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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 KalariaORCiD


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Abstract CADASIL is linked to mutations in the NOTCH3 gene, with accumulation of granular osmiophilic material (GOM) in vessel walls as the hallmark pathology. Two other dominantly inherited forms of SVD have been identified, hereditary multi-infarct dementia of Swedish type and Pontine Autosomal Dominant Microangiopathy and Leukoencephalopathy (PADMAL), where the causal genes remain unidentified but have been shown to be unrelated to NOTCH3 and without GOM accumulation (Low et al., 2006; Hagel et al., 2004). 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 characterise 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). Post-mortem material 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. Sclerotic index of arterioles, 50-350micron in diameter, was found to be significantly increased in vessels in CADASIL and Swedish cases in the WM of the basal ganglia (P<0.001), whereas the PADMAL vessels were no thicker than the VaD and control groups. In the frontal region, vessels in the WM were more affected than in the GM, but only the CADASIL group showed significant 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 (endothelial cells) and collagen IV (basement membrane). Vascular degeneration in CADASIL is mediated by loss of smooth muscle cells also affecting endothelial cell function. The degenerative feature in PADMAL and Swedish type is similar but less aggressive, suggesting differential mechanisms leading to SVD.

Publication metadata

Author(s): Craggs L, Hagel C, Kuhlenbaeumer G, Borjesson-Hanson A, Viitanen M, Kalimo H, Oakley AE, Kalaria RN

Publication type: Conference Proceedings (inc. Abstract)

Publication status: Published

Conference Name: 5th Congress of The International Society for Vascular Behavioural and Cognitive Disorders (VAS-COG 2011)

Year of Conference: 2011

Publisher: VASCOG Society