Design We compared demographic and clinical variables at the earliest visit during life at which subjects were found to have cognitive impairment, and pathological variables between persons ultimately found to have no or severe CAA at autopsy using logistic regression. Analyses were repeated separately for carriers and non-carriers of the APOE ε4 allele. Setting Data were obtained from the Uniform Data Set that comprises longitudinal clinical assessments performed in the Alzheimer’s Disease Centers funded by the National Institute on Aging. Participants 193 persons with severe CAA and 232 persons with no CAA. All subjects had cognitive impairment and met NIA-Reagan neuropathological criteria for AD. Main Outcome Measures Prevalence of demographic characteristics and the APOE ε4 allele and odds ratios of clinical variables for the prediction of severe CAA. Results Persons with severe CAA were more likely to carry an APOE ε4 allele (64.9% vs. 42.8%), to be Hispanic (6.8% vs. 1.3%, p = 0.003), to have had a transient ischemic attack (TIA, 12.5% vs. 6.1%, OR = 2.1, 95% CI = 1 – 4.4), and had lower degrees of diffuse amyloid plaque pathology (mean CERAD scores 1.2 vs. 1.4, p = 0.01) than persons with no CAA. Intracerebral hemorrhage (9.3% vs. 3.5%, p = 0.01), cortical microinfarcts (20.7% vs. 12.9%, p = 0.03), and subcortical leukoencephalopathy (20.5% vs. 12.1%, p = 0.02) were more common in persons with CAA. A higher prevalence of stroke (11.1% vs. 3.9%, OR = 3.8, 95% CI 1.0 – 14.6) and hypercholesterolemia (50% vs. 33.3%, OR = 2.3, CI 1.1 – 4.7) were found in non-carriers of the ε4 allele with

  12. Decreased cerebral metabolism in stroke-prone spontaneously hypertensive rats (SHRSP) with stroke and its possible improvement by Solcoseryl.

    PubMed

    Yamasaki, Y; Yamamoto, Y; Senga, Y; Isogai, M; Shimizu, H; Yamori, Y

    1991-01-01

    Local cerebral glucose utilization (LCGU) was decreased in SHRSP with stroke compared with normotensive Wistar rats. The decrement of LCGU was less in Solcoseryl-treated SHRSP with stroke than that in saline-treated SHRSP with stroke and these brain areas where LCGU was less damaged, in Solcoseryl-treated SHRSP were consistent with the important functioning sites of emotion, motor movement and memory. The result suggests that Solcoseryl may be useful for metabolic improvement of the brain damage after stroke.

  13. Treadmill exercise decreases amyloid-β burden possibly via activation of SIRT-1 signaling in a mouse model of Alzheimer's disease.

    PubMed

    Koo, Jung-Hoon; Kang, Eun-Bum; Oh, Yoo-Sung; Yang, Dae-Seung; Cho, Joon-Yong

    2017-02-01

    Accumulation of amyloid-β (Aβ) correlates significantly with progressive cognitive deficits, a main symptom of Alzheimer's disease (AD). Although treadmill exercise reduces Aβ levels, the molecular mechanisms underlying the effects are not fully understood. We hypothesize that treadmill exercise decreases Aβ production and alleviates cognitive deficits by activating the non-amyloidogenic pathway via SIRT-1 signaling. Treadmill exercise improved cognitive deficits and alleviated neurotoxicity. Most importantly, treadmill exercise increased SIRT-1 level, which subsequently resulted in increased ADAM-10 level by down-regulation of ROCK-1 and upregulation of RARβ, ultimately facilitating the non-amyloidogenic pathway. Treadmill exercise-induced activation in SIRT-1 level also elevated PGC-1α level and reduced BACE-1 and C-99 level, resulting in inhibition of the amyloidogenic pathway. Treadmill exercise may thus inhibit Aβ production via upregulation of SIRT-1, which biases amyloid precursor protein processing toward the non-amyloidogenic pathway. This study provides novel and valuable insight into the molecular mechanisms possibly by which treadmill exercise reduces Aβ production.

  14. Organo-Selenium (Sel-Plex) decreases amyloid burden and RNA and DNA oxidative damage in APP/PS1 mice

    PubMed Central

    Lovell, Mark A.; Xiong, Shuling; Lyubartseva, Ganna; Markesbery, William R.

    2009-01-01

    To evaluate potential antioxidant characteristics of organic selenium (Se), double knock-in transgenic mice expressing human mutations for the amyloid precursor protein (APP) and human presenilin-1 (PS-1) were provided a Se-deficient diet, a Se-enriched (Sel-Plex), or a control diet from 4 to 9 months of age followed by a control diet until 12 months of age. Levels of DNA, RNA, and protein oxidation as well as lipid peroxidation markers were determined in all mice and amyloid beta peptide (Aβ) plaques were quantified. APP/PS1 mice provided Sel-Plex showed significantly (P < 0.05) lower levels of Aβ plaque deposition and significantly decreased levels of DNA and RNA oxidation. Sel-Plex-treated mice showed no significant differences in levels of lipid peroxidation or protein oxidation compared to APP/PS1 mice on a control diet. To determine if diminished oxidative damage was associated with increased antioxidant enzyme activities, brain glutathione peroxidase (GSH-Px), glutathione reductase, and glutathione transferase activites were measured. Sel-Plex-treated mice showed a modest but significant increase in GSH-Px activity compared to mice on a normal diet (P< 0.5). Overall, these data suggest that organic Se can reduce Aβ burden and minimize DNA and RNA oxidation and support a role for it as a potential therapeutic agent in neurologic disorders with increased oxidative stress. PMID:19303433

  15. Adenosine mediates decreased cerebral metabolic rate and increased cerebral blood flow during acute moderate hypoxia in the near-term fetal sheep

    PubMed Central

    Blood, Arlin B; Hunter, Christian J; Power, Gordon G

    2003-01-01

    Exposure of the fetal sheep to moderate to severe hypoxic stress results in both increased cortical blood flow and decreased metabolic rate. Using intravenous infusion of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective adenosine A1 receptor antagonist that is permeable to the blood brain barrier, we examine the role of adenosine A1 receptors in mediating cortical blood flow and metabolic responses to moderate hypoxia. The effects of DPCPX blockade are compared to controls as well as animals receiving intravenous 8-(p-sulfophenyl)-theophylline) (8-SPT), a non-selective adenosine receptor antagonist which has been found to be blood brain barrier impermeable. Laser Doppler flow probes, tissue PO2, and thermocouples were implanted in the cerebral cortices of near-term fetal sheep. Catheters were placed in the brachial artery and sagittal sinus vein for collection of samples for blood gas analysis. Three to seven days later responses to a 30-min period of fetal hypoxemia (arterial PO2 10–12 mmHg) were studied with administration of 8-SPT, DPCPX, or vehicle. Cerebral metabolic rate was determined by calculation of both brain heat production and oxygen consumption. In response to hypoxia, control experiments demonstrated a 42 ± 7 % decrease in cortical heat production and a 35 ± 10 % reduction in oxygen consumption. In contrast, DPCPX infusion during hypoxia resulted in no significant change in brain heat production or oxygen consumption, suggesting the adenosine A1 receptor is involved in lowering metabolic rate during hypoxia. The decrease in cerebral metabolic rate was not altered by 8-SPT infusion, suggesting that the response is not mediated by adenosine receptors located outside the blood brain barrier. In response to hypoxia, control experiments demonstrated a 35 ± 7 % increase in cortical blood flow. DPCPX infusion did not change this increase in cortical blood flow, however 8-SPT infusion attenuated increases in flow, indicating that hypoxic

  16. Adenosine mediates decreased cerebral metabolic rate and increased cerebral blood flow during acute moderate hypoxia in the near-term fetal sheep.

    PubMed

    Blood, Arlin B; Hunter, Christian J; Power, Gordon G

    2003-12-15

    Exposure of the fetal sheep to moderate to severe hypoxic stress results in both increased cortical blood flow and decreased metabolic rate. Using intravenous infusion of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective adenosine A1 receptor antagonist that is permeable to the blood brain barrier, we examine the role of adenosine A1 receptors in mediating cortical blood flow and metabolic responses to moderate hypoxia. The effects of DPCPX blockade are compared to controls as well as animals receiving intravenous 8-(p-sulfophenyl)-theophylline) (8-SPT), a non-selective adenosine receptor antagonist which has been found to be blood brain barrier impermeable. Laser Doppler flow probes, tissue PO2, and thermocouples were implanted in the cerebral cortices of near-term fetal sheep. Catheters were placed in the brachial artery and sagittal sinus vein for collection of samples for blood gas analysis. Three to seven days later responses to a 30-min period of fetal hypoxemia (arterial PO2 10-12 mmHg) were studied with administration of 8-SPT, DPCPX, or vehicle. Cerebral metabolic rate was determined by calculation of both brain heat production and oxygen consumption. In response to hypoxia, control experiments demonstrated a 42 +/- 7 % decrease in cortical heat production and a 35 +/- 10 % reduction in oxygen consumption. In contrast, DPCPX infusion during hypoxia resulted in no significant change in brain heat production or oxygen consumption, suggesting the adenosine A1 receptor is involved in lowering metabolic rate during hypoxia. The decrease in cerebral metabolic rate was not altered by 8-SPT infusion, suggesting that the response is not mediated by adenosine receptors located outside the blood brain barrier. In response to hypoxia, control experiments demonstrated a 35 +/- 7 % increase in cortical blood flow. DPCPX infusion did not change this increase in cortical blood flow, however 8-SPT infusion attenuated increases in flow, indicating that hypoxic

  17. Ischemic brain injury decreases dynamin-like protein 1 expression in a middle cerebral artery occlusion animal model and glutamate-exposed HT22 cells

    PubMed Central

    Jang, Ah-Ram

    2016-01-01

    Dynamin-like protein I (DLP-1) is an important mitochondrial fission and fusion protein that is associated with apoptotic cell death in neurodegenerative diseases. In this study, we investigated DLP-1 expression in a focal cerebral ischemia animal model and glutamate-exposed hippocampal-derived cell line. Middle cerebral artery occlusion (MCAO) was surgically induced in adult male rats to induce focal cerebral ischemic injury. Brain tissues were collected 24 hours after the onset of MCAO. MCAO induces an increase in infarct volume and histopathological changes in the cerebral cortex. We identified a decrease in DLP-1 in the cerebral cortices of MCAO-injured animals using a proteomic approach and Western blot analysis. Moreover, glutamate treatment significantly decreased DLP-1 expression in a hippocampal-derived cell line. The decrease in DLP-1 indicates mitochondrial dysfunction. Thus, these results suggest that neuronal cell injury induces a decrease in DLP-1 levels and consequently leads to neuronal cell death. PMID:28053612

  18. Cerebral Blood Flow and Glucose Metabolism Measured With Positron Emission Tomography Are Decreased in Human Type 1 Diabetes

    PubMed Central

    van Golen, Larissa W.; Huisman, Marc C.; Ijzerman, Richard G.; Hoetjes, Nikie J.; Schwarte, Lothar A.; Lammertsma, Adriaan A.; Diamant, Michaela

    2013-01-01

    Subclinical systemic microvascular dysfunction exists in asymptomatic patients with type 1 diabetes. We hypothesized that microangiopathy, resulting from long-standing systemic hyperglycemia and hyperinsulinemia, may be generalized to the brain, resulting in changes in cerebral blood flow (CBF) and metabolism in these patients. We performed dynamic [15O]H2O and [18F]-fluoro-2-deoxy-d-glucose brain positron emission tomography scans to measure CBF and cerebral glucose metabolism (CMRglu), respectively, in 30 type 1 diabetic patients and 12 age-matched healthy controls after an overnight fast. Regions of interest were automatically delineated on coregistered magnetic resonance images and full kinetic analysis was performed. Plasma glucose and insulin levels were higher in patients versus controls. Total gray matter CBF was 9%, whereas CMRglu was 21% lower in type 1 diabetic subjects versus control subjects. We conclude that at real-life fasting glucose and insulin levels, type 1 diabetes is associated with decreased resting cerebral glucose metabolism, which is only partially explained by the decreased CBF. These findings suggest that mechanisms other than generalized microangiopathy account for the altered CMRglu observed in well-controlled type 1 diabetes. PMID:23530004

  19. Decrease in leptomeningeal ivy sign on fluid-attenuated inversion recovery images after cerebral revascularization in patients with Moyamoya disease.

    PubMed

    Kawashima, M; Noguchi, T; Takase, Y; Nakahara, Y; Matsushima, T

    2010-10-01

    The "ivy" sign that is identified on FLAIR images in patients with Moyamoya disease is considered to be leptomeningeal collaterals. The aim of our study was to evaluate the correlation between postoperative decrease in ivy sign and cerebral hemodynamic status in the bypass-established hemisphere. Twenty-two patients with Moyamoya disease were enrolled. Postoperative changes in the ivy sign on FLAIR images were examined in each patient after bypass surgery. The correlation between postoperative changes in the ivy sign and hemodynamic status was examined in 10 patients by using SPECT. Of the 22 preoperative ivy-positive patients, 21 showed decreased ivy signs on the operative side. Average intervals between the operation day and the date when the decreased or vanished ivy sign was first recognized were 157.6 days in patients who underwent direct bypass and 212.2 days in patients who underwent indirect bypass. A postoperative decrease in ivy signs was found to be significantly correlated with an improved hemodynamic status of the surgically treated hemisphere, resulting in a postoperative increase in regional vascular reserve and a decreased proportion of the misery perfusion area (P < .01). Postoperative changes in the ivy sign can be used as a marker for identifying improved hemodynamics and also for testing the effectiveness of cerebral revascularization.

  20. Murine cerebrovascular cells as a cell culture model for cerebral amyloid angiopathy: isolation of smooth muscle and endothelial cells from mouse brain.

    PubMed

    Gauthier, Sebastien A; Sahoo, Susmita; Jung, Sonia S; Levy, Efrat

    2012-01-01

    The use of murine cerebrovascular endothelial and smooth muscle cells has not been widely employed as a cell culture model for the investigation of cellular mechanisms involved in cerebral amyloid angiopathy (CAA). Difficulties in isolation and propagation of murine cerebrovascular cells and insufficient yields for molecular and cell culture studies have deterred investigators from using mice as a source for cerebrovascular cells in culture. Instead, cerebrovascular cells from larger mammals are preferred and several methods describing the isolation of endothelial and smooth muscle cells from human, canine, rat, and guinea pig have been published. In recent years, several transgenic mouse lines showing CAA pathology have been established; consequently murine cerebrovascular cells derived from these animals can serve as a key cellular model to study CAA. Here, we describe a procedure for isolating murine microvessels that yields healthy smooth muscle and endothelial cell populations and produce sufficient material for experimental purposes. Murine smooth muscle cells isolated using this protocol exhibit the classic "hill and valley" morphology and are immunoreactive for the smooth muscle cell marker α-actin. Endothelial cells display a "cobblestone" pattern phenotype and show the characteristic immunostaining for the von Willebrand factor and the factor VIII-related antigen. In addition, we describe methods designed to preserve these cells by storage in liquid nitrogen and reestablishing viable cell cultures. Finally, we compare our methods with protocols designed to isolate and maintain human cerebrovascular cell cultures.

  1. Amyloid fibrils in hereditary cerebral hemorrhage with amyloidosis of Icelandic type is a variant of gamma-trace basic protein (cystatin C).

    PubMed Central

    Ghiso, J; Jensson, O; Frangione, B

    1986-01-01

    A gamma-trace variant protein is the major constituent of the amyloid fibrils in patients from Iceland with hereditary cerebral hemorrhage with amyloidosis. The protein consists of 110 residues and is similar to human urinary gamma-trace basic protein (or cystatin C) beginning at its 11th amino-terminal residue. It has an amino acid substitution (glutamine for leucine) at position 58 (position 68 in gamma-trace numbering), which is near the proposed active site of related proteins--namely, cysteine protease inhibitors and kininogens. It is postulated that a point mutation has occurred, leading to the production of an unusual protein that is abnormally degraded, bound, and/or precipitated. Alternatively, gamma-trace basic protein may be genetically polymorphic, and the variant described here may represent an as-yet-undiscovered isotype or an allelic form that is linked to, but not responsible for, the deposition disease. Our data on the structure of a gamma-trace variant protein suggests that its gene expresses a polyprotein precursor in which active peptides are flanked by basic amino acid residues that permit cleavage to liberate small internal peptides. It is likely that the nucleotide sequence coding for Arg-Xaa and Lys-Xaa repeated several times in the molecule may function as alternative splicing sites for mRNA processing. Images PMID:3517880

  2. Total Magnetic Resonance Imaging Burden of Small Vessel Disease in Cerebral Amyloid Angiopathy: An Imaging-Pathologic Study of Concept Validation.

    PubMed

    Charidimou, Andreas; Martinez-Ramirez, Sergi; Reijmer, Yael D; Oliveira-Filho, Jamary; Lauer, Arne; Roongpiboonsopit, Duangnapa; Frosch, Matthew; Vashkevich, Anastasia; Ayres, Alison; Rosand, Jonathan; Gurol, Mahmut Edip; Greenberg, Steven M; Viswanathan, Anand

    2016-08-01

    Cerebral amyloid angiopathy (CAA) is characteristically associated with magnetic resonance imaging (MRI) biomarkers of small vessel brain injury, including strictly lobar cerebral microbleeds, cortical superficial siderosis, centrum semiovale perivascular spaces, and white matter hyperintensities. Although these neuroimaging markers reflect distinct pathophysiologic aspects in CAA, no studies to date have combined these structural imaging features to gauge total brain small vessel disease burden in CAA. To investigate whether a composite score can be developed to capture the total brain MRI burden of small vessel disease in CAA and to explore whether this score contributes independent and complementary information about CAA severity, defined as intracerebral hemorrhage during life or bleeding-related neuropathologic changes. This retrospective, cross-sectional study examined a single-center neuropathologic CAA cohort of eligible patients from the Massachusetts General Hospital from January 1, 1997, through December 31, 2012. Data analysis was performed from January 2, 2015, to January 9, 2016. Patients with pathologic evidence of CAA (ie, any presence of CAA from routinely collected brain biopsy specimen, biopsy specimen at hematoma evacuation, or autopsy) and available brain MRI sequences of adequate quality, including T2-weighted, T2*-weighted gradient-recalled echo, and/or susceptibility-weighted imaging and fluid-attenuated inversion recovery sequences, were considered for the study. Brain MRIs were rated for lobar cerebral microbleeds, cortical superficial siderosis, centrum semiovale perivascular spaces, and white matter hyperintensities. All 4 MRI lesions were incorporated into a prespecified ordinal total small vessel disease score, ranging from 0 to 6 points. Associations with severity of CAA-associated vasculopathic changes (fibrinoid necrosis and concentric splitting of the wall), clinical presentation, number of intracerebral hemorrhages, and other

  3. Noninvasive magnetic resonance imaging detection of cerebral amyloid angiopathy-related microvascular alterations using superparamagnetic iron oxide particles in APP transgenic mouse models of Alzheimer's disease: application to passive Abeta immunotherapy.

    PubMed

    Beckmann, Nicolau; Gérard, Christelle; Abramowski, Dorothée; Cannet, Catherine; Staufenbiel, Matthias

    2011-01-19

    Cerebral amyloid angiopathy (CAA) is a common feature of Alzheimer's disease (AD). More advanced stages are accompanied by microhemorrhages and vasculitis. Peripheral blood-borne macrophages are intimately linked to cerebrovascular pathology coincident with AD. Magnetic resonance imaging (MRI) was used to noninvasively study microvascular lesions in amyloid precursor protein transgenic mouse AD models. Foci of signal attenuation were detected in cortical and thalamic brain regions of aged APP23 mice. Their strength and number was considerably enhanced by intravenous administration of iron oxide nanoparticles, which are taken up by macrophages through absorptive endocytosis, 24 h before image acquisition. The number of cortical sites displaying signal attenuation increased with age. Histology at these sites demonstrated the presence of iron-containing macrophages in the vicinity of CAA-affected blood vessels. A fraction of the sites additionally showed thickened vessel walls and vasculitis. Consistent with the visualization of CAA-associated lesions, MRI detected a much smaller number of attenuated signal sites in APP23xPS45 mice, for which a strong presenilin mutation caused a shift toward amyloid β(42), thus reducing vascular amyloid. Similar results were obtained with APP24 and APP51 mice, which develop significantly less CAA and microvascular pathology than APP23. In a longitudinal study, we noninvasively demonstrated the reinforced formation of microvascular pathology during passive amyloid β immunotherapy of APP23 mice. Histology confirmed that foci of signal attenuation reflected an increase in CAA-related lesions. Our data demonstrate that MRI has the sensitivity to noninvasively monitor the development of vascular pathology and its possible enhancement by amyloid β immunotherapy in transgenic mice modeling AD.

  4. 3-N-butylphthalide improves neuronal morphology after chronic cerebral ischemia

    PubMed Central

    Zhao, Wanhong; Luo, Chao; Wang, Jue; Gong, Jian; Li, Bin; Gong, Yingxia; Wang, Jun; Wang, Hanqin

    2014-01-01

    3-N-butylphthalide is an effective drug for acute ischemic stroke. However, its effects on chronic cerebral ischemia-induced neuronal injury remain poorly understood. Therefore, this study ligated bilateral carotid arteries in 15-month-old rats to simulate chronic cerebral ischemia in aged humans. Aged rats were then intragastrically administered 3-n-butylphthalide. 3-N-butylphthalide administration improved the neuronal morphology in the cerebral cortex and hippocampus of rats with chronic cerebral ischemia, increased choline acetyltransferase activity, and decreased malondialdehyde and amyloid beta levels, and greatly improved cognitive function. These findings suggest that 3-n-butylphthalide alleviates oxidative stress caused by chronic cerebral ischemia, improves cholinergic function, and inhibits amyloid beta accumulation, thereby improving cerebral neuronal injury and cognitive deficits. PMID:25206879

  5. Decreased Flow Velocity with Transcranial Color-Coded Duplex Sonography Correlates with Delayed Cerebral Ischemia due to Peripheral Vasospasm of the Middle Cerebral Artery.

    PubMed

    Sadahiro, Hirokazu; Shirao, Satoshi; Yoneda, Hiroshi; Ishihara, Hideyuki; Oku, Takayuki; Inamura, Akinori; Yamane, Akiko; Sugimoto, Kazutaka; Fujiyama, Yuichi; Suzuki, Michiyasu

    2016-10-01

    Despite intensive therapy, vasospasm remains a major cause of delayed cerebral ischemia (DCI) in worsening patient outcome after aneurysmal subarachnoid hemorrhage (aSAH). Transcranial Doppler (TCD) and transcranial color-coded duplex sonography (TCCS) are noninvasive modalities that can be used to assess vasospasm. However, high flow velocity does not always reflect DCI. The purpose of this study was to investigate the utility of TCD/TCCS in decreasing permanent neurological deficits. We retrospectively enrolled patients with aSAH who were treated within 72 hours after onset. TCCS was performed every day from days 4 to 14. Peak systolic velocity (PSV), mean velocity (MV), and pulsatility index were recorded and compared between DCI and non-DCI patients. In patients with DCI, endovascular therapy was administered to improve vasospasm, which led to a documented change in velocity. Of the 73 patients, 7 (9.6%) exhibited DCI. In 5 of the 7 patients, DCI was caused by vasospasm of M2 or the more peripheral middle cerebral artery (MCA), and the PSV and MV of the DCI group were lower than those of the non-DCI group after day 7. Intra-arterial vasodilator therapy (IAVT) was performed for all patients with DCI immediately to increase the flow volume by the next day. Increasing flow velocity cannot always reveal vasospasm excluding M1. In patients with vasospasm of M2 or more distal arteries, decreasing flow velocity might be suggestive of DCI. IAVT led to increases in the flow velocity through expansion of the peripheral MCA. Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  6. Peptide multifunctionalized gold nanorods decrease toxicity of β-amyloid peptide in a Caenorhabditis elegans model of Alzheimer's disease.

    PubMed

    Morales-Zavala, Francisco; Arriagada, Hector; Hassan, Natalia; Velasco, Carolina; Riveros, Ana; Álvarez, Alejandra R; Minniti, Alicia N; Rojas-Silva, Ximena; Muñoz, Luis L; Vasquez, Rodrigo; Rodriguez, Katherine; Sanchez-Navarro, Macarena; Giralt, Ernest; Araya, Eyleen; Aldunate, Rebeca; Kogan, Marcelo J

    2017-10-01

    The properties of nanometric materials make nanotechnology a promising platform for tackling problems of contemporary medicine. In this work, gold nanorods were synthetized and stabilized with polyethylene glycols and modified with two kinds of peptides. The D1 peptide that recognizes toxic aggregates of Aβ, a peptide involved in Alzheimer's disease (AD); and the Angiopep 2 that can be used to deliver nanorods to the mammalian central nervous system. The nanoconjugates were characterized using absorption spectrophotometry, dynamic light scattering, and transmission electron microscopy, among other techniques. We determined that the nanoconjugate does not affect neuronal viability; it penetrates the cells, and decreases aggregation of Aβ peptide in vitro. We also showed that when we apply our nanosystem to a Caenorhabditis elegans AD model, the toxicity of aggregated Aβ peptide is decreased. This work may contribute to the development of therapies for AD based on metallic nanoparticles. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Thioredoxin-80 is a product of alpha-secretase cleavage that inhibits amyloid-beta aggregation and is decreased in Alzheimer's disease brain

    PubMed Central

    Gil-Bea, Francisco; Akterin, Susanne; Persson, Torbjörn; Mateos, Laura; Sandebring, Anna; Avila-Cariño, Javier; Gutierrez-Rodriguez, Angel; Sundström, Erik; Holmgren, Arne; Winblad, Bengt; Cedazo-Minguez, Angel

    2012-01-01

    Thioredoxin-1 (Trx1) is an endogenous dithiol reductant and antioxidant that was shown to be decreased in Alzheimer's disease (AD) neurons. A truncated form of Trx1, thioredoxin 80 (Trx80), was reported to be secreted from monocytes having cytokine activity. Here, we show that Trx80 is present in human brain in an aggregated form. Trx80 localizes mainly to neurons and is dramatically decreased in AD brains. Trx80 levels in cerebrospinal fluid (CSF) correlate with those of the classical AD biomarkers amyloid-β (Aβ) 1–42 and total tau. Moreover, Trx80 measurements in CSF discriminate between patients with stable mild cognitive impairment, prodomal AD and mild AD. We report that ADAM10 and 17, two α-secretases processing the Aβ precursor protein, are responsible for Trx80 generation. In contrast to the periphery, Trx80 has no pro-inflammatory effects in glia, either by itself or in combination with Aβ or apolipoprotein E. Instead, Trx80 inhibits Aβ(1–42) aggregation and protects against its toxicity. Thus, a reduction in Trx80 production would result in increased Aβ polymerization and enhanced neuronal vulnerability. Our data suggest that a deficit in Trx80 could participate in AD pathogenesis. PMID:22933306

  8. What is normal in normal aging? Effects of Aging, Amyloid and Alzheimer’s Disease on the Cerebral Cortex and the Hippocampus

    PubMed Central

    Fjell, Anders M.; McEvoy, Linda; Holland, Dominic; Dale, Anders M.; Walhovd, Kristine B

    2015-01-01

    What can be expected in normal aging, and where does normal aging stop and pathological neurodegeneration begin? With the slow progression of age-related dementias such as Alzheimer’s Disease (AD), it is difficult to distinguish age-related changes from effects of undetected disease. We review recent research on changes of the cerebral cortex and the hippocampus in aging and the borders between normal aging and AD. We argue that prominent cortical reductions are evident in fronto-temporal regions in elderly even with low probability of AD, including regions overlapping the default mode network. Importantly, these regions show high levels of amyloid deposition in AD, and are both structurally and functionally vulnerable early in the disease. This normalcy-pathology homology is critical to understand, since aging itself is the major risk factor for sporadic AD. Thus, rather than necessarily reflecting early signs of disease, these changes may be part of normal aging, and may inform on why the aging brain is so much more susceptible to AD than is the younger brain. We suggest that regions characterized by a high degree of life-long plasticity are vulnerable to detrimental effects of normal aging, and that this age-vulnerability renders them more susceptible to additional, pathological AD-related changes. We conclude that it will be difficult to understand AD without understanding why it preferably affects older brains, and that we need a model that accounts for age-related changes in AD-vulnerable regions independently of AD-pathology. PMID:24548606

  9. Development, appraisal, validation and implementation of a consensus protocol for the assessment of cerebral amyloid angiopathy in post-mortem brain tissue

    PubMed Central

    Love, Seth; Chalmers, Katy; Ince, Paul; Esiri, Margaret; Attems, Johannes; Kalaria, Raj; Jellinger, Kurt; Yamada, Masahito; McCarron, Mark; Minett, Thais; Matthews, Fiona; Greenberg, Steven; Mann, David; Kehoe, Patrick Gavin

    2015-01-01

    In a collaboration involving 11 groups with research interests in cerebral amyloid angiopathy (CAA), we used a two-stage process to develop and in turn validate a new consensus protocol and scoring scheme for the assessment of CAA and associated vasculopathic abnormalities in post-mortem brain tissue. Stage one used an iterative Delphi-style survey to develop the consensus protocol. The resultant scoring scheme was tested on a series of digital images and paraffin sections that were circulated blind to a number of scorers. The scoring scheme and choice of staining methods were refined by open-forum discussion. The agreed protocol scored parenchymal and meningeal CAA on a 0-3 scale, capillary CAA as present/absent and vasculopathy on 0-2 scale, in the 4 cortical lobes that were scored separately. A further assessment involving three centres was then undertaken. Neuropathologists in three centres (Bristol, Oxford and Sheffield) independently scored sections from 75 cases (25 from each centre) and high inter-rater reliability was demonstrated. Stage two used the results of the three-centre assessment to validate the protocol by investigating previously described associations between APOE genotype (previously determined), and both CAA and vasculopathy. Association of capillary CAA with or without arteriolar CAA with APOE ε4 was confirmed. However APOE ε2 was also found to be a strong risk factor for the development of CAA, not only in AD but also in elderly non-demented controls. Further validation of this protocol and scoring scheme is encouraged, to aid its wider adoption to facilitate collaborative and replication studies of CAA. PMID:26807344

  10. Erratum: Development, appraisal, validation and implementation of a consensus protocol for the assessment of cerebral amyloid angiopathy in post-mortem brain tissue.

    PubMed

    Love, Seth; Chalmers, Katy; Ince, Paul; Esiri, Margaret; Attems, Johannes; Kalaria, Raj; Jellinger, Kurt; Yamada, Masahito; McCarron, Mark; Minett, Thais; Matthews, Fiona; Greenberg, Steven; Mann, David; Kehoe, Patrick Gavin

    2015-01-01

    In a collaboration involving 11 groups with research interests in cerebral amyloid angiopathy (CAA), we used a two-stage process to develop and in turn validate a new consensus protocol and scoring scheme for the assessment of CAA and associated vasculopathic abnormalities in post-mortem brain tissue. Stage one used an iterative Delphi-style survey to develop the consensus protocol. The resultant scoring scheme was tested on a series of digital images and paraffin sections that were circulated blind to a number of scorers. The scoring scheme and choice of staining methods were refined by open-forum discussion. The agreed protocol scored parenchymal and meningeal CAA on a 0-3 scale, capillary CAA as present/absent and vasculopathy on 0-2 scale, in the 4 cortical lobes that were scored separately. A further assessment involving three centres was then undertaken. Neuropathologists in three centres (Bristol, Oxford and Sheffield) independently scored sections from 75 cases (25 from each centre) and high inter-rater reliability was demonstrated. Stage two used the results of the three-centre assessment to validate the protocol by investigating previously described associations between APOE genotype (previously determined), and both CAA and vasculopathy. Association of capillary CAA with or without arteriolar CAA with APOE ε4 was confirmed. However APOE ε2 was also found to be a strong risk factor for the development of CAA, not only in AD but also in elderly non-demented controls. Further validation of this protocol and scoring scheme is encouraged, to aid its wider adoption to facilitate collaborative and replication studies of CAA.[This corrects the article on p. 19 in vol. 3, PMID: 24754000.].

  11. Development, appraisal, validation and implementation of a consensus protocol for the assessment of cerebral amyloid angiopathy in post-mortem brain tissue.

    PubMed

    Love, Seth; Chalmers, Katy; Ince, Paul; Esiri, Margaret; Attems, Johannes; Jellinger, Kurt; Yamada, Masahito; McCarron, Mark; Minett, Thais; Matthews, Fiona; Greenberg, Steven; Mann, David; Kehoe, Patrick Gavin

    2014-01-01

    In a collaboration involving 11 groups with research interests in cerebral amyloid angiopathy (CAA), we used a two-stage process to develop and in turn validate a new consensus protocol and scoring scheme for the assessment of CAA and associated vasculopathic abnormalities in post-mortem brain tissue. Stage one used an iterative Delphi-style survey to develop the consensus protocol. The resultant scoring scheme was tested on a series of digital images and paraffin sections that were circulated blind to a number of scorers. The scoring scheme and choice of staining methods were refined by open-forum discussion. The agreed protocol scored parenchymal and meningeal CAA on a 0-3 scale, capillary CAA as present/absent and vasculopathy on 0-2 scale, in the 4 cortical lobes that were scored separately. A further assessment involving three centres was then undertaken. Neuropathologists in three centres (Bristol, Oxford and Sheffield) independently scored sections from 75 cases (25 from each centre) and high inter-rater reliability was demonstrated. Stage two used the results of the three-centre assessment to validate the protocol by investigating previously described associations between APOE genotype (previously determined), and both CAA and vasculopathy. Association of capillary CAA with or without arteriolar CAA with APOE ε4 was confirmed. However APOE ε2 was also found to be a strong risk factor for the development of CAA, not only in AD but also in elderly non-demented controls. Further validation of this protocol and scoring scheme is encouraged, to aid its wider adoption to facilitate collaborative and replication studies of CAA.

  12. Effect of general anesthesia on serum β-amyloid protein and regional cerebral oxygen saturation of elderly patients after subtotal gastrectomy

    PubMed Central

    Yu, Peng; Wang, Hua; Mu, Lei; Ding, Xuemei; Ding, Wei

    2016-01-01

    The aim of the present study was to investigate the influence of general anesthesia on serum β-amyloid protein (Aβ) and regional cerebral oxygen saturation (rSO2) of elderly patients after subtotal gastrectomy. From June, 2014 to December, 2015, among 168 patients undergoing subtotal gastrectomy, the Mini-Mental State Examination and Montreal Cognitive Assessment was administered the day prior to surgery and the second and ninth days after the operation. In addition, we administered the tests to 168 healthy adult volunteers (healthy controls) who were treated in our hospital medical center in the same period. Near-infrared spectroscopy technology was used for continuous monitoring of the intraoperative rSO2, and the mean of intraoperative rSO2 was then calculated. Of the 168 patients, 28 developed postoperative cognitive dysfunction (POCD) and the remaining 140 patients were normal (control). The ELISA method was used to test the expression levels of serum Aβ in the three groups and statistical analyses were conducted. Serum Aβ level in the POCD group was significantly higher than that in the control and healthy control groups, and the difference was statistically significant (P<0.05). The rSO2 level in the patients with POCD was significantly lower than the control group (P<0.05). The correlation analysis with Aβ as an independent variable and other factors as dependent variables revealed that the serum Aβ level negatively correlated with rSO2 (r=−1.6749, P<0.05). The combined Aβ and rSO2 may be useful for the diagnosis and prevention of POCD after subtotal gastrectomy under general anesthesia. PMID:28101151

  13. Development, appraisal, validation and implementation of a consensus protocol for the assessment of cerebral amyloid angiopathy in post-mortem brain tissue

    PubMed Central

    Love, Seth; Chalmers, Katy; Ince, Paul; Esiri, Margaret; Attems, Johannes; Jellinger, Kurt; Yamada, Masahito; McCarron, Mark; Minett, Thais; Matthews, Fiona; Greenberg, Steven; Mann, David; Kehoe, Patrick Gavin

    2014-01-01

    In a collaboration involving 11 groups with research interests in cerebral amyloid angiopathy (CAA), we used a two-stage process to develop and in turn validate a new consensus protocol and scoring scheme for the assessment of CAA and associated vasculopathic abnormalities in post-mortem brain tissue. Stage one used an iterative Delphi-style survey to develop the consensus protocol. The resultant scoring scheme was tested on a series of digital images and paraffin sections that were circulated blind to a number of scorers. The scoring scheme and choice of staining methods were refined by open-forum discussion. The agreed protocol scored parenchymal and meningeal CAA on a 0-3 scale, capillary CAA as present/absent and vasculopathy on 0-2 scale, in the 4 cortical lobes that were scored separately. A further assessment involving three centres was then undertaken. Neuropathologists in three centres (Bristol, Oxford and Sheffield) independently scored sections from 75 cases (25 from each centre) and high inter-rater reliability was demonstrated. Stage two used the results of the three-centre assessment to validate the protocol by investigating previously described associations between APOE genotype (previously determined), and both CAA and vasculopathy. Association of capillary CAA with or without arteriolar CAA with APOE ε4 was confirmed. However APOE ε2 was also found to be a strong risk factor for the development of CAA, not only in AD but also in elderly non-demented controls. Further validation of this protocol and scoring scheme is encouraged, to aid its wider adoption to facilitate collaborative and replication studies of CAA. PMID:24754000

  14. Decreased norepinephrine (NE) uptake in cerebral cortex and inferior colliculus of genetically epilepsy prone (GEP) rats

    SciTech Connect

    Browning, R.A.; Rigler-Daugherty, S.K.; Long, G.; Jobe, P.C.; Wade, D.R.

    1986-03-01

    GEP rats are characterized by an enhanced susceptibility to seizures caused by a variety of stimuli, most notably sound. Pharmacological treatments that reduce the synaptic concentration of NE increase seizure severity in GEP rats while elevations in NE have the opposite effect. GEP rats also display a widespread deficit in brain NE concentration suggesting that their increased seizure susceptibility is related to a deficit in noradrenergic transmission. The authors have compared the kinetics of /sup 3/H-NE uptake in the P/sub 2/ synaptosomal fraction isolated from the cerebral cortex of normal and GEP-rats. Although the apparent Kms were not significantly different (Normal +/- SEM:0.37 +/- 0.13..mu..M; GEP +/- SEM: 0.29 +/- 0.07..mu..M), the Vmax for GEP rats was 48% lower than that of normal rats (Normal +/- SEM: 474 +/- 45 fmole/mg/4min; GEP +/- SEM: 248 +/- 16 fmole/mg/4min). Because of the possible role of the inferior colliculus (IC) in the initiation of sound-induced seizures in GEP rats, the authors measured synaptosomal NE uptake in the IC using a NE concentration of 50 nM. The IC synaptosomal NE uptake was found to be 35% lower in GEP than in normal rats. These findings are consistent with the hypothesis that a deficit in noradrenergic transmission is related to the increased seizure susceptibility of GEP rats.

  15. Decreased microvascular cerebral blood flow assessed by diffuse correlation spectroscopy after repetitive concussions in mice

    PubMed Central

    Buckley, Erin M; Miller, Benjamin F; Golinski, Julianne M; Sadeghian, Homa; McAllister, Lauren M; Vangel, Mark; Ayata, Cenk; Meehan III, William P; Angela Franceschini, Maria; Whalen, Michael J

    2015-01-01

    Repetitive concussions are associated with long-term cognitive dysfunction that can be attenuated by increasing the time intervals between concussions; however, biomarkers of the safest rest interval between injuries remain undefined. We hypothesize that deranged cerebral blood flow (CBF) is a candidate biomarker for vulnerability to repetitive concussions. Using a mouse model of human concussion, we examined the effect of single and repetitive concussions on cognition and on an index of CBF (CBFi) measured with diffuse correlation spectroscopy. After a single mild concussion, CBFi was reduced by 35±4% at 4 hours (P<0.01 versus baseline) and returned to preinjury levels by 24 hours. After five concussions spaced 1 day apart, CBFi was also reduced from preinjury levels 4 hours after each concussion but had returned to preinjury levels by 72 hours after the final concussion. Interestingly, in this repetitive concussion model, lower CBFi values measured both preinjury and 4 hours after the third concussion were associated with worse performance on the Morris water maze assessed 72 hours after the final concussion. We conclude that low CBFi measured either before or early on in the evolution of injury caused by repetitive concussions could be a useful predictor of cognitive outcome. PMID:26154866

  16. Decreased microvascular cerebral blood flow assessed by diffuse correlation spectroscopy after repetitive concussions in mice.

    PubMed

    Buckley, Erin M; Miller, Benjamin F; Golinski, Julianne M; Sadeghian, Homa; McAllister, Lauren M; Vangel, Mark; Ayata, Cenk; Meehan, William P; Franceschini, Maria Angela; Whalen, Michael J

    2015-12-01

    Repetitive concussions are associated with long-term cognitive dysfunction that can be attenuated by increasing the time intervals between concussions; however, biomarkers of the safest rest interval between injuries remain undefined. We hypothesize that deranged cerebral blood flow (CBF) is a candidate biomarker for vulnerability to repetitive concussions. Using a mouse model of human concussion, we examined the effect of single and repetitive concussions on cognition and on an index of CBF (CBFi) measured with diffuse correlation spectroscopy. After a single mild concussion, CBFi was reduced by 35±4% at 4 hours (P<0.01 versus baseline) and returned to preinjury levels by 24 hours. After five concussions spaced 1 day apart, CBFi was also reduced from preinjury levels 4 hours after each concussion but had returned to preinjury levels by 72 hours after the final concussion. Interestingly, in this repetitive concussion model, lower CBFi values measured both preinjury and 4 hours after the third concussion were associated with worse performance on the Morris water maze assessed 72 hours after the final concussion. We conclude that low CBFi measured either before or early on in the evolution of injury caused by repetitive concussions could be a useful predictor of cognitive outcome.

  17. Depletion of vitamin E increases amyloid beta accumulation by decreasing its clearances from brain and blood in a mouse model of Alzheimer disease.

    PubMed

    Nishida, Yoichiro; Ito, Shingo; Ohtsuki, Sumio; Yamamoto, Naoki; Takahashi, Tsubura; Iwata, Nobuhisa; Jishage, Kou-Ichi; Yamada, Hiromi; Sasaguri, Hiroki; Yokota, Shigefumi; Piao, Wenying; Tomimitsu, Hiroyuki; Saido, Takaomi C; Yanagisawa, Katsuhiko; Terasaki, Tetsuya; Mizusawa, Hidehiro; Yokota, Takanori

    2009-11-27

    Increased oxidative damage is a prominent and early feature in Alzheimer disease. We previously crossed Alzheimer disease transgenic (APPsw) model mice with alpha-tocopherol transfer protein knock-out (Ttpa(-/-)) mice in which lipid peroxidation in the brain was significantly increased. The resulting double-mutant (Ttpa(-/-)APPsw) mice showed increased amyloid beta (Abeta) deposits in the brain, which was ameliorated with alpha-tocopherol supplementation. To investigate the mechanism of the increased Abeta accumulation, we here studied generation, degradation, aggregation, and efflux of Abeta in the mice. The clearance of intracerebral-microinjected (125)I-Abeta(1-40) from brain was decreased in Ttpa(-/-) mice to be compared with wild-type mice, whereas the generation of Abeta was not increased in Ttpa(-/-)APPsw mice. The activity of an Abeta-degrading enzyme, neprilysin, did not decrease, but the expression level of insulin-degrading enzyme was markedly decreased in Ttpa(-/-) mouse brain. In contrast, Abeta aggregation was accelerated in Ttpa(-/-) mouse brains compared with wild-type brains, and well known molecules involved in Abeta transport from brain to blood, low density lipoprotein receptor-related protein-1 (LRP-1) and p-glycoprotein, were up-regulated in the small vascular fraction of Ttpa(-/-) mouse brains. Moreover, the disappearance of intravenously administered (125)I-Abeta(1-40) was decreased in Ttpa(-/-) mice with reduced translocation of LRP-1 in the hepatocytes. These results suggest that lipid peroxidation due to depletion of alpha-tocopherol impairs Abeta clearances from the brain and from the blood, possibly causing increased Abeta accumulation in Ttpa(-/-)APPsw mouse brain and plasma.

  18. Decreased Rate of Plasma Arginine Appearance in Murine Malaria May Explain Hypoargininemia in Children With Cerebral Malaria.

    PubMed

    Alkaitis, Matthew S; Wang, Honghui; Ikeda, Allison K; Rowley, Carol A; MacCormick, Ian J C; Chertow, Jessica H; Billker, Oliver; Suffredini, Anthony F; Roberts, David J; Taylor, Terrie E; Seydel, Karl B; Ackerman, Hans C

    2016-12-15

     Plasmodium infection depletes arginine, the substrate for nitric oxide synthesis, and impairs endothelium-dependent vasodilation. Increased conversion of arginine to ornithine by parasites or host arginase is a proposed mechanism of arginine depletion.  We used high-performance liquid chromatography to measure plasma arginine, ornithine, and citrulline levels in Malawian children with cerebral malaria and in mice infected with Plasmodium berghei ANKA with or without the arginase gene. Heavy isotope-labeled tracers measured by quadrupole time-of-flight liquid chromatography-mass spectrometry were used to quantify the in vivo rate of appearance and interconversion of plasma arginine, ornithine, and citrulline in infected mice.  Children with cerebral malaria and P. berghei-infected mice demonstrated depletion of plasma arginine, ornithine, and citrulline. Knock out of Plasmodium arginase did not alter arginine depletion in infected mice. Metabolic tracer analysis demonstrated that plasma arginase flux was unchanged by P. berghei infection. Instead, infected mice exhibited decreased rates of plasma arginine, ornithine, and citrulline appearance and decreased conversion of plasma citrulline to arginine. Notably, plasma arginine use by nitric oxide synthase was decreased in infected mice.  Simultaneous arginine and ornithine depletion in malaria parasite-infected children cannot be fully explained by plasma arginase activity. Our mouse model studies suggest that plasma arginine depletion is driven primarily by a decreased rate of appearance. Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

  19. Fluorodeoxyglucose metabolism associated with tau-amyloid interaction predicts memory decline.

    PubMed

    Hanseeuw, Bernard J; Betensky, Rebecca A; Schultz, Aaron P; Papp, Kathryn V; Mormino, Elizabeth C; Sepulcre, Jorge; Bark, John S; Cosio, Danielle M; LaPoint, Molly; Chhatwal, Jasmeer P; Rentz, Dorene M; Sperling, Reisa A; Johnson, Keith A

    2017-04-01

    The aim of this article was to evaluate in normal older adults and preclinical Alzheimer's disease (AD) the impact of amyloid and regional tauopathy on cerebral glucose metabolism and subsequent memory decline. We acquired positron emission tomography using F18 flortaucipir (tau), C11 Pittsburgh compound B (amyloid), and F18 fluorodeoxyglucose (FDG) in 90 clinically normal elderly of the Harvard Aging Brain Study. Posterior cingulate metabolism decreased when both amyloid and neocortical tau were high and predicted subsequent memory decline in a larger sample of normal elderly. In contrast, frontal hypometabolism related to the common age-related entorhinal tauopathy, but this dysfunction was independent of amyloid, and did not predict significant memory decline. Neocortical tauopathy was positively associated with metabolism in individuals with subthreshold amyloid, suggesting that glucose metabolism increases before decreasing in the course of preclinical AD. Our study identified a synergistic effect of amyloid and tau deposits and demonstrated, for the first time, in normal elderly its link to AD-like hypometabolism and to AD-like memory decline. The amyloid effect was observed with tau in neocortex, but not with tau in entorhinal cortex, which is the common site of age-related tauopathy. Entorhinal tau was associated with frontal hypometabolism, but this dysfunction was not associated with memory loss. Ann Neurol 2017;81:583-596. © 2017 American Neurological Association.

  20. Is perivetricular hyperintensity region caused by decreased cerebral blood flow?; assessment by {sup 15}O-PET study

    SciTech Connect

    Kaminaga, T.; Hayashida, K.; Ishida, Y.

    1994-05-01

    The clinical significance of the regional cerebral blood flow (rCBF) and oxygen metabolism has not been established in patients who had periventricular hyperintensity (PVH) by magnetic resonance imaging (MRI). The aim of this study is to correlate the results of rCBF and oxygen metabolism by positron emission tomography (PET) with PVH by MRI. The subjects were 27 patients; 16 patient (group I) (male; 7, female; 9, age; 56.8{plus_minus}18.6) with PVH and age matched 11 patients (group II) (male; 6, female; 5, age; 55.3{plus_minus}13.6) without PVH. {sup 15}O-PET study was carried out by Headtome IV and rCBF, cerebral metabolic rate of oxygen (CMRO{sub 2}), oxygen extraction fraction (OEF) of PVH and cerebellum was calculated. T1- and T2-weighted images were obtained in all patients. Angiography was performed over 11 patients. The mean rCBF of group I in PVH (28.5{plus_minus}7.5 ml/100g/min) was significantly (p<0.01) lower than that of group II (38.6{plus_minus}5.7). The mean rCBF of group I and group II in cerebellum were 49.5{plus_minus}9.9 ml/100g/min and 50.2{plus_minus}8.9 respectively. There was no significant difference on CMRO{sub 2} and OEF between group I and group II. In MRI examination, PVH was detected in all group I patients and multiple high intensities were also detected in 7 patients of group I and 4 patients of group II on T2-weighted images. No significant stenosis (more than 75%) was detected in 11 patients by angiography. These data strongly indicate that PVH might be caused by decreased cerebral blood flow.

  1. Depletion of TDP-43 decreases fibril and plaque β-amyloid and exacerbates neurodegeneration in an Alzheimer's mouse model.

    PubMed

    LaClair, Katherine D; Donde, Aneesh; Ling, Jonathan P; Jeong, Yun Ha; Chhabra, Resham; Martin, Lee J; Wong, Philip C

    2016-12-01

    TDP-43 proteinopathy, initially associated with ALS and FTD, is also found in 30-60% of Alzheimer's disease (AD) cases and correlates with worsened cognition and neurodegeneration. A major component of this proteinopathy is depletion of this RNA-binding protein from the nucleus, which compromises repression of non-conserved cryptic exons in neurodegenerative diseases. To test whether nuclear depletion of TDP-43 may contribute to the pathogenesis of AD cases with TDP-43 proteinopathy, we examined the impact of depletion of TDP-43 in populations of neurons vulnerable in AD, and on neurodegeneration in an AD-linked context. Here, we show that some populations of pyramidal neurons that are selectively vulnerable in AD are also vulnerable to TDP-43 depletion in mice, while other forebrain neurons appear spared. Moreover, TDP-43 depletion in forebrain neurons of an AD mouse model exacerbates neurodegeneration, and correlates with increased prefibrillar oligomeric Aβ and decreased Aβ plaque burden. These findings support a role for nuclear depletion of TDP-43 in the pathogenesis of AD and provide strong rationale for developing novel therapeutics to alleviate the depletion of TDP-43 and functional antemortem biomarkers associated with its nuclear loss.

  2. Protective effects of astragalosides on dexamethasone and Aβ25-35 induced learning and memory impairments due to decrease amyloid precursor protein expression in 12-month male rats.

    PubMed

    Li, Wei-Zu; Wu, Wang-Yang; Huang, Da-Ke; Yin, Yan-Yan; Kan, Hong-Wei; Wang, Xin; Yao, Yu-You; Li, Wei-Ping

    2012-06-01

    Alzheimer's disease (AD) is a chronic neurodegenerative disorder of the elderly characterized by learning and memory impairment. Stress level glucocorticoids (GCs) and β-amyloid (Aβ) peptide deposition are found to be correlated with dementia progression in patients with AD. The astragalosides (AST) was extracted from traditional Chinese herb Astragalus membranaceous. In this study, 12 months male rats were treated with Aβ(25-35) (10 μg/rat, hippocampal CA1 injection) and dexamethasone (DEX, 1.5mg/kg, ig) and AST (8, 16 and 32 mg/kg, ig) or ginsenoside Rg1 (Rg1, 5 mg/kg, ig) for 14 days. We investigated the protective effect of AST against DEX+Aβ(25-35) injury in rats and its mechanisms of action. Our results indicate that DEX+Aβ(25-35) can induce learning and memory impairments and increase APP and Aβ(1-40) expression. AST (16, 32 mg/kg) or Rg1 (5mg/kg) treatment significantly improve learning and memory, down-regulate the mRNA levels of APP and β-secretase, decrease expression of APP and Aβ(1-40) in hippocampus. The results indicated that DEX might increase hippocampal vulnerability to Aβ(25-35) and highlight the potential neuronal protection of AST.

  3. Chronic cerebral hypoperfusion causes decrease of O-GlcNAcylation, hyperphosphorylation of tau and behavioral deficits in mice

    PubMed Central

    Zhao, Yang; Gu, Jin-hua; Dai, Chun-ling; Liu, Qun; Iqbal, Khalid; Liu, Fei; Gong, Cheng-Xin

    2014-01-01

    Chronic cerebral hypoperfusion (CCH) is one of the causes of vascular dementia (VaD) and is also an etiological factor for Alzheimer’s disease (AD). However, how CCH causes cognitive impairment and contributes to Alzheimer’s pathology is poorly understood. Here we produced a mouse model of CCH by unilateral common carotid artery occlusion (UCCAO) and studied the behavioral changes and brain abnormalities in mice 2.5 months after UCCAO. We found that CCH caused significant short-term memory deficits and mild long-term spatial memory impairment, as well as decreased level of protein O-GlcNAcylation, increased level of tau phosphorylation, dysregulated synaptic proteins and insulin signaling, and selective neurodegeneration in the brain. These findings provide mechanistic insight into the effects of CCH on memory and cognition and the likely link between AD and VaD. PMID:24575038

  4. Contributions of degradation and brain-to-blood elimination across the blood–brain barrier to cerebral clearance of human amyloid-β peptide(1-40) in mouse brain

    PubMed Central

    Ito, Shingo; Matsumiya, Kohta; Ohtsuki, Sumio; Kamiie, Junichi; Terasaki, Tetsuya

    2013-01-01

    The purpose of the present study was to estimate the relative contributions of degradation and brain-to-blood elimination processes to the clearance of microinjected human amyloid-β peptide(1-40) (hAβ(1-40)) from mouse cerebral cortex, using a solid-phase extraction method together with a newly developed ultraperformance liquid chromatography/tandem mass spectrometry (UPLC/MS/MS) quantitation method for intact hAβ(1-40). The clearance rate constant of hAβ(1-40) in mouse cerebral cortex was determined to be 3.21 × 10−2/min under conditions where the saturable brain-to-blood elimination process across the blood–brain barrier (BBB) was expected to be saturated. Thus, this clearance rate constant should mainly reflect degradation. The [125I]hAβ(1-40) elimination rate across the BBB under nonsaturating conditions was determined to be 1.48 × 10−2/min. Inhibition studies suggested that processes sensitive to insulin and phosphoramidon, which inhibit neprilysin, insulin-degrading enzyme, and endothelin-converting enzyme, are involved not only in degradation, but also in elimination of hAβ(1-40). In conclusion, our results suggest a dominant contribution of degradation to cerebral hAβ(1-40) clearance, and also indicate that a sequential process of degradation and elimination of degradation products is involved in cerebral hAβ(1-40) clearance. PMID:23963369

  5. Decreases in frontal and parietal lobe regional cerebral blood flow related to habituation.

    PubMed

    Warach, S; Gur, R C; Gur, R E; Skolnick, B E; Obrist, W D; Reivich, M

    1992-07-01

    We previously reported decreased mean CBF between consecutive resting conditions, ascribed to habituation. Here we address the regional specificity of habituation over three consecutive flow studies. Regional CBF (rCBF) was measured in 55 adults (12 right-handed men, 12 right-handed women, 14 left-handed men, 17 left-handed women), with the 133Xe inhalation technique, during three conditions: resting, verbal tasks (analogies), and spatial tasks (line orientation). Changes in rCBF attributable to the cognitive tasks were eliminated by correcting these values to a resting equivalent. There was a progressive decrease in mean rCBF over time, reflecting habituation. This effect differed by region, with specificity at frontal (prefrontal, inferior frontal, midfrontal, superior frontal) and inferior parietal regions. In the inferior parietal region, habituation was more marked in the left than the right hemisphere. Right-handers showed greater habituation than did left-handers. There was no sex difference in global habituation, but males showed greater left whereas females showed greater right hemispheric habituation. The results suggest that habituation to the experimental setting has measurable effects on rCBF, which are differently lateralized for men and women. These effects are superimposed on task activation and are most pronounced in regions that have been implicated in attentional processes. Thus, regional decrement in brain activity related to habituation seems to complement attentional effects, suggesting a neural network for habituation reciprocating that for attention.

  6. Traumatic brain injury-induced ependymal ciliary loss decreases cerebral spinal fluid flow.

    PubMed

    Xiong, Guoxiang; Elkind, Jaclynn A; Kundu, Suhali; Smith, Colin J; Antunes, Marcelo B; Tamashiro, Edwin; Kofonow, Jennifer M; Mitala, Christina M; Cole, Jeffrey; Stein, Sherman C; Grady, M Sean; Einhorn, Eugene; Cohen, Noam A; Cohen, Akiva S

    2014-08-15

    Traumatic brain injury (TBI) afflicts up to 2 million people annually in the United States and is the primary cause of death and disability in young adults and children. Previous TBI studies have focused predominantly on the morphological, biochemical, and functional alterations of gray matter structures, such as the hippocampus. However, little attention has been given to the brain ventricular system, despite the fact that altered ventricular function is known to occur in brain pathologies. In the present study, we investigated anatomical and functional alterations to mouse ventricular cilia that result from mild TBI. We demonstrate that TBI causes a dramatic decrease in cilia. Further, using a particle tracking technique, we demonstrate that cerebrospinal fluid flow is diminished, thus potentially negatively affecting waste and nutrient exchange. Interestingly, injury-induced ventricular system pathology resolves completely by 30 days after injury as ependymal cell ciliogenesis restores cilia density to uninjured levels in the affected lateral ventricle.

  7. Traumatic Brain Injury-Induced Ependymal Ciliary Loss Decreases Cerebral Spinal Fluid Flow

    PubMed Central

    Xiong, Guoxiang; Elkind, Jaclynn A.; Kundu, Suhali; Smith, Colin J.; Antunes, Marcelo B.; Tamashiro, Edwin; Kofonow, Jennifer M.; Mitala, Christina. M.; Stein, Sherman C.; Grady, M. Sean; Einhorn, Eugene; Cohen, Noam A.

    2014-01-01

    Abstract Traumatic brain injury (TBI) afflicts up to 2 million people annually in the United States and is the primary cause of death and disability in young adults and children. Previous TBI studies have focused predominantly on the morphological, biochemical, and functional alterations of gray matter structures, such as the hippocampus. However, little attention has been given to the brain ventricular system, despite the fact that altered ventricular function is known to occur in brain pathologies. In the present study, we investigated anatomical and functional alterations to mouse ventricular cilia that result from mild TBI. We demonstrate that TBI causes a dramatic decrease in cilia. Further, using a particle tracking technique, we demonstrate that cerebrospinal fluid flow is diminished, thus potentially negatively affecting waste and nutrient exchange. Interestingly, injury-induced ventricular system pathology resolves completely by 30 days after injury as ependymal cell ciliogenesis restores cilia density to uninjured levels in the affected lateral ventricle. PMID:24749541

  8. Cerebral Oedema, Blood-Brain Barrier Breakdown and the Decrease in Na(+),K(+)-ATPase Activity in the Cerebral Cortex and Hippocampus are Prevented by Dexamethasone in an Animal Model of Maple Syrup Urine Disease.

    PubMed

    Rosa, Luciana; Galant, Leticia S; Dall'Igna, Dhébora M; Kolling, Janaina; Siebert, Cassiana; Schuck, Patrícia F; Ferreira, Gustavo C; Wyse, Angela T S; Dal-Pizzol, Felipe; Scaini, Giselli; Streck, Emilio L

    2016-08-01

    Maple syrup urine disease (MSUD) is a rare metabolic disorder associated with acute and chronic brain dysfunction. This condition has been shown to lead to macroscopic cerebral alterations that are visible on imaging studies. Cerebral oedema is widely considered to be detrimental for MSUD patients; however, the mechanisms involved are still poorly understood. Therefore, we investigated whether acute administration of branched-chain amino acids (BCAA) causes cerebral oedema, modifies the Na(+),K(+)-ATPase activity, affects the permeability of the blood-brain barrier (BBB) and alters the levels of cytokines in the hippocampus and cerebral cortex of 10-day-old rats. Additionally, we investigated the influence of concomitant administration of dexamethasone on the alterations caused by BCAA. Our results showed that the animals submitted to the model of MSUD exhibited an increase in the brain water content, both in the cerebral cortex and in the hippocampus. By investigating the mechanism of cerebral oedema, we discovered an association between H-BCAA and the Na(+),K(+)-ATPase activity and the permeability of the BBB to small molecules. Moreover, the H-BCAA administration increases Il-1β, IL-6 and TNF-α levels in the hippocampus and cerebral cortex, whereas IL-10 levels were decreased in the hippocampus. Interestingly, we showed that the administration of dexamethasone successfully reduced cerebral oedema, preventing the inhibition of Na(+),K(+)-ATPase activity, BBB breakdown and the increase in the cytokines levels. In conclusion, these findings suggest that dexamethasone can improve the acute cerebral oedema and brain injury associated with high levels of BCAA, either through a direct effect on brain capillary Na(+),K(+)-ATPase or through a generalized effect on the permeability of the BBB to all compounds.

  9. Methylene Blue Modulates β-Secretase, Reverses Cerebral Amyloidosis, and Improves Cognition in Transgenic Mice*

    PubMed Central

    Mori, Takashi; Koyama, Naoki; Segawa, Tatsuya; Maeda, Masahiro; Maruyama, Nobuhiro; Kinoshita, Noriaki; Hou, Huayan; Tan, Jun; Town, Terrence

    2014-01-01

    Amyloid precursor protein (APP) proteolysis is required for production of amyloid-β (Aβ) peptides that comprise β-amyloid plaques in the brains of patients with Alzheimer disease (AD). Here, we tested whether the experimental agent methylene blue (MB), used for treatment of methemoglobinemia, might improve AD-like pathology and behavioral deficits. We orally administered MB to the aged transgenic PSAPP mouse model of cerebral amyloidosis and evaluated cognitive function and cerebral amyloid pathology. Beginning at 15 months of age, animals were gavaged with MB (3 mg/kg) or vehicle once daily for 3 months. MB treatment significantly prevented transgene-associated behavioral impairment, including hyperactivity, decreased object recognition, and defective spatial working and reference memory, but it did not alter nontransgenic mouse behavior. Moreover, brain parenchymal and cerebral vascular β-amyloid deposits as well as levels of various Aβ species, including oligomers, were mitigated in MB-treated PSAPP mice. These effects occurred with inhibition of amyloidogenic APP proteolysis. Specifically, β-carboxyl-terminal APP fragment and β-site APP cleaving enzyme 1 protein expression and activity were attenuated. Additionally, treatment of Chinese hamster ovary cells overexpressing human wild-type APP with MB significantly decreased Aβ production and amyloidogenic APP proteolysis. These results underscore the potential for oral MB treatment against AD-related cerebral amyloidosis by modulating the amyloidogenic pathway. PMID:25157105

  10. Caudolateral orbitofrontal regional cerebral blood flow is decreased in abstinent cocaine-addicted subjects in two separate cohorts.

    PubMed

    Adinoff, Bryon; Braud, Jacquelyn; Devous, Michael D; Harris, Thomas S

    2012-11-01

    The orbitofrontal cortex (OFC) is crucial for the inhibition of extraneous stimuli, evaluation of aversive information and emotional regulation-all behaviors impaired in cocaine addiction. Previous studies suggest that cocaine-addicted subjects have decreased basal activity in the OFC. In this study, we examined regional cerebral blood flow (rCBF) during a saline infusion in two independent populations of abstinent cocaine- (and mostly nicotine-) addicted (n=33 and 26) and healthy control (n=35 and 20) men and women. Isolated rCBF decreases (P<0.001) were observed in the left caudolateral OFC, as well as left superior temporal cortex, in cocaine-addicted subjects relative to controls in both cohorts and bilaterally in the combined cohort. An anatomically defined region of the caudolateral OFC showed similar findings and were evident in both male and female addicted subjects. The reliability of these findings across two cohorts reveals a functional disruption in the lateral OFC, a brain region implicated in the evaluation of behavior-terminating stimuli. This may contribute to an addicted individual's persistent drug use despite negative consequences.

  11. β-Secretase-1 elevation in aged monkey and Alzheimer's disease human cerebral cortex occurs around vasculature in partnership with multisystem axon terminal pathogenesis and β-amyloid accumulation

    PubMed Central

    Cai, Yan; Xiong, Kun; Zhang, Xue-Mei; Cai, Huaibin; Luo, Xue-Gang; Feng, Jia-Chun; Clough, Richard W.; Struble, Robert G.; Patrylo, Peter R.; Chu, Yaping; Kordower, Jeffrey H.; Yan, Xiao-Xin

    2010-01-01

    Alzheimer's disease (AD) is the most common dementia-causing disorder in the elderly, which may relate to multiple risk factors and is pathologically featured by cerebral hypometabolism, paravascular β-amyloid (Aβ) plaques, neuritic dystrophy and intra-neuronal aggregation of phosphorylated-tau. To explore potential pathogenic link among some of these lesions, we examined β-secretase-1 (BACE1) alteration relative to Aβ deposition, neuritic pathology and vascular organization in aged monkey and AD human cerebral cortex. Western blot analyses detected increased levels of BACE1 proteins and β-site-cleavage amyloid precursor protein C-terminal fragments in plaque-bearing human and monkey cortex relative to controls. In immunohistochemistry, locally elevated BACE1 immunoreactivity (IR) occurred in AD but not in control human cortex, with a trend of increased overall density among cases with greater plaque pathology. In double labeling preparations, BACE1 IR colocalized with immunolabeling for Aβ but not for phosphorylated tau. In perfusion-fixed monkey cortex, locally increased BACE1 IR co-existed with intra-axonal and extracellular Aβ IR among virtually all neuritic plaques ranging from primitive to typical cored forms. This BACE1 labeling localized to swollen/sprouting axon terminals that might co-express one or another neuronal phenotype marker (GABAergic, glutamatergic, cholinergic or catecholaminergic). Importantly, these BACE1-labeled dystrophic axons resided near or in direct contact with blood vessels. These finds implicate that plaque formation in AD or normal aging primates relate to a multisystem axonal pathogenesis that occurs in partnership with potential vascular or metabolic deficit. The data provide a tangible mechanistic explanation as to why senile plaques are present preferentially near cerebral vasculature. PMID:20726888

  12. Prion Protein Is Decreased in Alzheimer's Brain and Inversely Correlates with BACE1 Activity, Amyloid-β Levels and Braak Stage

    PubMed Central

    Whitehouse, Isobel J.; Miners, J. Scott; Glennon, Elizabeth B. C.; Kehoe, Patrick G.; Love, Seth; Kellett, Katherine A. B.; Hooper, Nigel M.

    2013-01-01

    The cellular prion protein (PrPC) has been implicated in the development of Alzheimer's disease (AD). PrPC decreases amyloid-β (Aβ) production, which is involved in AD pathogenesis, by inhibiting β-secretase (BACE1) activity. Contactin 5 (CNTN5) has also been implicated in the development of AD by a genome-wide association study. Here we measured PrPC and CNTN5 in frontal cortex samples from 24 sporadic AD and 24 age-matched control brains and correlated the expression of these proteins with markers of AD. PrPC was decreased in sporadic AD compared to controls (by 49%, p = 0.014) but there was no difference in CNTN5 between sporadic AD and controls (p = 0.217). PrPC significantly inversely correlated with BACE1 activity (rs = −0.358, p = 0.006), Aβ load (rs = −0.456, p = 0.001), soluble Aβ (rs = −0.283, p = 0.026) and insoluble Aβ (rs = −0.353, p = 0.007) and PrPC also significantly inversely correlated with the stage of disease, as indicated by Braak tangle stage (rs = −0.377, p = 0.007). CNTN5 did not correlate with Aβ load (rs = 0.040, p = 0.393), soluble Aβ (rs = 0.113, p = 0.223) or insoluble Aβ (rs = 0.169, p = 0.125). PrPC was also measured in frontal cortex samples from 9 Down's syndrome (DS) and 8 age-matched control brains. In contrast to sporadic AD, there was no difference in PrPC in the DS brains compared to controls (p = 0.625). These data are consistent with a role for PrPC in regulating Aβ production and indicate that brain PrPC level may be important in influencing the onset and progression of sporadic AD. PMID:23577068

  13. Dickkopf 3 (Dkk3) Improves Amyloid-β Pathology, Cognitive Dysfunction, and Cerebral Glucose Metabolism in a Transgenic Mouse Model of Alzheimer's Disease.

    PubMed

    Zhang, Li; Sun, Caixian; Jin, Yaxi; Gao, Kai; Shi, Xudong; Qiu, Wenying; Ma, Chao; Zhang, Lianfeng

    2017-09-08

    Dysfunctional Wnt signaling is associated with Alzheimer's disease (AD), and activation of the Wnt signaling pathway inhibits AD development. Dickkopf 3 (Dkk3) is a modulator of the Wnt signaling pathway and is physiologically expressed in the brain. The role of Dkk3 in the pathogenesis of AD has not been evaluated. In the present study, we determined that Dkk3 expression was significantly decreased in brain tissue from AD patients and the AD transgenic mouse model APPswe/PS1dE9 (AD mice). Transgenic mice with brain tissue-specific Dkk3 expression were generated or crossed with AD mice to study the effects of Dkk3 on AD. In AD mice, transgenic expression of Dkk3 improved abnormalities in learning, memory, and locomotor activity, reduced the accumulation of amyloid-β, and ameliorated glucose uptake deficits. Furthermore, we determined that Dkk3 downregulated GSK-3β, a central negative regulator in canonical Wnt signaling, and upregulated PKCβ1, a factor implicated in noncanonical Wnt signaling. This indicates that increased activation of GSK-3β and the inhibition of PKCβ1 in AD patients may be responsible for the dysfunctional Wnt signaling in AD. In summary, our data suggest that Dkk3 is an agonist of Wnt signaling, and the ability of transgenic expression of Dkk3 to compensate for the decrease in Dkk3 expression in AD mice, reverse dysfunctional Wnt signaling, and partially inhibit the pathological development of AD suggests that Dkk3 could serve as a therapeutic target for the treatment of AD.

  14. APOE4 Allele Disrupts Resting State fMRI Connectivity in the Absence of Amyloid Plaques or Decreased CSF Aβ42

    PubMed Central

    Sheline, Yvette I.; Morris, John C.; Snyder, Abraham Z.; Price, Joseph L.; Yan, Zhizi; D’Angelo, Gina; Liu, Collin; Dixit, Sachin; Benzinger, Tammie; Fagan, Anne; Goate, Alison; Mintun, Mark A.

    2010-01-01

    Identifying high risk populations is an important component of disease prevention strategies. One approach is examining neuroimaging parameters that differ in Alzheimer’s disease (AD), including functional connections known to be disrupted within the “default mode network” (DMN). We have previously shown these same disruptions in cognitively normal elderly, who have amyloid-beta (Aβ) plaques detected using PIB PET imaging, suggesting neuronal toxicity of plaques. Here we sought to determine if pathological effects of apolipoprotein E ε4 (APOE4) genotype could be seen independent of Aβ plaque toxicity by examining resting state fMRI functional connectivity (fcMRI ) in participants without preclinical fibrillar amyloid deposition (PIB−). Cognitively normal participants enrolled in longitudinal studies (n = 100, mean age = 62) who were PIB− were categorized into those with and without an APOE 4 allele and studied using fcMRI. APOE 4 allele carriers (E4+) differed significantly from E4− in functional connectivity of the precuneus to several regions previously defined as having abnormal connectivity in a group of AD participants. These effects were observed prior to any manifestations of cognitive changes and in the absence of brain fibrillar amyloid-beta (Aβ) plaque deposition, suggesting that early manifestations of a genetic effect can be detected using fcMRI and that these changes may antedate the pathological effects of fibrillar amyloid plaque toxicity. PMID:21159973

  15. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation.

    PubMed

    Oakley, Holly; Cole, Sarah L; Logan, Sreemathi; Maus, Erika; Shao, Pei; Craft, Jeffery; Guillozet-Bongaarts, Angela; Ohno, Masuo; Disterhoft, John; Van Eldik, Linda; Berry, Robert; Vassar, Robert

    2006-10-04

    Mutations in the genes for amyloid precursor protein (APP) and presenilins (PS1, PS2) increase production of beta-amyloid 42 (Abeta42) and cause familial Alzheimer's disease (FAD). Transgenic mice that express FAD mutant APP and PS1 overproduce Abeta42 and exhibit amyloid plaque pathology similar to that found in AD, but most transgenic models develop plaques slowly. To accelerate plaque development and investigate the effects of very high cerebral Abeta42 levels, we generated APP/PS1 double transgenic mice that coexpress five FAD mutations (5XFAD mice) and additively increase Abeta42 production. 5XFAD mice generate Abeta42 almost exclusively and rapidly accumulate massive cerebral Abeta42 levels. Amyloid deposition (and gliosis) begins at 2 months and reaches a very large burden, especially in subiculum and deep cortical layers. Intraneuronal Abeta42 accumulates in 5XFAD brain starting at 1.5 months of age (before plaques form), is aggregated (as determined by thioflavin S staining), and occurs within neuron soma and neurites. Some amyloid deposits originate within morphologically abnormal neuron soma that contain intraneuronal Abeta. Synaptic markers synaptophysin, syntaxin, and postsynaptic density-95 decrease with age in 5XFAD brain, and large pyramidal neurons in cortical layer 5 and subiculum are lost. In addition, levels of the activation subunit of cyclin-dependent kinase 5, p25, are elevated significantly at 9 months in 5XFAD brain, although an upward trend is observed by 3 months of age, before significant neurodegeneration or neuron loss. Finally, 5XFAD mice have impaired memory in the Y-maze. Thus, 5XFAD mice rapidly recapitulate major features of AD amyloid pathology and may be useful models of intraneuronal Abeta42-induced neurodegeneration and amyloid plaque formation.

  16. Decreased cholinergic function in the cerebral cortex of hypoxic neonatal rats: role of glucose, oxygen and epinephrine resuscitation.

    PubMed

    Anju, T R; Smijin, S; Chinthu, R; Paulose, C S

    2012-01-15

    Molecular processes regulating cholinergic functions play an important role in the control of respiration under hypoxia. Cholinergic alterations and its further complications in learning and memory due to hypoxic insult in neonatal rats and the effect of glucose, oxygen and epinephrine resuscitation was evaluated in the present study. Receptor binding and gene expression studies were done in the cerebral cortex to analyze the changes in total muscarinic receptors, muscarinic M1, M2, M3 receptors and the enzymes involved in acetylcholine metabolism - choline acetyltransferase and acetylcholine esterase. Neonatal hypoxia decreased total muscarinic receptors with reduced muscarinic M1, M2 and M3 receptor genes. The reduction in acetylcholine metabolism is indicated by the down regulated choline acetyltransferase and up regulated acetylcholine esterase expression. These cholinergic disturbances were reversed to near control in glucose resuscitated hypoxic neonates. The adverse effects of immediate oxygenation and epinephrine administration are also reported. This has immense clinical significance in establishing a proper resuscitation for the management of neonatal hypoxia.

  17. [The use of the transcranial micropolarization method for decreasing the manifestations of hyperkinesis in patients with infantile cerebral palsy].

    PubMed

    Bogdanov, O V; Pinchuk, D Iu; Pisar'kova, E V; Sheliakin, A M; Sirbiladze, K T

    1993-01-01

    Transcranial micropolarization was used in the treatment of children with hyperkinetic form of infantile cerebral paralysis. The method was found to be more effective than various stereotaxic interventions on the brain or routine physiotherapy. Transcranial micropolarization exposure resulted in alleviation of hyperkinesis, posture-tonic reflexes, in improvement of active movements of the joints, supporting system, etc. Clinical status of patients exposed to this treatment modality improved by six times as against those treated traditionally. Clinical data and data of stimulation electromyography permit us to suggest a possible effect of transcranial micropolarization on the function of cerebral subcortical structures in patients with hyperkinetic form of infantile cerebral paralysis.

  18. Neuritic Plaques and Cerebrovascular Amyloid in Alzheimer Disease are Antigenically Related

    NASA Astrophysics Data System (ADS)

    Wong, Caine W.; Quaranta, Vito; Glenner, George G.

    1985-12-01

    A synthetic peptide (Asp-Ala-Glu-Phe-Arg-His-Asp-Ser-Gly-Tyr), homologous to the amino terminus of a protein purified from cerebrovascular amyloid (β protein), induced antibodies in BALB/c mice that were used immunohistochemically to stain not only amyloid-laden cerebral vessels but neuritic plaques as well. These findings suggest that the amyloid in neuritic plaques shares antigenic determinants with β protein of cerebral vessels. Since the amino acid compositions of plaque amyloid and cerebrovascular amyloid are similar, it is likely that plaque amyloid also consists of β protein. This possibility suggests a model for the pathogenesis of Alzheimer disease involving β protein.

  19. APOE4 allele disrupts resting state fMRI connectivity in the absence of amyloid plaques or decreased CSF Aβ42.

    PubMed

    Sheline, Yvette I; Morris, John C; Snyder, Abraham Z; Price, Joseph L; Yan, Zhizi; D'Angelo, Gina; Liu, Collin; Dixit, Sachin; Benzinger, Tammie; Fagan, Anne; Goate, Alison; Mintun, Mark A

    2010-12-15

    Identifying high-risk populations is an important component of disease prevention strategies. One approach for identifying at-risk populations for Alzheimer's disease (AD) is examining neuroimaging parameters that differ between patients, including functional connections known to be disrupted within the default-mode network. We have previously shown these same disruptions in cognitively normal elderly who have amyloid-β (Aβ) plaques [detected using Pittsburgh Compound B (PIB) PET imaging], suggesting neuronal toxicity of plaques. Here we sought to determine if pathological effects of apolipoprotein E ε4 (APOE4) genotype could be seen independent of Aβ plaque toxicity by examining resting state fMRI functional connectivity (fcMRI) in participants without preclinical fibrillar amyloid deposition (PIB-). Cognitively normal participants enrolled in longitudinal studies (n = 100, mean age = 62) who were PIB- were categorized into those with and without an APOE4 allele and studied using fcMRI. APOE4 allele carriers (E4+) differed significantly from E4- in functional connectivity of the precuneus to several regions previously defined as having abnormal connectivity in a group of AD participants. These effects were observed before any manifestations of cognitive changes and in the absence of brain fibrillar Aβ plaque deposition, suggesting that early manifestations of a genetic effect can be detected using fcMRI and that these changes may antedate the pathological effects of fibrillar amyloid plaque toxicity.

  20. Amyloid neuropathies.

    PubMed

    Adams, David; Lozeron, Pierre; Lacroix, Catherine

    2012-10-01

    As amyloid neuropathies have benefited from recent major progress, this review is timely and relevant. The main recent articles on amyloid neuropathy cover its description, methods for diagnosis and therapies. Varied clinical presentations are described in transthyretin (TTR)-familial amyloidosis with polyneuropathy (FAP) and light chain amyloid neuropathy. Mass spectrometry is able to identify the biochemical nature of amyloidogenic protein in nerve biopsy and skin biopsy samples for diagnosis of small fiber polyneuropathy. Both nerve biopsy and TTR gene sequencing are important to identify sporadic cases of amyloid neuropathy. Nerve biopsy is useful in demonstrating the amyloid origin of neuropathies developing after domino liver transplant recipients. Liver transplantation improves long-term survival in Met30 TTR-FAP. Factors recognized as leading to cardiomyopathy progression or heart involvement after liver transplantation are late disease onset and fibril composition. Combined heart and liver transplantation is recommended in severe restrictive cardiomyopathy. Antiamyloid drugs are emerging: tafamidis, a TTR stabilizer, showed in a phase III controlled study its ability to slow stage 1 FAP progression. Other strategies are emerging for TTR-FAP (combination doxycycline-tauroursodeoxycholic acid, small interfering RNA, antisense oligonucleotide, monoclonal antibody antiserum amyloid P component). For light chain neuropathy, intensive chemotherapy may be helpful. There is better recognition of amyloid neuropathies, and hope for enrolling patients with FAP in future clinical trials testing new antiamyloid drugs.

  1. Evaluation of near infrared spectroscopy for detecting the β blocker-induced decrease in cerebral oxygenation during hemodilution in a swine model.

    PubMed

    Kurita, Tadayoshi; Morita, Koji; Sato, Shigehito

    2015-12-01

    β blockers reduce cerebral oxygenation after acute hemodilution and may contribute to the incidence of stroke when used perioperatively. The goal of the study was to investigate whether cerebral tissue oxygenation using near infrared spectroscopy can detect the β blocker-induced decrease in cerebral oxygenation depending on the severity of hemodilution and/or the dose of β blockers. Animals were anesthetized with 2% isoflurane and randomly assigned to a landiolol or esmolol group. After baseline measurement, landiolol or esmolol was administered at 40 µg/kg/min for 20 min, increased to 200 µg/kg/min for 20 min, and then stopped. Hemodynamic and arterial variables and the tissue oxygenation index (TOI) were recorded at each β blocker dose. Two stages of hemodilution were sequentially induced by repeated hemorrhage of 600 ml (33% of estimated blood volume) and infusion of the same volume of hydroxyethylstarch. During each stage, landiolol or esmolol was similarly administered and measurements were made. Landiolol and esmolol both dose-dependently decreased heart rate, mean arterial pressure and cardiac output, depending on the severity of hemodilution. Landiolol at 40 µg/kg/min was almost equivalent in potency to 200 µg/kg/min esmolol for decreasing HR before hemodilution. Based on the TOI, short-acting β blockers reduced cerebral oxygenation in a dose-dependent manner during hemodilution, and oxygenation returned to the baseline level after drug infusion was stopped. TOI may be useful for identification of a decrease in cerebral oxygenation for patients receiving β blockade during surgery associated with major bleeding.

  2. Juvenile methylphenidate modulates reward-related behaviors and cerebral blood flow by decreasing cortical D3 receptors.

    PubMed

    Andersen, Susan L; Napierata, Lee; Brenhouse, Heather C; Sonntag, Kai C

    2008-06-01

    Attention deficit hyperactivity disorder is associated with reduced cortical blood flow that is reversible with exposure to the psychostimulant methylphenidate (MPH). D3 dopamine receptors modulate stimulant-induced changes in blood flow and are associated with reward processing during young adulthood, but their role in the enduring effects of MPH during development is unknown. Rats were given vehicle (VEH) or MPH (2 mg/kg between postnatal days 20-35) and assessed in young adulthood for regional cerebral blood volume (rCBV) after MPH challenge and mRNA expression levels of dopamine receptors. To probe D3 receptor involvement, juvenile subjects were exposed to VEH, MPH, the D3-preferring agonist +/-7-OHDPAT (0.3 mg/kg), the D3 antagonist nafadotride (Naf; 0.05, 0.5 or 5.0 mg/kg) or a Naf (0.05 mg/kg)/MPH combination, and assessed biochemically and behaviorally. Juvenile MPH exposure increased MPH-induced rCBV in the cingulate and medial prefrontal cortex and thalamus in adulthood. Behaviorally, juvenile MPH- or +/-7-OHDPAT-exposed subjects demonstrated an aversion to cocaine-associated environments, which was prevented by juvenile co-treatment with MPH and Naf, or with adult cortical microinjections of +/-7-OHDPAT. Cortical D3 mRNA levels significantly decreased by 23.8 +/- 6.7% in MPH-treated subjects and normalized with combined Naf/MPH treatment, with no change in the other dopamine receptors. Enhanced cortical responsiveness to psychostimulants may occur through a reduction in D3 receptors, which in turn reduces drug-seeking behavior. These data provide evidence for a postnatal sensitive period when juvenile MPH exposure is able to alter cortical development.

  3. Decreased expression of transient receptor potential channels in cerebral vascular tissue from patients after hypertensive intracerebral hemorrhage.

    PubMed

    Thilo, Florian; Suess, Olaf; Liu, Ying; Tepel, Martin

    2011-01-01

    Recent data indicate that transient receptor potential (TRP) cation channels play an important role in hypertension. Now, we tested the hypothesis that TRP expression is altered in human cerebral vascular tissue in patients who had experienced hypertensive intracerebral hemorrhage. TRPC1, TRPC3, TRPC5, TRPC6, TRPM4, TRPM6, and TRPM7 channels were detected in cerebral vascular tissue by quantitative real-time RT-PCR. Control cerebral vascular tissue was obtained from normotensive patients who underwent neurosurgical operation because of brain tumor. To examine a possible relation between the expression of TRP expression and hypoxic conditions caused by the intracerebral bleeding, we examined the expression of hypoxia inducible factor 1a (HIF1a). Transcripts of TRPC3, TRPC5, TRPM6, and HIF1a were significantly reduced in cerebral vascular tissue from patients after hypertensive intracerebral hemorrhage compared to controls. TRPC3 mRNA correlated well with the expression of HIF1a mRNA (r(2) = 0.59; p = 0.01). TRPC3 expression is associated with hypertension and hypoxic conditions in human cerebral vascular tissue.

  4. Cerebrovascular lesions induce transient β-amyloid deposition

    PubMed Central

    Garcia-Alloza, Monica; Gregory, Julia; Kuchibhotla, Kishore V.; Fine, Sara; Wei, Ying; Ayata, Cenk; Frosch, Matthew P.; Greenberg, Steven M.

    2011-01-01

    Previous clinical studies have documented a close relationship between cerebrovascular disease and risk of Alzheimer's disease. We examined possible mechanistic interactions through use of experimental stroke models in a transgenic mouse model of β-amyloid deposition (APPswe/PS1dE9). Following middle cerebral artery occlusion, we observed a rapid increase in amyloid plaque burden in the region surrounding the infarction. In human tissue samples, however, we were unable to detect a localized increase in amyloid burden adjacent to cerebral infarcts. To resolve this discrepancy, we generated cerebral microstrokes in amyloid precursor protein mouse models with the photosensitive dye Rose bengal, and monitored plaque formation in real time using multiphoton microscopy. We observed a striking increase in the number of new plaques and amyloid angiopathy in the area immediately surrounding the infarcted area; however, the effect was transient, potentially resolving the discord between mouse and human tissue. We did not detect changes in candidate proteins related to β-amyloid generation or degradation such as β-amyloid-converting enzyme, amyloid precursor protein, presenilin 1, neprylisin or insulin-degrading enzyme. Together, these results demonstrate that strokes can trigger accelerated amyloid deposition, most likely through interference with amyloid clearance pathways. Additionally, this study indicates that focal ischaemia provides an experimental paradigm in which to study the mechanisms of plaque seeding and growth. PMID:22120142

  5. Amyloid in the brains of aged squirrel monkeys.

    PubMed

    Walker, L C; Masters, C; Beyreuther, K; Price, D L

    1990-01-01

    In this immunocytochemical study, the brains of nine squirrel monkeys (Saimiri sciureus), ranging from 8 to 27 years of age, were examined for the presence and distribution of beta/A4 amyloid, a 4-kilodalton peptide. In aged squirrel monkeys, amyloid is associated primarily with intracerebral and meningeal capillaries and arterioles and occurs to a lesser degree as small and/or diffuse deposits in the neural parenchyma and in the dense cores of senile plaques. Cerebrovascular amyloid is found primarily in neocortex, amygdala, and septum verum and is rare or nonexistent in other subcortical gray structures, white matter, cerebellum, and spinal cord; this pattern of localization is comparable to that in humans with cerebral amyloid angiopathy. There is a significant correlation between cerebrovascular and parenchymal deposits of amyloid. However, cerebrovascular amyloid is always the most abundant form in squirrel monkeys, even in cases of severe cerebral amyloidosis. In contrast to squirrel monkeys, aged rhesus monkeys (Macaca mulatta) develop mostly parenchymal deposits of amyloid and have relatively less vascular amyloid. This species difference in the histological distribution of amyloid suggests that separate mechanisms may influence the accumulation of amyloid in cerebral blood vessels and in the neural parenchyma. These data also indicate that the squirrel monkey can serve as a model for investigations of cerebrovascular amyloidosis.

  6. Restricted diffusion in the brain of transgenic mice with cerebral amyloidosis.

    PubMed

    Mueggler, Thomas; Meyer-Luehmann, Melanie; Rausch, Martin; Staufenbiel, Matthias; Jucker, Mathias; Rudin, Markus

    2004-08-01

    A prominent hallmark of Alzheimer's disease pathology is cerebral amyloidosis. However, it is not clear how extracellular amyloid-beta peptide (A beta) deposition and amyloid formation compromise brain function and lead to dementia. It has been argued that extracellular amyloid deposition is neurotoxic and/or that soluble A beta oligomers impair synaptic function. Amyloid deposits, by contrast, may affect diffusion properties of the brain interstitium with implications for the transport of endogenous signalling molecules during synaptic and/or extrasynaptic transmission. We have used diffusion-weighted magnetic resonance imaging to study diffusion properties in brains of young (6-month-old) and aged (25-month-old) APP23 transgenic mice and control littermates. Our results demonstrate that fibrillar amyloid deposits and associated gliosis in brains of aged APP23 transgenic mice are accompanied by a reduction in the apparent diffusion coefficient. This decrease was most pronounced in neocortical areas with a high percentage of congophilic amyloid and was not significant in the caudate putamen, an area with only modest and diffuse amyloid deposition. These findings suggest that extracellular deposition of fibrillar amyloid and/or associated glial proliferation and hypertrophy cause restrictions to interstitial fluid diffusion. Reduced diffusivity within the interstitial space may alter volume transmission and therefore contribute to the cognitive impairment in Alzheimer's disease.

  7. Intra-aortic balloon pump (IABP) counterpulsation improves cerebral perfusion in patients with decreased left ventricular function.

    PubMed

    Pfluecke, C; Christoph, M; Kolschmann, S; Tarnowski, D; Forkmann, M; Jellinghaus, S; Poitz, D M; Wunderlich, C; Strasser, R H; Schoen, S; Ibrahim, K

    2014-11-01

    The current goal of treatment after acute ischemic stroke is the increase of cerebral blood flow (CBF) in ischemic brain tissue. Intra-aortic balloon pump (IABP) counterpulsation in the setting of cardiogenic shock is able to reduce left ventricular afterload and increase coronary blood flow. The effects of an IABP on CBF have not been sufficiently examined. We hypothesize that the use of an IABP especially enhances cerebral blood flow in patients with pre-existing heart failure. In this pilot study, 36 subjects were examined to investigate the effect of an IABP on middle cerebral artery (MCA) transcranial Doppler (TCD) flow velocity change and relative CBF augmentation by determining velocity time integral changes (ΔVTI) in a constant caliber of the MCA compared to a baseline measurement without an IABP. Subjects were divided into two groups according to their left ventricular ejection fraction (LVEF): Group 1 LVEF >30% and Group 2 LVEF ≤30%. Both groups showed an increase in CBF using an IABP. Patients with a LVEF ≤30% showed a significantly higher increase of ΔVTI in the MCA under IABP augmentation compared to patients with a LVEF >30% (20.9% ± 3.9% Group 2 vs.10.5% ± 2.2% Group 1, p<0,05). The mean arterial pressure (MAP) increased only marginally in both groups under IABP augmentation. IABP improves cerebral blood flow, particularly in patients with pre-existing heart failure and highly impaired LVEF. Hence, an IABP might be a treatment option to improve cerebral perfusion in selected patients with cerebral misperfusion and simultaneously existing severe heart failure. © The Author(s) 2014.

  8. Estradiol reduces activity of the blood-brain barrier Na-K-Cl cotransporter and decreases edema formation in permanent middle cerebral artery occlusion.

    PubMed

    O'Donnell, Martha E; Lam, Tina I; Tran, Lien Q; Foroutan, Shahin; Anderson, Steven E

    2006-10-01

    Estrogen has been shown to protect against stroke-induced brain damage, yet the mechanism is unknown. During the early hours of stroke, cerebral edema forms as increased transport of Na and Cl from blood into brain occurs across an intact blood-brain barrier (BBB). We showed previously that a luminal BBB Na-K-Cl cotransporter is stimulated by hypoxia and arginine vasopressin (AVP), factors present during cerebral ischemia, and that inhibition of the cotransporter by intravenous bumetanide greatly reduces edema in rats subjected to permanent middle cerebral artery occlusion (MCAO). The present study was conducted to determine whether estrogen protects in stroke at least in part by reducing activity of the BBB cotransporter, thereby decreasing edema formation. Ovariectomized rats were subjected to 210 mins of permanent MCAO after 7-day or 30-min pretreatment with 17beta-estradiol and then brain swelling and 2,3,5-triphenyltetrazolium chloride staining were assessed as measures of brain edema and lesion volume, respectively. Diffusion-weighed imaging was used to monitor permanent MCAO-induced decreases in apparent diffusion coefficient (ADC) values, an index of changes in brain water distribution and mobility. Na-K-Cl cotransporter activity of cerebral microvascular endothelial cells (CMECs) was assessed as bumetanide-sensitive K influx and cotransporter abundance by Western blot analysis after estradiol treatment. Estradiol significantly decreased brain swelling and lesion volume and attenuated the decrease in ADC values during permanent MCAO. Estradiol also abolished CMEC cotransporter stimulation by chemical hypoxia or AVP and decreased cotransporter abundance. These findings support the hypothesis that estrogen attenuates stimulation of BBB Na-K-Cl cotransporter activity, reducing edema formation during stroke.

  9. Ischemic Postconditioning Decreases Cerebral Edema and Brain Blood Barrier Disruption Caused by Relief of Carotid Stenosis in a Rat Model of Cerebral Hypoperfusion

    PubMed Central

    Yang, Fuwei; Zhang, Xiaojie; Sun, Ying; Wang, Boyu; Zhou, Chuibing; Luo, Yinan; Ge, Pengfei

    2013-01-01

    Background and Purpose Complications due to brain edema and breakdown of blood brain barrier are an important factor affecting the treatment effects of patients with severe carotid stenosis. In this study, we investigated the protective effects of ischemic postconditioning on brain edema and disruption of blood brain barrier via establishing rat model of hypoperfusion due to severe carotid stenosis. Methods Wistar rat model of hypoperfusion due to severe carotid stenosis was established by binding a stainless microtube to both carotid arteries. Ischemic postconditioning procedure consisted of three cycles of 30 seconds ischemia and 30 seconds reperfusion. Brain edema was evaluated by measuring cerebral water content, and blood brain barrier permeability was assayed by examining cerebral concentration of Evans' Blue (EB) and fluorescein sodium (NaF). ELISA was used to analyze the expression of MMP-9, claudin-5 and occludin. The activity and location of MMP-9 was analyzed by gelatin zymography and in situ zymography, respectively. The distribution of tight junction proteins claudin-5 and occludin was observed by immunohistochemistry. Results The increased brain water content and cerebral concentration of EB and NaF were suppressed by administration of ischemic postconditioning prior to relief of carotid stenosis. Zymographic studies showed that MMP-9 was mainly located in the cortex and its activity was significantly improved by relief of carotid stenosis and, but the elevated MMP-9 activity was inhibited markedly by ischemic postconditioning. Immunohistochemistry revealed that ischemic postconditioning improved the discontinuous distribution of claudin-5 and occludin. ELISA detected that the expression of up-regulated MMP-9 and down-regulated claudin-5 and occludin caused by carotid relief were all attenuated by ischemic postconditioning. Conclusions Ischemic postconditioning is an effective method to prevent brain edema and improve BBB permeability and could be

  10. RAC1 inhibition targets amyloid precursor protein processing by gamma-secretase and decreases Abeta production in vitro and in vivo.

    PubMed

    Désiré, Laurent; Bourdin, Jérôme; Loiseau, Nadia; Peillon, Hélène; Picard, Virginie; De Oliveira, Catherine; Bachelot, Florence; Leblond, Bertrand; Taverne, Thierry; Beausoleil, Eric; Lacombe, Sandrine; Drouin, Dominique; Schweighoffer, Fabien

    2005-11-11

    beta-Amyloid peptides (Abeta) that form the senile plaques of Alzheimer disease consist mainly of 40- and 42-amino acid (Abeta 40 and Abeta 42) peptides generated from the cleavage of the amyloid precursor protein (APP). Generation of Abeta involves beta-secretase and gamma-secretase activities and is regulated by membrane trafficking of the proteins involved in Abeta production. Here we describe a new small molecule, EHT 1864, which blocks the Rac1 signaling pathways. In vitro, EHT 1864 blocks Abeta 40 and Abeta 42 production but does not impact sAPPalpha levels and does not inhibit beta-secretase. Rather, EHT 1864 modulates APP processing at the level of gamma-secretase to prevent Abeta 40 and Abeta 42 generation. This effect does not result from a direct inhibition of the gamma-secretase activity and is specific for APP cleavage, since EHT 1864 does not affect Notch cleavage. In vivo, EHT 1864 significantly reduces Abeta 40 and Abeta 42 levels in guinea pig brains at a threshold that is compatible with delaying plaque accumulation and/or clearing the existing plaque in brain. EHT 1864 is the first derivative of a new chemical series that consists of candidates for inhibiting Abeta formation in the brain of AD patients. Our findings represent the first pharmacological validation of Rac1 signaling as a target for developing novel therapies for Alzheimer disease.

  11. Decreased uric acid levels correlate with poor outcomes in acute ischemic stroke patients, but not in cerebral hemorrhage patients.

    PubMed

    Wu, Hongliang; Jia, Qian; Liu, Gaifen; Liu, Liping; Pu, Yuehua; Zhao, Xingquan; Wang, Chunxue; Wang, Yilong; Wang, Yongjun

    2014-03-01

    The relationship between uric acid and stroke prognosis is ambiguous. Some studies have explored this relationship in acute stroke but have different results. In this study, we explored the relationship between uric acid levels and 1-year outcomes and vascular events of acute ischemic stroke patients and cerebral hemorrhage patients. In all, 1452 continued first, acute ischemic stroke patients and 380 continued cerebral hemorrhage patients were admitted to our hospitals. Serum uric acid concentrations were measured in 1351 ischemic stroke patients and 380 cerebral hemorrhage patients at admission. We evaluated the relationship between uric acid levels and outcomes (modified Rankin scale [mRS] > 2, all-cause death, vascular events, stroke recurrent) at 14 days, 90 days, and 1 year after stroke onset. The median uric acid concentration was 303.0 μmol/L in ischemic stroke patients and 269 μmol/L in cerebral hemorrhage patients. In univariate analysis, uric acid levels were not correlated with outcomes in cerebral hemorrhage patients. We used multiple logistic regression analysis to show that lower serum uric acid levels independently predicted poor functional outcomes (mRS >2) at 1 year after ischemic stroke onset (odds ratio [OR] = .335, 95% confidence interval [CI]: .164-.684, P = .003). Also, lower serum uric acid levels were independently correlated with vascular events in the first year in ischemic stroke patients. By multiple cox proportional hazards analysis, we obtained data which reveal that serum uric acid levels were not correlated with all-cause death (OR = .992, 95% CI: .683-1.443, P = .969) in ischemic stroke patients. Serum uric acid may be neuroprotective in acute ischemic stroke patients. Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  12. 20-Hydroxyeicosatetraenoic Acid Inhibition by HET0016 Offers Neuroprotection, Decreases Edema, and Increases Cortical Cerebral Blood Flow in a Pediatric Asphyxial Cardiac Arrest Model in Rats.

    PubMed

    Shaik, Jafar Sadik B; Poloyac, Samuel M; Kochanek, Patrick M; Alexander, Henry; Tudorascu, Dana L; Clark, Robert Sb; Manole, Mioara D

    2015-11-01

    Vasoconstrictive and vasodilatory eicosanoids generated after cardiac arrest (CA) may contribute to cerebral vasomotor disturbances and neurodegeneration. We evaluated the balance of vasodilator/vasoconstrictor eicosanoids produced by cytochrome P450 (CYP) metabolism, and determined their role on cortical perfusion, functional outcome, and neurodegeneration after pediatric asphyxial CA. Cardiac arrest of 9 and 12 minutes was induced in 16- to 18-day-old rats. At 5 and 120 minutes after CA, we quantified the concentration of CYP eicosanoids in the cortex and subcortical areas. In separate rats, we inhibited 20-hydroxyeicosatetraenoic acid (20-HETE) synthesis after CA and assessed cortical cerebral blood flow (CBF), neurologic deficit score, neurodegeneration, and edema. After 9 minutes of CA, vasodilator eicosanoids markedly increased versus sham. Conversely, after 12 minutes of CA, vasoconstrictor eicosanoid 20-HETE increased versus sham, without compensatory increases in vasodilator eicosanoids. Inhibition of 20-HETE synthesis after 12 minutes of CA decreased cortical 20-HETE levels, increased CBF, reduced neurologic deficits at 3 hours, and reduced neurodegeneration and edema at 48 hours versus vehicle-treated rats. In conclusion, cerebral vasoconstrictor eicosanoids increased after a pediatric CA of 12 minutes. Inhibition of 20-HETE synthesis improved cortical perfusion and short-term neurologic outcome. These results suggest that alterations in CYP eicosanoids have a role in cerebral hypoperfusion and neurodegeneration after CA and may represent important therapeutic targets.

  13. The leptomeningeal "ivy sign" on fluid-attenuated inversion recovery MR imaging in Moyamoya disease: a sign of decreased cerebral vascular reserve?

    PubMed

    Mori, N; Mugikura, S; Higano, S; Kaneta, T; Fujimura, M; Umetsu, A; Murata, T; Takahashi, S

    2009-05-01

    Moyamoya disease is an idiopathic occlusive cerebrovascular disorder with abnormal microvascular proliferation. We investigated the clinical utility of leptomeningeal high signal intensity (ivy sign) sometimes seen on fluid-attenuated inversion recovery images in Moyamoya disease. We examined the relationship between the degree of the ivy sign and the severity of the ischemic symptoms in 96 hemispheres of 48 patients with Moyamoya disease. We classified each cerebral hemisphere into 4 regions from anterior to posterior. In 192 regions of 24 patients, we examined the relationship between the degree of the ivy sign and findings of single-photon emission CT, including the resting cerebral blood flow (CBF) and cerebral vascular reserve (CVR). The degree of the ivy sign showed a significant positive relationship with the severity of the ischemic symptoms (P < .001). Of the 4 regions, the ivy sign was most frequently and prominently seen in the anterior part of the middle cerebral artery region. The degree of the ivy sign showed a negative relationship with the resting CBF (P < .0034) and a more prominent negative relationship with the CVR (P < .001). The leptomeningeal ivy sign indicates decreased CVR in Moyamoya disease.

  14. Use of a Short-Acting β1 Blocker During Endotoxemia May Reduce Cerebral Tissue Oxygenation if Hemodynamics are Depressed by a Decrease in Heart Rate.

    PubMed

    Kurita, Tadayoshi; Kawashima, Shingo; Morita, Koji; Nakajima, Yoshiki

    2017-06-01

    A decrease in heart rate (HR) using a short-acting β blocker has potential benefits in sepsis; however, depression of hemodynamics and reduction of cerebral oxygenation may also occur in endotoxemia. Seventeen swine were allocated to landiolol or control groups. In the landiolol group, the dose was sequentially changed from 0 to 40 to 200 μg kg min, and stopped. Hemodynamics, blood variables, and the cerebral tissue oxygenation index (TOI) were recorded by near infrared spectroscopy at each dose. Lipopolysaccharide (LPS) was then administered continuously at 1 μg kg h after a 100 μg bolus administration. After 30 and 150 min, as two severity stages of endotoxemia (endotoxemia 1 and 2), landiolol was administered as above and measurements were made. In the control group, landiolol was not administered, but measurements were made. LPS increased HR and landiolol decreased HR, with similar effects in each endotoxemia stage. In endotoxemia 1, LPS decreased stroke volume (SV), but landiolol restored SV to a value similar to that before endotoxemia, and did not decrease cardiac output (CO), even at 200 μg kg min. In contrast, landiolol did not restore SV in endotoxemia 2, resulting in a decrease in CO and mean arterial pressure, accompanied with a dose-dependent decrease in TOI. A short-acting β blocker has various hemodynamic effects in endotoxemia. Use of a short-acting β blocker during endotoxemia may reduce cerebral tissue oxygenation if hemodynamics are depressed by a decrease in HR.

  15. Use of a Short-Acting β1 Blocker During Endotoxemia May Reduce Cerebral Tissue Oxygenation if Haemodynamics are Depressed by a Decrease in Heart Rate.

    PubMed

    Kurita, Tadayoshi; Kawashima, Shingo; Morita, Koji; Nakajima, Yoshiki

    2016-11-15

    A decrease in heart rate (HR) using a short-acting β blocker has potential benefits in sepsis; however, depression of haemodynamics and reduction of cerebral oxygenation may also occur in endotoxemia. Seventeen swine were allocated to landiolol or control groups. In the landiolol group, the dose was sequentially changed from 0 to 40 to 200 μg kg min, and stopped. Haemodynamics, blood variables and the cerebral tissue oxygenation index (TOI) were recorded by near infrared spectroscopy at each dose. Lipopolysaccharide (LPS) was then administered continuously at 1 μg kg h after a 100 μg bolus administration. After 30 and 150 min, as two severity stages of endotoxemia (endotoxemia 1 and 2), landiolol was administered as above and measurements were made. In the control group, landiolol was not administered, but measurements were made. LPS increased HR and landiolol decreased HR, with similar effects in each endotoxemia stage. In endotoxemia 1, LPS decreased stroke volume (SV), but landiolol restored SV to a value similar to that before endotoxemia, and did not decrease cardiac output (CO), even at 200 μg kg min. In contrast, landiolol did not restore SV in endotoxemia 2, resulting in a decrease in CO and mean arterial pressure (MAP), accompanied with a dose-dependent decrease in TOI. A short-acting β blocker has various haemodynamic effects in endotoxemia. Use of a short-acting β blocker during endotoxemia may reduce cerebral tissue oxygenation if haemodynamics are depressed by a decrease in HR.

  16. Elevated intrathoracic CO2 pressure during thoracoscopic surgery decreases regional cerebral oxygen saturation in neonates and infants-A pilot study.

    PubMed

    Neunhoeffer, Felix; Warmann, Steven W; Hofbeck, Michael; Müller, Alisa; Fideler, Frank; Seitz, Guido; Schuhmann, Martin U; Kirschner, Hans-Joachim; Kumpf, Matthias; Fuchs, Jörg

    2017-07-01

    Intraoperative hypercapnia and acidosis are risk factors during thoracoscopy in neonates and infants. In a prospective pilot study, we evaluated the effects of thoracoscopy in neonates and infants on cerebral microcirculation, oxygen saturation, and oxygen consumption. Regional cerebral oxygen saturation and blood flow were measured noninvasively using a new device combining laser Doppler flowmetry and white light spectrometry. Additionally, cerebral fractional tissue oxygen extraction and approximated oxygen consumption were calculated. Fifteen neonates and infants undergoing thoracoscopy were studied using the above-mentioned method. The chest was insufflated with carbon dioxide with a pressure of 2-6 mm Hg. Single lung ventilation was not used. As control group served 15 neonates and infants undergoing abdominal surgery. Data are presented as median and range. The 95% confidence intervals for differences of means (95% CI) are given for the mean difference from baseline values. We observed a correlation between intrathoracic pressure exceeding 4 mm Hg and transient decrease in regional cerebral oxygen saturation of 12.7% (95% CI: 9.7-17.2, P<.001). Peripheral oxygen saturation was normal at the same time. Intraoperative increase in arterial paCO2 (median maximum value: 48.8 mm Hg, range: [36.5-65.4]; 95% CI: -16.0 to -3.0, P=.002) and decrease in arterial pH (median minimum value: 7.3, range: [7.2-7.4]; 95% CI: 0.04-0.12, P=.008) were observed during thoracoscopy with both parameters recovering at the end of the procedure. Periods of regional cerebral oxygen saturation below 20% from baseline were significantly more frequent during thoracoscopy as compared to the control group (median maximum value: 1.3%min/h, range: [0.0-66.2] vs median maximum value: 0.0%min/h, range: [0.0-4.0]; 95% CI: -16.6 to -1.1, P=.028). We suggest that thoracoscopic surgery in neonates and infants, although generally safe, may be associated with a decrease in regional cerebral oxygen

  17. Hacking the code of amyloid formation: the amyloid stretch hypothesis.

    PubMed

    Pastor, M Teresa; Esteras-Chopo, Alexandra; Serrano, Luis

    2007-01-01

    Many research efforts in the last years have been directed towards understanding the factors determining protein misfolding and amyloid formation. Protein stability and amino acid composition have been identified as the two major factors in vitro. The research of our group has been focused on understanding the relationship between amino acid sequence and amyloid formation. Our approach has been the design of simple model systems that reproduce the biophysical properties of natural amyloids. An amyloid sequence pattern was extracted that can be used to detect amyloidogenic hexapeptide stretches in proteins. We have added evidence supporting that these amyloidogenic stretches can trigger amyloid formation by nonamyloidogenic proteins. Some experimental results in other amyloid proteins will be analyzed under the conclusions obtained in these studies. Our conclusions together with evidences from other groups suggest that amyloid formation is the result of the interplay between a decrease of protein stability, and the presence of highly amyloidogenic regions in proteins. As many of these results have been obtained in vitro, the challenge for the next years will be to demonstrate their validity in in vivo systems.

  18. Decreased damage from transient focal cerebral ischemia by transfusion of zero-link hemoglobin polymers in mouse

    PubMed Central

    Mito, Toshiaki; Nemoto, Masaaki; Kwansa, Herman; Sampei, Kenji; Habeeb, Murtuza; Murphy, Stephanie J.; Bucci, Enrico; Koehler, Raymond C.

    2008-01-01

    Background and Purpose Transfusion of large polymers of hemoglobin avoids the peripheral extravasation and hypertension associated with crosslinked tetrameric hemoglobin transfusion and may be more effective in rescuing brain from focal ischemia. Effects of transfusion of high-oxygen affinity, bovine hemoglobin polymers of different weight ranges were determined. Methods Hypervolemic exchange transfusion was performed during two hours of middle cerebral artery occlusion in mice. Results Compared to transfusion with a 5% albumin solution or no transfusion, infarct volume was reduced 40% by transfusion of a 6% solution containing hemoglobin polymers in the nominal range 500–14000 kDa. Infarct volume was not significantly reduced by transfusion of a lower concentration of 2–3% of this size range of polymers, 6% hemoglobin solutions without removal of polymers <500 kDa or >14000 kDa, or crosslinked hemoglobin tetramers with normal oxygen affinity. Exchange transfusion with the 6% solution of the 500–14000 kDa hemoglobin polymers did not improve the distribution of cerebral blood flow during focal ischemia and, in mice without ischemia, did not affect flow to brain or other major organs. Conclusion An intermediate size range of polymerized bovine hemoglobin possessing high oxygen affinity appears optimal for rescuing mouse brain from transient focal cerebral ischemia. A minimum concentration of a 6% solution is required, the rescue is superior to that obtained with crosslinked tetrameric hemoglobin possessing normal oxygen affinity, and tissue salvage is not associated with increased blood flow. This polymer solution avoids the adverse effects of severe renal and splanchnic vasoconstriction seen with crosslinked tetrameric hemoglobin. PMID:18988905

  19. Cold-water immersion decreases cerebral oxygenation but improves recovery after intermittent-sprint exercise in the heat.

    PubMed

    Minett, G M; Duffield, R; Billaut, F; Cannon, J; Portus, M R; Marino, F E

    2014-08-01

    This study examined the effects of post-exercise cooling on recovery of neuromuscular, physiological, and cerebral hemodynamic responses after intermittent-sprint exercise in the heat. Nine participants underwent three post-exercise recovery trials, including a control (CONT), mixed-method cooling (MIX), and cold-water immersion (10 °C; CWI). Voluntary force and activation were assessed simultaneously with cerebral oxygenation (near-infrared spectroscopy) pre- and post-exercise, post-intervention, and 1-h and 24-h post-exercise. Measures of heart rate, core temperature, skin temperature, muscle damage, and inflammation were also collected. Both cooling interventions reduced heart rate, core, and skin temperature post-intervention (P < 0.05). CWI hastened the recovery of voluntary force by 12.7 ± 11.7% (mean ± SD) and 16.3 ± 10.5% 1-h post-exercise compared to MIX and CONT, respectively (P < 0.01). Voluntary force remained elevated by 16.1 ± 20.5% 24-h post-exercise after CWI compared to CONT (P < 0.05). Central activation was increased post-intervention and 1-h post-exercise with CWI compared to CONT (P < 0.05), without differences between conditions 24-h post-exercise (P > 0.05). CWI reduced cerebral oxygenation compared to MIX and CONT post-intervention (P < 0.01). Furthermore, cooling interventions reduced cortisol 1-h post-exercise (P < 0.01), although only CWI blunted creatine kinase 24-h post-exercise compared to CONT (P < 0.05). Accordingly, improvements in neuromuscular recovery after post-exercise cooling appear to be disassociated with cerebral oxygenation, rather reflecting reductions in thermoregulatory demands to sustain force production. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. The Common Inhalational Anesthetic Sevoflurane Induces Apoptosis and Increases β-Amyloid Protein Levels

    PubMed Central

    Dong, Yuanlin; Zhang, Guohua; Zhang, Bin; Moir, Robert D.; Xia, Weiming; Marcantonio, Edward R.; Culley, Deborah J.; Crosby, Gregory; Tanzi, Rudolph E.; Xie, Zhongcong

    2009-01-01

    Objective: To assess the effects of sevoflurane, the most commonly used inhalation anesthetic, on apoptosis and β-amyloid protein (Aβ) levels in vitro and in vivo. Subjects: Naive mice, H4 human neuroglioma cells, and H4 human neuroglioma cells stably transfected to express full-length amyloid precursor protein. Interventions: Human H4 neuroglioma cells stably transfected to express full-length amyloid precursor protein were exposed to 4.1% sevoflurane for 6 hours. Mice received 2.5% sevoflurane for 2 hours. Caspase-3 activation, apoptosis, and Aβ levels were assessed. Results: Sevoflurane induced apoptosis and elevated levels of β-site amyloid precursor protein-cleaving enzyme and Aβ in vitro and in vivo. The caspase inhibitor Z-VAD decreased the effects of sevoflurane on apoptosis and Aβ. Sevoflurane-induced caspase-3 activation was attenuated by the γ-secretase inhibitor L-685,458 and was potentiated by Aβ. These results suggest that sevoflurane induces caspase activation which, in turn, enhances β-site amyloid precursor protein–cleaving enzyme and Aβ levels. Increased Aβ levels then induce further rounds of apoptosis. Conclusions: These results suggest that inhalational anesthetic sevoflurane may promote Alzheimer disease neuropathogenesis. If confirmed in human subjects, it may be prudent to caution against the use of sevoflurane as an anesthetic, especially in those suspected of possessing excessive levels of cerebral Aβ. PMID:19433662

  1. Fast and slow components of cerebral blood flow response to step decreases in end-tidal PCO2 in humans.

    PubMed

    Poulin, M J; Liang, P J; Robbins, P A

    1998-08-01

    This study examined the dynamics of the middle cerebral artery (MCA) blood flow response to hypocapnia in humans (n = 6) by using transcranial Doppler ultrasound. In a control protocol, end-tidal PCO2 (PETCO2) was held near eucapnia (1.5 Torr above resting) for 40 min. In a hypocapnic protocol, PETCO2 was held near eucapnia for 10 min, then at 15 Torr below eucapnia for 20 min, and then near eucapnia for 10 min. During both protocols, subjects hyperventilated throughout and PETCO2 and end-tidal PO2 were controlled by using the dynamic end-tidal forcing technique. Beat-by-beat values were calculated for the intensity-weighted mean velocity (VIWM), signal power (P), and their instantaneous product (P.VIWM). A simple model consisting of a delay, gain terms, time constants (tauf,on, tauf, off) and baseline levels of flow for the on- and off-transients, and a gain term (gs) and time constant (taus) for a second slower component was fitted to the hypocapnic protocol. The cerebral blood flow response to hypocapnia was characterized by a significant (P < 0.001) slow progressive adaptation in P.VIWM, with gs = 1.26 %/Torr and taus = 427 s, that persisted throughout the hypocapnic period. Finally, the responses at the onset and relief of hypocapnia were asymmetric (P < 0.001), with tauf,on (6.8 s) faster than tauf,off (14.3 s).

  2. Decrease in cerebral metabolic rate of glucose after high-dose methotrexate in childhood acute lymphocytic leukemia

    SciTech Connect

    Komatsu, K.; Takada, G.; Uemura, K.; Shishido, F.; Kanno, I. )

    1990-09-01

    We measured changes in the regional cerebral metabolic rate of glucose (rCMRGlu) using {sup 18}F-fluorodeoxyglucose and positron emission tomography for the assessment of neurotoxicity in childhood acute lymphocytic leukemia treated with high-dose methotrexate (HD-MTX) therapy. We studied 8 children with acute lymphocytic leukemia (mean age: 9.6 years) treated with HD-MTX (200 mg/kg or 2,000 mg/M2) therapy. CMRGlu after HD-MTX therapy was most reduced (40%) in the patient who had central nervous system leukemia and was treated with the largest total doses of both intrathecal MTX (IT-MTX) and HD-MTX. CMRGlu in the whole brain after HD-MTX therapy was reduced by an average of 21% (P less than 0.05). The reductions of CMRGlu in 8 patients were correlated with total doses of both IT-MTX (r = 0.717; P less than 0.05) and systemic HD-MTX (r = 0.784; P less than 0.05). CMRGlu of the cerebral cortex, especially the frontal and occipital cortex, was reduced more noticeably than that of the basal ganglia and white matter. We suggest that the measurement of changes in rCMRGlu after HD-MTX therapy is useful for detecting accumulated MTX neurotoxicity.

  3. Amyloid-β(25-35), an amyloid-β(1-42) surrogate, and proinflammatory cytokines stimulate VEGF-A secretion by cultured, early passage, normoxic adult human cerebral astrocytes.

    PubMed

    Chiarini, Anna; Whitfield, James; Bonafini, Clara; Chakravarthy, Balu; Armato, Ubaldo; Dal Prà, Ilaria

    2010-01-01

    Cerebrovascular angiopathy affects late-onset Alzheimer's disease (LOAD) brains by possibly increasing vascular endothelial growth factor (VEGF). A expression, thereby stimulating endothelial cell proliferation and migration. Indeed, VEGF-A gene upregulation, with increased VEGF-A protein content of reactive astrocytes and microglia, occurs in LOAD brains, and neovascularization was observed one week after injecting amyloid-β (Aβ)(1-42) into rat hippocampus. We have now found, with cultured 'normoxic' normal adult human astrocytes (NAHAs), that fibrillar Aβ(25-35) (an active Aβ(1-42) fragment) or a cytokine mixture (the (CM)-trio (interleukin [IL]-1β+interferon [IFN]-γ+tumor necrosis factor [TNF]-α), or pair (IFN-γ+TNF-α) like those produced in LOAD brains) stimulates the nuclear translocation of stabilized hypoxia-inducible factor (HIF)-1α protein and its binding to VEGF-A hypoxia-response elements; the mRNA synthesis for three VEGF-A splice variants (121, 165, 189); and the secretion of VEGF-A165. The CM-trio was the most powerful stimulus, IFN-γ+TNF-α was less potent, and other cytokine pairs or single cytokines or Aβ(35-25) were ineffective. While Aβ(25-35) did not change HIF-1β protein levels, the CM-trio increased both HIF-1α and HIF-1β protein levels, thereby giving an earlier and stronger stimulus to VEGF-A secretion by NAHAs. Thus, increased VEGF-A secretion from astrocytes stimulated by Aβ(1-42) and by microglia-released cytokines might restore angiogenesis and Aβ(1-42) vascular clearance.

  4. Age-Dependent Decrease and Alternative Splicing of Methionine Synthase mRNA in Human Cerebral Cortex and an Accelerated Decrease in Autism

    PubMed Central

    Muratore, Christina R.; Hodgson, Nathaniel W.; Trivedi, Malav S.; Abdolmaleky, Hamid M.; Persico, Antonio M.; Lintas, Carla; De La Monte, Suzanne; Deth, Richard C.

    2013-01-01

    The folate and vitamin B12-dependent enzyme methionine synthase (MS) is highly sensitive to cellular oxidative status, and lower MS activity increases production of the antioxidant glutathione, while simultaneously decreasing more than 200 methylation reactions, broadly affecting metabolic activity. MS mRNA levels in postmortem human cortex from subjects across the lifespan were measured and a dramatic progressive biphasic decrease of more than 400-fold from 28 weeks of gestation to 84 years was observed. Further analysis revealed alternative splicing of MS mRNA, including deletion of folate-binding domain exons and age-dependent deletion of exons from the cap domain, which protects vitamin B12 (cobalamin) from oxidation. Although three species of MS were evident at the protein level, corresponding to full-length and alternatively spliced mRNA transcripts, decreasing mRNA levels across the lifespan were not associated with significant changes in MS protein or methionine levels. MS mRNA levels were significantly lower in autistic subjects, especially at younger ages, and this decrease was replicated in cultured human neuronal cells by treatment with TNF-α, whose CSF levels are elevated in autism. These novel findings suggest that rather than serving as a housekeeping enzyme, MS has a broad and dynamic role in coordinating metabolism in the brain during development and aging. Factors adversely affecting MS activity, such as oxidative stress, can be a source of risk for neurological disorders across the lifespan via their impact on methylation reactions, including epigenetic regulation of gene expression. PMID:23437274

  5. Interleukin-1 receptor antagonist decreases the number of necrotic neurons in rats with middle cerebral artery occlusion.

    PubMed Central

    Garcia, J. H.; Liu, K. F.; Relton, J. K.

    1995-01-01

    Marked increases in the brain expression of interleukin (IL)-1 have been reported in rats after permanent occlusion of a large cerebral artery. Interactions between endothelial cells and leukocytes have been implicated in the pathogenesis of several types of ischemic injury to the myocardium and other organs. In this study we asked whether inhibiting the effects of IL-1 would affect the outcome of an experimental brain infarct. Adult male Wistar rats (n = 13) with permanent occlusion of the middle cerebral artery were given IL-1 receptor antagonist. A second group (n = 13) with the same type of brain injury was given a placebo. A third group, subjected to a sham operation, was given either IL-1 receptor antagonist (n = 2) or a placebo (n = 2). Experiments were terminated after either 24 hours or 7 days. Compared with the control group, animals treated with IL-1 receptor antagonist improved their neurological score (P < 0.05), experienced less pronounced changes in body weight (P < 0.05), and had fewer necrotic neurons (P < 0.001) and fewer leukocytes in the ischemic hemisphere (P < 0.001) as well as a smaller area of pallor (P < 0.05) in the ischemis hemisphere. The results suggest that inhibiting the proinflammatory effects of IL-1 with a receptor antagonist is an effective way of influencing the leukocyte responses elicited by an arterial occlusion. Such leukocyte inhibition seemingly attenuates the number of necrotic neurons resulting from the occlusion of a large brain artery. Images Figure 4 Figure 6 Figure 8 PMID:7485410

  6. [Amyloid goiter].

    PubMed

    Hrívó, A; Péter, I; Bánkúti, B; Péley, G; Baska, F; Besznyák, I

    1999-03-21

    Amyloid goitre is at an extremely rare occurrence. Authors review the origin of disease and its symptoms, diagnostic and therapeutic tools. The disease may be due to either primary or secondary systemic or local amyloidosis. Diagnosis may be made even before surgery on anamnestic data, on very rapid growth of thyroid glands, on diffuse appearance, on other symptoms of systemic amyloidosis, on findings of iconographic procedures and on detection of amyloid in aspirates. Final diagnosis is based on histology. Surgical therapy is aiming at avoidance of the existing and the threatening consequences of expanding mass. The outcome is independent from thyroid surgery, it is related to other manifestations of amyloidosis. Concerning with the present case the chronic superior vena cava syndrome and chylous pleural effusion as first described symptoms and asymptomatic hyperthyroxinaemia is emphasised. Neither other organ involvement, nor primary amyloidogenous molecula was found during the 18 months follow up, so patient has secondary and localised amyloidosis.

  7. Characterization of new polyclonal antibodies specific for 40 and 42 amino acid-long amyloid beta peptides: their use to examine the cell biology of presenilins and the immunohistochemistry of sporadic Alzheimer's disease and cerebral amyloid angiopathy cases.

    PubMed Central

    Barelli, H.; Lebeau, A.; Vizzavona, J.; Delaere, P.; Chevallier, N.; Drouot, C.; Marambaud, P.; Ancolio, K.; Buxbaum, J. D.; Khorkova, O.; Heroux, J.; Sahasrabudhe, S.; Martinez, J.; Warter, J. M.; Mohr, M.; Checler, F.

    1997-01-01

    BACKGROUND: In Alzheimer's disease (AD), the main histological lesion is a proteinaceous deposit, the senile plaque, which is mainly composed of a peptide called A beta. The aggregation process is thought to occur through enhanced concentration of A beta 40 or increased production of the more readily aggregating 42 amino acid-long A beta 42 species. MATERIALS AND METHODS: Specificity of the antibodies was assessed by dot blot, Western blot, ELISA, and immunoprecipitation procedures on synthetic and endogenous A beta produced by secreted HK293 cells. A beta and p3 production by wild-type and mutated presenilin 1-expressing cells transiently transfected with beta APP751 was monitored after metabolic labeling and immunoprecipitation procedures. Immunohistochemical analysis was performed on brains of sporadic and typical cerebrovascular amyloid angiopathy (CAA) cases. RESULTS: Dot and Western blot analyses indicate that IgG-purified fractions of antisera recognize native and denaturated A beta s. FCA3340 and FCA 3542 display full specificity for A beta 40 and A beta 42, respectively. Antibodies immunoprecipitate their respective synthetic A beta species but also A beta s and their related p3 counterparts endogenously secreted by transfected human kidney 293 cells. This allowed us to show that mutations on presenilin 1 triggered similar increased ratios of A beta 42 and its p 342 counterpart over total A beta and p3. ELISA assays allow detection of about 25-50 pg/ml of A beta s and remain linear up to 750 to 1500 pg/ml without any cross-reactivity. FCA18 and FCA3542 label diffuse and mature plaques of a sporadic AD case whereas FCA3340 only reveals the mature lesions and particularly labels their central dense core. In a CAA case, FCA18 and FCA3340 reveal leptomeningeal and cortical arterioles whereas FCA3542 only faintly labels such structures. CONCLUSIONS: Polyclonal antibodies exclusively recognizing A beta 40 (FCA 3340) or A beta 42 (FCA3542) were obtained. These

  8. Behavioral differences in an elevated plus-maze: correlation between anxiety and decreased number of GABA and benzodiazepine receptors in mouse cerebral cortex.

    PubMed

    Rägo, L; Kiivet, R A; Harro, J; Pŏld, M

    1988-06-01

    In an elevated plus-maze model of anxiety mice treated with the benzodiazepine inverse agonist DMCM (0.5-1.5 mg/kg i.p.) spent significantly less time on the open arms and showed the decreased number of open arm entries. The opposite i.e. increased time spent on the open arms and the higher number of open arm entries was registered after diazepam (1.5 mg/kg). The results are consistent with the results obtained in the other animal tests and support the idea that this procedure is suitable for detecting anxiolytic/anxiogenic effects of benzodiazepine receptor ligands. After testing of 84 mice in an elevated plus-maze substantial differences were detected between the individuals. According to the behavioral response two subgroups of animals with DMCM or diazepam like exploratory activity (as compared to the whole group data) termed as "anxious" or "non-anxious", respectively, were chosen for further binding studies. "Anxious" animals had significantly lower numbers of 3H-flunitrazepam and 3H-muscimol binding sites as compared to "non-anxious" animals in cerebral cortex but not in cerebellum. No differences in the affinity were found between the two groups studied. The results indicate that behavioral anxiety in mice is in correlation with the decreased number of GABA and benzodiazepine receptors in cerebral cortex.

  9. Horseback riding therapy in addition to conventional rehabilitation program decreases spasticity in children with cerebral palsy: A small sample study.

    PubMed

    Alemdaroğlu, Ebru; Yanıkoğlu, İnci; Öken, Öznur; Uçan, Halil; Ersöz, Murat; Köseoğlu, Belma Füsun; Kapıcıoğlu, Mehmet İsmail Safa

    2016-05-01

    To evaluate the short-term effects of horseback riding therapy in addition to a conventional rehabilitation program in children with cerebral palsy. Nine children receiving horseback riding therapy in addition to conventional rehabilitation (Group 1) and seven children receiving conventional rehabilitation alone (Group 2) were assessed at baseline and 5 weeks later. Assessed were: modified functional reach test (MFRT), hip abduction angle, the Ashworth Scale for hip adductor muscle spasticity, knee distance test, and the Gross Motor Function Classification System (GMFCS). The percentage change in hip adductor spasticity on the Ashworth Scale was 22% in Group 1 and 0% in Group 2 (significant difference; p = 0.016). Comparison of changes on the MFRT, GMFCS, knee distance test and hip abduction angle showed that the differences between Groups 1 and 2 were not significant. In these children, horseback riding therapy in addition to conventional rehabilitation resulted in significant improvement in adductor spasticity on short-term follow-up. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. Quantitative 3D In Silico Modeling (q3DISM) of Cerebral Amyloid-beta Phagocytosis in Rodent Models of Alzheimer's Disease.

    PubMed

    Guillot-Sestier, Marie-Victoire; Weitz, Tara M; Town, Terrence

    2016-12-26

    Neuroinflammation is now recognized as a major etiological factor in neurodegenerative disease. Mononuclear phagocytes are innate immune cells responsible for phagocytosis and clearance of debris and detritus. These cells include CNS-resident macrophages known as microglia, and mononuclear phagocytes infiltrating from the periphery. Light microscopy has generally been used to visualize phagocytosis in rodent or human brain specimens. However, qualitative methods have not provided definitive evidence of in vivo phagocytosis. Here, we describe quantitative 3D in silico modeling (q3DISM), a robust method allowing for true 3D quantitation of amyloid-β (Aβ) phagocytosis by mononuclear phagocytes in rodent Alzheimer's Disease (AD) models. The method involves fluorescently visualizing Aβ encapsulated within phagolysosomes in rodent brain sections. Large z-dimensional confocal datasets are then 3D reconstructed for quantitation of Aβ spatially colocalized within the phagolysosome. We demonstrate the successful application of q3DISM to mouse and rat brains, but this methodology can be extended to virtually any phagocytic event in any tissue.

  11. ApoER2 expression increases Aβ production while decreasing Amyloid Precursor Protein (APP) endocytosis: Possible role in the partitioning of APP into lipid rafts and in the regulation of γ-secretase activity

    PubMed Central

    Fuentealba, Rodrigo A; Barría, Maria Ines; Lee, Jiyeon; Cam, Judy; Araya, Claudia; Escudero, Claudia A; Inestrosa, Nibaldo C; Bronfman, Francisca C; Bu, Guojun; Marzolo, Maria-Paz

    2007-01-01

    Background The generation of the amyloid-β peptide (Aβ) through the proteolytic processing of the amyloid precursor protein (APP) is a central event in the pathogenesis of Alzheimer's disease (AD). Recent studies highlight APP endocytosis and localization to lipid rafts as important events favoring amyloidogenic processing. However, the precise mechanisms underlying these events are poorly understood. ApoER2 is a member of the low density lipoprotein receptor (LDL-R) family exhibiting slow endocytosis rate and a significant association with lipid rafts. Despite the important neurophysiological roles described for ApoER2, little is known regarding how ApoER2 regulates APP trafficking and processing. Results Here, we demonstrate that ApoER2 physically interacts and co-localizes with APP. Remarkably, we found that ApoER2 increases cell surface APP levels and APP association with lipid rafts. The increase of cell surface APP requires the presence of ApoER2 cytoplasmic domain and is a result of decreased APP internalization rate. Unexpectedly, ApoER2 expression correlated with a significant increase in Aβ production and reduced levels of APP-CTFs. The increased Aβ production was dependent on the integrity of the NPxY endocytosis motif of ApoER2. We also found that expression of ApoER2 increased APP association with lipid rafts and increased γ-secretase activity, both of which might contribute to increased Aβ production. Conclusion These findings show that ApoER2 negatively affects APP internalization. However, ApoER2 expression stimulates Aβ production by shifting the proportion of APP from the non-rafts to the raft membrane domains, thereby promoting β-secretase and γ-secretase mediated amyloidogenic processing and also by incrementing the activity of γ-secretase. PMID:17620134

  12. ApoER2 expression increases Abeta production while decreasing Amyloid Precursor Protein (APP) endocytosis: Possible role in the partitioning of APP into lipid rafts and in the regulation of gamma-secretase activity.

    PubMed

    Fuentealba, Rodrigo A; Barría, Maria Ines; Lee, Jiyeon; Cam, Judy; Araya, Claudia; Escudero, Claudia A; Inestrosa, Nibaldo C; Bronfman, Francisca C; Bu, Guojun; Marzolo, Maria-Paz

    2007-07-09

    The generation of the amyloid-beta peptide (Abeta) through the proteolytic processing of the amyloid precursor protein (APP) is a central event in the pathogenesis of Alzheimer's disease (AD). Recent studies highlight APP endocytosis and localization to lipid rafts as important events favoring amyloidogenic processing. However, the precise mechanisms underlying these events are poorly understood. ApoER2 is a member of the low density lipoprotein receptor (LDL-R) family exhibiting slow endocytosis rate and a significant association with lipid rafts. Despite the important neurophysiological roles described for ApoER2, little is known regarding how ApoER2 regulates APP trafficking and processing. Here, we demonstrate that ApoER2 physically interacts and co-localizes with APP. Remarkably, we found that ApoER2 increases cell surface APP levels and APP association with lipid rafts. The increase of cell surface APP requires the presence of ApoER2 cytoplasmic domain and is a result of decreased APP internalization rate. Unexpectedly, ApoER2 expression correlated with a significant increase in Abeta production and reduced levels of APP-CTFs. The increased Abeta production was dependent on the integrity of the NPxY endocytosis motif of ApoER2. We also found that expression of ApoER2 increased APP association with lipid rafts and increased gamma-secretase activity, both of which might contribute to increased Abeta production. These findings show that ApoER2 negatively affects APP internalization. However, ApoER2 expression stimulates Abeta production by shifting the proportion of APP from the non-rafts to the raft membrane domains, thereby promoting beta-secretase and gamma-secretase mediated amyloidogenic processing and also by incrementing the activity of gamma-secretase.

  13. Viral-induced inflammation is accompanied by beta-amyloid plaque reduction in brains of amyloid precursor protein transgenic Tg2576 mice.

    PubMed

    Stahl, Tobias; Reimers, Christine; Johne, Reimar; Schliebs, Reinhard; Seeger, Johannes

    2006-10-01

    Amyloid plaques, one of the neuropathological hallmarks of Alzheimer's disease, and their main constituent, the amyloid beta-peptide (Abeta), are triggers of the activation of innate inflammatory mechanisms involving the activation of microglia. To dissect the effects of a non-Abeta-specific microglial activation on the Abeta metabolism, we employed a viral infection-based model. Transgenic mice expressing a mutated form of the human amyloid precursor protein (Tg2576) were used. In preceding experiments, 2-week-old transgenic mice and non-transgenic littermates were infected intracerebrally with the neurotropic Borna disease virus and investigated at 2, 4 and 14 weeks post-infection. The Borna disease virus-inoculated mice showed a persisting, subclinical infection of cortical and limbic brain areas characterized by slight T-cell infiltrates, expression of cytokines and a massive microglial activation in the hippocampus and neocortex. Viral-induced effects reached their peak at 4 weeks post-infection. In 14-month-old Tg2576 mice, characterized by the deposition of diffuse and dense-core amyloid plaques in cortical brain regions, Borna disease virus-induced microglial activation in the vicinity of Abeta deposits was used to investigate the influence of a local inflammatory response on these deposits. At 4 weeks post-infection, histometric analyses employing Abeta immunohistochemistry revealed a decrease of the cortical and hippocampal Abeta-immunopositive area. This overall decrease was accompanied by a decrease of parenchymal thioflavin-S-positive amyloid deposits and an increase of such deposits in the walls of cerebral vessels, which indicates that the elicitation of a non-Abeta-specific microglial activation may contribute to a reduction of Abeta in the brain parenchyma.

  14. Purinergic 2Y1 receptor stimulation decreases cerebral edema and reactive gliosis in a traumatic brain injury model.

    PubMed

    Talley Watts, Lora; Sprague, Shane; Zheng, Wei; Garling, R Justin; Jimenez, David; Digicaylioglu, Murat; Lechleiter, James

    2013-01-01

    Traumatic brain injury (TBI) is the leading cause of death and disability in children and young adults. Neuroprotective agents that may promote repair or counteract damage after injury do not currently exist. We recently reported that stimulation of the purinergic receptor subtype P2Y(1)R using 2-methylthioladenosine 5' diphosphate (2MeSADP) significantly reduced cytotoxic edema induced by photothrombosis. Here, we tested whether P2Y(1)R stimulation was neuroprotective after TBI. A controlled closed head injury model was established for mice using a pneumatic impact device. Brains were harvested at 1, 3, or 7 days post-injury and assayed for morphological changes by immunocytochemistry, Western blot analysis, and wet/dry weight. Cerebral edema and expression of both aquaporin type 4 and glial fibrillary acidic protein were increased at all time points examined. Immunocytochemical measurements in both cortical and hippocampal slices also revealed significant neuronal swelling and reactive gliosis. Treatment of mice with 2MeSADP (100 μM) or MRS2365 (100 μM) 30 min after trauma significantly reduced all post-injury symptoms of TBI including edema, neuronal swelling, reactive gliosis, and AQ4 expression. The neuroprotective effect was lost in IP(3)R2-/- mice treated with 2MeSADP. Immunocytochemical labeling of brain slices confirmed that P2Y(1)R expression was defined to cortical and hippocampal astrocytes, but not neurons. Taken together, the data show that stimulation of astrocytic P2Y(1)Rs significantly reduces brain injury after acute trauma and is mediated by the IP(3)-signaling pathway. We suggest that enhancing astrocyte mitochondrial metabolism offers a promising neuroprotective strategy for a broad range of brain injuries.

  15. Copper-zinc superoxide dismutase prevents the early decrease of apurinic/apyrimidinic endonuclease and subsequent DNA fragmentation after transient focal cerebral ischemia in mice.

    PubMed

    Fujimura, M; Morita-Fujimura, Y; Narasimhan, P; Copin, J C; Kawase, M; Chan, P H

    1999-11-01

    DNA damage and its repair mechanism are thought to be involved in ischemia/reperfusion injury in the brain. We have previously shown that apurinic/apyrimidinic endonuclease (APE/Ref-1), a multifunctional protein in the DNA base excision repair pathway, rapidly decreased after transient focal cerebral ischemia (FCI) before the peak of DNA fragmentation. To further investigate the role of reactive oxygen species in APE/Ref-1 expression in vivo, we examined the expression of APE/Ref-1 and DNA damage after FCI in wild-type and transgenic mice overexpressing copper-zinc superoxide dismutase. Transgenic mice overexpressing copper-zinc superoxide dismutase and wild-type littermates were subjected to 60 minutes of transient FCI by intraluminal blockade of the middle cerebral artery. APE/Ref-1 protein expression was analyzed by immunohistochemistry and Western blot analysis. DNA damage was evaluated by gel electrophoresis and terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end-labeling (TUNEL). A similar level of APE/Ref-1 was detected in the control brains from both groups. APE/Ref-1 was significantly reduced 1 hour after transient FCI in both groups, whereas the transgenic mice had less reduction than that seen in wild-type mice 1 and 4 hours after FCI. DNA laddering was detected 24 hours after FCI and was decreased in transgenic mice. Double staining with APE/Ref-1 and TUNEL showed that the neurons that lost APE/Ref-1 immunoreactivity became TUNEL positive. These results suggest that reactive oxygen species contribute to the early decrease of APE/Ref-1 and thereby exacerbate DNA fragmentation after transient FCI in mice.

  16. Lactuside B decreases aquaporin-4 and caspase-3 mRNA expression in the hippocampus and striatum following cerebral ischaemia-reperfusion injury in rats

    PubMed Central

    LI, PING-FA; ZHAN, HE-QIN; LI, SHENG-YING; LIU, RUI-LI; YAN, FU-LIN; CUI, TAI-ZHEN; YANG, YU-PING; LI, PENG; WANG, XIN-YAO

    2014-01-01

    This study aimed to investigate the effects of lactuside B (LB) on aquaporin-4 (AQP4) and caspase-3 mRNA expression in the hippocampus and the striatum following cerebral ischaemia-reperfusion (I/R) injury in rats. Cerebral I/R injury was established in Sprague-Dawley rats by occluding the middle cerebral artery for 2 h and then inducing reperfusion. Rats in the I/R + LB groups were treated with various doses of LB following reperfusion. Neurological deficit scores and brain water content were obtained to determine the pharmacodynamics of LB. Reverse transcription polymerase chain reaction was performed to determine the expression levels of AQP4 and caspase-3 mRNA in the hippocampus and the striatum. The results of the present study indicate that LB decreased the neurological deficit scores and the brain water content. In the hippocampus, AQP4 and caspase-3 mRNA expression levels were significantly downregulated in the I/R + LB groups at 24 and 72 h following drug administration, compared with those in the I/R group (P<0.05). In the striatum, LB was also shown to significantly reduce AQP4 and caspase-3 mRNA expression levels at 24 and 72 h following drug administration, compared with those in the I/R group (P<0.05). The effects became stronger as the LB dose was increased. The most significant reductions in AQP4 and caspase-3 mRNA expression were noted in the I/R + LB 25 mg/kg and I/R + LB 50 mg/kg groups at 72 h following drug administration. The results of the present study show that LB is capable of significantly downregulating AQP4 and caspase-3 mRNA expression in the hippocampus and striatum following cerebral I/R injury in rats. The mechanism by which LB improved ischaemic brain injury may be associated with changes in AQP4 and caspase-3 mRNA expression in the hippocampus and the striatum. PMID:24520266

  17. AMYLOID NEUROPATHIES

    PubMed Central

    Shin, Susan C.; Robinson-Papp, Jessica

    2012-01-01

    Peripheral neuropathy is a common complication of many of the systemic amyloidoses. Although the cause of neuropathy is not entirely clear, it is likely related to amyloid deposition within the nerve. This may lead to focal, multifocal, or diffuse neuropathies involving sensory, motor and/or autonomic fibers. The presenting symptoms depend on the distribution of nerves affected. One of the most common phenotypes is sensorimotor polyneuropathy, which is characterized by symptoms of neuropathic pain, numbness, and in advanced cases weakness. Symptoms begin in the feet and ultimately progress to the proximal legs and hands. The most common focal neuropathy is a median neuropathy at the wrist, or clinically known as carpal tunnel syndrome. Carpal tunnel symptoms may include pain and sensory disturbances in the lateral palm and fingers; hand weakness may ensue if the focal neuropathy is severe. Autonomic neuropathy may affect a variety of organ systems such as the cardiovascular, gastrointestinal, and genitourinary systems. Symptoms may be non-specific making the diagnosis of autonomic neuropathy more difficult to identify. However, it is important to recognize and distinguish autonomic neuropathy from diseases of the end-organs themselves. This chapter reviews the inherited and acquired amyloidoses that affect the peripheral nervous system including familial amyloid polyneuropathy, and primary, secondary and senile amyloidosis. We emphasize the clinical presentation of the neurologic aspects of these diseases, physical examination findings, appropriate diagnostic evaluation, treatment and prognosis. PMID:23239211

  18. Amyloid neuropathies.

    PubMed

    Shin, Susan C; Robinson-Papp, Jessica

    2012-01-01

    Peripheral neuropathy is a common complication of many of the systemic amyloidoses. Although the cause of neuropathy is not entirely clear, it is likely related to amyloid deposition within the nerve. This may lead to focal, multifocal, or diffuse neuropathies involving sensory, motor and/or autonomic fibers. The presenting symptoms depend on the distribution of nerves affected. One of the most common phenotypes is sensorimotor polyneuropathy, which is characterized by symptoms of neuropathic pain, numbness, and in advanced cases weakness. Symptoms begin in the feet and ultimately progress to the proximal legs and hands. The most common focal neuropathy is a median neuropathy at the wrist, clinically known as carpal tunnel syndrome. Carpal tunnel symptoms may include pain and sensory disturbances in the lateral palm and fingers; hand weakness may ensue if the focal neuropathy is severe. Autonomic neuropathy may affect a variety of organ systems such as the cardiovascular, gastrointestinal, and genitourinary systems. Symptoms may be non-specific making the diagnosis of autonomic neuropathy more difficult to identify. However, it is important to recognize and distinguish autonomic neuropathy from diseases of the end-organs themselves. This article reviews the inherited and acquired amyloidoses that affect the peripheral nervous system including familial amyloid polyneuropathy, and primary, secondary and senile amyloidosis. We emphasize the clinical presentation of the neurologic aspects of these diseases, physical examination findings, appropriate diagnostic evaluation, treatment and prognosis. © 2012 Mount Sinai School of Medicine.

  19. Overexpression of Pyruvate Dehydrogenase Kinase 1 and Lactate Dehydrogenase A in Nerve Cells Confers Resistance to Amyloid β and Other Toxins by Decreasing Mitochondrial Respiration and Reactive Oxygen Species Production*

    PubMed Central

    Newington, Jordan T.; Rappon, Tim; Albers, Shawn; Wong, Daisy Y.; Rylett, R. Jane; Cumming, Robert C.

    2012-01-01

    We previously demonstrated that nerve cell lines selected for resistance to amyloid β (Aβ) peptide exhibit elevated aerobic glycolysis in part due to increased expression of pyruvate dehydrogenase kinase 1 (PDK1) and lactate dehydrogenase A (LDHA). Here, we show that overexpression of either PDK1 or LDHA in a rat CNS cell line (B12) confers resistance to Aβ and other neurotoxins. Treatment of Aβ-sensitive cells with various toxins resulted in mitochondrial hyperpolarization, immediately followed by rapid depolarization and cell death, events accompanied by increased production of cellular reactive oxygen species (ROS). In contrast, cells expressing either PDK1 or LDHA maintained a lower mitochondrial membrane potential and decreased ROS production with or without exposure to toxins. Additionally, PDK1- and LDHA-overexpressing cells exhibited decreased oxygen consumption but maintained levels of ATP under both normal culture conditions and following Aβ treatment. Interestingly, immunoblot analysis of wild type mouse primary cortical neurons treated with Aβ or cortical tissue extracts from 12-month-old APPswe/PS1dE9 transgenic mice showed decreased expression of LDHA and PDK1 when compared with controls. Additionally, post-mortem brain extracts from patients with Alzheimer disease exhibited a decrease in PDK1 expression compared with nondemented patients. Collectively, these findings indicate that key Warburg effect enzymes play a central role in mediating neuronal resistance to Αβ or other neurotoxins by decreasing mitochondrial activity and subsequent ROS production. Maintenance of PDK1 or LDHA expression in certain regions of the brain may explain why some individuals tolerate high levels of Aβ deposition without developing Alzheimer disease. PMID:22948140

  20. Should optimal timing between two intrauterine transfusions be based on estimated daily decrease of hemoglobin or on measurement of fetal middle cerebral artery peak systolic velocity?

    PubMed

    Ghesquière, Louise; Houfflin-Debarge, Véronique; Behal, Hélène; Coulon, Capucine; Subtil, Damien; Vaast, Pascal; Garabedian, Charles

    2017-04-01

    To best predict the recurrence of fetal anemia after intrauterine transfusion (IUT), the measurement of middle cerebral artery peak systolic velocity (PSV) and the estimation of hemoglobin (Hb) daily decrease are compared. A retrospective study including 38 patients who had at least two IUTs in a context of red blood cell alloimmunization was conducted. PSV values before first, second, and third IUTs were collected and expected Hb level was calculated according to various Hb daily decrease formulas as proposed in the literature. Comparison of PSV receiver operating characteristic curves with the various Hb levels did not find any significant difference between first and second IUTs. On the other hand, we found a significant difference between the second and third IUTs, with better prediction of fetal anemia through Hb decrease calculation, whatever the formula. Between the second and third IUTs, no formula was significantly better than the others. The timing of a second transfusion can be difficult to determine with certainty, but PSV can give an accurate assessment of when to resample the fetus with probably a higher recommended threshold for the diagnosis of fetal anemia. Subsequent to a second transfusion, the intertransfusion interval should be based on estimated Hb decrease rather than PSV thresholds, whatever the chosen formula proposed in the literature. Larger numbers are needed to definitely make this recommendation and it will be interesting to evaluate correlation between different antibodies. © 2017 AABB.

  1. Loss of clusterin shifts amyloid deposition to the cerebrovasculature via disruption of perivascular drainage pathways.

    PubMed

    Wojtas, Aleksandra M; Kang, Silvia S; Olley, Benjamin M; Gatherer, Maureen; Shinohara, Mitsuru; Lozano, Patricia A; Liu, Chia-Chen; Kurti, Aishe; Baker, Kelsey E; Dickson, Dennis W; Yue, Mei; Petrucelli, Leonard; Bu, Guojun; Carare, Roxana O; Fryer, John D

    2017-08-15

    Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) peptide deposition in brain parenchyma as plaques and in cerebral blood vessels as cerebral amyloid angiopathy (CAA). CAA deposition leads to several clinical complications, including intracerebral hemorrhage. The underlying molecular mechanisms that regulate plaque and CAA deposition in the vast majority of sporadic AD patients remain unclear. The clusterin (CLU) gene is genetically associated with AD and CLU has been shown to alter aggregation, toxicity, and blood-brain barrier transport of Aβ, suggesting it might play a key role in regulating the balance between Aβ deposition and clearance in both brain and blood vessels. Here, we investigated the effect of CLU on Aβ pathology using the amyloid precursor protein/presenilin 1 (APP/PS1) mouse model of AD amyloidosis on a Clu(+/+) or Clu(-/-) background. We found a marked decrease in plaque deposition in the brain parenchyma but an equally striking increase in CAA within the cerebrovasculature of APP/PS1;Clu(-/-) mice. Surprisingly, despite the several-fold increase in CAA levels, APP/PS1;Clu(-/-) mice had significantly less hemorrhage and inflammation. Mice lacking CLU had impaired clearance of Aβ in vivo and exogenously added CLU significantly prevented Aβ binding to isolated vessels ex vivo. These findings suggest that in the absence of CLU, Aβ clearance shifts to perivascular drainage pathways, resulting in fewer parenchymal plaques but more CAA because of loss of CLU chaperone activity, complicating the potential therapeutic targeting of CLU for AD.

  2. Exercise alters the immune profile in Tg2576 Alzheimer mice toward a response coincident with improved cognitive performance and decreased amyloid

    PubMed Central

    Nichol, Kathryn E; Poon, Wayne W; Parachikova, Anna I; Cribbs, David H; Glabe, Charles G; Cotman, Carl W

    2008-01-01

    Background Inflammation is associated with Aβ pathology in Alzheimer's disease (AD) and transgenic AD models. Previously, it has been demonstrated that chronic stimulation of the immune response induces pro-inflammatory cytokines IL-1β and TNF-α which contribute to neurodegeneration. However, recent evidence has shown that inducing the adaptive immune response reduces Aβ pathology and is neuroprotective. Low concentrations of IFN-γ modulate the adaptive immune response by directing microglia to differentiate to antigen presenting cells. Our objective was to determine if exercise could induce a shift from the immune profile in aged (17–19 months) Tg2576 mice to a response that reduces Aβ pathology. Methods TG (n = 29) and WT (n = 27) mice were divided into sedentary (SED) and exercised (RUN) groups. RUN animals were provided an in-cage running wheel for 3 weeks. Tissue was harvested and hippocampus and cortex dissected out. Quantitative data was analyzed using 2 × 2 ANOVA and student's t-tests. Results IL-1β and TNF-α were significantly greater in hippocampi from sedentary Tg2576 (TGSED) mice than in wildtype (WTSED) (p = 0.04, p = 0.006). Immune response proteins IFN-γ and MIP-1α are lower in TGSED mice than in WTSED (p = 0.03, p = 0.07). Following three weeks of voluntary wheel running, IL-1β and TNF-α decreased to levels indistinguishable from WT. Concurrently, IFN-γ and MIP-1α increased in TGRUN. Increased CD40 and MHCII, markers of antigen presentation, were observed in TGRUN animals compared to TGSED, as well as CD11c staining in and around plaques and vasculature. Additional vascular reactivity observed in TGRUN is consistent with an alternative activation immune pathway, involving perivascular macrophages. Significant decreases in soluble Aβ40 (p = 0.01) and soluble fibrillar Aβ (p = 0.01) were observed in the exercised transgenic animals. Conclusion Exercise shifts the immune response from innate to an adaptive or alternative response

  3. Peripheral administration of the soluble TNF inhibitor XPro1595 modifies brain immune cell profiles, decreases beta-amyloid plaque load, and rescues impaired long-term potentiation in 5xFAD mice.

    PubMed

    MacPherson, Kathryn P; Sompol, Pradoldej; Kannarkat, George T; Chang, Jianjun; Sniffen, Lindsey; Wildner, Mary E; Norris, Christopher M; Tansey, Malú G

    2017-06-01

    Clinical and animal model studies have implicated inflammation and peripheral immune cell responses in the pathophysiology of Alzheimer's disease (AD). Peripheral immune cells including T cells circulate in the cerebrospinal fluid (CSF) of healthy adults and are found in the brains of AD patients and AD rodent models. Blocking entry of peripheral macrophages into the CNS was reported to increase amyloid burden in an AD mouse model. To assess inflammation in the 5xFAD (Tg) mouse model, we first quantified central and immune cell profiles in the deep cervical lymph nodes and spleen. In the brains of Tg mice, activated (MHCII(+), CD45(high), and Ly6C(high)) myeloid-derived CD11b(+) immune cells are decreased while CD3(+) T cells are increased as a function of age relative to non-Tg mice. These immunological changes along with evidence of increased mRNA levels for several cytokines suggest that immune regulation and trafficking patterns are altered in Tg mice. Levels of soluble Tumor Necrosis Factor (sTNF) modulate blood-brain barrier (BBB) permeability and are increased in CSF and brain parenchyma post-mortem in AD subjects and Tg mice. We report here that in vivo peripheral administration of XPro1595, a novel biologic that sequesters sTNF into inactive heterotrimers, reduced the age-dependent increase in activated immune cells in Tg mice, while decreasing the overall number of CD4(+) T cells. In addition, XPro1595 treatment in vivo rescued impaired long-term potentiation (LTP) measured in brain slices in association with decreased Aβ plaques in the subiculum. Selective targeting of sTNF may modulate brain immune cell infiltration, and prevent or delay neuronal dysfunction in AD.

  4. Melatonin decreases neurovascular oxidative/nitrosative damage and protects against early increases in the blood-brain barrier permeability after transient focal cerebral ischemia in mice.

    PubMed

    Chen, Hung-Yi; Chen, Tsung-Ying; Lee, Ming-Yang; Chen, Shur-Tzu; Hsu, Yun-Shang; Kuo, Yen-Liang; Chang, Guan-Liang; Wu, Tian-Shung; Lee, E-Jian

    2006-09-01

    We have recently shown that melatonin decreases the late (24 hr) increase in blood-brain barrier (BBB) permeability and the risk of tissue plasminogen activator-induced hemorrhagic transformation following ischemic stroke in mice. In the study, we further explored whether melatonin would reduce postischemic neurovascular oxidative/nitrosative damage and, therefore, improve preservation of the early increase in the BBB permeability at 4 hr after transient focal cerebral ischemia for 60 min in mice. Melatonin (5 mg/kg) or vehicle was given intraperitoneally at the beginning of reperfusion. Hydroethidine (HEt) in situ detection and immunohistochemistry for nitrotyrosine were used to evaluate postischemic accumulation in reactive oxygen and nitrogen species, respectively, in the ischemic neurovascular unit. BBB permeability was evaluated by spectrophotometric and microscopic quantitation of Evans Blue leakage. Relative to controls, melatonin-treated animals not only had a significantly reduced superoxide accumulation in neurovascular units in boundary zones of infarction, by reducing 35% and 54% cytosolic oxidized HEt in intensity and cell-expressing percentage, respectively (P < 0.001), but also exhibited a reduction in nitrotyrosine by 52% (P < 0.01). Additionally, melatonin-treated animals had significantly reduced early postischemic disruption in the BBB permeability by 53% (P < 0.001). Thus, melatonin reduced postischemic oxidative/nitrosative damage to the ischemic neurovascular units and improved the preservation of BBB permeability at an early phase following transient focal cerebral ischemia in mice. The findings further highlight the ability of melatonin in anatomical and functional preservation for the ischemic neurovascular units and its relevant potential in the treatment of ischemic stroke.

  5. Interaction of Fibronectin With Semen Amyloids Synergistically Enhances HIV Infection

    PubMed Central

    Roan, Nadia R.; Chu, Simon; Liu, Haichuan; Neidleman, Jason; Witkowska, H. Ewa; Greene, Warner C.

    2014-01-01

    Semen harbors amyloids that enhance human immunodeficiency virus type 1 (HIV-1) infection. We set out to identify factors that bind these amyloids and to determine whether these factors modulate amyloid-mediated HIV-enhancing activity. Using biochemical and mass spectrometric approaches, we identified fibronectin as a consistent interaction partner. Although monomeric fibronectin did not enhance HIV infection, it synergistically increased the infectivity enhancement activity of the amyloids. Depletion of fibronectin decreased the enhancing activity of semen, suggesting that interfering with the binding interface between fibronectin and the amyloids could be an approach to developing a novel class of microbicides targeting the viral-enhancing activity of semen. PMID:24719472

  6. Withdrawal from fixed-dose injection of methamphetamine decreases cerebral levels of 3-methoxy-4-hydroxyphenylglycol and induces the expression of anxiety-related behavior in mice.

    PubMed

    Kitanaka, Nobue; Kitanaka, Junichi; Tatsuta, Tomohiro; Tanaka, Koh-ichi; Watabe, Kaname; Nishiyama, Nobuyoshi; Morita, Yoshio; Takemura, Motohiko

    2010-05-01

    A variety of drug treatment regimens have been proposed to model the dysphoric state observed during methamphetamine (METH) withdrawal in rats, but little has been established in experiments using mice. In male ICR mice, a fixed-dose injection regimen of METH (1.0 or 2.5 mg/kg, i.p., twice daily for 10 consecutive days) induced a significant decrease in the time spent in open arms in an elevated plus maze after 5 days of drug abstinence. Under an escalating-dose injection regimen (0.2-2.0 mg/kg, i.p., 3 times daily for 4 days, total: 15 mg/kg/animal) or continuous subcutaneous administration with osmotic mini-pumps (15 or 76 mg/kg of METH for 2 weeks), no significant behavioral change was observed after 5 days of drug abstinence, compared with control animals. Reduced gains in body weight were observed during repeated treatment with METH in the fixed-dose injection and mini-pump treatment regimens, but not the escalating-dose injection regimen. HPLC analysis revealed significant decreases in the level of cerebral 3-methoxy-4-hydroxyphenylglycol, a norepinephrine metabolite, and norepinephrine turnover, which may be attributed to the expression of anxiety-related behavior in the elevated plus maze. These observations suggest that the mice treated with a fixed-dose of METH may model the anxiety-related behavior observed in the dysphoric state induced by METH withdrawal in humans.

  7. Dissociation of ERK and Akt signaling in endothelial cell angiogenic responses to {beta}-amyloid

    SciTech Connect

    Magrane, Jordi; Christensen, Rial A.; Rosen, Kenneth M.; Veereshwarayya, Vimal; Querfurth, Henry W. . E-mail: hquerf01@granite.tufts.edu

    2006-04-15

    Cerebrovascular deposits of {beta}-amyloid (A{beta}) peptides are found in Alzheimer's disease and cerebral amyloid angiopathy with stroke or dementia. Dysregulations of angiogenesis, the blood-brain barrier and other critical endothelial cell (EC) functions have been implicated in aggravating chronic hypoperfusion in AD brain. We have used cultured ECs to model the effects of {beta}-amyloid on the activated phosphorylation states of multifunctional serine/threonine kinases since these are differentially involved in the survival, proliferation and migration aspects of angiogenesis. Serum-starved EC cultures containing amyloid-{beta} peptides underwent a 2- to 3-fold increase in nuclear pyknosis. Under growth conditions with sublethal doses of {beta}-amyloid, loss of cell membrane integrity and inhibition of cell proliferation were observed. By contrast, cell migration was the most sensitive to A{beta} since inhibition was significant already at 1 {mu}M (P = 0.01, migration vs. proliferation). In previous work, intracellular A{beta} accumulation was shown toxic to ECs and Akt function. Here, extracellular A{beta} peptides do not alter Akt activation, resulting instead in proportionate decreases in the phosphorylations of the MAPKs: ERK1/2 and p38 (starting at 1 {mu}M). This inhibitory action occurs proximal to MEK1/2 activation, possibly through interference with growth factor receptor coupling. Levels of phospho-JNK remained unchanged. Addition of PD98059, but not LY294002, resulted in a similar decrease in activated ERK1/2 levels and inhibition of EC migration. Transfection of ERK1/2 into A{beta}-poisoned ECs functionally rescued migration. The marked effect of extracellular A{beta} on the migration component of angiogenesis is associated with inhibition of MAPK signaling, while Akt-dependent cell survival appears more affected by cellular A{beta}.

  8. Cerebrolysin reduces amyloid-β deposits, apoptosis and autophagy in the thalamus and improves functional recovery after cortical infarction.

    PubMed

    Xing, Shihui; Zhang, Jian; Dang, Chao; Liu, Gang; Zhang, Yusheng; Li, Jingjing; Fan, Yuhua; Pei, Zhong; Zeng, Jinsheng

    2014-02-15

    Focal cerebral infarction causes amyloid-β (Aβ) deposits and secondary thalamic neuronal degeneration. The present study aimed to determine the protective effects of Cerebrolysin on Aβ deposits and secondary neuronal damage in thalamus after cerebral infarction. At 24h after distal middle cerebral artery occlusion (MCAO), Cerebrolysin (5 ml/kg) or saline as control was once daily administered for consecutive 13 days by intraperitoneal injection. Sensory function and secondary thalamic damage were assessed with adhesive-removal test, Nissl staining and immunofluorescence at 14 days after MCAO. Aβ deposits, activity of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1), apoptosis and autophagy were determined by TUNEL staining, immunofluorescence and immunoblot. The results showed that Cerebrolysin significantly improved sensory deficit compared to controls (p<0.05). Aβ deposits and BACE1 were obviously reduced by Cerebrolysin, which was accompanied by decreases in neuronal loss and astroglial activation compared to controls (all p < 0.05). Coincidently, Cerebrolysin markedly inhibited cleaved caspase-3, conversion of LC3-II, downregulation of Bcl-2 and upregulation of Bax in the ipsilateral thalamus compared to controls (all p<0.05). These findings suggest that Cerebrolysin reduces Aβ deposits, apoptosis and autophagy in the ipsilateral thalamus, which may be associated with amelioration of secondary thalamic damage and functional recovery after cerebral infarction.

  9. Diphenyl diselenide, a simple organoselenium compound, decreases methylmercury-induced cerebral, hepatic and renal oxidative stress and mercury deposition in adult mice.

    PubMed

    de Freitas, Andressa Sausen; Funck, Vinícius Rafael; Rotta, Mariana dos Santos; Bohrer, Denise; Mörschbächer, Vanessa; Puntel, Robson Luís; Nogueira, Cristina Wayne; Farina, Marcelo; Aschner, Michael; Rocha, João Batista Teixeira

    2009-04-06

    Oxidative stress has been pointed out as an important molecular mechanism in methylmercury (MeHg) intoxication. At low doses, diphenyl diselenide ((PhSe)2), a structurally simple organoselenium compound, has been shown to possess antioxidant and neuroprotective properties. Here we have examined the possible in vivo protective effect of diphenyl diselenide against the potential pro-oxidative effects of MeHg in mouse liver, kidney, cerebrum and cerebellum. The effects of MeHg exposure (2 mg/(kg day) of methylmercury chloride 10 ml/kg, p.o.), as well as the possible antagonist effect of diphenyl diselenide (1 and 0.4 mg/(kg day); s.c.) on body weight gain and on hepatic, cerebellar, cerebral and renal levels of thiobarbituric acid reactive substances (TBARS), non-protein thiols (NPSH), ascorbic acid content, mercury concentrations and activities of antioxidant enzymes (glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD)) were evaluated after 35 days of treatment. MeHg caused an increase in TBARS and decreased NPSH levels in all tissues. MeHg also induced a decrease in hepatic ascorbic acid content and in renal GPx and CAT activities. Diphenyl diselenide (1 mg/kg) conferred protection against MeHg-induced hepatic and renal lipid peroxidation and at both doses prevented the reduction in hepatic NPSH levels. Diphenyl diselenide also conferred a partial protection against MeHg-induced oxidative stress (TBARS and NPSH) in liver and cerebellum. Of particular importance, diphenyl diselenide decreased the deposition of Hg in cerebrum, cerebellum, kidney and liver. The present results indicate that diphenyl diselenide can protect against some toxic effects of MeHg in mice. This protection may be related to its antioxidant properties and its ability to reduce Hg body burden. We posit that formation of a selenol intermediate, which possesses high nucleophilicity and high affinity for MeHg, accounts for the ability of diphenyl diselenide to ameliorate Me

  10. Decreased cerebral cortical serotonin transporter binding in ecstasy users: a positron emission tomography/[11C]DASB and structural brain imaging study

    PubMed Central

    Lerch, Jason; Furukawa, Yoshiaki; Tong, Junchao; McCluskey, Tina; Wilkins, Diana; Houle, Sylvain; Meyer, Jeffrey; Mundo, Emanuela; Wilson, Alan A.; Rusjan, Pablo M.; Saint-Cyr, Jean A.; Guttman, Mark; Collins, D. Louis; Shapiro, Colin; Warsh, Jerry J.; Boileau, Isabelle

    2010-01-01

    Animal data indicate that the recreational drug ecstasy (3,4-methylenedioxymethamphetamine) can damage brain serotonin neurons. However, human neuroimaging measurements of serotonin transporter binding, a serotonin neuron marker, remain contradictory, especially regarding brain areas affected; and the possibility that structural brain differences might account for serotonin transporter binding changes has not been explored. We measured brain serotonin transporter binding using [11C] N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine in 50 control subjects and in 49 chronic (mean 4 years) ecstasy users (typically one to two tablets bi-monthly) withdrawn from the drug (mean 45 days). A magnetic resonance image for positron emission tomography image co-registration and structural analyses was acquired. Hair toxicology confirmed group allocation but also indicated use of other psychoactive drugs in most users. Serotonin transporter binding in ecstasy users was significantly decreased throughout all cerebral cortices (range –19 to –46%) and hippocampus (–21%) and related to the extent of drug use (years, maximum dose), but was normal in basal ganglia and midbrain. Substantial overlap was observed between control and user values except for insular cortex, in which 51% of ecstasy user values fell below the lower limit of the control range. Voxel-based analyses confirmed a caudorostral gradient of cortical serotonin transporter binding loss with occipital cortex most severely affected. Magnetic resonance image measurement revealed no overall regional volume differences between groups; however, a slight left-hemispheric biased cortical thinning was detected in methamphetamine-using ecstasy users. The serotonin transporter binding loss was not related to structural changes or partial volume effect, use of other stimulant drugs, blood testosterone or oestradiol levels, major serotonin transporter gene promoter polymorphisms, gender, psychiatric status, or self

  11. Matrix metalloproteinase-9 reduces islet amyloid formation by degrading islet amyloid polypeptide.

    PubMed

    Aston-Mourney, Kathryn; Zraika, Sakeneh; Udayasankar, Jayalakshmi; Subramanian, Shoba L; Green, Pattie S; Kahn, Steven E; Hull, Rebecca L

    2013-02-01

    Deposition of islet amyloid polypeptide (IAPP) as amyloid is a pathological hallmark of the islet in type 2 diabetes, which is toxic to β-cells. We previously showed that the enzyme neprilysin reduces islet amyloid deposition and thereby reduces β-cell apoptosis, by inhibiting fibril formation. Two other enzymes, matrix metalloproteinase (MMP)-2 and MMP-9, are extracellular gelatinases capable of degrading another amyloidogenic peptide, Aβ, the constituent of amyloid deposits in Alzheimer disease. We therefore investigated whether MMP-2 and MMP-9 play a role in reducing islet amyloid deposition. MMP-2 and MMP-9 mRNA were present in mouse islets but only MMP-9 activity was detectable. In an islet culture model where human IAPP (hIAPP) transgenic mouse islets develop amyloid but nontransgenic islets do not, a broad spectrum MMP inhibitor (GM6001) and an MMP-2/9 inhibitor increased amyloid formation and the resultant β-cell apoptosis. In contrast, a specific MMP-2 inhibitor had no effect on either amyloid deposition or β-cell apoptosis. Mass spectrometry demonstrated that MMP-9 degraded amyloidogenic hIAPP but not nonamyloidogenic mouse IAPP. Thus, MMP-9 constitutes an endogenous islet protease that limits islet amyloid deposition and its toxic effects via degradation of hIAPP. Because islet MMP-9 mRNA levels are decreased in type 2 diabetic subjects, islet MMP-9 activity may also be decreased in human type 2 diabetes, thereby contributing to increased islet amyloid deposition and β-cell loss. Approaches to increase islet MMP-9 activity could reduce or prevent amyloid deposition and its toxic effects in type 2 diabetes.

  12. Effects of lovastatin and pravastatin on amyloid processing and inflammatory response in TgCRND8 brain.

    PubMed

    Chauhan, Neelima B; Siegel, George J; Feinstein, Douglas L

    2004-10-01

    Previous studies suggest that treatment with statins reduce beta amyloid (Abeta) deposition in brains of mouse models of Alzheimer's disease (AD) and may reduce the prevalence of AD in humans. Since lipophilicity influences the biological efficacy of statins, we compared the effects of lovastatin, a lipophilic statin, to effects of the hydrophilic pravastatin on amyloid processing and inflammatory responses in brain. Three-month old TgCRND8 mice expressing mutant human amyloid precursor protein (mHuAPP) were treated daily with various doses of either statin. After 1 month, levels of cerebral soluble and fibrillar Abeta peptides, soluble sAPPalpha, and inflammatory cytokines were measured. Both statins caused dose-dependent reductions in total Abeta peptides with parallel increases in total sAPPalpha. At all doses, slightly greater effects were observed with lovastatin than with pravastatin. In contrast, only lovastatin significantly increased levels of IL-1beta and of TNFalpha in a dose-dependent manner. Lovastatin, but not pravastatin, decreased succinic dehydrogenase and increased lactate dehydrogenase activities in skeletal muscle and increased TUNEL staining in liver. Our data demonstrate that both statins shift the balance of APP processing from excessive beta-toward the normal alpha-cleavage while reducing the total amyloid burden in TgCRND8 brain and that lovastatin, but not pravastatin, potentiates cerebral inflammation and is associated with liver and muscle histotoxicity in these animals. These data show that pravastatin can reduce amyloid burden without potentiating inflammatory responses in brain and, therefore, may have a wider dose-range of safety than have lipophilic statins in the treatment or prevention of AD.

  13. Fish oil supplementation associated with decreased cellular degeneration and increased cellular proliferation 6 weeks after middle cerebral artery occlusion in the rat.

    PubMed

    Pascoe, Michaela C; Howells, David W; Crewther, David P; Carey, Leeanne M; Crewther, Sheila G

    2015-01-01

    Anti-inflammatory long-chain omega-3 polyunsaturated fatty acids (n-3-LC-PUFAs) are both neuroprotective and have antidepressive effects. However the influence of dietary supplemented n-3-LC-PUFAs on inflammation-related cell death and proliferation after middle cerebral artery occlusion (MCAo)-induced stroke is unknown. We have previously demonstrated that anxiety-like and hyperactive locomotor behaviors are reduced in n-3-LC-PUFA-fed MCAo animals. Thus in the present study, male hooded Wistar rats were exposed to MCAo or sham surgeries and examined behaviorally 6 weeks later, prior to euthanasia and examination of lesion size, cell death and proliferation in the dentate gyrus, cornu ammonis region of the hippocampus of the ipsilesional hemispheres, and the thalamus of the ipsilesional and contralesional hemispheres. Markers of cell genesis and cell degeneration in the hippocampus or thalamus of the ipsilesional hemisphere did not differ between surgery and diet groups 6 weeks post MCAo. Dietary supplementation with n-3-LC-PUFA decreased cell degeneration and increased cell proliferation in the thalamic region of the contralesional hemisphere. MCAo-associated cell degeneration in the hippocampus and thalamus positively correlated with anxiety-like and hyperactive locomotor behaviors previously reported in these animals. These results suggest that anti-inflammatory n-3-LC-PUFA supplementation appears to have cellular protective effects after MCAo in the rat, which may affect behavioral outcomes.

  14. The Levels of Pro-Inflammatory Factors Are Significantly Decreased in Cerebral Palsy Patients Following an Allogeneic Umbilical Cord Blood Cell Transplant

    PubMed Central

    Bae, Sang-Hun; Lee, Hyun-Seob; Kang, Myung-Seo; Strupp, Barbara J; Chopp, Michael; Moon, Jisook

    2012-01-01

    Background and Objectives: The transplantation of human umbilical cord blood cells (hUCBCs) has been shown to attenuate the unregulated activation of microglia in a rat model of cerebral palsy (CP). To investigate whether hUCBCs transplantation is also anti-inflammatory in humans, we performed a clinical trial in patients with CP. Methods and Results: Allogeneic or autologous hUCBCs and erythropoietin (EPO) were intravenously injected into human patients with CP (mean age of approximately 38 weeks), and patients were analyzed for their motor function and social behavior. Blood samples were tested for cytokine levels. The most surprising finding in the study was that the cytokine levels were dependent on the donor cell source (allogeneic or autologous). Interestingly, the allogeneic treatment group demonstrated significantly decreased levels of pro-inflammatory factors, such as IL-1α, IL-6, TNF-β, and RANTES, and showed a statistically significant improvement in motor and social behavior compared to the autologous treatment group. Conclusions: Given that inflammation plays a pivotal role in CP, our results suggest that allogeneic hUCBCs therapy may be an appropriate strategy for CP treatment. In addition, prior to transplantation, a detailed analysis of the amount of proinflammatory cytokines in cord blood may be needed to avoid exacerbating inflammatory responses. PMID:24298353

  15. Cerebral Blood Flow in Posterior Cortical Nodes of the Default Mode Network Decreases with Task Engagement but Remains Higher than in Most Brain Regions

    PubMed Central

    Pfefferbaum, Adolf; Chanraud, Sandra; Pitel, Anne-Lise; Müller-Oehring, Eva; Shankaranarayanan, Ajit; Alsop, David C.; Rohlfing, Torsten

    2011-01-01

    Functional neuroimaging studies provide converging evidence for existence of intrinsic brain networks activated during resting states and deactivated with selective cognitive demands. Whether task-related deactivation of the default mode network signifies depressed activity relative to the remaining brain or simply lower activity relative to its resting state remains controversial. We employed 3D arterial spin labeling imaging to examine regional cerebral blood flow (CBF) during rest, a spatial working memory task, and a second rest. Change in regional CBF from rest to task showed significant normalized and absolute CBF reductions in posterior cingulate, posterior-inferior precuneus, and medial frontal lobes . A Statistical Parametric Mapping connectivity analysis, with an a priori seed in the posterior cingulate cortex, produced deactivation connectivity patterns consistent with the classic “default mode network” and activation connectivity anatomically consistent with engagement in visuospatial tasks. The large task-related CBF decrease in posterior-inferior precuneus relative to its anterior and middle portions adds evidence for the precuneus' heterogeneity. The posterior cingulate and posterior-inferior precuneus were also regions of the highest CBF at rest and during task performance. The difference in regional CBF between intrinsic (resting) and evoked (task) activity levels may represent functional readiness or reserve vulnerable to diminution by conditions affecting perfusion. PMID:20484322

  16. Pentylenetetrazol-induced seizures are associated with Na⁺,K⁺-ATPase activity decrease and alpha subunit phosphorylation state in the mice cerebral cortex.

    PubMed

    Marquezan, Bárbara P; Funck, Vinícius R; Oliveira, Clarissa V; Pereira, Letícia M; Araújo, Stífani M; Zarzecki, Micheli S; Royes, Luiz Fernando F; Furian, Ana Flávia; Oliveira, Mauro S

    2013-08-01

    The present study aimed to investigate whether Na(+),K(+)-ATPase activity and phosphorylation state of the catalytic α subunit are altered by pentylenetetrazol (PTZ)-induced seizures. PTZ (30, 45 or 60 g/kg, i.p.) was administered to adult male Swiss mice, and Na(+),K(+)-ATPase activity and phosphorylation state were measured in the cerebral cortex 15 min after PTZ administration. Na(+),K(+)-ATPase activity significantly decreased after PTZ-induced seizures (60 mg/kg). Immunoreactivity of phosphorylated Ser943 at α subunit was increased after PTZ-induced seizures. A significant positive correlation between Na(+),K(+)-ATPase activity and latency to myoclonic jerks and generalized seizures was found. Conversely, a strong negative correlation between Ser943 phosphorylation and latency to generalized seizures was detected. Given the role of Na(+),K(+)-ATPase as a major regulator of brain excitability, Ser943 at Na(+),K(+)-ATPase α subunit may represent a potentially valuable new target for drug development for seizure disorders.

  17. New insights concerning insulin synthesis and its secretion in rat hippocampus and cerebral cortex: amyloid-β1-42-induced reduction of proinsulin level via glycogen synthase kinase-3β.

    PubMed

    Nemoto, Takayuki; Toyoshima-Aoyama, Fumiyo; Yanagita, Toshihiko; Maruta, Toyoaki; Fujita, Hiroshi; Koshida, Tomohiro; Yonaha, Tetsu; Wada, Akihiko; Sawaguchi, Akira; Murakami, Manabu

    2014-02-01

    The reduction of insulin levels in hippocampal areas is associated with Alzheimer's disease. The present study using rat brain explores the mechanisms of insulin synthesis and secretion, as well as amyloid-β1-42 (Aβ(1-42))-induced reduction of proinsulin expression. After confirming the expression of insulin mRNA and proinsulin in rat brain, we visualized and analyzed the motion of insulin secretion in rat hippocampal neurons using pH-sensitive green fluorescent protein (pHluorin) fused to the insulin. In the rat hippocampal neurons expressing insulin-pHluorin, time-lapse confocal laser scanning microscopy revealed the appearance of fluorescent spots induced by depolarization after stimulation with 50 mM KCl. In these fluorescent spots, Ca(2+)-dependent activator protein for secretion 2 (CAPS2), which is the regulator of the dense-core vesicle involving neuronal peptides, was co-localized with insulin-pHluorin. However, Aβ(1-42)-induced reduction of proinsulin in rat hippocampal neurons was inhibited by treatment with lithium and transfection with glycogen synthase kinase-3β (GSK-3β) siRNA. These results demonstrate that synthesized insulin is secreted from rat hippocampal and cortical neuron's dense-core vesicles, and that activation of GSK-3β in Aβ(1-42)-induced Alzheimer's model hippocampal neurons decreases the insulin synthesis.

  18. Artemether and artesunate show the highest efficacies in rescuing mice with late-stage cerebral malaria and rapidly decrease leukocyte accumulation in the brain.

    PubMed

    Clemmer, L; Martins, Y C; Zanini, G M; Frangos, J A; Carvalho, L J M

    2011-04-01

    The murine model of cerebral malaria (ECM) caused by Plasmodium berghei ANKA (PbA) infection in susceptible mice has been extensively used for studies of pathogenesis and identification of potential targets for human CM therapeutics. However, the model has been seldom explored to evaluate adjunctive therapies for this malaria complication. A first step toward this goal is to define a treatment protocol with an effective antimalarial drug able to rescue mice presenting late-stage ECM. We evaluated the efficacy of artemisinin, artemether, artesunate, and quinine given intraperitoneally once a day, and combinations with mefloquine, in suppressing PbA infection in mice with moderate parasitemia. Artemether, artesunate, and quinine were then evaluated for efficacy in rescuing PbA-infected mice with ECM, strictly defined by using objective criteria based on the presentation of clinical signs of neurological involvement, degree of hypothermia, and performance in a set of six motor behavior tests. Artemether at 25 mg/kg presented the fastest parasite killing ability in 24 h and fully avoided recrudescence in a 5-day treatment protocol. Artemether and artesunate were equally effective in rescuing mice with late-stage ECM (46 and 43% survival, respectively), whereas quinine had a poor performance (12.5% survival). Artemether caused a marked decrease in brain leukocyte accumulation 24 h after the first dose. In conclusion, artemether and artesunate are effective in rescuing mice with late-stage ECM and decrease brain inflammation. In addition, the described protocols for more strict clinical evaluation and for rescue treatment provide a framework for studies of CM adjunctive therapies using this mouse model.

  19. Systemic amyloid deposits in familial British dementia.

    PubMed

    Ghiso, J A; Holton, J; Miravalle, L; Calero, M; Lashley, T; Vidal, R; Houlden, H; Wood, N; Neubert, T A; Rostagno, A; Plant, G; Revesz, T; Frangione, B

    2001-11-23

    Familial British dementia (FBD) is an early onset inherited disorder that, like familial Alzheimer's disease (FAD), is characterized by progressive dementia, amyloid deposition in the brain, and neurofibrillary degeneration of limbic neurons. The primary structure of the amyloid subunit (ABri) extracted from FBD brain tissues (Vidal, R., Frangione, B., Rostagno, A., Mead, S., Revesz, T., Plant, G., and Ghiso, J. (1999) Nature 399, 776-781) is entirely different and unrelated to any previously known amyloid protein. Patients with FBD have a single nucleotide substitution at codon 267 in the BRI2 gene, resulting in an arginine replacing the stop codon and a longer open reading frame of 277 amino acids instead of 266. The ABri peptide comprises the 34 C-terminal residues of the mutated precursor ABriPP-277 and is generated via furin-like proteolytic processing. Here we report that carriers of the Stop-to-Arg mutation have a soluble form of the amyloid peptide (sABri) in the circulation with an estimated concentration in the range of 20 ng/ml, several fold higher than that of soluble Abeta. In addition, ABri species identical to those identified in the brain were also found as fibrillar components of amyloid deposits predominantly in the blood vessels of several peripheral tissues, including pancreas and myocardium. We hypothesize that the high concentration of the soluble de novo created amyloidogenic peptide and/or the insufficient tissue clearance are the main causative factors for the formation of amyloid deposits outside the brain. Thus, FBD constitutes the first documented cerebral amyloidosis associated with neurodegeneration and dementia in which the amyloid deposition is also systemic.

  20. Peripherally Applied Synthetic Tetrapeptides HAEE and RADD Slow Down the Development of Cerebral β-Amyloidosis in AβPP/PS1 Transgenic Mice.

    PubMed

    Tsvetkov, Philipp O; Cheglakov, Ivan B; Ovsepyan, Armen A; Mediannikov, Oleg Y; Morozov, Alexander O; Telegin, Georgy B; Kozin, Sergey A

    2015-01-01

    Two tetrapeptides, HAEE and RADD, which are ionic-complementary to the primary zinc recognition site of amyloid-β (Aβ), have been reported to inhibit zinc-induced dimerization of the Aβ metal-binding domain and slow Aβ aggregation in vitro. In the present study, we investigate the impact of HAEE and RADD on the development of cerebral β-amyloidosis in a mouse model of Alzheimer's disease. We have found chronic intravenous administration of each peptide results in significant decrease of amyloid plaque burden in the treated mice.

  1. Plasma β-amyloid in Alzheimer’s disease and vascular disease

    PubMed Central

    Janelidze, Shorena; Stomrud, Erik; Palmqvist, Sebastian; Zetterberg, Henrik; van Westen, Danielle; Jeromin, Andreas; Song, Linan; Hanlon, David; Tan Hehir, Cristina A.; Baker, David; Blennow, Kaj; Hansson, Oskar

    2016-01-01

    Implementation of amyloid biomarkers in clinical practice would be accelerated if such biomarkers could be measured in blood. We analyzed plasma levels of Aβ42 and Aβ40 in a cohort of 719 individuals (the Swedish BioFINDER study), including patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), Alzheimer’s disease (AD) dementia and cognitively healthy elderly, using a ultrasensitive immunoassay (Simoa platform). There were weak positive correlations between plasma and cerebrospinal fluid (CSF) levels for both Aβ42 and Aβ40, and negative correlations between plasma Aβ42 and neocortical amyloid deposition (measured with PET). Plasma levels of Aβ42 and Aβ40 were reduced in AD dementia compared with all other diagnostic groups. However, during the preclinical or prodromal AD stages (i.e. in amyloid positive controls, SCD and MCI) plasma concentration of Aβ42 was just moderately decreased whereas Aβ40 levels were unchanged. Higher plasma (but not CSF) levels of Aβ were associated with white matter lesions, cerebral microbleeds, hypertension, diabetes and ischemic heart disease. In summary, plasma Aβ is overtly decreased during the dementia stage of AD indicating that prominent changes in Aβ metabolism occur later in the periphery compared to the brain. Further, increased levels of Aβ in plasma are associated with vascular disease. PMID:27241045

  2. Hacking the Code of Amyloid Formation

    PubMed Central

    Pastor, M Teresa; Esteras-Chopo, Alexandra

    2007-01-01

    Many research efforts in the last years have been directed towards understanding the factors determining protein misfolding and amyloid formation. Protein stability and amino acid composition have been identified as the two major factors in vitro. The research of our group has been focused on understanding the relationship between amino acid sequence and amyloid formation. Our approach has been the design of simple model systems that reproduce the biophysical properties of natural amyloids. An amyloid sequence pattern was extracted that can be used to detect amyloidogenic hexapeptide stretches in proteins. We have added evidence supporting that these amyloidogenic stretches can trigger amyloid formation by nonamyloidogenic proteins. Some experimental results in other amyloid proteins will be analyzed under the conclusions obtained in these studies. Our conclusions together with evidences from other groups suggest that amyloid formation is the result of the interplay between a decrease of protein stability, and the presence of highly amyloidogenic regions in proteins. As many of these results have been obtained in vitro, the challenge for the next years will be to demonstrate their validity in in vivo systems. PMID:19164912

  3. White matter hyperintensities predict amyloid increase in Alzheimer's disease.

    PubMed

    Grimmer, Timo; Faust, Maximilian; Auer, Florian; Alexopoulos, Panagiotis; Förstl, Hans; Henriksen, Gjermund; Perneczky, Robert; Sorg, Christian; Yousefi, Behrooz H; Drzezga, Alexander; Kurz, Alexander

    2012-12-01

    Impaired amyloid clearance probably contributes to increased amyloid deposition in sporadic Alzheimer's disease (AD). Diminished perivascular drainage due to cerebral small-vessel disease (CSVD) has been proposed as a cause of reduced amyloid clearance. White matter hyperintensities (WMHs) are considered to reflect CSVD and can be measured using fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI). Amyloid deposition can be determined in vivo using Pittsburgh compound B ([11C]PiB) positron emission tomography (PET). We aimed to elucidate the association between WMH and the progression of amyloid deposition in patients with AD. Twenty-two patients with probable AD underwent FLAIR-MRI and [11C]PiB-PET examinations at baseline (BL) and after a mean follow-up (FU) interval of 28 months. The relationship between BL-WMH and the progression of cerebral amyloid between BL and FU was examined using a regions-of-interest (ROI) approach. The region-specific variability of this relationship was analyzed using a voxel-based method. The longitudinal analysis revealed a statistically significant association between the amount of BL-WMH and the progression of amyloid load between BL and FU (p = 0.006, adjusted R2 = 0.375, standardized coefficient β = 0.384). The association was particularly observed in parieto-occipital regions and tended to be closer in regions adjacent to the brain surface. According to our knowledge, this is the first in vivo study in human being supporting the hypothesis that impaired amyloid clearance along perivascular drainage pathways may contribute to β-amyloid deposition in sporadic AD. The extent of WMH might be a relevant factor to be assessed in antiamyloid drug trials.

  4. Age-related spatial cognitive impairment is correlated with a decrease in ChAT in the cerebral cortex, hippocampus and forebrain of SAMP8 mice.

    PubMed

    Wang, Feng; Chen, Hong; Sun, Xiaojiang

    2009-05-01

    At present, the mechanisms underlying cognitive disorders remain unclear. The senescence-accelerated mice (SAM) prone/8 (P8) has been proposed as a useful model for the study of aging, and SAM resistant/1 (R1) is its control as a normal aging strain. The purpose of this study was to investigate choline acetyltransferase (ChAT) expression in SAM brain. The age-related decline of learning and memory ability in P8 mice (4, 8 and 12 months old, n=10 for each group) was proved in Morris water maze test (MWM). After the behavioral test, protein and mRNA levels of ChAT were determined in the cerebral cortex, hippocampus and forebrain by means of immunostaining, Western blotting, and real time quantitative PCR (QPCR). Comparing with 4-month-old P8 and R1, 8- and 12-month-old P8 showed age-related cognitive impairment in MWM test. The latencies of the 4-month-old P8 in a hidden platform trial were significantly shorter, and the retention time was significantly longer than that of the older P8 groups. In addition, significantly low level of ChAT protein was observed in older P8 groups. Comparing with the 4-month-old P8, ChAT mRNA in the 12-month-old P8 declined significantly in all three regions of P8 brain. Pearson correlation test showed that the latencies in the MWM were positively correlated with the level of ChAT in P8. Such phenomenon could not be detected in normal aging R1 mice. These findings suggest that the decrease of ChAT in P8 mice was responsible for the age-related learning and memory impairments in some sense.

  5. Functional amyloids in bacteria.

    PubMed

    Romero, Diego; Kolter, Roberto

    2014-06-01

    The term amyloidosis is used to refer to a family of pathologies altering the homeostasis of human organs. Despite having a name that alludes to starch content, the amyloid accumulations are made up of proteins that polymerize as long and rigid fibers. Amyloid proteins vary widely with respect to their amino acid sequences but they share similarities in their quaternary structure; the amyloid fibers are enriched in β-sheets arranged perpendicular to the axis of the fiber. This structural feature provides great robustness, remarkable stability, and insolubility. In addition, amyloid proteins specifically stain with certain dyes such as Congo red and thioflavin-T. The aggregation into amyloid fibers, however, it is not restricted to pathogenic processes, rather it seems to be widely distributed among proteins and polypeptides. Amyloid fibers are present in insects, fungi and bacteria, and they are important in maintaining the homeostasis of the organism. Such findings have motivated the use of the term "functional amyloid" to differentiate these amyloid proteins from their toxic siblings. This review focuses on systems that have evolved in bacteria that control the expression and assembly of amyloid proteins on cell surfaces, such that the robustness of amyloid proteins are used towards a beneficial end.

  6. Methods to monitor monocytes-mediated amyloid-beta uptake and phagocytosis in the context of adjuvanted immunotherapies.

    PubMed

    Hallé, Maxime; Tribout-Jover, Pascale; Lanteigne, Anne-Marie; Boulais, Jonathan; St-Jean, Julien R; Jodoin, Rachel; Girouard, Marie-Pier; Constantin, Florin; Migneault, Annik; Renaud, Frédéric; Didierlaurent, Arnaud M; Mallett, Corey P; Burkhart, David; Pilorget, Anthony; Palmantier, Rémi; Larocque, Daniel

    2015-09-01

    Antibody-mediated capture of amyloid-beta (Aβ) in peripheral blood was identified as an attractive strategy to eliminate cerebral toxic amyloid in Alzheimer's disease (AD) patients and murine models. Alternatively, defective capacity of peripheral monocytes to engulf Aβ was reported in individuals with AD. In this report, we developed different approaches to investigate cellular uptake and phagocytosis of Aβ, and to examine how two immunological devices--an immunostimulatory Adjuvant System and different amyloid specific antibodies--may affect these biological events. Between one and thirteen months of age, APPswe X PS1.M146V (TASTPM) AD model mice had decreasing concentrations of Aβ in their plasma. In contrast, the proportion of blood monocytes containing Aβ tended to increase with age. Importantly, the TLR-agonist containing Adjuvant System AS01B primed monocytes to promote de novo Aβ uptake capacity, particularly in the presence of anti-Aβ antibodies. Biochemical experiments demonstrated that cells achieved Aβ uptake and internalization followed by Aβ degradation via mechanisms that required effective actin polymerization and proteolytic enzymes such as insulin-degrading enzyme. We further demonstrated that both Aβ-specific monoclonal antibodies and plasma from Aβ-immunized mice enhanced the phagocytosis of 1 μm Aβ-coated particles. Together, our data highlight a new biomarker testing to follow amyloid clearance within the blood and a mechanism of Aβ uptake by peripheral monocytes in the context of active or passive immunization, and emphasize on novel approaches to investigate this phenomenon.

  7. Biochemistry of Amyloid β-Protein and Amyloid Deposits in Alzheimer Disease

    PubMed Central

    Masters, Colin L.; Selkoe, Dennis J.

    2012-01-01

    Progressive cerebral deposition of the amyloid β-protein (Aβ) in brain regions serving memory and cognition is an invariant and defining feature of Alzheimer disease. A highly similar but less robust process accompanies brain aging in many nondemented humans, lower primates, and some other mammals. The discovery of Aβ as the subunit of the amyloid fibrils in meningocerebral blood vessels and parenchymal plaques has led to innumerable studies of its biochemistry and potential cytotoxic properties. Here we will review the discovery of Aβ, numerous aspects of its complex biochemistry, and current attempts to understand how a range of Aβ assemblies, including soluble oligomers and insoluble fibrils, may precipitate and promote neuronal and glial alterations that underlie the development of dementia. Although the role of Aβ as a key molecular factor in the etiology of Alzheimer disease remains controversial, clinical trials of amyloid-lowering agents, reviewed elsewhere in this book, are poised to resolve the question of its pathogenic primacy. PMID:22675658

  8. Amyloid burden in cognitively normal elderly is associated with preferential hippocampal subfield volume loss

    PubMed Central

    Hsu, Phillip J.; Shou, Haochang; Benzinger, Tammie; Marcus, Daniel; Durbin, Tony; Morris, John C.; Sheline, Yvette I.

    2015-01-01

    The earliest sites of brain atrophy in Alzheimer’s disease are in the medial temporal lobe, following widespread cerebral cortical amyloid deposition. We assessed 74 cognitively normal participants with clinical measurements, Aβ-PET imaging, MRI, and a newly developed technique for MRI-based hippocampal subfield segmentation to determine the differential association of amyloid deposition and hippocampal subfield volume. Compared to amyloid-negative participants, amyloid-positive participants had significantly smaller hippocampal tail, presubiculum, subiculum, and total hippocampal gray matter volumes. We conclude that, prior to the development of cognitive impairment, atrophy in particular hippocampal subfields (HS) occurs preferentially with Aβ accumulation. PMID:25428255

  9. Amyloid Beta as a Modulator of Synaptic Plasticity

    PubMed Central

    Parihar, Mordhwaj S; Brewer, Gregory J

    2011-01-01

    Alzheimer’s disease is associated with synapse loss, memory dysfunction and pathological accumulation of amyloid beta in plaques. However, an exclusively pathological role for amyloid beta is being challenged by new evidence for an essential function of amyloid beta at the synapse. Amyloid beta protein exists in different assembly states in the central nervous system and plays distinct roles ranging from synapse and memory formation to memory loss and neuronal cell death. Amyloid beta is present in the brain of symptom-free people where it likely performs important physiological roles. New evidence indicates that synaptic activity directly evokes the release of amyloid beta at the synapse. At physiological levels, amyloid beta is a normal, soluble product of neuronal metabolism that regulates synaptic function beginning early in life. Monomeric amyloid beta 40 and 42 are the predominant forms required for synaptic plasticity and neuronal survival. With age, some assemblies of amyloid beta are associated with synaptic failure and Alzheimer’s disease pathology, possibly targeting the N-methyl-D-aspartic acid (NMDA) receptor through the α7-nicotinic acetylcholine receptor (α7-nAChR), mitochondrial amyloid-β alcohol dehydrogenase (ABAD) and cyclophilin D. But emerging data suggests a distinction between age effects on the target response in contrast to the assembly state or the accumulation of the peptide. Both aging and beta amyloid independently decrease neuronal plasticity. Our laboratory has reported that amyloid beta, glutamate and lactic acid are each increasingly toxic with neuron age. The basis of the age-related toxicity partly resides in age-related mitochondrial dysfunction and an oxidative shift in mitochondrial and cytoplasmic redox potential. In turn, signaling through phosphorylated extracellular signal-regulated protein kinases (pERK) is affected along with an age-independent increase in phosphorylated cAMP response element-binding protein (p

  10. Pyrroloquinoline quinone inhibits the fibrillation of amyloid proteins

    PubMed Central

    Kim, Jihoon; Kobayashi, Masaki; Fukuda, Makoto; Ogasawara, Daisuke; Kobayashi, Natsuki; Han, Sungwoong; Nakamura, Chikashi; Inada, Masaki; Miyaura, Chisato; Ikebukuro, Kazunori

    2010-01-01

    Several neurodegenerative diseases involve the selective damage of neuron cells resulting from the accumulation of amyloid fibril formation. Considering that the formation of amyloid fibrils as well as their precursor oligomers is cytotoxic, the agents that prevent the formation of oligomers and/or fibrils might allow the development of a novel therapeutic approach to neurodegenerative diseases. Here, we show pyrroloquinoline quinone (PQQ) inhibits the amyloid fibril formation of the amyloid proteins, amyloid β (1–42) and mouse prion protein. The fibril formation of mouse prion protein in the presence of PQQ was dramatically prevented. Similarly, the fibril formation of amyloid β (1–42) also decreased. With further advanced pharmacological approaches, PQQ may become a leading anti-neurodegenerative compound in the treatment of neurodegenerative diseases. PMID:20083898

  11. Uncommon Causes of Cerebral Microbleeds.

    PubMed

    Noorbakhsh-Sabet, Nariman; Pulakanti, Varun Chandi; Zand, Ramin

    2017-10-01

    Cerebral microbleeds (CMBs) are small and round perivascular hemosiderin depositions detectable by gradient echo sequences or susceptibility-weighted imaging. Cerebral microbleeds are common among patients with hypertension, cerebral ischemia, or cerebral amyloid angiopathy. In this article, we describe uncommon causes of CMBs. We searched Pubmed with the keyword CMBs for relevant studies and looked for different uncommon causes of CMBs. CMBs have several uncommon etiologies including posterior reversible encephalopathy syndrome, infective endocarditis, brain radiation therapy, cocaine abuse, thrombotic thrombocytopenic purpura, traumatic brain injury, intravascular lymphomatosis or proliferating angio-endotheliomatosis, moyamoya disease, sickle cell anemia/β-thalassemia, cerebral autosomal dominant arteriopathy subcortical infarcts, and leukoencephalopathy (CADASIL), genetic syndromes, or obstructive sleep apnea. Understanding the uncommon causes of CMBs is not only helpful in diagnosis and prognosis of some of these rare diseases, but can also help in better understanding different pathophysiology involved in the development of CMBs. Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  12. [Relation between expression of cerebral beta-APP in the chronic alcoholism rats and death caused by TSAH].

    PubMed

    Wei, Lai; Lei, Huai-Cheng; Yu, Xiao-Jun; Lai, Xiao-Ping; Qian, Hong; Xu, Xiao-Hu; Zhu, Fang-Cheng

    2013-04-01

    By observing the cerebral beta-amyloid precursor protein (beta-APP) expression in the chronic alcoholism rats with slight cerebral injury, to discuss the correlation of chronic alcoholism and death caused by traumatic subarachnoid haemorrhage (TSAH). Sixty male SD rats were randomly divided into watering group, watering group with strike, alcoholism group and alcoholism group with strike. Among them, the alcohol was used for continuous 4 weeks in alcoholism groups and the concussion was made in groups with strike. In each group, HE staining and immunohistochemical staining of the cerebral tissues were done and the results were analyzed by the histopathologic image system. In watering group, there was no abnormal. In watering group with strike, mild neuronic congestion was found. In alcoholism group, vascular texture on cerebral surface was found. And the neurons arranged in disorder with dilated intercellular space. In alcoholism group with strike, diffuse congestion on cerebral surface was found. And there was TSAH with thick-layer patches around brainstem following irregular axonotmesis. The quantity of beta-APP IOD in alcoholism group was significantly higher in the frontal lobe, hippocampus, cerebellum, brainstem than those in watering group with strike and alcoholism group with strike. The cerebral tissues with chronic alcoholism, due to the decreasing tolerance, could cause fatal TSAH and pathological changes in cerebral tissues of rats under slight cerebral injury.

  13. Propofol post-conditioning protects the blood brain barrier by decreasing matrix metalloproteinase-9 and aquaporin-4 expression and improves the neurobehavioral outcome in a rat model of focal cerebral ischemia-reperfusion injury.

    PubMed

    Ji, Feng-Tao; Liang, Jian-Jun; Miao, Li-Ping; Wu, Qiang; Cao, Ming-Hui

    2015-08-01

    Propofol, an intravenous anesthetic, inhibits neuronal apoptosis induced by ischemic stroke, protects the brain from ischemia/reperfusion injury and improves neuronal function. However, whether propofol is able to protect the blood brain barrier (BBB) and the underlying mechanisms have remained to be elucidated. In the present study, a rat model of cerebral ischemia/reperfusion was established, using a thread embolism to achieve middle cerebral artery occlusion. Rats were treated with propofol (propofol post-conditioning) or physiological saline (control) administered by intravenous injection 30 min following reperfusion. Twenty-four hours following reperfusion, neurobehavioral manifestations were assessed. The levels of cephaloedema, damage to the BBB and expression levels of matrix metalloproteinase-9 (MMP-9), aquaporin-4 (AQP-4) and phosphorylated c-Jun N-terminal kinase (pJNK) were determined in order to evaluate the effects of propofol on the BBB. In comparison to the cerebral ischemia/reperfusion group, the levels of brain water content and Evans blue content, as well as the expression levels of MMP-9, AQP-4 and pJNK were significantly reduced in the propofol post-conditioning group. These results indicated that propofol post-conditioning improved the neurobehavioral manifestations and attenuated the BBB damage and cephaloedema induced following cerebral ischemia/reperfusion. This effect may be due to the inhibition of MMP-9 and AQP-4 expression, and the concurrent decrease in JNK phosphorylation.

  14. An amyloid lung

    PubMed Central

    Zundel, W. E.; Prior, A. P.

    1971-01-01

    A 55-year-old housewife died from an illness characterized by progressive respiratory incapacity. Changes were confined to the lungs and consisted of a diffuse infiltration by amyloid. No adequate cause was found for this amyloid, and we suggest that this is a case of primary alveolar septal amyloidosis. Images PMID:5559913

  15. Neurotoxicity of a Fragment of the Amyloid Precursor Associated with Alzheimer's Disease

    NASA Astrophysics Data System (ADS)

    Yankner, Bruce A.; Dawes, Linda R.; Fisher, Shannon; Villa-Komaroff, Lydia; Oster-Granite, Mary Lou; Neve, Rachael L.

    1989-07-01

    Amyloid deposition in senile plaques and the cerebral vasculature is a marker of Alzheimer's disease. Whether amyloid itself contributes to the neurodegenerative process or is simply a by-product of that process is unknown. Pheochromocytoma (PC12) and fibroblast (NIH 3T3) cell lines were transfected with portions of the gene for the human amyloid precursor protein. Stable PC12 cell transfectants expressing a specific amyloid-containing fragment of the precursor protein gradually degenerated when induced to differentiate into neuronal cells with nerve growth factor. Conditioned medium from these cells was toxic to neurons in primary hippocampal cultures, and the toxic agent could be removed by immunoabsorption with an antibody directed against the amyloid polypeptide. Thus, a peptide derived from the amyloid precursor may be neurotoxic.

  16. Structures for amyloid fibrils.

    PubMed

    Makin, O Sumner; Serpell, Louise C

    2005-12-01

    Alzheimer's disease and Creutzfeldt-Jakob disease are the best-known examples of a group of diseases known as the amyloidoses. They are characterized by the extracellular deposition of toxic, insoluble amyloid fibrils. Knowledge of the structure of these fibrils is essential for understanding the process of pathology of the amyloidoses and for the rational design of drugs to inhibit or reverse amyloid formation. Structural models have been built using information from a wide variety of techniques, including X-ray diffraction, electron microscopy, solid state NMR and EPR. Recent advances have been made in understanding the architecture of the amyloid fibril. Here, we describe and compare postulated structural models for the mature amyloid fibril and discuss how the ordered structure of amyloid contributes to its stability.

  17. A bifunctional curcumin analogue for two-photon imaging and inhibiting crosslinking of amyloid beta in Alzheimer's disease.

    PubMed

    Zhang, Xueli; Tian, Yanli; Yuan, Peng; Li, Yuyan; Yaseen, Mohammad A; Grutzendler, Jaime; Moore, Anna; Ran, Chongzhao

    2014-10-09

    In this report, we designed a highly bright bifunctional curcumin analogue CRANAD-28. In vivo two-photon imaging suggested that CRANAD-28 could penetrate the blood brain barrier (BBB) and label plaques and cerebral amyloid angiopathies (CAAs). We also demonstrated that this imaging probe could inhibit the crosslinking of amyloid beta induced either by copper or by natural conditions.

  18. Loss of clusterin shifts amyloid deposition to the cerebrovasculature via disruption of perivascular drainage pathways

    PubMed Central

    Wojtas, Aleksandra M.; Kang, Silvia S.; Olley, Benjamin M.; Gatherer, Maureen; Shinohara, Mitsuru; Lozano, Patricia A.; Liu, Chia-Chen; Kurti, Aishe; Baker, Kelsey E.; Dickson, Dennis W.; Yue, Mei; Petrucelli, Leonard; Bu, Guojun; Carare, Roxana O.; Fryer, John D.

    2017-01-01

    Alzheimer’s disease (AD) is characterized by amyloid-β (Aβ) peptide deposition in brain parenchyma as plaques and in cerebral blood vessels as cerebral amyloid angiopathy (CAA). CAA deposition leads to several clinical complications, including intracerebral hemorrhage. The underlying molecular mechanisms that regulate plaque and CAA deposition in the vast majority of sporadic AD patients remain unclear. The clusterin (CLU) gene is genetically associated with AD and CLU has been shown to alter aggregation, toxicity, and blood–brain barrier transport of Aβ, suggesting it might play a key role in regulating the balance between Aβ deposition and clearance in both brain and blood vessels. Here, we investigated the effect of CLU on Aβ pathology using the amyloid precursor protein/presenilin 1 (APP/PS1) mouse model of AD amyloidosis on a Clu+/+ or Clu−/− background. We found a marked decrease in plaque deposition in the brain parenchyma but an equally striking increase in CAA within the cerebrovasculature of APP/PS1;Clu−/− mice. Surprisingly, despite the several-fold increase in CAA levels, APP/PS1;Clu−/− mice had significantly less hemorrhage and inflammation. Mice lacking CLU had impaired clearance of Aβ in vivo and exogenously added CLU significantly prevented Aβ binding to isolated vessels ex vivo. These findings suggest that in the absence of CLU, Aβ clearance shifts to perivascular drainage pathways, resulting in fewer parenchymal plaques but more CAA because of loss of CLU chaperone activity, complicating the potential therapeutic targeting of CLU for AD. PMID:28701379

  19. Contrasting effects of nanoparticle-protein attraction on amyloid aggregation.

    PubMed

    Radic, Slaven; Davis, Thomas P; Ke, Pu Chun; Ding, Feng

    2015-01-01

    Nanoparticles (NPs) have been experimentally found to either promote or inhibit amyloid aggregation of proteins, but the molecular mechanisms for such complex behaviors remain unknown. Using coarse-grained molecular dynamics simulations, we investigated the effects of varying the strength of nonspecific NP-protein attraction on amyloid aggregation of a model protein, the amyloid-beta peptide implicated in Alzheimer's disease. Specifically, with increasing NP-peptide attraction, amyloid aggregation on the NP surface was initially promoted due to increased local protein concentration on the surface and destabilization of the folded state. However, further increase of NP-peptide attraction decreased the stability of amyloid fibrils and reduced their lateral diffusion on the NP surface necessary for peptide conformational changes and self-association, thus prohibiting amyloid aggregation. Moreover, we found that the relative concentration between protein and NPs also played an important role in amyloid aggregation. With a high NP/protein ratio, NPs that intrinsically promote protein aggregation may display an inhibitive effect by depleting the proteins in solution while having a low concentration of the proteins on each NP's surface. Our coarse-grained molecular dynamics simulation study offers a molecular mechanism for delineating the contrasting and seemingly conflicting effects of NP-protein attraction on amyloid aggregation and highlights the potential of tailoring anti-aggregation nanomedicine against amyloid diseases.

  20. Coenzyme Q10 Protects Human Endothelial Cells from β-Amyloid Uptake and Oxidative Stress-Induced Injury

    PubMed Central

    Durán-Prado, Mario; Frontiñán, Javier; Santiago-Mora, Raquel; Peinado, Juan Ramón; Parrado-Fernández, Cristina; Gómez-Almagro, María Victoria; Moreno, María; López-Domínguez, José Alberto; Villalba, José Manuel; Alcaín, Francisco J.

    2014-01-01

    Neuropathological symptoms of Alzheimer's disease appear in advances stages, once neuronal damage arises. Nevertheless, recent studies demonstrate that in early asymptomatic stages, ß-amyloid peptide damages the cerebral microvasculature through mechanisms that involve an increase in reactive oxygen species and calcium, which induces necrosis and apoptosis of endothelial cells, leading to cerebrovascular dysfunction. The goal of our work is to study the potential preventive effect of the lipophilic antioxidant coenzyme Q (CoQ) against ß-amyloid-induced damage on human endothelial cells. We analyzed the protective effect of CoQ against Aβ-induced injury in human umbilical vein endothelial cells (HUVECs) using fluorescence and confocal microscopy, biochemical techniques and RMN-based metabolomics. Our results show that CoQ pretreatment of HUVECs delayed Aβ incorporation into the plasma membrane and mitochondria. Moreover, CoQ reduced the influx of extracellular Ca2+, and Ca2+ release from mitochondria due to opening the mitochondrial transition pore after β-amyloid administration, in addition to decreasing O2.− and H2O2 levels. Pretreatment with CoQ also prevented ß-amyloid-induced HUVECs necrosis and apoptosis, restored their ability to proliferate, migrate and form tube-like structures in vitro, which is mirrored by a restoration of the cell metabolic profile to control levels. CoQ protected endothelial cells from Aβ-induced injury at physiological concentrations in human plasma after oral CoQ supplementation and thus could be a promising molecule to protect endothelial cells against amyloid angiopathy. PMID:25272163

  1. Nanophotonics of protein amyloids

    NASA Astrophysics Data System (ADS)

    Bhattacharya, Mily; Mukhopadhyay, Samrat

    2014-04-01

    Technological breakthroughs in the super-resolution optical imaging techniques have enriched our current understanding of a range of biological systems and biomolecular processes at the nanoscopic spatial resolution. Protein amyloids are an important class of ordered protein assemblies consisting of misfolded proteins that are implicated in a wide range of devastating human diseases. In order to decipher the structural basis of the supramolecular protein assembly in amyloids and their detrimental interactions with the cell membranes, it is important to employ high-resolution optical imaging techniques. Additionally, amyloids could serve as novel biological nanomaterials for a variety of potential applications. In this review, we summarize a few examples of the utility of near-field scanning optical imaging methodologies to obtain a wealth of structural information into the nanoscale amyloid assembly. Although the near-field technologies were developed several decades ago, it is only recently that these methodologies are being applied and adapted for amyloid research to yield novel information pertaining to the exciting nanoscopic world of protein aggregates. We believe that the account on the nanophotonics of amyloids described in this review will be useful for the future studies on the biophysics of amyloids.

  2. Amyloid Fibrils from Hemoglobin

    PubMed Central

    Jayawardena, Nadishka; Kaur, Manmeet; Nair, Smitha; Malmstrom, Jenny; Goldstone, David; Negron, Leonardo; Gerrard, Juliet A.; Domigan, Laura J.

    2017-01-01

    Amyloid fibrils are a class of insoluble protein nanofibers that are formed via the self-assembly of a wide range of peptides and proteins. They are increasingly exploited for a broad range of applications in bionanotechnology, such as biosensing and drug delivery, as nanowires, hydrogels, and thin films. Amyloid fibrils have been prepared from many proteins, but there has been no definitive characterization of amyloid fibrils from hemoglobin to date. Here, nanofiber formation was carried out under denaturing conditions using solutions of apo-hemoglobin extracted from bovine waste blood. A characteristic amyloid fibril morphology was confirmed by transmission electron microscopy (TEM) and atomic force microscopy (AFM), with mean fibril dimensions of approximately 5 nm diameter and up to several microns in length. The thioflavin T assay confirmed the presence of β-sheet structures in apo-hemoglobin fibrils, and X-ray fiber diffraction showed the characteristic amyloid cross-β quaternary structure. Apo-hemoglobin nanofibers demonstrated high stability over a range of temperatures (−20 to 80 °C) and pHs (2–10), and were stable in the presence of organic solvents and trypsin, confirming their potential as nanomaterials with versatile applications. This study conclusively demonstrates the formation of amyloid fibrils from hemoglobin for the first time, and also introduces a cost-effective method for amyloid fibril manufacture using meat industry by-products. PMID:28398221

  3. Peptide Amyloid Surface Display

    PubMed Central

    2015-01-01

    Homomeric self-assembly of peptides into amyloid fibers is a feature of many diseases. A central role has been suggested for the lateral fiber surface affecting gains of toxic function. To investigate this, a protein scaffold that presents a discrete, parallel β-sheet surface for amyloid subdomains up to eight residues in length has been designed. Scaffolds that present the fiber surface of islet amyloid polypeptide (IAPP) were prepared. The designs show sequence-specific surface effects apparent in that they gain the capacity to attenuate rates of IAPP self-assembly in solution and affect IAPP-induced toxicity in insulin-secreting cells. PMID:25541905

  4. Engineering theranostic nanovehicles capable of targeting cerebrovascular amyloid deposits.

    PubMed

    Agyare, Edward K; Jaruszewski, Kristen M; Curran, Geoffry L; Rosenberg, Jens T; Grant, Samuel C; Lowe, Val J; Ramakrishnan, Subramanian; Paravastu, Anant K; Poduslo, Joseph F; Kandimalla, Karunya K

    2014-07-10

    Cerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid beta (Aβ) proteins within the walls of the cerebral vasculature with subsequent aggressive vascular inflammation leading to recurrent hemorrhagic strokes. The objective of the study was to develop theranostic nanovehicles (TNVs) capable of a) targeting cerebrovascular amyloid; b) providing magnetic resonance imaging (MRI) contrast for the early detection of CAA; and c) treating cerebrovascular inflammation resulting from CAA. The TNVs comprised of a polymeric nanocore made from Magnevist (MRI contrast agent) conjugated chitosan. The nanocore was also loaded with cyclophosphamide (CYC), an immunosuppressant shown to reduce the cerebrovascular inflammation in CAA. Putrescine modified F(ab')2 fragment of anti-amyloid antibody, IgG4.1 (pF(ab')24.1) was conjugated to the surface of the nanocore to target cerebrovascular amyloid. The average size of the control chitosan nanoparticles (conjugated with albumin and are devoid of Magnevist, CYC, and pF(ab')24.1) was 164±1.2 nm and that of the TNVs was 239±4.1 nm. The zeta potential values of the CCNs and TNVs were 21.6±1.7 mV and 11.9±0.5 mV, respectively. The leakage of Magnevist from the TNVs was a modest 0.2% over 4 days, and the CYC release from the TNVs followed Higuchi's model that describes sustained drug release from polymeric matrices. The studies conducted in polarized human microvascular endothelial cell monolayers (hCMEC/D3) in vitro as well as in mice in vivo have demonstrated the ability of TNVs to target cerebrovascular amyloid. In addition, the TNVs provided contrast for imaging cerebrovascular amyloid using MRI and single photon emission computed tomography. Moreover, the TNVs were shown to reduce pro-inflammatory cytokine production by the Aβ challenged blood brain barrier (BBB) endothelium more effectively than the cyclophosphamide alone.

  5. Pregnancy prevents hypertensive remodeling and decreases myogenic reactivity in posterior cerebral arteries from Dahl salt-sensitive rats: a role in eclampsia?

    PubMed

    Aukes, Annet M; Vitullo, Lisa; Zeeman, Gerda G; Cipolla, Marilyn J

    2007-02-01

    Previous studies have demonstrated that pregnancy prevents protective hypertension-induced remodeling of cerebral arteries using nitric oxide synthase (NOS) inhibition to raise mean arterial pressure (MAP). In the present study, we investigated whether this effect of pregnancy was specific to NOS inhibition by using the Dahl salt-sensitive (SS) rat as a model of hypertension. Nonpregnant (n = 16) and late-pregnant (n = 17) Dahl SS rats were fed either a high-salt diet (8% NaCl) to raise blood pressure or a low-salt diet (<0.7% NaCl). Third-order posterior cerebral arteries were isolated and pressurized in an arteriograph chamber to measure active responses to pressure and passive remodeling. Several vessels from each group were stained for protein gene product 9.5 to determine perivascular nerve density. Blood pressure was elevated in both groups on high salt. The elevated MAP was associated with significantly smaller active and passive diameters (P < 0.05) and inward remodeling in the nonpregnant hypertensive group only. Whereas no structural changes were observed in the late-pregnant hypertensive animals, both late-pregnant groups had diminished myogenic reactivity (P < 0.05). Nerve density in both the late-pregnant groups was significantly greater when compared with the nonpregnant groups, suggesting that pregnancy has a trophic influence on perivascular innervation of the posterior cerebral artery. However, hypertension lowered the nerve density in both nonpregnant and late-pregnant animals. It therefore appears that pregnancy has an overall effect to prevent hypertension-induced remodeling regardless of the mode of hypertension. This effect may predispose the brain to autoregulatory breakthrough, hyperperfusion, and eclampsia when MAP is elevated.

  6. Homocysteine metabolism is associated with cerebrospinal fluid levels of soluble amyloid precursor protein and amyloid beta.

    PubMed

    Oikonomidi, Aikaterini; Lewczuk, Piotr; Kornhuber, Johannes; Smulders, Yvo; Linnebank, Michael; Semmler, Alexander; Popp, Julius

    2016-10-01

    Disturbed homocysteine metabolism may contribute to amyloidogenesis by modulating the amyloid precursor protein (APP) production and processing. The objective of this study was to investigate the relationships between cerebral amyloid production and both blood and cerebrospinal fluid (CSF) markers of the homocysteine metabolism. We assessed CSF concentrations of soluble APPα, soluble APPβ, and amyloid β1-42 (Aβ1-42), as well as plasma levels of homocysteine (Hcys), total vitamin B12, and folate, and CSF concentrations of homocysteine (Hcys-CSF), 5-methyltetrahydrofolate (5-MTHF), S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH) in 59 subjects with normal cognition. Linear regression analyses were performed to assess associations between homocysteine metabolism parameters and amyloid production. The study was approved by the Ethical Committee of the University of Bonn. After controlling for age, gender, APOEe4 status, and albumin ratio (Qalb), higher Aβ1-42 CSF levels were associated with high Hcys and low vitamin B12 plasma levels as well as with high Hcys, high SAH, and low 5-MTHF CSF levels. Higher CSF concentrations of sAPPα and sAPPβ were associated with high SAH levels. The results suggest that disturbed homocysteine metabolism is related to increased CSF levels of sAPP forms and Aβ1-42, and may contribute to the accumulation of amyloid pathology in the brain. Disturbed homocysteine metabolism may contribute to amyloidogenesis by modulating the amyloid precursor protein (APP) production and processing. We found associations between CSF levels of soluble APP forms and Aβ1-42, and markers of the homocysteine metabolism in both plasma and CSF in adults with normal cognition. Disturbed homocysteine metabolism may represent a target for preventive and early disease-modifying interventions in Alzheimer's disease. © 2016 International Society for Neurochemistry.

  7. Multiple low-dose infusions of human umbilical cord blood cells improve cognitive impairments and reduce amyloid-β-associated neuropathology in Alzheimer mice.

    PubMed

    Darlington, Donna; Deng, Juan; Giunta, Brian; Hou, Huayan; Sanberg, Cyndy D; Kuzmin-Nichols, Nicole; Zhou, Hua-Dong; Mori, Takashi; Ehrhart, Jared; Sanberg, Paul R; Tan, Jun

    2013-02-01

    Alzheimer's disease (AD) is the most common progressive age-related dementia in the elderly and the fourth major cause of disability and mortality in that population. The disease is pathologically characterized by deposition of β-amyloid plaques neurofibrillary tangles in the brain. Current strategies for the treatment of AD are symptomatic only. As such, they are less than efficacious in terms of significantly slowing or halting the underlying pathophysiological progression of the disease. Modulation by cell therapy may be new promising disease-modifying therapy. Recently, we showed reduction in amyloid-β (Aβ) levels/β-amyloid plaques and associated astrocytosis following low-dose infusions of mononuclear human umbilical cord blood cells (HUCBCs). Our current study extended our previous findings by examining cognition via (1) the rotarod test, (2) a 2-day version of the radial-arm water maze test, and (3) a subsequent observation in an open pool platform test to characterize the effects of monthly peripheral HUCBC infusion (1×10(6) cells/μL) into the transgenic PSAPP mouse model of cerebral amyloidosis (bearing mutant human APP and presenilin-1 transgenes) from 6 to 12 months of age. We show that HUCBC therapy correlates with decreased (1) cognitive impairment, (2) Aβ levels/β-amyloid plaques, (3) amyloidogenic APP processing, and (4) reactive microgliosis after a treatment of 6 or 10 months. As such, this report lays the groundwork for an HUCBC therapy as potentially novel alternative to oppose AD at the disease-modifying level.

  8. When amyloids become prions.

    PubMed

    Sabate, Raimon

    2014-01-01

    The conformational diseases, linked to protein aggregation into amyloid conformations, range from non-infectious neurodegenerative disorders, such as Alzheimer disease (AD), to highly infectious ones, such as human transmissible spongiform encephalopathies (TSEs). They are commonly known as prion diseases. However, since all amyloids could be considered prions (from those involved in cell-to-cell transmission to those responsible for real neuronal invasion), it is necessary to find an underlying cause of the different capacity to infect that each of the proteins prone to form amyloids has. As proposed here, both the intrinsic cytotoxicity and the number of nuclei of aggregation per cell could be key factors in this transmission capacity of each amyloid.

  9. When amyloids become prions

    PubMed Central

    Sabate, Raimon

    2014-01-01

    The conformational diseases, linked to protein aggregation into amyloid conformations, range from non-infectious neurodegenerative disorders, such as Alzheimer's disease (AD), to highly infectious ones, such as human transmissible spongiform encephalopathies (TSEs). They are commonly known as prion diseases. However, since all amyloids could be considered prions (from those involved in cell-to-cell transmission to those responsible for real neuronal invasion), it is necessary to find an underlying cause of the different capacity to infect that each of the proteins prone to form amyloids has. As proposed here, both the intrinsic cytotoxicity and the number of nuclei of aggregation per cell could be key factors in this transmission capacity of each amyloid. PMID:24831240

  10. Progressive decrease in N-acetylaspartate/Creatine ratio in a teenager with type 1 diabetes and repeated episodes of ketoacidosis without clinically apparent cerebral edema: Evidence for permanent brain injury.

    PubMed

    Wootton-Gorges, S L; Buonocore, M H; Caltagirone, R A; Kuppermann, N; Glaser, N S

    2010-04-01

    Recent data suggest that DKA may contribute to cognitive impairment in children with type 1 DM. We measured the NAA/Cr ratio in a teenager during and following 2 separate episodes of DKA without clinically apparent cerebral edema. The NAA/Cr ratio decreased during DKA and improved following recovery. However, the NAA/Cr value was lower after the second episode of DKA (1.76) than after the first (1.97). These findings provide support for the hypothesis that neuronal injury may result from DKA.

  11. Cigarette smoking impairs nitric oxide-mediated cerebral blood flow increase: Implications for Alzheimer's disease.

    PubMed

    Toda, Noboru; Okamura, Tomio

    2016-08-01

    Cerebral blood flow is mainly regulated by nitrergic (parasympathetic, postganglionic) nerves and nitric oxide (NO) liberated from endothelial cells in response to shear stress and stretch of vasculature, whereas sympathetic vasoconstrictor control is quite weak. On the other hand, peripheral vascular resistance and blood flow are mainly controlled by adrenergic vasoconstrictor nerves; endothelium-derived NO and nitrergic nerves play some roles as vasodilator factors. Cigarette smoking impairs NO synthesis in cerebral vascular endothelial cells and nitrergic nerves leading to interference with cerebral blood flow and glucose metabolism in the brain. Smoking-induced cerebral hypoperfusion is induced by impairment of synthesis and actions of NO via endothelial nitric oxide synthase (eNOS)/neuronal NOS (nNOS) inhibition and by increased production of oxygen radicals, resulting in decreased actions of NO on vascular smooth muscle. Nicotine acutely and chronically impairs the action of endothelial NO and also inhibits nitrergic nerve function in chronic use. Impaired cerebral blood supply promotes the synthesis of amyloid β that accelerates blood flow decrease. This vicious cycle is thought to be one of the important factors involving in Alzheimer's disease (AD). Quitting smoking is undoubtedly one of the important ways to prevent and delay the genesis or slow the progress of impaired cognitive function and AD. Copyright © 2016 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  12. Brain Accumulation of Amyloid-beta in Non-Alzheimer Neurodegeneration.

    PubMed

    Primavera, James; Lu, Bing-Xun; Riskind, Peter J.; Iulian, Maria; De La Monte, Suzanne M.

    1999-10-01

    We report an unusual case of amyotrophic lateral sclerosis (ALS) marked by extensive cerebral amyloid-beta deposition in small and medium-size vessels, capillaries, and perivascular plaques in the cerebral cortex, and in most leptomeningeal vessels. Despite considerable cerebral amyloidosis, the patient remained cognitively intact until death. For comparison with other neuro-degenerative diseases and normal aging, we assessed the densities of amyloid-beta-immunoreactive cortical vessels and plaques in matched frontal and temporal lobe sections from archival uncomplicated cases of Alzheimer's disease (N=10), Pick's disease (PkD; N=4), Parkinson's disease (PD; N=6), Diffuse Lewy body disease (DLBD; N=7), progressive supranuclear palsy (PSP; N=5), multiple systems atrophy (MSA; N=4), ALS (N=7), or normal aging (N=10) by semi-quantitative grading (0 to 3+). Moderate (2+) or abundant (3+) cerebrovascular amyloid-beta immunoreactivity was detected in 8/10 AD, 3/7 DLBD, 3/6 PD, 1 each with PSP or PkD, and 2/10 controls. Moderate or abundant densities of amyloid-beta-immunoreactive diffuse plaques were detected in all cases of AD or DLBD, 4/6 with PD, 3/5 with PSP, and 2/10 controls. Moderate or abundant amyloid-beta-immunoreactive mature (dense core) plaques were present in all cases of AD or DLBD, and 3 each with PD or PSP. Importantly, amyloid-beta-immunoreactivity was not observed in the 4 MSA or 7 archival ALS cases. This study demonstrates that prominent amyloid-beta accumulation in cerebral vessels and plaques occurs frequently in AD, DLBD, PSP, and PD, but not in ALS or MSA, indicating that the case described is unique. The lack of cognitive impairment in the case presented argues against the idea that extensive amyloid-beta deposition in the brain causes dementia.

  13. Highly potent soluble amyloid-β seeds in human Alzheimer brain but not cerebrospinal fluid

    PubMed Central

    Kaeser, Stephan A.; Maia, Luis F.; Portelius, Erik; Pinotsi, Dorothea; Kaminski, Clemens F.; Winkler, David T.; Maetzler, Walter; Keyvani, Kathy; Spitzer, Philipp; Wiltfang, Jens; Kaminski Schierle, Gabriele S.; Zetterberg, Henrik; Staufenbiel, Matthias; Jucker, Mathias

    2017-01-01

    The soluble fraction of brain samples from patients with Alzheimer’s disease contains highly biologically active amyloid-β seeds. In this study, we sought to assess the potency of soluble amyloid-β seeds derived from the brain and cerebrospinal fluid. Soluble Alzheimer’s disease brain extracts were serially diluted and then injected into the hippocampus of young, APP transgenic mice. Eight months later, seeded amyloid-β deposition was evident even when the hippocampus received subattomole amounts of brain-derived amyloid-β. In contrast, cerebrospinal fluid from patients with Alzheimer’s disease, which contained more than 10-fold higher levels of amyloid-β peptide than the most concentrated soluble brain extracts, did not induce detectable seeding activity in vivo. Similarly, cerebrospinal fluid from aged APP-transgenic donor mice failed to induce cerebral amyloid-β deposition. In comparison to the soluble brain fraction, cerebrospinal fluid largely lacked N-terminally truncated amyloid-β species and exhibited smaller amyloid-β-positive particles, features that may contribute to the lack of in vivo seeding by cerebrospinal fluid. Interestingly, the same cerebrospinal fluid showed at least some seeding activity in an in vitro assay. The present results indicate that the biological seeding activity of soluble amyloid-β species is orders of magnitude greater in brain extracts than in the cerebrospinal fluid. PMID:25212850

  14. Amyloid-β and Astrocytes Interplay in Amyloid-β Related Disorders

    PubMed Central

    Batarseh, Yazan S.; Duong, Quoc-Viet; Mousa, Youssef M.; Al Rihani, Sweilem B.; Elfakhri, Khaled; Kaddoumi, Amal

    2016-01-01

    Amyloid-β (Aβ) pathology is known to promote chronic inflammatory responses in the brain. It was thought previously that Aβ is only associated with Alzheimer’s disease and Down syndrome. However, studies have shown its involvement in many other neurological disorders. The role of astrocytes in handling the excess levels of Aβ has been highlighted in the literature. Astrocytes have a distinctive function in both neuronal support and protection, thus its involvement in Aβ pathological process may tip the balance toward chronic inflammation and neuronal death. In this review we describe the involvement of astrocytes in Aβ related disorders including Alzheimer’s disease, Down syndrome, cerebral amyloid angiopathy, and frontotemporal dementia. PMID:26959008

  15. CD45 Deficiency Drives Amyloid-β Peptide Oligomers and Neuronal Loss in Alzheimer's Disease Mice

    PubMed Central

    Zhu, Yuyan; Hou, Huayan; Rezai-Zadeh, Kavon; Giunta, Brian; Ruscin, Amanda; Gemma, Carmelina; Jin, JingJi; Dragicevic, Natasa; Bradshaw, Patrick; Rasool, Suhail; Glabe, Charles G.; Ehrhart, Jared; Bickford, Paula; Mori, Takashi; Obregon, Demian; Town, Terrence; Tan, Jun

    2011-01-01

    Converging lines of evidence indicate dysregulation of the key immunoregulatory molecule CD45 (also known as leukocyte common antigen) in Alzheimer's disease (AD). We report that transgenic mice overproducing amyloid-β peptide (Aβ) but deficient in CD45 (PSAPP/CD45–/– mice) faithfully recapitulate AD neuropathology. Specifically, we find increased abundance of cerebral intracellular and extracellular soluble oligomeric and insoluble Aβ, decreased plasma soluble Aβ, increased abundance of microglial neurotoxic cytokines tumor necrosis factor-α and interleukin-1β, and neuronal loss in PSAPP/CD45–/– mice compared with CD45-sufficient PSAPP littermates (bearing mutant human amyloid precursor protein and mutant human presenilin-1 transgenes). After CD45 ablation, in vitro and in vivo studies demonstrate an anti-Aβ phagocytic but proinflammatory microglial phenotype. This form of microglial activation occurs with elevated Aβ oligomers and neural injury and loss as determined by decreased ratio of anti-apoptotic Bcl-xL to proapoptotic Bax, increased activated caspase-3, mitochondrial dysfunction, and loss of cortical neurons in PSAPP/CD45–/– mice. These data show that deficiency in CD45 activity leads to brain accumulation of neurotoxic Aβ oligomers and validate CD45-mediated microglial clearance of oligomeric Aβ as a novel AD therapeutic target. PMID:21273420

  16. Anti-ApoE Antibody Given after Plaque Onset Decreases Aβ Accumulation and Improves Brain Function in a Mouse Model of Aβ Amyloidosis

    PubMed Central

    Liao, Fan; Hori, Yukiko; Hudry, Eloise; Bauer, Adam Q.; Jiang, Hong; Mahan, Thomas E.; Lefton, Katheryn B.; Zhang, Tony J.; Dearborn, Joshua T.; Kim, Jungsu; Culver, Joseph P.; Betensky, Rebecca; Wozniak, David F.; Hyman, Bradley T.

    2014-01-01

    Apolipoprotein E (apoE) is the strongest known genetic risk factor for late onset Alzheimer's disease (AD). It influences amyloid-β (Aβ) clearance and aggregation, which likely contributes in large part to its role in AD pathogenesis. We recently found that HJ6.3, a monoclonal antibody against apoE, significantly reduced Aβ plaque load when given to APPswe/PS1ΔE9 (APP/PS1) mice starting before the onset of plaque deposition. To determine whether the anti-apoE antibody HJ6.3 affects Aβ plaques, neuronal network function, and behavior in APP/PS1 mice after plaque onset, we administered HJ6.3 (10 mg/kg/week) or PBS intraperitoneally to 7-month-old APP/PS1 mice for 21 weeks. HJ6.3 mildly improved spatial learning performance in the water maze, restored resting-state functional connectivity, and modestly reduced brain Aβ plaque load. There was no effect of HJ6.3 on total plasma cholesterol or cerebral amyloid angiopathy. To investigate the underlying mechanisms of anti-apoE immunotherapy, HJ6.3 was applied to the brain cortical surface and amyloid deposition was followed over 2 weeks using in vivo imaging. Acute exposure to HJ6.3 affected the course of amyloid deposition in that it prevented the formation of new amyloid deposits, limited their growth, and was associated with occasional clearance of plaques, a process likely associated with direct binding to amyloid aggregates. Topical application of HJ6.3 for only 14 d also decreased the density of amyloid plaques assessed postmortem. Collectively, these studies suggest that anti-apoE antibodies have therapeutic potential when given before or after the onset of Aβ pathology. PMID:24849360

  17. Anti-ApoE antibody given after plaque onset decreases Aβ accumulation and improves brain function in a mouse model of Aβ amyloidosis.

    PubMed

    Liao, Fan; Hori, Yukiko; Hudry, Eloise; Bauer, Adam Q; Jiang, Hong; Mahan, Thomas E; Lefton, Katheryn B; Zhang, Tony J; Dearborn, Joshua T; Kim, Jungsu; Culver, Joseph P; Betensky, Rebecca; Wozniak, David F; Hyman, Bradley T; Holtzman, David M

    2014-05-21

    Apolipoprotein E (apoE) is the strongest known genetic risk factor for late onset Alzheimer's disease (AD). It influences amyloid-β (Aβ) clearance and aggregation, which likely contributes in large part to its role in AD pathogenesis. We recently found that HJ6.3, a monoclonal antibody against apoE, significantly reduced Aβ plaque load when given to APPswe/PS1ΔE9 (APP/PS1) mice starting before the onset of plaque deposition. To determine whether the anti-apoE antibody HJ6.3 affects Aβ plaques, neuronal network function, and behavior in APP/PS1 mice after plaque onset, we administered HJ6.3 (10 mg/kg/week) or PBS intraperitoneally to 7-month-old APP/PS1 mice for 21 weeks. HJ6.3 mildly improved spatial learning performance in the water maze, restored resting-state functional connectivity, and modestly reduced brain Aβ plaque load. There was no effect of HJ6.3 on total plasma cholesterol or cerebral amyloid angiopathy. To investigate the underlying mechanisms of anti-apoE immunotherapy, HJ6.3 was applied to the brain cortical surface and amyloid deposition was followed over 2 weeks using in vivo imaging. Acute exposure to HJ6.3 affected the course of amyloid deposition in that it prevented the formation of new amyloid deposits, limited their growth, and was associated with occasional clearance of plaques, a process likely associated with direct binding to amyloid aggregates. Topical application of HJ6.3 for only 14 d also decreased the density of amyloid plaques assessed postmortem. Collectively, these studies suggest that anti-apoE antibodies have therapeutic potential when given before or after the onset of Aβ pathology. Copyright © 2014 the authors 0270-6474/14/347281-12$15.00/0.

  18. Red mold rice ameliorates impairment of memory and learning ability in intracerebroventricular amyloid beta-infused rat by repressing amyloid beta accumulation.

    PubMed

    Lee, Chun-Lin; Kuo, Tzong-Fu; Wang, Jyh-Jye; Pan, Tzu-Ming

    2007-11-01

    Amyloid beta (Abeta) peptide related to the onset of Alzheimer's disease (AD) damaged neurons and further resulted in dementia. Monascus-fermented red mold rice (RMR), a traditional Chinese medicine as well as health food, includes monacolins (with the same function as statins) and multifunctional metabolites. In this study, ethanol extract of RMR (RE) was used to evaluate neuroprotection against Abeta40 neurotoxicity in PC12 cells. Furthermore, the effects of dietary administration of RMR on memory and learning abilities are confirmed in an animal model of AD rats infused with Abeta40 into the cerebral ventricle. During continuous Abeta40 infusion for 28 days, the rats of test groups were administered RMR or lovastatin. Memory and learning abilities were evaluated in the water maze and passive avoidance tasks. After sacrifice, cerebral cortex and hippocampus were collected for the examination of AD risk factors. The in vitro results clearly indicate that RE provides stronger neuroprotection in rescuing cell viability as well as repressing inflammatory response and oxidative stress. RMR administration potently reverses the memory deficit in the memory task. Abeta40 infusion increases acetylcholinesterase activity, reactive oxygen species, and lipid peroxidation and decreases total antioxidant status and superoxide dismutase activity in brain, but these damages were potently reversed by RMR administration, and the protection was more significant than that with lovastatin administration. The protection provided by RMR is able to prevent Abeta fibrils from being formed and deposited in hippocampus and further decrease Abeta40 accumulation, even though Abeta40 solution was infused into brain continuously.

  19. Sustained (S)-roscovitine delivery promotes neuroprotection associated with functional recovery and decrease in brain edema in a randomized blind focal cerebral ischemia study.

    PubMed

    Rousselet, Estelle; Létondor, Anne; Menn, Bénédicte; Courbebaisse, Yann; Quillé, Marie-Lise; Timsit, Serge

    2017-01-01

    Stroke is a devastating disorder that significantly contributes to death, disability and healthcare costs. In ischemic stroke, the only current acute therapy is recanalization, but the narrow therapeutic window less than 6 h limits its application. The current challenge is to prevent late cell death, with concomitant therapy targeting the ischemic cascade to widen the therapeutic window. Among potential neuroprotective drugs, cyclin-dependent kinase inhibitors such as (S)-roscovitine are of particular relevance. We previously showed that (S)-roscovitine crossed the blood-brain barrier and was neuroprotective in a dose-dependent manner in two models of middle cerebral artery occlusion (MCAo). According to the Stroke Therapy Academic Industry Roundtable guidelines, the pharmacokinetics of (S)-roscovitine and the optimal mode of delivery and therapeutic dose in rats were investigated. Combination of intravenous (IV) and continuous sub-cutaneous (SC) infusion led to early and sustained delivery of (S)-roscovitine. Furthermore, in a randomized blind study on a transient MCAo rat model, we showed that this mode of delivery reduced both infarct and edema volume and was beneficial to neurological outcome. Within the framework of preclinical studies for stroke therapy development, we here provide data to improve translation of pre-clinical studies into successful clinical human trials.

  20. Age-dependent decreases of high energy phosphates in cerebral gray matter of patients with bipolar I disorder: a preliminary phosphorus-31 magnetic resonance spectroscopic imaging study.

    PubMed

    Dudley, Jonathan A; Lee, Jing-Huei; Durling, Michelle; Strakowski, Stephen M; Eliassen, James C

    2015-04-01

    To identify abnormalities in high energy phosphate cerebral metabolism in euthymic bipolar disorder. Phosphorus-31 magnetic resonance spectroscopic imaging ((31)P MRSI) data were acquired from the entire brain of 9 euthymic adults with bipolar disorder and 13 healthy adults. Estimates of phosphocreatine (PCr) and adenosine triphosphate (ATP) in homogeneous gray and white matter were obtained by tissue regression analysis. Analyses of covariance revealed the effect of age to be significantly different between bipolar and healthy groups for concentrations of PCr (p=0.0018) and ATP (p=0.013) in gray matter. These metabolites were negatively correlated with age in gray matter in bipolar subjects while PCr was positively correlated with age in gray matter of healthy subjects. Additionally, age-corrected concentrations of PCr in gray matter were significantly elevated in bipolar subjects (p=0.0048). Given that this cross-sectional study possessed a small sample and potentially confounding effects of medication status, we recommend a larger, longitudinal study to more robustly study relationships between bioenergetic impairment and duration of disease. Our results suggest bioenergetic impairment related to mitochondrial function may be progressive in multi-episode bipolar subjects as they age. Copyright © 2015 Elsevier B.V. All rights reserved.

  1. Amyloid Beta Mediates Memory Formation

    ERIC Educational Resources Information Center

    Garcia-Osta, Ana; Alberini, Cristina M.

    2009-01-01

    The amyloid precursor protein (APP) undergoes sequential cleavages to generate various polypeptides, including the amyloid [beta] (1-42) peptide (A[beta][1-42]), which is believed to play a major role in amyloid plaque formation in Alzheimer's disease (AD). Here we provide evidence that, in contrast with its pathological role when accumulated,…

  2. Amyloid Beta Mediates Memory Formation

    ERIC Educational Resources Information Center

    Garcia-Osta, Ana; Alberini, Cristina M.

    2009-01-01

    The amyloid precursor protein (APP) undergoes sequential cleavages to generate various polypeptides, including the amyloid [beta] (1-42) peptide (A[beta][1-42]), which is believed to play a major role in amyloid plaque formation in Alzheimer's disease (AD). Here we provide evidence that, in contrast with its pathological role when accumulated,…

  3. Hydrogen Sulfide Inhibits Amyloid Formation

    PubMed Central

    2015-01-01

    Amyloid fibrils are large aggregates of misfolded proteins, which are often associated with various neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s, and vascular dementia. The amount of hydrogen sulfide (H2S) is known to be significantly reduced in the brain tissue of people diagnosed with Alzheimer’s disease relative to that of healthy individuals. These findings prompted us to investigate the effects of H2S on the formation of amyloids in vitro using a model fibrillogenic protein hen egg white lysozyme (HEWL). HEWL forms typical β-sheet rich fibrils during the course of 70 min at low pH and high temperatures. The addition of H2S completely inhibits the formation of β-sheet and amyloid fibrils, as revealed by deep UV resonance Raman (DUVRR) spectroscopy and ThT fluorescence. Nonresonance Raman spectroscopy shows that disulfide bonds undergo significant rearrangements in the presence of H2S. Raman bands corresponding to disulfide (RSSR) vibrational modes in the 550–500 cm–1 spectral range decrease in intensity and are accompanied by the appearance of a new 490 cm–1 band assigned to the trisulfide group (RSSSR) based on the comparison with model compounds. The formation of RSSSR was proven further using a reaction with TCEP reduction agent and LC-MS analysis of the products. Intrinsic tryptophan fluorescence study shows a strong denaturation of HEWL containing trisulfide bonds. The presented evidence indicates that H2S causes the formation of trisulfide bridges, which destabilizes HEWL structure, preventing protein fibrillation. As a result, small spherical aggregates of unordered protein form, which exhibit no cytotoxicity by contrast with HEWL fibrils. PMID:25545790

  4. In situ hybridization of nucleus basalis neurons shows increased. beta. -amyloid mRNA in Alzheimer disease

    SciTech Connect

    Cohen, M.L.; Golde, T.E.; Usiak, M.F.; Younkin, L.H.; Younkin, S.G.

    1988-02-01

    To determine which cells within the brain produce ..beta..-amyloid mRNA and to assess expression of the ..beta..-amyloid gene in Alzheimer disease, the authors analyzed brain tissue from Alzheimer and control patients by in situ hybridization. The results demonstrate that ..beta..-amyloid mRNA is produced by neurons in the nucleus basalis of Meynert and cerebral cortex and that nuclues basalis perikarya from Alzheimer patients consistently hybridize more ..beta..-amyloid probe than those from controls. These observations support the hypothesis that increased expression of the ..beta..-amyloid gene plays an important role in the deposition of amyloid in the brains of patients with Alzheimer disease.

  5. Characterization of amyloid in equine recurrent uveitis as AA amyloid.

    PubMed

    Ostevik, L; de Souza, G A; Wien, T N; Gunnes, G; Sørby, R

    2014-01-01

    Two horses with chronic uveitis and histological lesions consistent with equine recurrent uveitis (ERU) were examined. Microscopical findings in the ciliary body included deposits of amyloid lining the non-pigmented epithelium, intracytoplasmic, rod-shaped, eosinophilic inclusions and intraepithelial infiltration of T lymphocytes. Ultrastructural examination of the ciliary body of one horse confirmed the presence of abundant extracellular deposits of non-branching fibrils (9-11 nm in diameter) consistent with amyloid. Immunohistochemistry revealed strong positive labelling for AA amyloid and mass spectrometry showed the amyloid to consist primarily of serum amyloid A1 in both cases. The findings suggest that localized, intraocular AA amyloidosis may occur in horses with ERU.

  6. Amyloid Fibril Solubility.

    PubMed

    Rizzi, L G; Auer, S

    2015-11-19

    It is well established that amyloid fibril solubility is protein specific, but how solubility depends on the interactions between the fibril building blocks is not clear. Here we use a simple protein model and perform Monte Carlo simulations to directly measure the solubility of amyloid fibrils as a function of the interaction between the fibril building blocks. Our simulations confirms that the fibril solubility depends on the fibril thickness and that the relationship between the interactions and the solubility can be described by a simple analytical formula. The results presented in this study reveal general rules how side-chain-side-chain interactions, backbone hydrogen bonding, and temperature affect amyloid fibril solubility, which might prove to be a powerful tool to design protein fibrils with desired solubility and aggregation properties in general.

  7. Targeting vascular amyloid in arterioles of Alzheimer disease transgenic mice with amyloid β protein antibody-coated nanoparticles.

    PubMed

    Poduslo, Joseph F; Hultman, Kristi L; Curran, Geoffry L; Preboske, Gregory M; Chamberlain, Ryan; Marjańska, Małgorzata; Garwood, Michael; Jack, Clifford R; Wengenack, Thomas M

    2011-08-01

    The relevance of cerebral amyloid angiopathy (CAA) to the pathogenesis of Alzheimer disease (AD) and dementia in general emphasizes the importance of developing novel targeting approaches for detecting and treating cerebrovascular amyloid (CVA) deposits. We developed a nanoparticle-based technology that uses a monoclonal antibody against fibrillar human amyloid-β42 that is surface coated onto a functionalized phospholipid monolayer. We demonstrate that this conjugated nanoparticle binds to CVA deposits in arterioles of AD transgenic mice (Tg2576) after infusion into the external carotid artery using 3 different approaches. The first 2 approaches use a blood vessel enrichment of homogenized brain and a leptomeningeal vessel preparation from thin tangential brain slices from the surface of the cerebral cortex. Targeting of CVA by the antibody-coated nanoparticle was visualized using fluorescent lissamine rhodamine-labeled phospholipids in the nanoparticles, which were compared with fluorescent staining of the endothelial cells and amyloid deposits using confocal laser scanning microscopy. The third approach used high-field strength magnetic resonance imaging of antibody-coated iron oxide nanoparticles after infusion into the external carotid artery. Dark foci of contrast enhancement in cortical arterioles were observed in T2*-weighted images of ex vivo AD mouse brains that correlated histologically with CVA deposits. The targeting ability of these nanoparticles to CVA provides opportunities for the prevention and treatment of CAA.

  8. Targeting Vascular Amyloid in Arterioles of Alzheimer Disease Transgenic Mice with Amyloid Beta Protein Antibody-Coated Nanoparticles

    PubMed Central

    Poduslo, Joseph F.; Hultman, Kristi L.; Curran, Geoffry L.; Preboske, Gregory M.; Chamberlain, Ryan; Marjańska, Małgorzata; Garwood, Michael; Jack, Clifford R.; Wengenack, Thomas M.

    2015-01-01

    The relevance of cerebral amyloid angiopathy (CAA) to the pathogenesis of Alzheimer disease (AD) and dementia in general emphasizes the importance of developing novel targeting approaches for detecting and treating cerebrovascular amyloid (CVA) deposits. We developed a nanoparticle-based technology that utilizes a monoclonal antibody against fibrillar human amyloid-β42 that is surface-coated onto a functionalized phospholipid monolayer. We demonstrate that this conjugated nanoparticle binds to CVA deposits in arterioles of AD transgenic mice (Tg2576) following infusion into the external carotid artery using 3 different approaches. The first 2 approaches utilize a blood vessel enrichment of homogenized brain and a leptomeningeal vessel preparation from thin tangential brain slices from the surface of the cerebral cortex. Targeting of CVA by the antibody-coated nanoparticle was visualized using fluorescent lissamine rhodamine-labeled phospholipids in the nanoparticles, which were compared with fluorescent staining of the endothelial cells and amyloid deposits utilizing confocal laser scanning microscopy. The third approach utilized high field strength magnetic resonance imaging of antibody-coated iron oxide nanoparticles (MIONs) following infusion into the external carotid artery. Dark foci of contrast enhancement in cortical arterioles were observed in T2*-weighted images of ex vivo AD mouse brains that correlated histologically with CVA deposits. The targeting ability of these nanoparticles to CVA provides opportunities for the prevention and treatment of CAA. PMID:21760540

  9. Chungsim-Yeunja-Tang decreases the inflammatory response in peripheral blood mononuclear cells from patients with cerebral infarction through an NF-κB dependent mechanism

    PubMed Central

    2010-01-01

    Background Chungsim-Yeunja-Tang (CYT) has been used as a medicine for cerebral infarction (CI) patients in Korea. The objective of this study was to determine precisely the effect of CYT on CI patients using peripheral blood mononuclear cells (PBMCs). Methods For a clinical study, 47 CI patients were identified who had taken CYT (0.01 g/kg) 3 times a day after meals for 2 weeks by oral administration. For ex vivo experiments, peripheral blood mononuclear cells (PBMCs) were isolated from CI patients. We analyzed the effect of CYT and its main components on lipopolysaccharide (LPS)-induced cytokine production and mechanism on PBMCs of CI patients by using ELISA, western blot analysis, transcription factor enzyme-linked immunoassay, and caspase assay. Results Clinical signs of CI significantly disappeared about 2 weeks after oral administration of CYT to CI patients (P < 0.05). CYT and quercetin, an active compound of CYT, significantly inhibited LPS-induced interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α production and expression in PBMCs. CYT and quercetin also inhibited LPS-induced nuclear translocation and DNA binding activities of nuclear factor-κB and degradation of IκBα. In addition, CYT and quercetin inhibited LPS-induced IL-32 expression and caspase-1 activation. Conclusion These results suggest a mechanism that might explain the beneficial effect of CYT in treating CI patients. Taken together, our findings indicate that inhibition of IL-32 expression and caspase-1 activation may be a novel biomarker and potential therapeutic target in CI. PMID:21108840

  10. Effects of age and amyloid deposition on Aβ dynamics in the human central nervous system.

    PubMed

    Huang, Yafei; Potter, Rachel; Sigurdson, Wendy; Santacruz, Anna; Shih, Shirley; Ju, Yo-El; Kasten, Tom; Morris, John C; Mintun, Mark; Duntley, Stephen; Bateman, Randall J

    2012-01-01

    The amyloid hypothesis predicts that increased production or decreased clearance of β-amyloid (Aβ) leads to amyloidosis, which ultimately culminates in Alzheimer disease (AD). To investigate whether dynamic changes in Aβ levels in the human central nervous system may be altered by aging or by the pathology of AD and thus contribute to the risk of AD. Repeated-measures case-control study. Washington University School of Medicine in St Louis, Missouri. Participants with amyloid deposition, participants without amyloid deposition, and younger normal control participants. In this study, hourly cerebrospinal fluid (CSF) Aβ concentrations were compared with age, status of amyloid deposition, electroencephalography, and video recording data. Linear increases were observed over time in the Aβ levels in CSF samples obtained from the younger normal control participants and the older participants without amyloid deposition, but not from the older participants with amyloid deposition. Significant circadian patterns were observed in the Aβ levels in CSF samples obtained from the younger control participants; however, circadian amplitudes decreased in both older participants without amyloid deposition and older participants with amyloid deposition. Aβ diurnal concentrations were correlated with the amount of sleep but not with the various activities that the participants participated in while awake. A reduction in the linear increase in the Aβ levels in CSF samples that is associated with amyloid deposition and a decreased CSF Aβ diurnal pattern associated with increasing age disrupt the normal physiology of Aβ dynamics and may contribute to AD.

  11. Nanomaterials for reducing amyloid cytotoxicity.

    PubMed

    Zhang, Min; Mao, Xiaobo; Yu, Yue; Wang, Chen-Xuan; Yang, Yan-Lian; Wang, Chen

    2013-07-26

    This review is intended to reflect the recent progress on therapeutic applications of nanomaterials in amyloid diseases. The progress on anti-amyloid functions of various nanomaterials including inorganic nanoparticles, polymeric nanoparticles, carbon nanomaterials and biomolecular aggregates, is reviewed and discussed. The main functionalization strategies for general nanoparticle modifications are reviewed for potential applications of targeted therapeutics. The interaction mechanisms between amyloid peptides and nanomaterials are discussed from the perspectives of dominant interactions and kinetics. The encapsulation of anti-amyloid drugs, targeted drug delivery, controlled drug release and drug delivery crossing blood brain barrier by application of nanomaterials would also improve the therapeutics of amyloid diseases.

  12. Will PET amyloid imaging lead to overdiagnosis of Alzheimer dementia?

    PubMed

    Dubroff, Jacob G; Nasrallah, Ilya M

    2015-08-01

    Alzheimer disease (AD), a progressive neurodegenerative disease that causes dementia, affects millions of elderly Americans and represents a growing problem with the aging of the population. There has been an increasing effort for improved and earlier diagnosis for AD. Several newly developed radiolabeled compounds targeting β-amyloid plaques, one of the major pathologic biomarkers of AD, have recently become available for clinical use. These radiopharmaceuticals allow for in vivo noninvasive visualization of abnormal β-amyloid deposits in the brain using positron emission tomography (PET). Amyloid PET imaging has demonstrated high sensitivity for pathologic cerebral amyloid deposition in multiple studies. Principal drawbacks to this new diagnostic test are declining specificity in older age groups and uncertain clinical role given lack of disease-modifying therapy for AD. Although there is strong evidence for the utility of amyloid PET in certain situations, detailed in a set of guidelines for appropriate use from the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging, the question of overdiagnosis, the diagnosis of a disease that would result in neither symptoms nor deaths, using this new medical tool needs to be carefully considered in light of efforts to secure reimbursement for the new technology that is already widely available for use as a clinical tool. Copyright © 2015 AUR. Published by Elsevier Inc. All rights reserved.

  13. Preferential association of serum amyloid P component with fibrillar deposits in familial British and Danish dementias: similarities with Alzheimer's disease.

    PubMed

    Rostagno, Agueda; Lashley, Tammaryn; Ng, Douglas; Meyerson, Jordana; Braendgaard, Hans; Plant, Gordon; Bojsen-Møller, Marie; Holton, Janice; Frangione, Blas; Revesz, Tamas; Ghiso, Jorge

    2007-06-15

    Two hereditary forms of cerebrovascular amyloidosis, familial British and Danish dementias (FBD and FDD), share striking similarities with Alzheimer's disease (AD) despite structural differences among their amyloid subunits (ABri in FBD, ADan in FDD, and Abeta in AD). Neuropathological lesions in these disorders include neurofibrillary tangles, parenchymal amyloid and pre-amyloid deposits and overwhelming cerebral amyloid angiopathy co-localizing with reactive microglia and multiple amyloid associated proteins including activation products of the complement cascade. Immunohistochemical analysis of FBD and FDD brain lesions unveiled the presence of serum amyloid P-component (SAP) primarily associated with thioflavin positive amyloid deposits in spite of the significant pre-amyloid burden existing in both disorders. Using affinity chromatography and ELISA binding assays we demonstrated specific, calcium-dependent, saturable, high affinity binding interactions between SAP and ABri/ADan peptides, with dissociation constant values in the sub-nanomolar range and within the same order of magnitude as those resulting from the interaction of SAP with Alzheimer's Abeta1-40 and Abeta1-42. The preferential association of SAP with fibrillar amyloid lesions and not with non-fibrillar pre-amyloid deposits is puzzling, suggesting that SAP modulates the assembly and stability of the final fibril rather than participating in the early steps of protein misfolding and oligomerization.

  14. Young to Middle-Aged Dogs with High Amyloid-β Levels in Cerebrospinal Fluid are Impaired on Learning in Standard Cognition tests.

    PubMed

    Borghys, Herman; Van Broeck, Bianca; Dhuyvetter, Deborah; Jacobs, Tom; de Waepenaert, Katja; Erkens, Tim; Brooks, Melissa; Thevarkunnel, Sandy; Araujo, Joseph A

    2017-01-01

    Understanding differences in Alzheimer's disease biomarkers before the pathology becomes evident can contribute to an improved understanding of disease pathogenesis and treatment. A decrease in amyloid-β (Aβ)42 in cerebrospinal fluid (CSF) is suggested to be a biomarker for Aβ deposition in brain. However, the relevance of CSF Aβ levels prior to deposition is not entirely known. Dogs are similar to man with respect to amyloid-β protein precursor (AβPP)-processing, age-related amyloid plaque deposition, and cognitive dysfunction. In the current study, we evaluated the relation between CSF Aβ42 levels and cognitive performance in young to middle-aged dogs (1.5-7 years old). Additionally, CSF sAβPPα and sAβPPβ were measured to evaluate AβPP processing, and CSF cytokines were measured to determine the immune status of the brain. We identified two groups of dogs showing consistently low or high CSF Aβ42 levels. Based on prior studies, it was assumed that at this age no cerebral amyloid plaques were likely to be present. The cognitive performance was evaluated in standard cognition tests. Low or high Aβ concentrations coincided with low or high sAβPPα, sAβPPβ, and CXCL-1 levels, respectively. Dogs with high Aβ concentrations showed significant learning impairments on delayed non-match to position (DNMP), object discrimination, and reversal learning compared to dogs with low Aβ concentrations. Our data support the hypothesis that high levels of CSF Aβ in dogs coincide with lower cognitive performance prior to amyloid deposition. Further experiments are needed to investigate this link, as well as the relevance with respect to Alzheimer's disease pathology progression.

  15. Young to Middle-Aged Dogs with High Amyloid-β Levels in Cerebrospinal Fluid are Impaired on Learning in Standard Cognition tests

    PubMed Central

    Borghys, Herman; Van Broeck, Bianca; Dhuyvetter, Deborah; Jacobs, Tom; de Waepenaert, Katja; Erkens, Tim; Brooks, Melissa; Thevarkunnel, Sandy; Araujo, Joseph A.

    2016-01-01

    Understanding differences in Alzheimer’s disease biomarkers before the pathology becomes evident can contribute to an improved understanding of disease pathogenesis and treatment. A decrease in amyloid-β (Aβ)42 in cerebrospinal fluid (CSF) is suggested to be a biomarker for Aβ deposition in brain. However, the relevance of CSF Aβ levels prior to deposition is not entirely known. Dogs are similar to man with respect to amyloid-β protein precursor (AβPP)-processing, age-related amyloid plaque deposition, and cognitive dysfunction. In the current study, we evaluated the relation between CSF Aβ42 levels and cognitive performance in young to middle-aged dogs (1.5–7 years old). Additionally, CSF sAβPPα and sAβPPβ were measured to evaluate AβPP processing, and CSF cytokines were measured to determine the immune status of the brain. We identified two groups of dogs showing consistently low or high CSF Aβ42 levels. Based on prior studies, it was assumed that at this age no cerebral amyloid plaques were likely to be present. The cognitive performance was evaluated in standard cognition tests. Low or high Aβ concentrations coincided with low or high sAβPPα, sAβPPβ, and CXCL-1 levels, respectively. Dogs with high Aβ concentrations showed significant learning impairments on delayed non-match to position (DNMP), object discrimination, and reversal learning compared to dogs with low Aβ concentrations. Our data support the hypothesis that high levels of CSF Aβ in dogs coincide with lower cognitive performance prior to amyloid deposition. Further experiments are needed to investigate this link, as well as the relevance with respect to Alzheimer’s disease pathology progression. PMID:28035921

  16. ABCA7 Mediates Phagocytic Clearance of Amyloid-β in the Brain.

    PubMed

    Fu, YuHong; Hsiao, Jen-Hsiang T; Paxinos, George; Halliday, Glenda M; Kim, Woojin Scott

    2016-09-06

    Alzheimer's disease (AD) is a neurodegenerative disorder characterized by dementia and abnormal deposits of aggregated amyloid-β in the brain. Recent genome-wide association studies have revealed that ABCA7 is strongly associated with AD. In vitro evidence suggests that the role of ABCA7 is related to phagocytic activity. Deletion of ABCA7 in a mouse model of AD exacerbates cerebral amyloid-β plaque load. However, the biological role of ABCA7 in AD brain pathogenesis is unknown. We show that ABCA7 is highly expressed in microglia and when monocytes are differentiated into macrophages. We hypothesized that ABCA7 plays a protective role in the brain that is related to phagocytic clearance of amyloid-β. We isolated microglia and macrophages from Abca7-/- and wild type mice and tested them for their capacity to phagocytose amyloid-β oligomers. We found that the phagocytic clearance of amyloid-β was substantially reduced in both microglia and macrophages from Abca7-/- mice compared to wild type mice. Consistent with these results, in vivo phagocytic clearance of amyloid-β oligomers in the hippocampus was reduced in Abca7-/- mice. Furthermore, ABCA7 transcription was upregulated in AD brains and in amyloidogenic mouse brains specifically in the hippocampus as a response to the amyloid-β pathogenic state. Together these results indicate that ABCA7 mediates phagocytic clearance of amyloid-β in the brain, and reveal a mechanism by which loss of function of ABCA7 increases the susceptibility to AD.

  17. Toxicity of substrate-bound amyloid peptides on vascular smooth muscle cells is enhanced by homocysteine.

    PubMed

    Mok, Su San; Turner, Bradley J; Beyreuther, Konrad; Masters, Colin L; Barrow, Colin J; Small, David H

    2002-06-01

    Tauhe main component of cerebral amyloid angiopathy (CAA) in Alzheimer's disease is the amyloid-beta protein (Abeta), a 4-kDa polypeptide derived from the beta-amyloid protein precursor (APP). The accumulation of Abeta in the basement membrane has been implicated in the degeneration of adjacent vascular smooth muscle cells (VSMC). However, the mechanism of Abeta toxicity is still unclear. In this study, we examined the effect of substrate-bound Abeta on VSMC in culture. The use of substrate-bound proteins in cell culture mimics presentation of the proteins to cells as if bound to the basement membrane. Substrate-bound Abeta peptides were found to be toxic to the cells and to increase the rate of cell death. This toxicity was dependent on the length of time the peptide was allowed to 'age', a process by which Abeta is induced to aggregate over several hours to days. Oxidative stress via hydrogen peroxide (H2O2) release was not involved in the toxic effect, as no decrease in toxicity was observed in the presence of catalase. However, substrate-bound Abeta significantly reduced cell adhesion compared to cells grown on plastic alone, indicating that cell-substrate adhesion may be important in maintaining cell viability. Abeta also caused an increase in the number of apoptotic cells. This increase in apoptosis was accompanied by activation of caspase-3. Homocysteine, a known risk factor for cerebrovascular disease, increased Abeta-induced toxicity and caspase-3 activation in a dose-dependent manner. These studies suggest that Abeta may activate apoptotic pathways to cause loss of VSMC in CAA by inhibiting cell-substrate interactions. Our studies also suggest that homocysteine, a known risk factor for other cardiovascular diseases, could also be a risk factor for hemorrhagic stroke associated with CAA.

  18. The Mechanism of Amyloid Spherulite Formation by Bovine Insulin

    PubMed Central

    Krebs, M. R. H.; Bromley, E. H. C.; Rogers, S. S.; Donald, A. M.

    2005-01-01

    The formation of amyloid-containing spherulite-like structures has been observed in some instances of amyloid diseases, as well as in amyloid fibril-containing solutions in vitro. In this article we describe the structure and kinetics of bovine insulin amyloid fibril spherulites formed in the presence and absence of different salts and at different salt concentrations. The general spherulite structure consists of radially oriented amyloid fibrils, as shown by optical microscopy and environmental scanning electron microscopy. In the center of each spherulite, a “core” of less regularly oriented material is observed, whose size decreases when the spherulites are formed in the presence of increasing concentrations of NaCl. Similarly, amyloid fibrils form faster in the presence of NaCl than in its absence. A smaller enhancement of the rate of formation with salt concentration is observed for spherulites. These data suggest that both amyloid fibril formation and random aggregation occur concurrently under the conditions tested. Changes in their relative rates result in the different-sized cores observed in the spherulites. This mechanism can be likened to that leading to the formation of spherulites of polyethylene, in agreement with observations that polypeptide chains under partially denaturing conditions can exhibit behavior not dissimilar to that of synthetic polymers. PMID:15596515

  19. Altered Processing of Amyloid Precursor Protein in Cells Undergoing Apoptosis

    PubMed Central

    Fiorelli, Tina; Kirouac, Lisa; Padmanabhan, Jaya

    2013-01-01

    Altered proteolysis of amyloid precursor protein is an important determinant of pathology development in Alzheimer's disease. Here, we describe the detection of two novel fragments of amyloid precursor protein in H4 neuroglioma cells undergoing apoptosis. Immunoreactivity of these 25–35 kDa fragments to two different amyloid precursor protein antibodies suggests that they contain the amyloid-β region and an epitope near the C-terminus of amyloid precursor protein. Generation of these fragments is associated with cleavage of caspase-3 and caspase-7, suggesting activation of these caspases. Studies in neurons undergoing DNA damage-induced apoptosis also showed similar results. Inclusion of caspase inhibitors prevented the generation of these novel fragments, suggesting that they are generated by a caspase-dependent mechanism. Molecular weight prediction and immunoreactivity of the fragments generated suggested that such fragments could not be generated by cleavage at any previously identified caspase, secretase, or calpain site on amyloid precursor protein. Bioinformatic analysis of the amino acid sequence of amyloid precursor protein revealed that fragments fitting the observed size and immunoreactivity could be generated by either cleavage at a novel, hitherto unidentified, caspase site or at a previously identified matrix metalloproteinase site in the extracellular domain. Proteolytic cleavage at any of these sites leads to a decrease in the generation of α-secretase cleaved secreted APP, which has both anti-apoptotic and neuroprotective properties, and thus may contribute to neurodegeneration in Alzheimer's disease. PMID:23469123

  20. Incidental Cerebral Microbleeds and Cerebral Blood Flow in Elderly Individuals.

    PubMed

    Gregg, Nicholas M; Kim, Albert E; Gurol, M Edip; Lopez, Oscar L; Aizenstein, Howard J; Price, Julie C; Mathis, Chester A; James, Jeffrey A; Snitz, Beth E; Cohen, Ann D; Kamboh, M Ilyas; Minhas, Davneet; Weissfeld, Lisa A; Tamburo, Erica L; Klunk, William E

    2015-09-01

    Cerebral microbleeds (CMBs) are collections of blood breakdown products that are a common incidental finding in magnetic resonance imaging of elderly individuals. Cerebral microbleeds are associated with cognitive deficits, but the mechanism is unclear. Studies show that individuals with CMBs related to symptomatic cerebral amyloid angiopathy have abnormal vascular reactivity and cerebral blood flow (CBF), but, to our knowledge, abnormalities in cerebral blood flow have not been reported for healthy individuals with incidental CMBs. To evaluate the association of incidental CMBs with resting-state CBF, cerebral metabolism, cerebrovascular disease, β-amyloid (Aβ), and cognition. A cross-sectional study of 55 cognitively normal individuals with a mean (SD) age of 86.8 (2.7) years was conducted from May 1, 2010, to May 1, 2013, in an academic medical center in Pittsburgh; data analysis was performed between June 10, 2013, and April 9, 2015. 3-Tesla magnetic resonance imaging was performed with susceptibility-weighted imaging or gradient-recalled echo to assess CMBs, arterial spin labeling for CBF, and T1- and T2-weighted imaging for atrophy, white matter hyperintensities, and infarcts. Positron emission tomography was conducted with fluorodeoxyglucose to measure cerebral metabolism and Pittsburgh compound B for fibrillar Aβ. Neuropsychological evaluation, including the Clinical Dementia Rating scale, was performed. Magnetic resonance images were rated for the presence and location of CMBs. Lobar CMBs were subclassified as cortical or subcortical. Measurements of CBF, metabolism, and Aβ were compared with the presence and number of CMBs with voxelwise and region-of-interest analyses. The presence of cortical CMBs was associated with significantly reduced CBF in multiple regions on voxelwise and region-of-interest analyses (percentage difference in global CBF, -25.3%; P = .0003), with the largest reductions in the parietal cortex (-37.6%; P < .0001) and

  1. Assessment of the Incremental Diagnostic Value of Florbetapir F 18 Imaging in Patients With Cognitive Impairment: The Incremental Diagnostic Value of Amyloid PET With [18F]-Florbetapir (INDIA-FBP) Study.

    PubMed

    Boccardi, Marina; Altomare, Daniele; Ferrari, Clarissa; Festari, Cristina; Guerra, Ugo Paolo; Paghera, Barbara; Pizzocaro, Claudio; Lussignoli, Giulia; Geroldi, Cristina; Zanetti, Orazio; Cotelli, Maria Sofia; Turla, Marinella; Borroni, Barbara; Rozzini, Luca; Mirabile, Dario; Defanti, Carlo; Gennuso, Michele; Prelle, Alessandro; Gentile, Simona; Morandi, Alessandro; Vollaro, Stefano; Volta, Giorgio Dalla; Bianchetti, Angelo; Conti, Marta Zaffira; Cappuccio, Melania; Carbone, Pasqualina; Bellandi, Daniele; Abruzzi, Luciano; Bettoni, Luigi; Villani, Daniele; Raimondi, Maria Clara; Lanari, Alessia; Ciccone, Alfonso; Facchi, Emanuela; Di Fazio, Ignazio; Rozzini, Renzo; Boffelli, Stefano; Manzoni, Laura; Salvi, Giovanni Pietro; Cavaliere, Sabina; Belotti, Gloria; Avanzi, Stefano; Pasqualetti, Patrizio; Muscio, Cristina; Padovani, Alessandro; Frisoni, Giovanni B

    2016-12-01

    Cerebral amyloidosis is a key abnormality in Alzheimer disease (AD) and can be detected in vivo with positron emission tomography (PET) ligands. Although amyloid PET has clearly demonstrated analytical validity, its clinical utility is debated. To evaluate the incremental diagnostic value of amyloid PET with florbetapir F 18 in addition to the routine clinical diagnostic assessment of patients evaluated for cognitive impairment. The Incremental Diagnostic Value of Amyloid PET With [18F]-Florbetapir (INDIA-FBP) Study is a multicenter study involving 18 AD evaluation units from eastern Lombardy, Northern Italy, 228 consecutive adults with cognitive impairment were evaluated for AD and other causes of cognitive decline, with a prescan diagnostic confidence of AD between 15% and 85%. Participants underwent routine clinical and instrumental diagnostic assessment. A prescan diagnosis was made, diagnostic confidence was estimated, and drug treatment was provided. At the time of this workup, an amyloid PET/computed tomographic scan was performed, and the result was communicated to physicians after workup completion. Physicians were asked to review the diagnosis, diagnostic confidence, and treatment after the scan. The study was conducted from August 5, 2013, to December 31, 2014. Primary outcomes were prescan to postscan changes of diagnosis, diagnostic confidence, and treatment. Of the 228 participants, 107 (46%) were male; mean (SD) age was 70.5 (7) years. Diagnostic change occurred in 46 patients (79%) having both a previous diagnosis of AD and an amyloid-negative scan (P < .001) and in 16 (53%) of those with non-AD diagnoses and an amyloid-positive scan (P < .001). Diagnostic confidence in AD diagnosis increased by 15.2% in amyloid-positive (P < .001; effect size Cohen d = 1.04) and decreased by 29.9% in amyloid-negative (P < .001; d = -1.19) scans. Acetylcholinesterase inhibitors and memantine hydrochloride were introduced in 61 (65

  2. Hypoxic stress, brain vascular system, and β-amyloid: a primary cell culture study.

    PubMed

    Muche, Abebe; Bürger, Susanne; Arendt, Thomas; Schliebs, Reinhard

    2015-01-01

    This study stresses the hypothesis whether hypoxic events contribute to formation and deposition of β-amyloid (Aβ) in cerebral blood vessels by affecting the processing of endothelial amyloid precursor protein (APP). Therefore, cerebral endothelial cells (ECs) derived from transgenic Tg2576 mouse brain, were subjected to short periods of hypoxic stress, followed by assessment of formation and secretion of APP cleavage products sAPPα, sAPPβ, and Aβ as well as the expression of endothelial APP. Hypoxic stress of EC leads to enhanced secretion of sAPPβ into the culture medium as compared to normoxic controls, which is accompanied by increased APP expression, induction of vascular endothelial growth factor (VEGF) synthesis, nitric oxide production, and differential changes in endothelial p42/44 (ERK1/2) expression. The hypoxia-mediated up-regulation of p42/44 at a particular time of incubation was accompanied by a corresponding down-regulation of the phosphorylated form of p42/44. To reveal any role of hypoxia-induced VEGF in endothelial APP processing, ECs were exposed by VEGF. VEGF hardly affected the amount of sAPPβ and Aβ(1-40) secreted into the culture medium, whereas the suppression of the VEGF receptor action by SU-5416 resulted in decreased release of sAPPβ and Aβ(1-40) in comparison to control incubations, suggesting a role of VEGF in controlling the activity of γ-secretase, presumably via the VEGF receptor-associated tyrosine kinase. The data suggest that hypoxic stress represents a mayor risk factor in causing Aβ deposition in the brain vascular system by favoring the amyloidogenic route of endothelial APP processing. The hypoxic-stress-induced changes in β-secretase activity are presumably mediated by altering the phosphorylation status of p42/44, whereas the stress-induced up-regulation of VEGF appears to play a counteracting role by maintaining the balance of physiological APP processing.

  3. Origins of amyloid

    PubMed Central

    2013-01-01

    Background Amyloid-β plaques are a defining characteristic of Alzheimer Disease. However, Amyloid-β deposition is also found in other forms of dementia and in non-pathological contexts. Amyloid-β deposition is variable among vertebrate species and the evolutionary emergence of the amyloidogenic property is currently unknown. Evolutionary persistence of a pathological peptide sequence may depend on the functions of the precursor gene, conservation or mutation of nucleotides or peptide domains within the precursor gene, or a species-specific physiological environment. Results In this study, we asked when amyloidogenic Amyloid-β first arose using phylogenetic trees constructed for the Amyloid-β Precursor Protein gene family and by modeling the potential for Amyloid-β aggregation across species in silico. We collected the most comprehensive set of sequences for the Amyloid-β Precursor Protein family using an automated, iterative meta-database search and constructed a highly resolved phylogeny. The analysis revealed that the ancestral gene for invertebrate and vertebrate Amyloid-β Precursor Protein gene families arose around metazoic speciation during the Ediacaran period. Synapomorphic frequencies found domain-specific conservation of sequence. Analyses of aggregation potential showed that potentially amyloidogenic sequences are a ubiquitous feature of vertebrate Amyloid-β Precursor Protein but are also found in echinoderm, nematode, and cephalochordate, and hymenoptera species homologues. Conclusions The Amyloid-β Precursor Protein gene is ancient and highly conserved. The amyloid forming Amyloid-β domains may have been present in early deuterostomes, but more recent mutations appear to have resulted in potentially unrelated amyoid forming sequences. Our results further highlight that the species-specific physiological environment is as critical to Amyloid-β formation as the peptide sequence. PMID:23627794

  4. Amyloid Aggregation and Membrane Disruption by Amyloid Proteins

    NASA Astrophysics Data System (ADS)

    Ramamoorthy, Ayyalusamy

    2013-03-01

    Amyloidogenesis has been the focus of intense basic and clinical research, as an increasing number of amyloidogenic proteins have been linked to common and incurable degenerative diseases including Alzheimer's, type II diabetes, and Parkinson's. Recent studies suggest that the cell toxicity is mainly due to intermediates generated during the assembly process of amyloid fibers, which have been proposed to attack cells in a variety of ways. Disruption of cell membranes is believed to be one of the key components of amyloid toxicity. However, the mechanism by which this occurs is not fully understood. Our research in this area is focused on the investigation of the early events in the aggregation and membrane disruption of amyloid proteins, Islet amyloid polypeptide protein (IAPP, also known as amylin) and amyloid-beta peptide, on the molecular level. Structural insights into the mechanisms of membrane disruption by these amyloid proteins and the role of membrane components on the membrane disruption will be presented.

  5. Amyloid imaging in dementias with atypical presentation.

    PubMed

    Wolk, David A; Price, Julie C; Madeira, Charles; Saxton, Judy A; Snitz, Beth E; Lopez, Oscar L; Mathis, Chester A; Klunk, William E; DeKosky, Steven T

    2012-09-01

    With the potential emergence of disease specific therapies, an accurate biomarker of Alzheimer's Disease pathology is needed in cases in which the underlying etiology is uncertain. We explored the potential value of amyloid imaging in patients with atypical presentations of dementia. Twenty-eight patients with atypical dementia underwent positron emission tomography imaging with the amyloid imaging tracer Pittsburgh compound B (PiB). Twenty-six had [18F]fluoro-2-deoxy-D-glucose positron emission tomography scans. After extensive clinical evaluation, this group of patients generated considerable diagnostic uncertainty and received working diagnoses that included possible Alzheimer's disease (AD), focal dementias (e.g., posterior cortical atrophy [PCA]), or cases in which no clear diagnostic category could be determined (dementia of uncertain etiology). Patients were classified as PiB-positive, PiB-negative, or PiB-intermediate, based on objective criteria. Anterior-posterior and left-right indices of PiB and [18F]fluoro-2-deoxy-D-glucose uptake were calculated to examine differences in distribution of amyloid pathology and metabolic changes associated with clinical phenotype. Eleven patients (39%) were PiB positive, 16 were PiB negative (57%), and one (4%) was PiB intermediate. By diagnostic category, three of 10 patients (30%) with dementia of uncertain etiology, one of five (20%) with primary progressive aphasia, three of five (60%) with PCA, and four of seven (57%) with possible AD were PiB positive. Brain metabolism of both PiB-positive and PiB-negative patients was generally similar by phenotype, but appeared to differ from typical AD. PCA patients also appeared to differ in their relative distribution of PiB compared with typical AD, consistent with their atypical phenotype. AD pathology is frequently present in atypical presentations of dementia and can be identified by amyloid imaging. Clinical phenotype is more related to the pattern of cerebral

  6. Mechanical deformation mechanisms and properties of amyloid fibrils.

    PubMed

    Choi, Bumjoon; Yoon, Gwonchan; Lee, Sang Woo; Eom, Kilho

    2015-01-14

    Amyloid fibrils have recently received attention due to their remarkable mechanical properties, which are highly correlated with their biological functions. We have studied the mechanical deformation mechanisms and properties of amyloid fibrils as a function of their length scales by using atomistic simulations. It is shown that the length of amyloid fibrils plays a role in their deformation and fracture mechanisms in such a way that the competition between shear and bending deformations is highly dependent on the fibril length, and that as the fibril length increases, so does the bending strength of the fibril while its shear strength decreases. The dependence of rupture force for amyloid fibrils on their length is elucidated using the Bell model, which suggests that the rupture force of the fibril is determined from the hydrogen bond rupture mechanism that critically depends on the fibril length. We have measured the toughness of amyloid fibrils, which is shown to depend on the fibril length. In particular, the toughness of the fibril with its length of ∼3 nm is estimated to be ∼30 kcal mol(-1) nm(-3), comparable to that of a spider silk crystal with its length of ∼2 nm. Moreover, we have shown the important effect of the pulling rate on the mechanical deformation mechanisms and properties of amyloid fibril. It is found that as the pulling rate increases, so does the contribution of the shear effect to the elastic deformation of the amyloid fibril with its length of <10 nm. However, we found that the deformation mechanism of the amyloid fibril with its length of >15 nm is almost independent of the pulling rate. Our study sheds light on the role of the length scale of amyloid fibrils and the pulling rate in their mechanical behaviors and properties, which may provide insights into how the excellent mechanical properties of protein fibrils can be determined.

  7. A subcutaneous cellular implant for passive immunization against amyloid-β reduces brain amyloid and tau pathologies.

    PubMed

    Lathuilière, Aurélien; Laversenne, Vanessa; Astolfo, Alberto; Kopetzki, Erhard; Jacobsen, Helmut; Stampanoni, Marco; Bohrmann, Bernd; Schneider, Bernard L; Aebischer, Patrick

    2016-05-01

    Passive immunization against misfolded toxic proteins is a promising approach to treat neurodegenerative disorders. For effective immunotherapy against Alzheimer's disease, recent clinical data indicate that monoclonal antibodies directed against the amyloid-β peptide should be administered before the onset of symptoms associated with irreversible brain damage. It is therefore critical to develop technologies for continuous antibody delivery applicable to disease prevention. Here, we addressed this question using a bioactive cellular implant to deliver recombinant anti-amyloid-β antibodies in the subcutaneous tissue. An encapsulating device permeable to macromolecules supports the long-term survival of myogenic cells over more than 10 months in immunocompetent allogeneic recipients. The encapsulated cells are genetically engineered to secrete high levels of anti-amyloid-β antibodies. Peripheral implantation leads to continuous antibody delivery to reach plasma levels that exceed 50 µg/ml. In a proof-of-concept study, we show that the recombinant antibodies produced by this system penetrate the brain and bind amyloid plaques in two mouse models of the Alzheimer's pathology. When encapsulated cells are implanted before the onset of amyloid plaque deposition in TauPS2APP mice, chronic exposure to anti-amyloid-β antibodies dramatically reduces amyloid-β40 and amyloid-β42 levels in the brain, decreases amyloid plaque burden, and most notably, prevents phospho-tau pathology in the hippocampus. These results support the use of encapsulated cell implants for passive immunotherapy against the misfolded proteins, which accumulate in Alzheimer's disease and other neurodegenerative disorders. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  8. Current and future treatment of amyloid diseases

    PubMed Central

    Ankarcrona, M.; Winblad, B.; Monteiro, C.; Fearns, C.; Powers, E. T.; Johansson, J.; Westermark, G. T.; Presto, J.; Ericzon, B-G.; Kelly, J. W.

    2016-01-01

    There are more than 30 human proteins whose aggregation appears to cause degenerative maladies referred to as amyloid diseases or amyloidoses. These disorders are named after the characteristic cross-β-sheet amyloid fibrils that accumulate systemically or are localized to specific organs. In most cases current treatment is limited to symptomatic approaches and thus disease-modifying therapies are needed. Alzheimer’s disease is a neurodegenerative disorder with amyloid β-peptide (Aβ) plaques and tau neurofibrillary tangles as pathological hallmarks. Numerous clinical trials have been conducted with vaccines and small molecules to target Aβ formation and aggregation and also enhance Aβ clearance; so far such clinical trials have been unsuccessful. Novel strategies are therefore required and here we will discuss the possibility of utilizing the chaperone BRICHOS to prevent Aβ aggregation and toxicity. Type 2 diabetes mellitus is symptomatically treated with insulin. However the disease is linked to the aggregation and progressive accumulation of islet amyloid polypeptide and oligomers of this peptide are cytotoxic. Several compounds have been shown to inhibit islet amyloid aggregation and cytotoxicity in vitro. Future animal studies and clinical trials have to be be conducted to determine their efficacy in vivo. Transthyretin (TTR) amyloidoses are a group of systemic degenerative diseases involving multiple organ systems and caused by TTR aggregation. Liver transplantation decreases the generation of misfolded TTR and improves the quality of life for a subgroup of this patient population. Compounds that stabilize the natively folded, non-amyloidogenic, tetrameric conformation of TTR have been developed and the drug tafamidis is available as treatment. PMID:27165517

  9. Current and future treatment of amyloid diseases.

    PubMed

    Ankarcrona, M; Winblad, B; Monteiro, C; Fearns, C; Powers, E T; Johansson, J; Westermark, G T; Presto, J; Ericzon, B-G; Kelly, J W

    2016-08-01

    There are more than 30 human proteins whose aggregation appears to cause degenerative maladies referred to as amyloid diseases or amyloidoses. These disorders are named after the characteristic cross-β-sheet amyloid fibrils that accumulate systemically or are localized to specific organs. In most cases, current treatment is limited to symptomatic approaches and thus disease-modifying therapies are needed. Alzheimer's disease is a neurodegenerative disorder with extracellular amyloid β-peptide (Aβ) fibrils and intracellular tau neurofibrillary tangles as pathological hallmarks. Numerous clinical trials have been conducted with passive and active immunotherapy, and small molecules to inhibit Aβ formation and aggregation or to enhance Aβ clearance; so far such clinical trials have been unsuccessful. Novel strategies are therefore required and here we will discuss the possibility of utilizing the chaperone BRICHOS to prevent Aβ aggregation and toxicity. Type 2 diabetes mellitus is symptomatically treated with insulin. However, the underlying pathology is linked to the aggregation and progressive accumulation of islet amyloid polypeptide as fibrils and oligomers, which are cytotoxic. Several compounds have been shown to inhibit islet amyloid aggregation and cytotoxicity in vitro. Future animal studies and clinical trials have to be conducted to determine their efficacy in vivo. The transthyretin (TTR) amyloidoses are a group of systemic degenerative diseases compromising multiple organ systems, caused by TTR aggregation. Liver transplantation decreases the generation of misfolded TTR and improves the quality of life for a subgroup of this patient population. Compounds that stabilize the natively folded, nonamyloidogenic, tetrameric conformation of TTR have been developed and the drug tafamidis is available as a promising treatment.

  10. A combined VBM and DTI study of schizophrenia: bilateral decreased insula volume and cerebral white matter disintegrity corresponding to subinsular white matter projections unlinked to clinical symptomatology.

    PubMed

    Onay, Aslıhan; Yapıcı Eser, Hale; Ulaşoğlu Yıldız, Çiğdem; Aslan, Selçuk; Talı, Erhan Turgut

    2017-01-01

    Grey matter and white matter changes within the brain are well defined in schizophrenia. However, most studies focused on either grey matter changes or white matter integrity separately; only in limited number of studies these changes were interpreted in the same frame. In addition, the relationship of these findings with clinical variables is not clearly established. Here, we aimed to investigate the grey matter and white matter changes in schizophrenia patients and exhibit the relation of these imaging findings with clinical variables. A total of 20 schizophrenia patients and 16 matched healthy controls underwent magnetic resonance imaging to investigate the grey matter and white matter alterations that occur in schizophrenia patients using voxel-based morphometry (VBM) and whole brain voxel-wise analysis of diffusion tensor imaging (DTI) parameters with SPM8, respectively. While the preprocessing steps of VBM were performed with the default parameters of VBM8 toolbox, the preprocessing steps of DTI were carried out using FSL. Additionally, VBM results were correlated with clinical variables. Bilateral insula showed decreased grey matter volume in schizophrenia patients compared with healthy controls (P < 0.01). The opposite contrast did not show a significant difference. Psychiatric scores, duration of illness, and age were not correlated with the decreased grey matter volume of insula in schizophrenia patients. DTI analysis revealed a significant increase in mean, radial, and axial diffusivity, mainly of the fibers of bilateral anterior thalamic radiation and superior longitudinal fasciculus with left predominance, which intersected with bilateral subinsular white matter (P < 0.05). Our findings suggest that insula may be the main affected brain region in schizophrenia, which is also well supported by the literature. Our results were independent of disease duration and schizophrenia symptoms. White matter alterations were observed within bilateral anterior

  11. Cerebral Small Vessel Disease: Targeting Oxidative Stress as a Novel Therapeutic Strategy?

    PubMed Central

    De Silva, T. Michael; Miller, Alyson A.

    2016-01-01

    Cerebral small vessel disease (SVD) is a major contributor to stroke, and a leading cause of cognitive impairment and dementia. Despite the devastating effects of cerebral SVD, the pathogenesis of cerebral SVD is still not completely understood. Moreover, there are no specific pharmacological strategies for its prevention or treatment. Cerebral SVD is characterized by marked functional and structural abnormalities of the cerebral microcirculation. The clinical manifestations of these pathological changes include lacunar infarcts, white matter hyperintensities, and cerebral microbleeds. The main purpose of this review is to discuss evidence implicating oxidative stress in the arteriopathy of both non-amyloid and amyloid (cerebral amyloid angiopathy) forms of cerebral SVD and its most important risk factors (hypertension and aging), as well as its contribution to cerebral SVD-related brain injury and cognitive impairment. We also highlight current evidence of the involvement of the NADPH oxidases in the development of oxidative stress, enzymes that are a major source of reactive oxygen species in the cerebral vasculature. Lastly, we discuss potential pharmacological strategies for oxidative stress in cerebral SVD, including some of the historical and emerging NADPH oxidase inhibitors. PMID:27014073

  12. Cerebral Aneurysms

    MedlinePlus

    ... cerebral aneurysm may be required to restore deteriorating respiration and reduce abnormally high pressure within the brain. ... cerebral aneurysm may be required to restore deteriorating respiration and reduce abnormally high pressure within the brain. ...

  13. Cerebral Palsy

    MedlinePlus

    ... ol (Spanish) Recommend on Facebook Tweet Share Compartir Cerebral palsy (CP) is a group of disorders that affect ... resource—it highlights the ADDM Network’s data on cerebral palsy in a way that is useful for stakeholders ...

  14. Cerebral Palsy

    MedlinePlus

    Cerebral palsy is a group of disorders that affect a person's ability to move and to maintain balance ... do not get worse over time. People with cerebral palsy may have difficulty walking. They may also have ...

  15. Combination of serine protease inhibitor FUT-175 and thromboxane synthetase inhibitor OKY-046 decreases cerebral vasospasm in patients with subarachnoid hemorrhage.

    PubMed

    Kaminogo, M; Yonekura, M; Onizuka, M; Yasunaga, A; Shibata, S

    1998-11-01

    The preventive effect of the serine protease inhibitor FUT-175 (nafamostat mesilate), a potent inhibitor of the complement system, against vasospasm was evaluated in 34 high risk patients with thick and diffuse subarachnoid hemorrhage (SAH) demonstrated by computed tomography corresponding to Fisher group 3. All patients underwent surgery within 96 hours following SAH and received the thromboxane A2 synthetase inhibitor, OKY-046, as part of standard care. FUT-175 (40-160 mg/day) was administered during the initial 4 days following surgery. 455 patients treated without FUT-175 in the Nagasaki SAH Data Bank (non-FUT group) formed the control group. FUT-175 significantly decreased the incidence of symptomatic vasospasm in patients with severe neurological grade (Hunt and Hess grade 3, p < 0.02; Hunt and Hess grade 4, p < 0.02). The incidence of favorable outcome was 76.5% in the FUT group and 60.4% in the non-FUT group, but not statistically different. However, when patients of Hunt and Hess grade 5 were excluded, the FUT group had a significantly improved outcome (p < 0.05). This study suggests that FUT-175 has an additive effect to OKY-046 in preventing vasospasm in high risk patients with severe SAH.

  16. Amyloids: from Pathogenesis to Function.

    PubMed

    Nizhnikov, A A; Antonets, K S; Inge-Vechtomov, S G

    2015-09-01

    The term "amyloids" refers to fibrillar protein aggregates with cross-β structure. They have been a subject of intense scrutiny since the middle of the previous century. First, this interest is due to association of amyloids with dozens of incurable human diseases called amyloidoses, which affect hundreds of millions of people. However, during the last decade the paradigm of amyloids as pathogens has changed due to an increase in understanding of their role as a specific variant of quaternary protein structure essential for the living cell. Thus, functional amyloids are found in all domains of the living world, and they fulfill a variety of roles ranging from biofilm formation in bacteria to long-term memory regulation in higher eukaryotes. Prions, which are proteins capable of existing under the same conditions in two or more conformations at least one of which having infective properties, also typically have amyloid features. There are weighty reasons to believe that the currently known amyloids are only a minority of their real number. This review provides a retrospective analysis of stages in the development of amyloid biology that during the last decade resulted, on one hand, in reinterpretation of the biological role of amyloids, and on the other hand, in the development of systems biology of amyloids, or amyloidomics.

  17. Antimicrobial Properties of Amyloid Peptides

    PubMed Central

    Kagan, Bruce L.; Jang, Hyunbum; Capone, Ricardo; Arce, Fernando Teran; Ramachandran, Srinivasan; Lal, Ratnesh; Nussinov, Ruth

    2011-01-01

    More than two dozen clinical syndromes known as amyloid diseases are characterized by the buildup of extended insoluble fibrillar deposits in tissues. These amorphous Congo red staining deposits known as amyloids exhibit a characteristic green birefringence and cross-β structure. Substantial evidence implicates oligomeric intermediates of amyloids as toxic species in the pathogenesis of these chronic disease states. A growing body of data has suggested that these toxic species form ion channels in cellular membranes causing disruption of calcium homeostasis, membrane depolarization, energy drainage, and in some cases apoptosis. Amyloid peptide channels exhibit a number of common biological properties including the universal U-shape β-strand-turn-β-strand structure, irreversible and spontaneous insertion into membranes, production of large heterogeneous single-channel conductances, relatively poor ion selectivity, inhibition by Congo red, and channel blockade by zinc. Recent evidence has suggested that increased amounts of amyloids are not only toxic to its host target cells but also possess antimicrobial activity. Furthermore, at least one human antimicrobial peptide, protegrin-1, which kills microbes by a channel-forming mechanism, has been shown to possess the ability to form extended amyloid fibrils very similar to those of classic disease-forming amyloids. In this paper, we will review the reported antimicrobial properties of amyloids and the implications of these discoveries for our understanding of amyloid structure and function. PMID:22081976

  18. Inhibitory Activities of Antioxidant Flavonoids from Tamarix gallica on Amyloid Aggregation Related to Alzheimer's and Type 2 Diabetes Diseases.

    PubMed

    Ben Hmidene, Asma; Hanaki, Mizuho; Murakami, Kazuma; Irie, Kazuhiro; Isoda, Hiroko; Shigemori, Hideyuki

    2017-01-01

    The prevention of amyloid aggregation is promising for the treatment of age-related diseases such as Alzheimer's (AD) and type 2 diabetes (T2D). Ten antioxidant flavonoids isolated from the medicinal halophyte Tamarix gallica were tested for their amyloid aggregation inhibition potential. Glucuronosylated flavonoids show relatively strong inhibitory activity of Amyloid β (Aβ) and human islet amyloid polypeptide (hIAPP) aggregation compared to their aglycone analogs. Structure-activity relationship of the flavonoids suggests that the catechol moiety is important for amyloid aggregation inhibition, while the methylation of the carboxyl group in the glucuronide moiety and of the hydroxyl group in the aglycone flavonoids decreased it.

  19. Possible roles of amyloids in malaria pathophysiology.

    PubMed

    Moles, Ernest; Valle-Delgado, Juan José; Urbán, Patricia; Azcárate, Isabel G; Bautista, José M; Selva, Javier; Egea, Gustavo; Ventura, Salvador; Fernàndez-Busquets, Xavier

    2015-09-01

    The main therapeutic and prophylactic tools against malaria have been locked for more than a century in the classical approaches of using drugs targeting metabolic processes of the causing agent, the protist Plasmodium spp., and of designing vaccines against chosen antigens found on the parasite's surface. Given the extraordinary resources exhibited by Plasmodium to escape these traditional strategies, which have not been able to free humankind from the scourge of malaria despite much effort invested in them, new concepts have to be explored in order to advance toward eradication of the disease. In this context, amyloid-forming proteins and peptides found in the proteome of the pathogen should perhaps cease being regarded as mere anomalous molecules. Their likely functionality in the pathophysiology of Plasmodium calls for attention being paid to them as a possible Achilles' heel of malaria. Here we will give an overview of Plasmodium-encoded amyloid-forming polypeptides as potential therapeutic targets and toxic elements, particularly in relation to cerebral malaria and the blood-brain barrier function. We will also discuss the recent finding that the genome of the parasite contains an astonishingly high proportion of prionogenic domains.

  20. Hemi-ovariectomies promote a decrease in the dendritic lengths of CA1 and CA3 neurons: A dimorphic effect of the cerebral hemispheres.

    PubMed

    Durán, Dolores Adriana Bravo; Silva Gómez, Adriana Berenice; Rosas, Ana Coral Gutiérrez; Trujillo, Angélica

    2017-03-03

    Certain structures of the central nervous system (CNS) are morphologically and functionally related to the ovaries. Ovariectomy has been used to study the functional role of the ovaries in the CNS, as well as the role of the CNS on the reproductive system. In the present study, the effects of left and right hemi-ovariectomy on the morphology of pyramidal neurons from the CA1 and CA3 regions of the ventral hippocampus were studied. During the estrus phase, female Long-Evans rats underwent either left and right hemi-ovariectomies or left and right sham surgeries. Three estrous cycles later, the animals were sacrificed, and their brains were processed in Golgi-Cox stain and analyzed by the Sholl method to calculate the dendritic length of the CA1 and CA3 neurons of the left and right hemispheres. The results indicate that the dendritic lengths of the basilar and apical arbors of the CA1 neurons from the left hemisphere were shorter after both left and right hemi-ovariectomy, while the CA1 neurons from the right hemisphere were not affected by either procedure. However, the basilar dendritic arbors of the CA3 neurons from both hemispheres were affected by right hemi-ovariectomy. The spine density only decreased in the apical arbors in the CA3 neurons from the left hemisphere of rats that underwent right hemi-ovariectomy. This study's results indicate that hemi-ovariectomy in adult rats changes in the morphology of the CA1 and CA3 pyramidal neurons in the ventral hippocampus and that there are dimorphic responses between the hemispheres.

  1. Cilostazol decreases cerebral arterial pulsatility in patients with mild white matter hyperintensities: subgroup analysis from the Effect of Cilostazol in Acute Lacunar Infarction Based on Pulsatility Index of Transcranial Doppler (ECLIPse) study.

    PubMed

    Han, Sang Won; Song, Tae Jin; Bushnell, Cheryl D; Lee, Sung-Soo; Kim, Seo Hyun; Lee, Jun Hong; Kim, Gyu Sik; Kim, Ok-Joon; Koh, Im-Seok; Lee, Jong Yun; Suk, Seung-Han; Lee, Sung Ik; Nam, Hyo Suk; Kim, Won-Joo; Lee, Kyung-Yul; Park, Joong Hyun; Kim, Jeong Yeon; Park, Jae Hyeon

    2014-01-01

    The Effect of Cilostazol in Acute Lacunar Infarction Based on Pulsatility Index of the Transcranial Doppler (ECLIPse) study showed a significant decrease in the transcranial Doppler (TCD) pulsatility index (PI) with cilostazol treatment at 90 days after acute lacunar infarction. The aim of the present study was to perform a subgroup analysis of the ECLIPse study in order to explore the effect of cilostazol in acute lacunar infarction based on cerebral white matter hyperintensities (WMH) volume. The ECLIPse study was a multicenter, randomized, double-blind, placebo-controlled trial that evaluated the difference between the efficacy of cilostazol and a placebo to reduce the PI in patients with acute lacunar infarction using serial TCD examinations. The primary outcome was changes in the PIs of the middle cerebral artery (MCA) and basilar artery at 14 and 90 days from the baseline TCD study. For this subgroup analysis, using semi-automated computerized software, the WMH volume was measured for those subjects for whom fluid-attenuated inversion recovery (FLAIR) images were available. Of the 203 patients in eight hospitals in the ECLIPse study, 130 participants from six hospitals were included in this subgroup analysis. Cilostazol was given to 63 patients (48.5%) and placebo to 67 patients (51.5%). All baseline characteristics were well balanced across the two groups, and there were no significant differences in these characteristics except in the changes of PI from the baseline to the 90-day point. There was a significant decrease of TCD PIs at 90-day study from baseline in the cilostazol group (p = 0.02). The mean WMH volume was 11.57 cm(3) (0.13-68.45, median 4.86) and the mean MCA PI was 0.95 (0.62-1.50). The changes in PIs from the baseline to 14 days and to 90 days were 0.09 (-0.21 to 0.33) and 0.10 (-0.22 to 0.36). While there were no significant correlations between WMH volume and the changes in PIs, a trend of inverse correlation was observed between the WMH

  2. Genetic ablation of luteinizing hormone receptor improves the amyloid pathology in a mouse model of Alzheimer disease.

    PubMed

    Lin, Jing; Li, Xian; Yuan, Fangping; Lin, Ling; Cook, Christine L; Rao, Ch V; Lei, Zhenmin

    2010-03-01

    Amyloid-beta peptide (Abeta) plays an essential pathophysiologic role in Alzheimer disease, and elevation of luteinizing hormone (LH) levels during aging has been implicated in its pathogenesis. To assess the effect of LH receptor deficiency on Abeta accumulation, we generated a bigenic mouse model, APPsw(+)/Lhr(-/-), which expresses human amyloid precursor protein (APPsw) in the background of LH receptor (Lhr) knockout. Genetic ablation of Lhr resulted in a significant decrease in the number of Abeta plaques and protein content in the hippocampus and cerebral cortex in both male and female mice. Accordingly, several Abeta deposition-related neuropathologic features and functionally relevant molecules were markedly improved, including decreased astrogliosis, reductions of elevated phosphorylated tau, c-fos, alpha7-nicotinic acetylcholine receptor, and restoration of the altered neuropeptide Y receptors Y1 and Y2. Diminution of Abeta accumulation in the absence of LH receptor supports the contention that dysregulation of LH may impact the pathogenesis of Alzheimer disease. The APPsw(+)/Lhr(-/-) mouse may be a useful tool for advancing understanding of the role of LH-mediated events in Alzheimer disease and a model in which to test therapeutic interventions.

  3. Post-mortem histopathology underlying β-amyloid PET imaging following flutemetamol F 18 injection.

    PubMed

    Ikonomovic, Milos D; Buckley, Chris J; Heurling, Kerstin; Sherwin, Paul; Jones, Paul A; Zanette, Michelle; Mathis, Chester A; Klunk, William E; Chakrabarty, Aruna; Ironside, James; Ismail, Azzam; Smith, Colin; Thal, Dietmar R; Beach, Thomas G; Farrar, Gill; Smith, Adrian P L

    2016-12-12

    In vivo imaging of fibrillar β-amyloid deposits may assist clinical diagnosis of Alzheimer's disease (AD), aid treatment selection for patients, assist clinical trials of therapeutic drugs through subject selection, and be used as an outcome measure. A recent phase III trial of [(18)F]flutemetamol positron emission tomography (PET) imaging in 106 end-of-life subjects demonstrated the ability to identify fibrillar β-amyloid by comparing in vivo PET to post-mortem histopathology. Post-mortem analyses demonstrated a broad and continuous spectrum of β-amyloid pathology in AD and other dementing and non-dementing disease groups. The GE067-026 trial demonstrated 91% sensitivity and 90% specificity of [(18)F]flutemetamol PET by majority read for the presence of moderate or frequent plaques. The probability of an abnormal [(18)F]flutemetamol scan increased with neocortical plaque density and AD diagnosis. All dementia cases with non-AD neurodegenerative diseases and those without histopathological features of β-amyloid deposits were [(18)F]flutemetamol negative. Majority PET assessments accurately reflected the amyloid plaque burden in 90% of cases. However, ten cases demonstrated a mismatch between PET image interpretations and post-mortem findings. Although tracer retention was best associated with amyloid in neuritic plaques, amyloid in diffuse plaques and cerebral amyloid angiopathy best explain three [(18)F]flutemetamol positive cases with mismatched (sparse) neuritic plaque burden. Advanced cortical atrophy was associated with the seven false negative [(18)F]flutemetamol images. The interpretation of images from pathologically equivocal cases was associated with low reader confidence and inter-reader agreement. Our results support that amyloid in neuritic plaque burden is the primary form of β-amyloid pathology detectable with [(18)F]flutemetamol PET imaging. ClinicalTrials.gov NCT01165554. Registered June 21, 2010; NCT02090855. Registered March 11, 2014.

  4. Oleocanthal Enhances Amyloid-β Clearance from the Brains of TgSwDI Mice and in Vitro across a Human Blood-Brain Barrier Model

    PubMed Central

    2015-01-01

    Numerous clinical and preclinical studies have suggested several health promoting effects for the dietary consumption of extra-virgin olive oil (EVOO) that could protect and decrease the risk of developing Alzheimer’s disease (AD). Moreover, recent studies have linked this protective effect to oleocanthal, a phenolic secoiridoid component of EVOO. This protective effect of oleocanthal against AD has been related to its ability to prevent amyloid-β (Aβ) and tau aggregation in vitro, and enhance Aβ clearance from the brains of wild type mice in vivo; however, its effect in a mouse model of AD is not known. In the current study, we investigated the effect of oleocanthal on pathological hallmarks of AD in TgSwDI, an animal model of AD. Mice treatment for 4 weeks with oleocanthal significantly decreased amyloid load in the hippocampal parenchyma and microvessels. This reduction was associated with enhanced cerebral clearance of Aβ across the blood-brain barrier (BBB). Further mechanistic studies demonstrated oleocanthal to increase the expression of important amyloid clearance proteins at the BBB including P-glycoprotein and LRP1, and to activate the ApoE-dependent amyloid clearance pathway in the mice brains. The anti-inflammatory effect of oleocanthal in the brains of these mice was also obvious where it was able to reduce astrocytes activation and IL-1β levels. Finally, we could recapitulate the observed protective effect of oleocanthal in an in vitro human-based model, which could argue against species difference in response to oleocanthal. In conclusion, findings from in vivo and in vitro studies provide further support for the protective effect of oleocanthal against the progression of AD. PMID:26348065

  5. Morin hydrate inhibits amyloid formation by islet amyloid polypeptide and disaggregates amyloid fibers

    PubMed Central

    Noor, Harris; Cao, Ping; Raleigh, Daniel P

    2012-01-01

    The polypeptide hormone Islet Amyloid Polypeptide (IAPP, amylin) is responsible for islet amyloid formation in type-2 diabetes and in islet cell transplants, where it may contribute to graft failure. Human IAPP is extremely amyloidogenic and fewer inhibitors of IAPP amyloid formation have been reported than for the Alzheimer's Aβ peptide or for α-synuclein. The ability of a set of hydroxyflavones to inhibit IAPP amyloid formation was tested. Fluorescence detected thioflavin-T-binding assays are the most popular methods for measuring the kinetics of amyloid formation and for screening potential inhibitors; however, we show that they can lead to false positives with hydroxyflavones. Several of the compounds inhibit thioflavin-T fluorescence, but not amyloid formation; a result which highlights the hazards of relying solely on thioflavin-T assays to screen potential inhibitors. Transmission electron microscopy (TEM) and right-angle light scattering show that Morin hydrate (2′,3,4′,5,7-Pentahydroxyflavone) inhibits amyloid formation by human IAPP and disaggregates preformed IAPP amyloid fibers. In contrast, Myricetin, Kaempferol, and Quercetin, which differ only in hydroxyl groups on the B-ring, are not effective inhibitors. Morin hydrate represents a new type of IAPP amyloid inhibitor and the results with the other compounds highlight the importance of the substitution pattern on the B-ring. PMID:22238175

  6. Neuronal and glial alterations, increased anxiety, and cognitive impairment before hippocampal amyloid deposition in PDAPP mice, model of Alzheimer's disease.

    PubMed

    Beauquis, Juan; Vinuesa, Angeles; Pomilio, Carlos; Pavía, Patricio; Galván, Verónica; Saravia, Flavia

    2014-03-01

    In the context of Alzheimer's disease (AD), hippocampal alterations have been well described in advanced stages of the pathology, when amyloid deposition, inflammation and glial activation occur, but less attention has been directed to studying early brain and behavioral changes. Using an animal model of AD, the transgenic PDAPP-J20 mouse at 5 months of age, when no amyloid plaques are present and low cerebral levels of amyloid peptides are detectable, we found structural, morphological, and cellular alterations in the hippocampus. Young transgenic mice showed a reduced hippocampal volume with less number of pyramidal and granular neurons, which additionally exhibited cell atrophy. The neurogenic capability in this zone, measured as DCX+ cells, was strongly diminished and associated to alterations in cell maturity. A decrease in presynaptic synaptophysin optical density was detected in mossy fibers reaching CA3 subfield but not in Golgi stained- CA1 dendritic spine density. Employing confocal microscopy and accurate stereological tools we also found a reduction in the number of GFAP+ cells, along with decreased astrocyte complexity, suggesting a potential detriment of neural support. According with untimely neuroglial alterations, young PDAPP mice failed in the novel location recognition test, that depends on hippocampal function. Moreover, multivariate statistical analysis of the behavioral outcome in the open-field test evidenced an elevated anxiety score in Tg mice compared with age-matched control mice. In line with this, the transgenic group showed a higher number of c-Fos+ nuclei in central and basolateral amygdala, a result that supports the early involvement of the emotionality factor in AD pathology. Applying an integrative approach, this work focuses on early structural, morphological and functional changes and provides new and compelling evidence of behavioral alterations that precede manifest AD. Copyright © 2013 Wiley Periodicals, Inc.

  7. Brain Endothelial Cells Produce Amyloid β from Amyloid Precursor Protein 770 and Preferentially Secrete the O-Glycosylated Form*

    PubMed Central

    Kitazume, Shinobu; Tachida, Yuriko; Kato, Masaki; Yamaguchi, Yoshiki; Honda, Takashi; Hashimoto, Yasuhiro; Wada, Yoshinao; Saito, Takashi; Iwata, Nobuhisa; Saido, Takaomi; Taniguchi, Naoyuki

    2010-01-01

    Deposition of amyloid β (Aβ) in the brain is closely associated with Alzheimer disease (AD). Aβ is generated from amyloid precursor protein (APP) by the actions of β- and γ-secretases. In addition to Aβ deposition in the brain parenchyma, deposition of Aβ in cerebral vessel walls, termed cerebral amyloid angiopathy, is observed in more than 80% of AD individuals. The mechanism for how Aβ accumulates in blood vessels remains largely unknown. In the present study, we show that brain endothelial cells expressed APP770, a differently spliced APP mRNA isoform from neuronal APP695, and produced Aβ40 and Aβ42. Furthermore, we found that the endothelial APP770 had sialylated core 1 type O-glycans. Interestingly, Ο-glycosylated APP770 was preferentially processed by both α- and β-cleavage and secreted into the media, suggesting that O-glycosylation and APP processing involved related pathways. By immunostaining human brain sections with an anti-APP770 antibody, we found that APP770 was expressed in vascular endothelial cells. Because we were able to detect O-glycosylated sAPP770β in human cerebrospinal fluid, this unique soluble APP770β has the potential to serve as a marker for cortical dementias such as AD and vascular dementia. PMID:20952385

  8. Light Chain Amyloid Fibrils Cause Metabolic Dysfunction in Human Cardiomyocytes

    DOE PAGES

    McWilliams-Koeppen, Helen P.; Foster, James S.; Hackenbrack, Nicole; ...

    2015-09-22

    Light chain (AL) amyloidosis is the most common form of systemic amyloid disease, and cardiomyopathy is a dire consequence, resulting in an extremely poor prognosis. AL is characterized by the production of monoclonal free light chains that deposit as amyloid fibrils principally in the heart, liver, and kidneys causing organ dysfunction. We have studied the effects of amyloid fibrils, produced from recombinant λ6 light chain variable domains, on metabolic activity of human cardiomyocytes. The data indicate that fibrils at 0.1 μM, but not monomer, significantly decrease the enzymatic activity of cellular NAD(P)H-dependent oxidoreductase, without causing significant cell death. The presencemore » of amyloid fibrils did not affect ATP levels; however, oxygen consumption was increased and reactive oxygen species were detected. Confocal fluorescence microscopy showed that fibrils bound to and remained at the cell surface with little fibril internalization. Ultimately, these data indicate that AL amyloid fibrils severely impair cardiomyocyte metabolism in a dose dependent manner. These data suggest that effective therapeutic intervention for these patients should include methods for removing potentially toxic amyloid fibrils.« less

  9. Light Chain Amyloid Fibrils Cause Metabolic Dysfunction in Human Cardiomyocytes

    SciTech Connect

    McWilliams-Koeppen, Helen P.; Foster, James S.; Hackenbrack, Nicole; Ramirez-Alvarado, Marina; Donohoe, Dallas; Williams, Angela; Macy, Sallie; Wooliver, Craig; Wortham, Dale; Morrell-Falvey, Jennifer; Foster, Carmen M.; Kennel, Stephen J.; Wall, Jonathan S.

    2015-09-22

    Light chain (AL) amyloidosis is the most common form of systemic amyloid disease, and cardiomyopathy is a dire consequence, resulting in an extremely poor prognosis. AL is characterized by the production of monoclonal free light chains that deposit as amyloid fibrils principally in the heart, liver, and kidneys causing organ dysfunction. We have studied the effects of amyloid fibrils, produced from recombinant λ6 light chain variable domains, on metabolic activity of human cardiomyocytes. The data indicate that fibrils at 0.1 μM, but not monomer, significantly decrease the enzymatic activity of cellular NAD(P)H-dependent oxidoreductase, without causing significant cell death. The presence of amyloid fibrils did not affect ATP levels; however, oxygen consumption was increased and reactive oxygen species were detected. Confocal fluorescence microscopy showed that fibrils bound to and remained at the cell surface with little fibril internalization. Ultimately, these data indicate that AL amyloid fibrils severely impair cardiomyocyte metabolism in a dose dependent manner. These data suggest that effective therapeutic intervention for these patients should include methods for removing potentially toxic amyloid fibrils.

  10. Light Chain Amyloid Fibrils Cause Metabolic Dysfunction in Human Cardiomyocytes

    PubMed Central

    McWilliams-Koeppen, Helen P.; Foster, James S.; Hackenbrack, Nicole; Ramirez-Alvarado, Marina; Donohoe, Dallas; Williams, Angela; Macy, Sallie; Wooliver, Craig; Wortham, Dale; Morrell-Falvey, Jennifer; Foster, Carmen M.; Kennel, Stephen J.; Wall, Jonathan S.

    2015-01-01

    Light chain (AL) amyloidosis is the most common form of systemic amyloid disease, and cardiomyopathy is a dire consequence, resulting in an extremely poor prognosis. AL is characterized by the production of monoclonal free light chains that deposit as amyloid fibrils principally in the heart, liver, and kidneys causing organ dysfunction. We have studied the effects of amyloid fibrils, produced from recombinant λ6 light chain variable domains, on metabolic activity of human cardiomyocytes. The data indicate that fibrils at 0.1 μM, but not monomer, significantly decrease the enzymatic activity of cellular NAD(P)H-dependent oxidoreductase, without causing significant cell death. The presence of amyloid fibrils did not affect ATP levels; however, oxygen consumption was increased and reactive oxygen species were detected. Confocal fluorescence microscopy showed that fibrils bound to and remained at the cell surface with little fibril internalization. These data indicate that AL amyloid fibrils severely impair cardiomyocyte metabolism in a dose dependent manner. These data suggest that effective therapeutic intervention for these patients should include methods for removing potentially toxic amyloid fibrils. PMID:26393799

  11. Towards a Pharmacophore for Amyloid

    SciTech Connect

    Landau, Meytal; Sawaya, Michael R.; Faull, Kym F.; Laganowsky, Arthur; Jiang, Lin; Sievers, Stuart A.; Liu, Jie; Barrio, Jorge R.; Eisenberg, David

    2011-09-16

    Diagnosing and treating Alzheimer's and other diseases associated with amyloid fibers remains a great challenge despite intensive research. To aid in this effort, we present atomic structures of fiber-forming segments of proteins involved in Alzheimer's disease in complex with small molecule binders, determined by X-ray microcrystallography. The fiber-like complexes consist of pairs of {beta}-sheets, with small molecules binding between the sheets, roughly parallel to the fiber axis. The structures suggest that apolar molecules drift along the fiber, consistent with the observation of nonspecific binding to a variety of amyloid proteins. In contrast, negatively charged orange-G binds specifically to lysine side chains of adjacent sheets. These structures provide molecular frameworks for the design of diagnostics and drugs for protein aggregation diseases. The devastating and incurable dementia known as Alzheimer's disease affects the thinking, memory, and behavior of dozens of millions of people worldwide. Although amyloid fibers and oligomers of two proteins, tau and amyloid-{beta}, have been identified in association with this disease, the development of diagnostics and therapeutics has proceeded to date in a near vacuum of information about their structures. Here we report the first atomic structures of small molecules bound to amyloid. These are of the dye orange-G, the natural compound curcumin, and the Alzheimer's diagnostic compound DDNP bound to amyloid-like segments of tau and amyloid-{beta}. The structures reveal the molecular framework of small-molecule binding, within cylindrical cavities running along the {beta}-spines of the fibers. Negatively charged orange-G wedges into a specific binding site between two sheets of the fiber, combining apolar binding with electrostatic interactions, whereas uncharged compounds slide along the cavity. We observed that different amyloid polymorphs bind different small molecules, revealing that a cocktail of compounds

  12. Familial amyloid polyneuropathy.

    PubMed

    Planté-Bordeneuve, Violaine; Said, Gerard

    2011-12-01

    Familial amyloid polyneuropathies (FAPs) are a group of life-threatening multisystem disorders transmitted as an autosomal dominant trait. Nerve lesions are induced by deposits of amyloid fibrils, most commonly due to mutated transthyretin (TTR). Less often the precursor of amyloidosis is mutant apolipoprotein A-1 or gelsolin. The first identified cause of FAP-the TTR Val30Met mutation-is still the most common of more than 100 amyloidogenic point mutations identified worldwide. The penetrance and age at onset of FAP among people carrying the same mutation vary between countries. The symptomatology and clinical course of FAP can be highly variable. TTR FAP typically causes a nerve length-dependent polyneuropathy that starts in the feet with loss of temperature and pain sensations, along with life-threatening autonomic dysfunction leading to cachexia and death within 10 years on average. TTR is synthesised mainly in the liver, and liver transplantation seems to have a favourable effect on the course of neuropathy, but not on cardiac or eye lesions. Oral administration of tafamidis meglumine, which prevents misfolding and deposition of mutated TTR, is under evaluation in patients with TTR FAP. In future, patients with FAP might benefit from gene therapy; however, genetic counselling is recommended for the prevention of all types of FAP.

  13. Structural analysis of oligomeric and protofibrillar Aβ amyloid pair structures considering F20L mutation effects using molecular dynamics simulations.

    PubMed

    Lee, Myeongsang; Chang, Hyun Joon; Baek, Inchul; Na, Sungsoo

    2017-04-01

    amyloid proteins are involved in neuro-degenerative diseases such as Alzheimer's, Parkinson's, and so forth. Because of its structurally stable feature under physiological conditions, Aβ amyloid protein disrupts the normal cell function. Because of these concerns, understanding the structural feature of Aβ amyloid protein in detail is crucial. There have been some efforts on lowering the structural stabilities of Aβ amyloid fibrils by decreasing the aromatic residues characteristic and hydrophobic effect. Yet, there is a lack of understanding of Aβ amyloid pair structures considering those effects. In this study, we provide the structural characteristics of wildtype (WT) and phenylalanine residue mutation to leucine (F20L) Aβ amyloid pair structures using molecular dynamics simulation in detail. We also considered the polymorphic feature of F20L and WT Aβ pair amyloids based on the facing β-strand directions between the amyloid pairs. As a result, we were able to observe the varying effects of mutation, polymorphism, and protofibril lengths on the structural stability of pair amyloids. Furthermore, we have also found that opposite structural stability exists on a certain polymorphic Aβ pair amyloids depending on its oligomeric or protofibrillar state, which can be helpful for understanding the amyloid growth mechanism via repetitive fragmentation and elongation mechanism. Proteins 2017; 85:580-592. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  14. Role of gut microbiota and nutrients in amyloid formation and pathogenesis of Alzheimer disease.

    PubMed

    Pistollato, Francesca; Sumalla Cano, Sandra; Elio, Iñaki; Masias Vergara, Manuel; Giampieri, Francesca; Battino, Maurizio

    2016-10-01

    It has been hypothesized that alterations in the composition of the gut microbiota might be associated with the onset of certain human pathologies, such as Alzheimer disease, a neurodegenerative syndrome associated with cerebral accumulation of amyloid-β fibrils. It has been shown that bacteria populating the gut microbiota can release significant amounts of amyloids and lipopolysaccharides, which might play a role in the modulation of signaling pathways and the production of proinflammatory cytokines related to the pathogenesis of Alzheimer disease. Additionally, nutrients have been shown to affect the composition of the gut microbiota as well as the formation and aggregation of cerebral amyloid-β. This suggests that modulating the gut microbiome and amyloidogenesis through specific nutritional interventions might prove to be an effective strategy to prevent or reduce the risk of Alzheimer disease. This review examines the possible role of the gut in the dissemination of amyloids, the role of the gut microbiota in the regulation of the gut-brain axis, the potential amyloidogenic properties of gut bacteria, and the possible impact of nutrients on modulation of microbiota composition and amyloid formation in relation to the pathogenesis of Alzheimer disease.

  15. Independent information from cerebrospinal fluid amyloid-β and florbetapir imaging in Alzheimer's disease

    PubMed Central

    Insel, Philip S.; Donohue, Michael; Landau, Susan; Jagust, William J.; Shaw, Leslie M.; Trojanowski, John Q.; Zetterberg, Henrik; Blennow, Kaj; Weiner, Michael W.

    2015-01-01

    Reduced cerebrospinal fluid amyloid-β42 and increased retention of florbetapir positron emission tomography are biomarkers reflecting cortical amyloid load in Alzheimer's disease. However, these measurements do not always agree and may represent partly different aspects of the underlying Alzheimer's disease pathology. The goal of this study was therefore to test if cerebrospinal fluid and positron emission tomography amyloid-β biomarkers are independently related to other Alzheimer's disease markers, and to examine individuals who are discordantly classified by these two biomarker modalities. Cerebrospinal fluid and positron emission tomography amyloid-β were measured at baseline in 769 persons [161 healthy controls, 68 subjective memory complaints, 419 mild cognitive impairment and 121 Alzheimer's disease dementia, mean age 72 years (standard deviation 7 years), 47% females] and used to predict diagnosis, APOE ε4 carriage status, cerebral blood flow, cerebrospinal fluid total-tau and phosphorylated-tau levels (cross-sectionally); and hippocampal volume, fluorodeoxyglucose positron emission tomography results and Alzheimer's Disease Assessment Scale-cognitive subscale scores (longitudinally). Cerebrospinal fluid and positron emission tomography amyloid-β were highly correlated, but adjusting one of these predictors for the other revealed that they both provided partially independent information when predicting diagnosis, APOE ε4, hippocampal volume, metabolism, cognition, total-tau and phosphorylated-tau (the 95% confidence intervals of the adjusted effects did not include zero). Cerebrospinal fluid amyloid-β was more strongly related to APOE ε4 whereas positron emission tomography amyloid-β was more strongly related to tau levels (P < 0.05). Discordance (mainly isolated cerebrospinal fluid amyloid-β positivity) differed by diagnostic group (P < 0.001) and was seen in 21% of cognitively healthy people but only 6% in dementia patients. The finding that

  16. Independent information from cerebrospinal fluid amyloid-β and florbetapir imaging in Alzheimer's disease.

    PubMed

    Mattsson, Niklas; Insel, Philip S; Donohue, Michael; Landau, Susan; Jagust, William J; Shaw, Leslie M; Trojanowski, John Q; Zetterberg, Henrik; Blennow, Kaj; Weiner, Michael W

    2015-03-01

    Reduced cerebrospinal fluid amyloid-β42 and increased retention of florbetapir positron emission tomography are biomarkers reflecting cortical amyloid load in Alzheimer's disease. However, these measurements do not always agree and may represent partly different aspects of the underlying Alzheimer's disease pathology. The goal of this study was therefore to test if cerebrospinal fluid and positron emission tomography amyloid-β biomarkers are independently related to other Alzheimer's disease markers, and to examine individuals who are discordantly classified by these two biomarker modalities. Cerebrospinal fluid and positron emission tomography amyloid-β were measured at baseline in 769 persons [161 healthy controls, 68 subjective memory complaints, 419 mild cognitive impairment and 121 Alzheimer's disease dementia, mean age 72 years (standard deviation 7 years), 47% females] and used to predict diagnosis, APOE ε4 carriage status, cerebral blood flow, cerebrospinal fluid total-tau and phosphorylated-tau levels (cross-sectionally); and hippocampal volume, fluorodeoxyglucose positron emission tomography results and Alzheimer's Disease Assessment Scale-cognitive subscale scores (longitudinally). Cerebrospinal fluid and positron emission tomography amyloid-β were highly correlated, but adjusting one of these predictors for the other revealed that they both provided partially independent information when predicting diagnosis, APOE ε4, hippocampal volume, metabolism, cognition, total-tau and phosphorylated-tau (the 95% confidence intervals of the adjusted effects did not include zero). Cerebrospinal fluid amyloid-β was more strongly related to APOE ε4 whereas positron emission tomography amyloid-β was more strongly related to tau levels (P < 0.05). Discordance (mainly isolated cerebrospinal fluid amyloid-β positivity) differed by diagnostic group (P < 0.001) and was seen in 21% of cognitively healthy people but only 6% in dementia patients. The finding that

  17. Autoregulated paracellular clearance of amyloid-β across the blood-brain barrier

    PubMed Central

    Keaney, James; Walsh, Dominic M.; O’Malley, Tiernan; Hudson, Natalie; Crosbie, Darragh E.; Loftus, Teresa; Sheehan, Florike; McDaid, Jacqueline; Humphries, Marian M.; Callanan, John J.; Brett, Francesca M.; Farrell, Michael A.; Humphries, Peter; Campbell, Matthew

    2015-01-01

    The blood-brain barrier (BBB) is essential for maintaining brain homeostasis and protecting neural tissue from damaging blood-borne agents. The barrier is characterized by endothelial tight junctions that limit passive paracellular diffusion of polar solutes and macromolecules from blood to brain. Decreased brain clearance of the neurotoxic amyloid-β (Aβ) peptide is a central event in the pathogenesis of Alzheimer’s disease (AD). Whereas transport of Aβ across the BBB can occur via transcellular endothelial receptors, the paracellular movement of Aβ has not been described. We show that soluble human Aβ(1–40) monomers can diffuse across the paracellular pathway of the BBB in tandem with a decrease in the tight junction proteins claudin-5 and occludin in the cerebral vascular endothelium. In a murine model of AD (Tg2576), plasma Aβ(1–40) levels were significantly increased, brain Aβ(1–40) levels were decreased, and cognitive function was enhanced when both claudin-5 and occludin were suppressed. Furthermore, Aβ can cause a transient down-regulation of claudin-5 and occludin, allowing for its own paracellular clearance across the BBB. Our results show, for the first time, the involvement of the paracellular pathway in autoregulated Aβ movement across the BBB and identify both claudin-5 and occludin as potential therapeutic targets for AD. These findings also indicate that controlled modulation of tight junction components at the BBB can enhance the clearance of Aβ from the brain. PMID:26491725

  18. Apoptosis Repressor With Caspase Recruitment Domain Ameliorates Amyloid-Induced β-Cell Apoptosis and JNK Pathway Activation.

    PubMed

    Templin, Andrew T; Samarasekera, Tanya; Meier, Daniel T; Hogan, Meghan F; Mellati, Mahnaz; Crow, Michael T; Kitsis, Richard N; Zraika, Sakeneh; Hull, Rebecca L; Kahn, Steven E

    2017-10-01

    Islet amyloid is present in more than 90% of individuals with type 2 diabetes, where it contributes to β-cell apoptosis and insufficient insulin secretion. Apoptosis repressor with caspase recruitment domain (ARC) binds and inactivates components of the intrinsic and extrinsic apoptosis pathways and was recently found to be expressed in islet β-cells. Using a human islet amyloid polypeptide transgenic mouse model of islet amyloidosis, we show ARC knockdown increases amyloid-induced β-cell apoptosis and loss, while ARC overexpression decreases amyloid-induced apoptosis, thus preserving β-cells. These effects occurred in the absence of changes in islet amyloid deposition, indicating ARC acts downstream of amyloid formation. Because islet amyloid increases c-Jun N-terminal kinase (JNK) pathway activation, we investigated whether ARC affects JNK signaling in amyloid-forming islets. We found ARC knockdown enhances JNK pathway activation, whereas ARC overexpression reduces JNK, c-Jun phosphorylation, and c-Jun target gene expression (Jun and Tnf). Immunoprecipitation of ARC from mouse islet lysates showed ARC binds JNK, suggesting interaction between JNK and ARC decreases amyloid-induced JNK phosphorylation and downstream signaling. These data indicate that ARC overexpression diminishes amyloid-induced JNK pathway activation and apoptosis in the β-cell, a strategy that may reduce β-cell loss in type 2 diabetes. © 2017 by the American Diabetes Association.

  19. Intracellular cleavage of amyloid β by a viral protease NIa prevents amyloid β-mediated cytotoxicity.

    PubMed

    Shin, Baehyun; Oh, Hyejin; Park, Sang Min; Han, Hye-Eun; Ye, Michael; Song, Woo Keun; Park, Woo Jin

    2014-01-01

    Nuclear inclusion a (NIa) of turnip mosaic virus is a cytosolic protease that cleaves amyloid β (Aβ) when heterologously overexpressed. Lentivirus-mediated expression of NIa in the brains of APP(sw)/PS1 mice significantly reduces cerebral Aβ levels and plaque depositions, and improves behavioral deficits. Here, the effects of NIa and neprilysin (NEP), a well-known Aβ-cleaving protease, on oligomeric Aβ-induced cell death were evaluated. NIa cleaved monomeric and oligomeric Aβ at a similar rate, whereas NEP only cleaved monomeric Aβ. Oligomeric Aβ-induced cytotoxicity and mitochondrial dysfunction were significantly ameliorated by NIa, but not by NEP. Endocytosed fluorescently-labeled Aβ localized to mitochondria, and this was significantly reduced by NIa, but not by NEP. These data suggest that NIa may exerts its protective roles by degrading Aβ and thus preventing mitochondrial deposition of Aβ.

  20. Intracellular Cleavage of Amyloid β by a Viral Protease NIa Prevents Amyloid β-Mediated Cytotoxicity

    PubMed Central

    Shin, Baehyun; Oh, Hyejin; Park, Sang Min; Han, Hye-Eun; Ye, Michael; Song, Woo Keun; Park, Woo Jin

    2014-01-01

    Nuclear inclusion a (NIa) of turnip mosaic virus is a cytosolic protease that cleaves amyloid β (Aβ) when heterologously overexpressed. Lentivirus-mediated expression of NIa in the brains of APP(sw)/PS1 mice significantly reduces cerebral Aβ levels and plaque depositions, and improves behavioral deficits. Here, the effects of NIa and neprilysin (NEP), a well-known Aβ-cleaving protease, on oligomeric Aβ-induced cell death were evaluated. NIa cleaved monomeric and oligomeric Aβ at a similar rate, whereas NEP only cleaved monomeric Aβ. Oligomeric Aβ-induced cytotoxicity and mitochondrial dysfunction were significantly ameliorated by NIa, but not by NEP. Endocytosed fluorescently-labeled Aβ localized to mitochondria, and this was significantly reduced by NIa, but not by NEP. These data suggest that NIa may exerts its protective roles by degrading Aβ and thus preventing mitochondrial deposition of Aβ. PMID:24915567

  1. Theoretical impact of Florbetapir (18F) amyloid imaging on diagnosis of alzheimer dementia and detection of preclinical cortical amyloid.

    PubMed

    Beach, Thomas G; Schneider, Julie A; Sue, Lucia I; Serrano, Geidy; Dugger, Brittany N; Monsell, Sarah E; Kukull, Walter

    2014-10-01

    In 2012, florbetapir (F) (Amyvid) received US Food and Drug Administration approval as a diagnostic agent for detecting neuritic (β-amyloid) plaques in living patients. Although such approval is specifically not extended to the use of florbetapir as a single definitive diagnostic test for Alzheimer disease dementia (ADD), it is of considerable importance to examine its potential in this regard. To estimate the ability of florbetapir amyloid imaging to detect specified densities of postmortem-identified neuritic plaques, we used the data of Clark et al [Clark CM, Pontecorvo MJ, Beach TG, et al. Cerebral PET with florbetapir compared with neuropathology at autopsy for detection of neuritic amyloid-beta plaques: A prospective cohort study. Lancet Neurol 2012;11:669-78]. We then used the data of Beach et al [Beach TG, Monsell SE, Phillips LE, et al. Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers, 2005-2010. J Neuropathol Exp Neurol 2012;71:266-73], derived from the National Alzheimer's Coordinating Center, to estimate the fraction of subjects who would have been called florbetapir-positive and, among these, the fraction of subjects who would also meet neuropathologic criteria for the presence of ADD. The accuracy of a positive florbetapir β-amyloid scan for the detection of neuropathologically defined ADD is estimated at between 69% and 95% sensitivity and between 83% and 89% specificity. From the same National Alzheimer's Coordinating Center data set, 144 subjects were recorded as having normal cognition. Amo