Abstract 44: Enlarged Perivascular Spaces Correlate With CSF Biomarkers for Abnormal Blood-brain Barrier Permeability and Neuroinflammation in Patients With Vascular Cognitive Impairment

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Laith Maali ◽  
Branko Huisa ◽  
Jillian Prestopnik ◽  
Clifford Qualls ◽  
Jeffrey Thompson ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
White Matter ◽  
Blood Brain Barrier ◽  
Vascular Cognitive Impairment ◽  
Brain Barrier ◽  
Csf Biomarkers ◽  
Perivascular Spaces ◽  
Albumin Ratio ◽  
Blood Brain ◽  
Bbb Permeability

Background: Enlarged perivascular spaces (PVS) in the brain are common but their etiology and specificity are unclear. Multiple studies have shown a correlation between enlarged PVS and white matter hyperintensities (WMHs), but the relationship with vascular disease is uncertain. We used albumin CSF to blood ratio as a method to measure permeability of the blood-brain barrier (BBB) in patients with vascular cognitive impairment (VCI). It is possible that the enlarged PVS are associated with an increase in BBB permeability, which could interfere with perivascular fluid flow. Therefore, we hypothesized that enlarged PVS correlate with CSF markers of increased BBB permeability and neuroinflammation. Methods: We prospectively recruited 107 VCI patients with white matter disease. At entry, they had brain MRIs with standardized ranking for enlarged PVS. Sixty-one had lumbar puncture to obtain CSF for analysis of albumin ratio, matrix metalloproteinases-2 (MMP-2) index, and amyloid-beta1-42 (Abeta42). The data was analyzed statistically with nonparametric correlation methods. Results: Enlarged PVS had a positive correlation with CSF albumin ratio, which is a biomarker for increased BBB permeability ( p <0.01), and a negative correlation with the neuroinflammatory biomarker, MMP2 index ( p <0.02), and with Abeta42 ( p <0.02), which is cleared by the PVS. Conclusion: Our results suggest an association between PVS, MMP-mediated increased BBB permeability, and clearance of Abeta42. The role of perivascular fluid movement and its relationship with CSF biomarkers will require further investigation.

scholarly journals Targeting Transcription Factor Nrf2 (Nuclear Factor Erythroid 2-Related Factor 2) for the Intervention of Vascular Cognitive Impairment and Dementia

2020 ◽  
Author(s):  
Tuo Yang ◽  
Feng Zhang
Keyword(s):  
Oxidative Stress ◽  
Cognitive Impairment ◽  
White Matter ◽  
Blood Brain Barrier ◽  
Vascular Cognitive Impairment ◽  
Brain Barrier ◽  
Brain Diseases ◽  
Related Factor ◽  
Nuclear Factor ◽  
Blood Brain

Vascular cognitive impairment and dementia (VCID) is an age-related, mild to severe mental disability due to a broad panel of cerebrovascular disorders. Its pathobiology involves neurovascular dysfunction, blood-brain barrier disruption, white matter damage, microRNAs, oxidative stress, neuroinflammation, and gut microbiota alterations, etc. Nrf2 (Nuclear factor erythroid 2-related factor 2) is the master regulator of redox status and controls the transcription of a panel of antioxidative and anti-inflammatory genes. By interacting with NF-κB (nuclear factor-κB), Nrf2 also fine-tunes the cellular oxidative and inflammatory balance. Aging is associated with Nrf2 dysfunction, and increasing evidence has proved the role of Nrf2 in mitigating the VCID process. Based on VCID pathobiologies and Nrf2 studies from VCID and other brain diseases, we point out several hypothetical Nrf2 targets for VCID management, including restoration of endothelial function and neurovascular coupling, preservation of blood-brain barrier integrity, reduction of amyloidopathy, promoting white matter integrity, and mitigating oxidative stress and neuroinflammation. Collectively, the Nrf2 pathway could be a promising direction for future VCID research. Targeting Nrf2 would shed light on VCID managing strategies.

scholarly journals Baseline Blood-Brain Barrier Leakage and Longitudinal Microstructural Tissue Damage in the Periphery of White Matter Hyperintensities

Neurology ◽  
2021 ◽  
Vol 96 (17) ◽  
pp. e2192-e2200
Author(s):  
Danielle Kerkhofs ◽  
Sau May Wong ◽  
Eleana Zhang ◽  
Julie Staals ◽  
Jacobus F.A. Jansen ◽  
...  
Keyword(s):  
White Matter ◽  
Blood Brain Barrier ◽  
White Matter Hyperintensities ◽  
Small Vessel Disease ◽  
Vascular Cognitive Impairment ◽  
Brain Barrier ◽  
Blood Brain ◽  
Diffusion Technique ◽  
Bbb Permeability ◽  
Motion Imaging

ObjectiveTo investigate the 2-year change in parenchymal diffusivity, a quantitative marker of microstructural tissue condition, and the relationship with baseline blood-brain barrier (BBB) permeability, in tissue at risk, i.e., the perilesional zone surrounding white matter hyperintensities (WMH) in patients with cerebral small vessel disease (cSVD).MethodsPatients with sporadic cSVD (lacunar stroke or mild vascular cognitive impairment) underwent 3T MRI at baseline, including dynamic contrast-enhanced MRI to quantify BBB permeability (i.e., leakage volume and rate) and intravoxel incoherent motion imaging (IVIM), a diffusion technique that provides parenchymal diffusivity D. After 2 years, IVIM was repeated. We assessed the relation between BBB leakage measures at baseline and change in parenchymal diffusivity (∆D) over 2 years in the perilesional zones (divided in 2-mm contours) surrounding WMH.ResultsWe analyzed 43 patients (age 68 ± 12 years, 58% male). In the perilesional zones, ∆D increased 0.10% (confidence interval [CI] 0.07–0.013%) (p < 0.01) per 2 mm closer to the WMH. Furthermore, ∆D over 2 years showed a positive correlation with both baseline BBB leakage volume (r = 0.29 [CI 0.06–0.52], p = 0.013) and leakage rate (r = 0.24 [CI 0.02–0.47], p = 0.034).ConclusionBBB leakage at baseline is related to the 2-year change in parenchymal diffusivity in the perilesional zone of WMH. These results support the hypothesis that BBB impairment might play an early role in subsequent microstructural white matter degeneration as part of the pathophysiology of cSVD.

scholarly journals Disturbance of Intracerebral Fluid Clearance and Blood–Brain Barrier in Vascular Cognitive Impairment

2019 ◽  
Vol 20 (10) ◽  
pp. 2600 ◽  
Author(s):  
Masaki Ueno ◽  
Yoichi Chiba ◽  
Ryuta Murakami ◽  
Koichi Matsumoto ◽  
Ryuji Fujihara ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Blood Brain Barrier ◽  
Brain Function ◽  
Vascular Cognitive Impairment ◽  
Brain Dysfunction ◽  
Brain Parenchyma ◽  
The Other ◽  
Brain Barrier ◽  
Blood Brain ◽  
The Brain

The entry of blood-borne macromolecular substances into the brain parenchyma from cerebral vessels is blocked by the blood–brain barrier (BBB) function. Accordingly, increased permeability of the vessels induced by insult noted in patients suffering from vascular dementia likely contributes to the cognitive impairment. On the other hand, blood-borne substances can enter extracellular spaces of the brain via endothelial cells at specific sites without the BBB, and can move to brain parenchyma, such as the hippocampus and periventricular areas, adjacent to specific sites, indicating the contribution of increased permeability of vessels in the specific sites to brain function. It is necessary to consider influx and efflux of interstitial fluid (ISF) and cerebrospinal fluid (CSF) in considering effects of brain transfer of intravascular substances on brain function. Two pathways of ISF and CSF are recently being established. One is the intramural peri-arterial drainage (IPAD) pathway of ISF. The other is the glymphatic system of CSF. Dysfunction of the two pathways could also contribute to brain dysfunction. We review the effects of several kinds of insult on vascular permeability and the failure of fluid clearance on the brain function.

scholarly journals Sleep Deprivation Induces Cognitive Impairment by Increasing Blood-Brain Barrier Permeability via CD44

2020 ◽  
Vol 11 ◽  
Author(s):  
Jing Sun ◽  
Jusheng Wu ◽  
Fuzhou Hua ◽  
Yong Chen ◽  
Fenfang Zhan ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Sleep Deprivation ◽  
Rna Sequencing ◽  
Blood Brain Barrier ◽  
Nervous System Development ◽  
Brain Barrier ◽  
Receptor Interaction ◽  
Blood Brain ◽  
Bbb Permeability

Sleep deprivation occurs frequently in older adults, which can result in delirium and cognitive impairment. CD44 is a key molecular in blood-brain barrier (BBB) regulation. However, whether CD44 participates in the role of sleep deprivation in cognitive impairment remains unclear. In this study, the effect of sleep deprivation on cognitive ability, tissue inflammation, BBB permeability, and astrocyte activity were evaluated in vivo. The differentially expressed genes (DEGs) were identified by RNA sequencing. A CD44 overexpression in the BBB model was performed in vitro to assess the effect and mechanisms of CD44. Sleep deprivation impaired the learning and memory ability and increased the levels of inflammatory cytokines, along with increased BBB permeability and activated astrocytes in hippocampus tissue. RNA sequencing of the hippocampus tissue revealed that 329 genes were upregulated in sleep deprivation-induced mice compared to control mice, and 147 genes were downregulated. GO and pathways showed that DEGs were mainly involved in BBB permeability and astrocyte activation, including nervous system development, neuron development, and brain development, and neuroactive ligand-receptor interaction. Moreover, the PCR analysis revealed that CD44 was dramatically increased in mice with sleep deprivation induction. The overexpression of CD44 in astrocytes promoted BBB permeability in vitro and induced the expression of the downstream gene NANOG. Our results indicate that sleep deprivation upregulated CD44 expression in hippocampus tissue, and increased BBB permeability, resulting in cognitive impairment.

scholarly journals Blood-brain barrier impairment and hypoperfusion are linked in cerebral small vessel disease

Neurology ◽  
2019 ◽  
Vol 92 (15) ◽  
pp. e1669-e1677 ◽  
Author(s):  
Sau May Wong ◽  
Jacobus F.A. Jansen ◽  
C. Eleana Zhang ◽  
Erik I. Hoff ◽  
Julie Staals ◽  
...  
Keyword(s):  
White Matter ◽  
Blood Brain Barrier ◽  
Small Vessel Disease ◽  
Cerebral Small Vessel Disease ◽  
Brain Barrier ◽  
Small Vessel ◽  
Dynamic Susceptibility ◽  
Vessel Disease ◽  
Blood Brain ◽  
Bbb Permeability

ObjectiveTo investigate the link between blood-brain-barrier (BBB) permeability and cerebral blood flow (CBF) and the relation with white matter hyperintensities (WMH) in cerebral small vessel disease (cSVD).MethodsTwenty-seven patients with cSVD received dynamic susceptibility contrast and dynamic contrast-enhanced MRI to determine CBF and BBB permeability (expressed as leakage rate and volume), respectively. Structural MRI were segmented into normal-appearing white matter (NAWM) and WMH, for which a perilesional zone was defined. In these regions, we investigated the BBB permeability, CBF, and their relation using Pearson correlation r.ResultsWe found a decrease in CBF of 2.2 mL/min/100 g (p < 0.01) and an increase in leakage volume of 0.7% (p < 0.01) per mm closer to the WMH in the perilesional zones. Lower CBF values correlated with higher leakage measures in the NAWM and WMH (−0.53 < r < −0.40, p < 0.05). This relation was also observed in the perilesional zones, which became stronger in the proximity of WMH (p = 0.03).ConclusionBBB impairment and hypoperfusion appear in the WMH and NAWM, which increase in the proximity of the WMH, and are linked. Both BBB and CBF are regulated in the neurovascular unit (NVU) and the observed link might be due to the physiologic regulation mechanism of the NVU. This link may suggest an early overall deterioration of this unit.

scholarly journals Deficiency of Nrf2 exacerbates white matter damage and microglia/macrophage levels in a mouse model of vascular cognitive impairment

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Emma Sigfridsson ◽  
Martina Marangoni ◽  
Giles E. Hardingham ◽  
Karen Horsburgh ◽  
Jill H. Fowler
Keyword(s):  
White Matter ◽  
Blood Brain Barrier ◽  
Vascular Cognitive Impairment ◽  
Chronic Cerebral Hypoperfusion ◽  
Brain Barrier ◽  
Cerebral Hypoperfusion ◽  
Blood Brain ◽  
Barrier Breakdown ◽  
White Matter Pathology ◽  
Blood Brain Barrier Breakdown

Abstract Background Chronic cerebral hypoperfusion causes damage to the brain’s white matter underpinning vascular cognitive impairment. Inflammation and oxidative stress have been proposed as key pathophysiological mechanisms of which the transcription factor Nrf2 is a master regulator. We hypothesised that white matter pathology, microgliosis, blood-brain barrier breakdown and behavioural deficits induced by chronic hypoperfusion would be exacerbated in mice deficient in the transcription factor Nrf2. Methods Mice deficient in Nrf2 (male heterozygote or homozygous for Nrf2 knockout) or wild-type littermates on a C57Bl6/J background underwent bilateral carotid artery stenosis (BCAS) to induce chronic cerebral hypoperfusion or sham surgery and survived for a further 6 weeks. White matter pathology was assessed with MAG immunohistochemistry as a marker of altered axon-glial integrity; alterations to astrocytes and microglia/macrophages were assessed with GFAP and Iba1 immunohistochemistry, and blood-brain barrier breakdown was assessed with IgG immunohistochemistry. Behavioural alterations were assessed using 8-arm radial arm maze, and alterations to Nrf2-related and inflammatory-related genes were assessed with qRT-PCR. Results Chronic cerebral hypoperfusion induced white matter pathology, elevated microglial/macrophage levels and blood-brain barrier breakdown in white matter tracts that were increased in Nrf2+/− mice and further exacerbated by the complete absence of Nrf2. Chronic hypoperfusion induced white matter astrogliosis and induced an impairment in behaviour assessed with radial arm maze; however, these measures were not affected by Nrf2 deficiency. Although Nrf2-related antioxidant gene expression was not altered by chronic cerebral hypoperfusion, there was evidence for elevated pro-inflammatory related gene expression following chronic hypoperfusion that was not affected by Nrf2 deficiency. Conclusions The results demonstrate that the absence of Nrf2 exacerbates white matter pathology and microgliosis following cerebral hypoperfusion but does not affect behavioural impairment.

Assessing the roles of inflammation and blood brain barrier permeability in cognitive impairment: A nationwide longitudinal study of patients receiving chemotherapy and non-cancer controls.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 12070-12070
Author(s):  
Elizabeth Belcher ◽  
Nikesha Gilmore ◽  
Amber Kleckner ◽  
Ian Kleckner ◽  
Eva Culakova ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Blood Brain Barrier ◽  
Inflammatory Cytokine ◽  
Brain Barrier ◽  
Barrier Permeability ◽  
Blood Brain Barrier Permeability ◽  
Blood Brain ◽  
Brain Barrier Permeability ◽  
Bbb Permeability ◽  
Over Time

12070 Background: Cognitive impairment is a prevalent side effect of chemotherapy. We have previously shown that chemotherapy treatment is associated with worse performance on the Rapid Visual Processing test (RVP), an objective measure of sustained attention, over time compared to non-cancer controls. Better understanding of the biologic mechanisms underlying cognitive impairment in cancer patients is needed. The pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) has been implicated in increasing blood brain barrier (BBB) permeability, which in turn is associated with cognitive impairment. This study assessed the relationships of TNFα and S100β, a biomarker of BBB permeability, to each other and to RVP performance over time. Methods: We analyzed a subset of participants (n = 89 patients, n = 52 controls, mean age = 60) from a prospective longitudinal study of women with breast cancer receiving chemotherapy and non-cancer controls. TNFα and S100β were measured in serum pre-chemotherapy (T1, ≤7 days before first treatment) and post-chemotherapy (T2, ≤1 month after last treatment) and at corresponding times for controls. Sustained attention was assessed by total correct rejections on the RVP test at T1 and T2. Separate linear regression models including all participants were used to relate 1) baseline TNFα and S100β levels to change in RVP performance over time, 2) change in TNFα and S100β to change in RVP performance over time, and 3) change in TNFα to change in S100β. Models were adjusted for age. 4) T-tests were used to compare the TNFα and S100β change scores (T1 to T2) of patients vs controls. Results: Greater increase (T1 to T2) in the pro-inflammatory cytokine TNFα was associated with worse cognition, measured by performance on RVP over time (p = 0.02). Higher baseline S100β, a biomarker of BBB permeability, was associated with worse performance on RVP over time (p = 0.09). Increase in TNFα was associated with increase in S100β (p = 0.11). S100β increased from T1 to T2 in patients relative to controls (p = 0.09). Conclusions: These results suggest that higher TNFα may be related to increases in blood brain barrier permeability and worse cognition. Future studies will further define the link between inflammation, blood brain barrier permeability and chemotherapy-related cognitive decline, with the goal of informing the development of new interventions. Funding: R01CA231014, T32CA102618, DP2CA195765, UG1CA189961.

scholarly journals Blood brain barrier leakage is not a consistent feature of white matter lesions in CADASIL

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Rikesh M. Rajani ◽  
Julien Ratelade ◽  
Valérie Domenga-Denier ◽  
Yoshiki Hase ◽  
Hannu Kalimo ◽  
...  
Keyword(s):  
White Matter ◽  
Blood Brain Barrier ◽  
Small Vessel Disease ◽  
White Matter Lesions ◽  
Brain Barrier ◽  
Perivascular Spaces ◽  
Pericyte Coverage ◽  
Blood Brain ◽  
Post Mortem Brain ◽  
Pericyte Loss

AbstractCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic paradigm of small vessel disease (SVD) caused by NOTCH3 mutations that stereotypically lead to the vascular accumulation of NOTCH3 around smooth muscle cells and pericytes. White matter (WM) lesions (WMLs) are the earliest and most frequent abnormalities, and can be associated with lacunar infarcts and enlarged perivascular spaces (ePVS). The prevailing view is that blood brain barrier (BBB) leakage, possibly mediated by pericyte deficiency, plays a pivotal role in the formation of WMLs. Herein, we investigated the involvement of BBB leakage and pericyte loss in CADASIL WMLs. Using post-mortem brain tissue from 12 CADASIL patients and 10 age-matched controls, we found that WMLs are heterogeneous, and that BBB leakage reflects the heterogeneity. Specifically, while fibrinogen extravasation was significantly increased in WMLs surrounding ePVS and lacunes, levels of fibrinogen leakage were comparable in WMLs without other pathology (“pure” WMLs) to those seen in the normal appearing WM of patients and controls. In a mouse model of CADASIL, which develops WMLs but no lacunes or ePVS, we detected no extravasation of endogenous fibrinogen, nor of injected small or large tracers in WMLs. Moreover, there was no evidence of pericyte coverage modification in any type of WML in either CADASIL patients or mice. These data together indicate that WMLs in CADASIL encompass distinct classes of WM changes and argue against the prevailing hypothesis that pericyte coverage loss and BBB leakage are the primary drivers of WMLs. Our results also have important implications for the interpretation of studies on the BBB in living patients, which may misinterpret evidence of BBB leakage within WM hyperintensities as suggesting a BBB related mechanism for all WMLs, when in fact this may only apply to a subset of these lesions.

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