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

Lucinda J L Craggs, Yumi Yamamoto, Masafumi Ihara, Richard Fenwick, Matthew Burke, Arthur E. Oakley, Sigrun Roeber, Marco Duering, Hans Kretzschmar, Raj N. Kalaria

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Background: Magnetic resonance imaging indicates diffuse white matter (WM) changes are associated with cognitive impairment in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (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 immunohistochemistry 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 with 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 projection neurones connecting to targets in the subcortical structures.

Original languageEnglish
Pages (from-to)591-602
Number of pages12
JournalNeuropathology and Applied Neurobiology
Issue number5
Early online date1 Jul 2014
Publication statusPublished - Aug 2014
Externally publishedYes


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