Blood–Brain Barrier Disruption in White Matter Lesions in a Rat Model of Chronic Cerebral Hypoperfusion

Blood–brain barrier damage has been implicated in the pathogenesis of cerebrovascular white matter lesions. This type of lesion is responsible for cognitive impairment in the elderly and can be induced by permanent ligation of the bilateral common carotid arteries in the rat. Because it is unclear whether the blood–brain barrier is impaired, we examined whether vascular permeability to horseradish peroxidase is altered using this model. According to light microscopic results, the reaction product of horseradish peroxidase was most intensely localized to the paramedian part of the corpus callosum in the brain, occurring to a small degree at 3 hours, day 1, markedly on day 3, but reduced on days 7 and 14. By electron microscopic study of the same area, the reaction product of horseradish peroxidase was localized to the plasmalemmal vesicles in the endothelial cells 3 hours after ligation, but appeared in the cytoplasm on days 1 and 3, suggesting a diffuse leakage of horseradish peroxidase. In addition, the reaction product was dispersed into the cytoplasm of glial cells in the perivascular regions on day 3. The luminal surface of the endothelial cell cytoplasm appeared irregular on day 7, suggesting a conformational change of the endothelial cells. Collagen fibrils proliferated in the thickened basal lamina and mitochondria degenerated in the pericyte on days 7 and 14. Perivascular glial endfeet were swollen throughout the survival period. In sham-operated rats, the reaction product of horseradish peroxidase was not observed at any time interval, except in vesicular structures. These findings indicate that chronic cerebral hypoperfusion induces blood–brain barrier damage with subsequent morphologic changes of the vascular structures in the corpus callosum. An extravasation of macromolecules, such as proteases and immunoglobulins, may contribute to the pathogenesis of white matter lesions.

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Blood-brain barrier breakdown in non-enhancing multiple sclerosis lesions detected by 7-Tesla MP2RAGE ΔT1 mapping

PLoS ONE ◽

10.1371/journal.pone.0249973 ◽

2021 ◽

Vol 16 (4) ◽

pp. e0249973

Author(s):

Seongjin Choi ◽

Margaret Spini ◽

Jun Hua ◽

Daniel M. Harrison

Keyword(s):

Multiple Sclerosis ◽

Relaxation Time ◽

White Matter ◽

Blood Brain Barrier ◽

White Matter Lesions ◽

Brain Barrier ◽

7 Tesla ◽

T1 Relaxation Time ◽

T1 Relaxation ◽

Blood Brain

Although the blood-brain barrier (BBB) is altered in most multiple sclerosis (MS) lesions, gadolinium enhancement is seen only in acute lesions. In this study, we aimed to investigate gadolinium-induced changes in T1 relaxation time in MS lesions on 7-tesla (7T) MRI as a means to quantify BBB breakdown in non-enhancing MS lesions. Forty-seven participants with MS underwent 7T MRI of the brain with a magnitude-prepared rapid acquisition of 2 gradient echoes (MP2RAGE) sequence before and after contrast. Subtraction of pre- and post-contrast T1 maps was used to measure T1 relaxation time change (ΔT1) from gadolinium. ΔT1 values were interrogated in enhancing white matter lesions (ELs), non-enhancing white matter lesions (NELs), and normal appearing white matter (NAWM) and metrics were compared to clinical data. ΔT1 was measurable in NELs (median: -0.139 (-0.304, 0.174) seconds; p < 0.001) and was negligible in NAWM (median: -0.001 (-0.036, 0.155) seconds; p = 0.516). Median ΔT1 in NELs correlated with disability as measured by Expanded Disability Status Scale (EDSS) (rho = -0.331, p = 0.026). Multiple measures of NEL ΔT1 variability also correlated with EDSS. NEL ΔT1 values were greater and more variable in patients with progressive forms of MS and greater in those not on MS treatment. Measurement of the changes in T1 relaxation time caused by contrast on 7T MP2RAGE reveals clinically relevant evidence of BBB breakdown in NELs in MS. This data suggests that NEL ΔT1 should be evaluated further as a biomarker for disease severity and treatment effect in MS.

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

Journal of Neuroinflammation ◽

10.1186/s12974-020-02038-2 ◽

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.

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

Acta Neuropathologica Communications ◽

10.1186/s40478-019-0844-x ◽

2019 ◽

Vol 7 (1) ◽

Cited By ~ 6

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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Role of Caspase-3-Mediated Apoptosis in Chronic Caspase-3-Cleaved Tau Accumulation and Blood–Brain Barrier Damage in the Corpus Callosum after Traumatic Brain Injury in Rats

Journal of Neurotrauma ◽

10.1089/neu.2017.4999 ◽

2018 ◽

Vol 35 (1) ◽

pp. 157-173 ◽

Cited By ~ 22

Author(s):

Olena Y. Glushakova ◽

Andriy O. Glushakov ◽

Cesar V. Borlongan ◽

Alex B. Valadka ◽

Ronald L. Hayes ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Corpus Callosum ◽

Blood Brain Barrier ◽

Caspase 3 ◽

Brain Barrier ◽

Blood Brain ◽

Blood Brain Barrier Damage

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Abstract T P363: Blood-Brain Barrier Damage in Vascular Risk Factor Associated White Matter Disease

Stroke ◽

10.1161/str.45.suppl_1.tp363 ◽

2014 ◽

Vol 45 (suppl_1) ◽

Author(s):

Richard Leigh ◽

Peter B Barker ◽

Argye E Hillis

Keyword(s):

Risk Factor ◽

White Matter ◽

Blood Brain Barrier ◽

Vascular Risk Factor ◽

Brain Barrier ◽

White Matter Disease ◽

Vascular Risk ◽

Post Contrast ◽

Blood Brain ◽

Blood Brain Barrier Damage

Background: Vascular risk factor associated white matter disease (WMD), or leukoaraiosis, has been shown to demonstrate blood brain barrier damage (BBB) in patients with vascular dementia even when not detectable with standard clinical T1 post-contrast imaging. Purpose: We sought to study the prevalence of white matter BBB damage in a population of patients admitted to an inpatient stroke service. Methods: MRI scans of patients admitted for TIA or stroke were reviewed for evidence of confluent WMD in the centrum semiovale (CSO). To be included in the study patients must also have undergone a successful DSC image acquisition, also known as perfusion weighted image (PWI). The source images of the PWI were analyzed to generate blood-brain permeability images (BBPI) as described in a previous publication (Leigh et al, PLOS One 2012). The CSO in the first image above the lateral ventricles was used in each patient to generate BBPI measures. The pre-injection images of the PWI are T2* weighted and were therefore used to outline the area of confluent T2 signal change bilaterally. No acute strokes were present in any CSO analyzed as confirmed on DWI. The mean percent leakage (MPL) of contrast was calculated for each patient. A threshold of 2% of cerebral blood volume (CBV) was used to differentiate BBB damage from noise. Results: 20 patients were included in the study, 8 were female, with a mean age of 65 years. The diagnosis was stroke in 15 patients and TIA in 5 patients. The location of the strokes were 5 pons, 3 basil ganglia, 3 periventricular, 1 thalamus, 1 cerebellar, 1 PCA, and 1 embolic shower. Of the 20 patients, 11 stroke patients and 3 TIA patients demonstrated BBB damage. The MPL ranged from 2.1% to 23.7% with an average value of 6.9% (of CBV). The MPL was even higher for the TIA group (12.2%) than for the for the stroke group (5.4%), although this difference failed to reach significance (p=0.056) . Conclusions: In patients admitted for stroke evaluation, BBB damage in confluent WMD is common. The relevance of this finding remains unclear. However there appears to be a trend towards increased BBB damage in patients who present with events that do not localize to an acute stroke; further research should be directed at establishing the clinical implications of BBB damage in this population.

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Blood-brain Barrier Disruption May Contribute to White Matter Lesions in the Setting of Internal Jugular Venous Stenosis

Current Neurovascular Research ◽

10.2174/1567202616666191001110421 ◽

2019 ◽

Vol 16 (4) ◽

pp. 328-334

Author(s):

Yali Wu ◽

Ran Meng ◽

Gary B. Rajah ◽

Yuchuan Ding ◽

Yaoming Xu ◽

...

Keyword(s):

White Matter ◽

Blood Brain Barrier ◽

Statistical Significance ◽

White Matter Lesions ◽

Brain Barrier ◽

Control Group ◽

Imaging Features ◽

Blood Brain ◽

Venous Stenosis ◽

Significant Difference

Background and Purpose: Cloudy white matter lesions are associated imaging features of internal jugular venous stenosis (IJVS). However, the mechanism of the IJVS associated cloudy white matter lesions is still unclear. This study aims to evaluate blood-brain barrier integrity of the patients with IJVS. Materials and Methods: A total of 45 eligible patients with IJVS confirmed by computed tomography venography (CTV) and 45 healthy controls were enrolled into this study. The levels of serum MMP-9 and the markers of tight junctions, including occludin and ZO-1 obtained from IJVS patients and control group were tested by enzyme-linked immune-sorbent assay and compared. Results: Both the levels of serum MMP-9 (0.2ng/ml) and occludin (0.05ng/ml) in IJVS group were higher than in the control group (0.01ng/ml vs. 0 ng/ml, all p<0.001). While, the levels of serum ZO-1 showed no statistical significance between the two groups (0.55ng/ml vs 0.735ng/ml, P=0.34). The levels of serum MMP-9 between the subset with or without white matter lesions in IJVS group showed a significant difference (0.22 [0.06, 0.43] vs. 0.01 [0.01, 0.06], P =0.019). Conclusions: BBB disruption may participate in the formation of IJVS-associated white matter lesions; the mechanism of BBB disruption may involve MMP-9 and occludin.

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