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Lookup NU author(s): Dr Lucinda Craggs, Matthew Burke, Arthur Oakley, Professor Raj KalariaORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
BACKGROUND: Magnetic resonance imaging indicates diffuse white matter (WM) changes are associated with cognitive impairment in CADASIL. We examined whether the distribution of axonal abnormalities is related to microvascular pathology in the underlying WM. METHODS: We used post-mortem brains from CADASIL subjects and similar age cognitively normal controls to examine WM axonal changes, microvascular pathology, and glial reaction in up to 16 different regions extending rostro-caudally through the cerebrum. Using unbiased stereological methods, we estimated length densities of affected axons immunostained with neurofilament antibody SMI32. Standard immunohistochemsitry was used to assess amyloid precursor protein immunoreactivity per WM area. To relate WM changes to microvascular pathology, we also determined the sclerotic index (SI) in WM arterioles. RESULTS: The degree of WM pathology consistently scored higher across all brain regions in CADASIL subjects (p<0.01) with the WM underlying the primary motor cortex exhibiting the most severe change. SMI32 immunoreactive axons in CADASIL were invariably increased compared to controls (p<0.01), with most prominent axonal abnormalities observed in the frontal WM (p<0.05). The SIs of arterioles in CADASIL were increased by 25-45% throughout the regions assessed, with the highest change in the mid-frontal region (p=0.000). CONCLUSIONS: Our results suggest disruption of either cortico-cortical or subcortical-cortical networks in the WM of the frontal lobe that may explain motor deficits and executive dysfunction in CADASIL. Widespread WM axonal changes arise from differential stenosis and sclerosis of arterioles in the WM of CADASIL subjects, possibly affecting some axons of projections connecting to targets in the subcortical structures.
Author(s): Craggs LJL, Yamamoto Y, Ihara M, Fenwick R, Burke M, Oakley AE, Roeber S, Duering M, Kretzschmar H, Kalaria RN
Publication type: Article
Publication status: Published
Journal: Neuropathology and Applied Neurobiology
Year: 2014
Volume: 40
Issue: 5
Pages: 591-602
Print publication date: 01/08/2014
Online publication date: 01/07/2014
Acceptance date: 04/07/2013
Date deposited: 21/07/2014
ISSN (print): 0305-1846
ISSN (electronic): 1365-2990
Publisher: John Wiley & Sons Ltd
URL: http://dx.doi.org/10.1111/nan.12073
DOI: 10.1111/nan.12073
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