Toggle Main Menu Toggle Search

Open Access padlockePrints

White matter pathology and disconnection in the frontal lobe in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Lookup NU author(s): Dr Lucinda Craggs, Matthew Burke, Arthur Oakley, Professor Raj KalariaORCiD

Downloads


Licence

This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

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.


Publication metadata

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


Altmetrics

Altmetrics provided by Altmetric


Funding

Funder referenceFunder name
Medical Research Council (UK)
Overseas Research Studentship Awards
BrainNet II Europe, Germany
RCUK Newcastle Centre for Brain Ageing and Vitality
G0700718Medical Research Council (MRC)

Share