A novel sensitive assay for detection of a biomarker of pericyte injury in cerebrospinal fluid

Sweeney, Melanie D.; Sagare, Abhay P.; Pachicano, Maricarmen; Harrington, Michael G.; Joe, Elizabeth; Chui, Helena C.; Schneider, Lon S.; Montagne, Axel; Ringman, John M.; Fagan, Anne M.; Morris, John C.; Pa, Judy; Nation, Daniel A.; Toga, Arthur W.; Zloković, Berislav V.

doi:10.1002/alz.12061

Cited by 53 publications

(59 citation statements)

References 43 publications

(145 reference statements)

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“…Neuron-specific enolase (NSE) and GFAP are also promising biomarkers that can be detected in the CSF to identify BBB breakdown (Kadry et al, 2020 ). A study reported that the elevated level of sPDGFRβ is associated with damage to the pericytes and BBB disruption leading to a decline in cognition (Sweeney et al, 2020 ). Soluble PDGFRβ as a biomarker was also observed in VaD (Iadecola, 2017 ; Sweeney et al, 2019a ) and various other neurological diseases (Sweeney et al, 2018a , 2019b ).…”

Section: Biomarkers Associated With Bbb Breakdownmentioning

confidence: 99%

Blood–Brain Barrier Breakdown: An Emerging Biomarker of Cognitive Impairment in Normal Aging and Dementia

2021

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The blood–brain barrier (BBB) plays a vital role in maintaining the specialized microenvironment of the neural tissue. It separates the peripheral circulatory system from the brain parenchyma while facilitating communication. Alterations in the distinct physiological properties of the BBB lead to BBB breakdown associated with normal aging and various neurodegenerative diseases. In this review, we first briefly discuss the aging process, then review the phenotypes and mechanisms of BBB breakdown associated with normal aging that further cause neurodegeneration and cognitive impairments. We also summarize dementia such as Alzheimer's disease (AD) and vascular dementia (VaD) and subsequently discuss the phenotypes and mechanisms of BBB disruption in dementia correlated with cognition decline. Overlaps between AD and VaD are also discussed. Techniques that could identify biomarkers associated with BBB breakdown are briefly summarized. Finally, we concluded that BBB breakdown could be used as an emerging biomarker to assist to diagnose cognitive impairment associated with normal aging and dementia.

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Section: Biomarkers Associated With Bbb Breakdownmentioning

confidence: 99%

Blood–Brain Barrier Breakdown: An Emerging Biomarker of Cognitive Impairment in Normal Aging and Dementia

2021

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“…BBB deterioration has also been observed in these same neurodegenerative conditions (10,64,65). Recently, a blood biomarker of BBB deterioration was also proposed for AD (66), and the two-hit vascular hypothesis of AD proposes the BBB disruption is an initiating event in amyloid beta deposition in the brain (54). In support of this, human studies have identified alteration in BBB permeability at the earliest stages of cognitive decline and AD (67,68).…”

Section: Discussionmentioning

confidence: 99%

P7C3-A20 treatment one year after TBI in mice repairs the blood–brain barrier, arrests chronic neurodegeneration, and restores cognition

Vázquez‐Rosa

Shin

Dhar

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Chronic neurodegeneration in survivors of traumatic brain injury (TBI) is a major cause of morbidity, with no effective therapies to mitigate this progressive and debilitating form of nerve cell death. Here, we report that pharmacologic restoration of the blood–brain barrier (BBB), 12 mo after murine TBI, is associated with arrested axonal neurodegeneration and cognitive recovery, benefits that persisted for months after treatment cessation. Recovery was achieved by 30 d of once-daily administration of P7C3-A20, a compound that stabilizes cellular energy levels. Four months after P7C3-A20, electron microscopy revealed full repair of TBI-induced breaks in cortical and hippocampal BBB endothelium. Immunohistochemical staining identified additional benefits of P7C3-A20, including restoration of normal BBB endothelium length, increased brain capillary pericyte density, increased expression of BBB tight junction proteins, reduced brain infiltration of immunoglobulin, and attenuated neuroinflammation. These changes were accompanied by cessation of TBI-induced chronic axonal degeneration. Specificity for P7C3-A20 action on the endothelium was confirmed by protection of cultured human brain microvascular endothelial cells from hydrogen peroxide-induced cell death, as well as preservation of BBB integrity in mice after exposure to toxic levels of lipopolysaccharide. P7C3-A20 also protected mice from BBB degradation after acute TBI. Collectively, our results provide insights into the pathophysiologic mechanisms behind chronic neurodegeneration after TBI, along with a putative treatment strategy. Because TBI increases the risks of other forms of neurodegeneration involving BBB deterioration (e.g., Alzheimer’s disease, Parkinson’s disease, vascular dementia, chronic traumatic encephalopathy), P7C3-A20 may have widespread clinical utility in the setting of neurodegenerative conditions.

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“…Evidence of these pathological events could be detected using imaging approaches that indicate WMH, ischemic manifestations, subcortical hemorrhages, and microbleeds. A new sensitive assay was recently developed allowing pericyte injury detection in the CSF, a new technology that could serve as a diagnostic tool for WMD (Sweeney et al, 2020). CADASIL develops gradually over time and the earliest symptoms appear on average around 30 years of age, usually 10 years earlier in women than men, and are manifested as migraines with aura (Guey et al, 2016;Di Donato et al, 2017).…”

Section: Genetic Csvdmentioning

confidence: 99%

Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors

Lecordier

Manrique-Castano

Moghrabi

et al. 2021

Front. Aging Neurosci.

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Vascular dementia (VaD) constitutes the second most prevalent cause of dementia in the world after Alzheimer’s disease (AD). VaD regroups heterogeneous neurological conditions in which the decline of cognitive functions, including executive functions, is associated with structural and functional alterations in the cerebral vasculature. Among these cerebrovascular disorders, major stroke, and cerebral small vessel disease (cSVD) constitute the major risk factors for VaD. These conditions alter neurovascular functions leading to blood-brain barrier (BBB) deregulation, neurovascular coupling dysfunction, and inflammation. Accumulation of neurovascular impairments over time underlies the cognitive function decline associated with VaD. Furthermore, several vascular risk factors, such as hypertension, obesity, and diabetes have been shown to exacerbate neurovascular impairments and thus increase VaD prevalence. Importantly, air pollution constitutes an underestimated risk factor that triggers vascular dysfunction via inflammation and oxidative stress. The review summarizes the current knowledge related to the pathological mechanisms linking neurovascular impairments associated with stroke, cSVD, and vascular risk factors with a particular emphasis on air pollution, to VaD etiology and progression. Furthermore, the review discusses the major challenges to fully elucidate the pathobiology of VaD, as well as research directions to outline new therapeutic interventions.

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A novel sensitive assay for detection of a biomarker of pericyte injury in cerebrospinal fluid

Cited by 53 publications

References 43 publications

Blood–Brain Barrier Breakdown: An Emerging Biomarker of Cognitive Impairment in Normal Aging and Dementia

Blood–Brain Barrier Breakdown: An Emerging Biomarker of Cognitive Impairment in Normal Aging and Dementia

P7C3-A20 treatment one year after TBI in mice repairs the blood–brain barrier, arrests chronic neurodegeneration, and restores cognition

Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors

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