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

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

Neurology ◽

10.1212/wnl.0000000000007263 ◽

2019 ◽

Vol 92 (15) ◽

pp. e1669-e1677 ◽

Cited By ~ 19

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.

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Integrity of normal-appearing white matter: Influence of age, visible lesion burden and hypertension in patients with small-vessel disease

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x16635657 ◽

2016 ◽

Vol 37 (2) ◽

pp. 644-656 ◽

Cited By ~ 67

Author(s):

Susana Muñoz Maniega ◽

Francesca M Chappell ◽

Maria C Valdés Hernández ◽

Paul A Armitage ◽

Stephen D Makin ◽

...

Keyword(s):

White Matter ◽

Blood Brain Barrier ◽

White Matter Hyperintensities ◽

Small Vessel Disease ◽

Mean Diffusivity ◽

Signal Enhancement ◽

Brain Barrier ◽

Normal Appearing White Matter ◽

Tissue Interactions ◽

Blood Brain

White matter hyperintensities accumulate with age and occur in patients with stroke, but their pathogenesis is poorly understood. We measured multiple magnetic resonance imaging biomarkers of tissue integrity in normal-appearing white matter and white matter hyperintensities in patients with mild stroke, to improve understanding of white matter hyperintensities origins. We classified white matter into white matter hyperintensities and normal-appearing white matter and measured fractional anisotropy, mean diffusivity, water content (T1-relaxation time) and blood–brain barrier leakage (signal enhancement slope from dynamic contrast-enhanced magnetic resonance imaging). We studied the effects of age, white matter hyperintensities burden (Fazekas score) and vascular risk factors on each biomarker, in normal-appearing white matter and white matter hyperintensities, and performed receiver-operator characteristic curve analysis. Amongst 204 patients (34.3–90.9 years), all biomarkers differed between normal-appearing white matter and white matter hyperintensities ( P < 0.001). In normal-appearing white matter and white matter hyperintensities, mean diffusivity and T1 increased with age ( P < 0.001), all biomarkers varied with white matter hyperintensities burden ( P < 0.001; P = 0.02 signal enhancement slope), but only signal enhancement slope increased with hypertension ( P = 0.028). Fractional anisotropy showed complex age-white matter hyperintensities-tissue interactions; enhancement slope showed white matter hyperintensities-tissue interactions. Mean diffusivity distinguished white matter hyperintensities from normal-appearing white matter best at all ages. Blood–brain barrier leakage increases with hypertension and white matter hyperintensities burden at all ages in normal-appearing white matter and white matter hyperintensities, whereas water mobility and content increase as tissue damage accrues, suggesting that blood–brain barrier leakage mediates small vessel disease-related brain damage.

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

Stroke ◽

10.1161/str.47.suppl_1.44 ◽

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.

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An intrinsic endothelial dysfunction causes cerebral small vessel disease

10.1101/2021.12.13.472377 ◽

2021 ◽

Author(s):

Sophie Quick ◽

Tessa V. Procter ◽

Jonathan Moss ◽

Angus Lawson ◽

Serena Baker ◽

...

Keyword(s):

White Matter ◽

Endothelial Dysfunction ◽

Blood Brain Barrier ◽

Small Vessel Disease ◽

Brain Barrier ◽

Small Vessel ◽

Extrinsic Factors ◽

Vessel Disease ◽

Brain White Matter ◽

Blood Brain

Small Vessel Disease (SVD) is the leading cause of vascular dementia, causes a quarter of strokes, and worsens stroke outcomes(1, 2). The disease is characterised by cerebral small vessel and white matter pathology, but the underlying mechanisms are poorly understood. Classically, the microvascular and tissue damage has been considered secondary to extrinsic factors, such as hypertension, consisting of microvessel stiffening, impaired vasoreactivity and blood-brain barrier dysfunction identified in human sporadic SVDs. However, increasing evidence points to an underlying vulnerability to SVD-related brain damage, not just extrinsic factors. Here, in a novel normotensive transgenic rat model where the phospholipase flippase Atp11b is deleted, we show pathological, imaging and behavioural changes typical of those in human sporadic SVD, but that occur without hypertension. These changes are due to an intrinsic endothelial cell dysfunction, identified in vessels of the brain white matter and the retina, with pathological evidence of vasoreactivity and blood-brain barrier deficits, which precipitate a secondary maturation block in oligodendroglia and myelin disruption around the small vessels. This highlights that an intrinsic endothelial dysfunction may underlie vulnerability to human sporadic SVD, providing alternative therapeutic targets to prevent a major cause of stroke and dementia.

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

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-200201000-00012 ◽

2002 ◽

Vol 22 (1) ◽

pp. 97-104 ◽

Cited By ~ 91

Author(s):

Masaki Ueno ◽

Hidekazu Tomimoto ◽

Ichiro Akiguchi ◽

Hideaki Wakita ◽

Haruhiko Sakamoto

Keyword(s):

Endothelial Cells ◽

White Matter ◽

Horseradish Peroxidase ◽

Corpus Callosum ◽

Blood Brain Barrier ◽

White Matter Lesions ◽

Brain Barrier ◽

Cerebral Hypoperfusion ◽

Blood Brain ◽

Blood Brain Barrier Damage

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 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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