Abstract
Cerebral 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.
Highlights
Cerebral small vessel disease (SVD) is the leading cause of vascular dementia and a major contributor to stroke and disability [37]
white matter lesion (WML) in CADASIL patients encompass at least three categories of damage magnetic resonance imaging (MRI) studies in CADASIL patients have shown that lacunes and enlarged perivascular spaces (ePVS) can occur in the same areas as white matter hyperintensities (WMH) [6]
We studied 12 CADASIL patients from two separate cohorts and focused mostly on the frontal white matter (WM), as we have shown previously that the frontal lobe including WM bears the brunt of vascular pathology in CADASIL patients [8,9,10, 22]
Summary
Cerebral small vessel disease (SVD) is the leading cause of vascular dementia and a major contributor to stroke and disability [37]. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of SVD, affecting 2–5 in 100,000 people [43]. It is caused by mutations in the NOTCH3 gene which lead to the characteristic and early accumulation of the NOTCH3 extracellular domain (Notch3ECD) around smooth muscle cells. CADASIL resembles sporadic SVD to such an extent that it has been used as a model in trials of drugs to treat vascular dementia [16].
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