Characterization of the neurovascular pathology in CADASIL : a model for subcortical vascular dementia

Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is one of the most common forms of hereditary vascular dementia (VaD). Characterised by early-onset strokes and cognitive impairment in the absence of vascular risk factors, CADASIL is an ideal model to understand the pathophysiology of VaD. Pathogenic mutations in the NOTCH3 gene, which encodes a single-pass transmembrane cell surface receptor expressed predominantly in vascular smooth muscle cells (VSMC), cause severe vascular alterations including VSMC degeneration, hyalinosis, deposition of CADASIL-specific granular osmiophilic material (GOM) and white matter (WM) changes. While these changes have been well-described, their causative mechanism or difference between sporadic VaD is poorly understood. The aim of the project was to quantitatively characterise various aspects of cerebral pathology of CADASIL in order to reveal the pathological basis of CADASIL phenotypes, especially of cognitive dysfunction. Firstly, we assessed vascular and perivascular changes in CADASIL brain areas and found significant vessel wall thickening and perivascular space enlargement, even compared to sporadic VaD. Secondly, by using immunogold electron microscopy, NOTCH3 extracellular domain (N3ECD) was located within GOM in the wall of cerebral arteries/arterioles/capillaries, establishing at least one component of GOM and its wide-spread existence in the vasculature. This study also suggested the possible existence of intracellular N3ECD accumulation and involvement of inflammatory response in the pathogenesis of CADASIL. Finally, we provide neuronal density data from the hippocampal formation in CADASIL brains to identify the neural substrates of VaD in CADASIL. Overall, the number of neurons in CA1, CA2 and entorhinal cortex was relatively spared in CADASIL while pyramidal neuronal subpopulation, as shown by SMI32 immunoreactivity, was slightly decreased. In addition, SMI32 staining revealed extensive chronic damage to WM tracts, especially those in the frontal-parietal area. These data suggest that vascular dysfunction and inflammation result in frontal disconnection, which could underlie cognitive impairment in CADASIL patients.