Vascular Pathology in familial forms of Small Vessel Disease: Phenotyping CADASIL, PADMAL and hereditary MID of Swedish type

Craggs, L; Hagel, C; Kuhlenbaeumer, G; Borjesson-Hanson, A; Viitanen, M; Kalimo, H; Oakley, AE; Kalaria, RN

doi:10.1111/j.1365-2990.2011.01241.x

Vascular Pathology in familial forms of Small Vessel Disease: Phenotyping CADASIL, PADMAL and hereditary MID of Swedish type

Lookup NU author(s): Dr Lucinda Craggs, Arthur Oakley, Professor Raj Kalaria ORCiD

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Abstract

Introduction: CADASIL is characterized by mutations in the NOTCH3 gene and accumulation of granular osmiophilic material (GOM) in the vascular walls as hall mark pathology. Two other dominantly inherited forms of SVD have been identiﬁ ed, hereditary multi-infarct dementia of Swedish type and Pontine Autosomal Dominant Microangiopathy and Leukoencephalopathy (PADMAL), where the causal genes remain unidentiﬁ ed but have been shown to be unrelated to NOTCH3 and without GOM accumulation (1, 2). The cerebral distribution of infarcts appears discriminating between disease forms, resulting in characteristically different clinical phenotypes. However, the vascular pathologies of these diseases are strikingly similar. We aimed to characterize the extent of arteriolosclerosis and identify some of the mechanisms of vessel degeneration within two distinct regions of the brain, the basal ganglia and frontal cortical regions, comparing vessels in both the grey (GM) and white matter (WM).Material and methods: Postmortem brains included 9 CADASIL, 4 PADMAL and 6 Swedish affected cases compared to 11 young controls, 10 VaD and 10 older controls matched to VaD cases.Results: Sclerotic index of arterioles, 50–350 micron in diameter, was found to be signiﬁ cantly increased in vessels in CADASIL and Swedish cases in the WM of the basal ganglia (P < 0.001), whereas the PADMAL vessels were not thicker than the VaD and control groups. Vessels in the WM were more affected than in the GM, but only the CADASIL group showed signiﬁ cant vessel wall thickening (P < 0.05). Protein markers of each vessel component were assessed by immunohistochemistry; smooth muscle alpha actin (vascular smooth muscle cells), glucose transporter-1 (endothelium) and collagen IV (basement membrane).Conclusions: Vascular degeneration in CADASIL is mediated by loss of smooth muscle cells also affecting endothelial cell function. The degenerative features in PADMAL and Swedish type are similar but less aggressive suggesting differential mechanisms leading to SVD.