Abstract
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common form of hereditary cerebral small vessel disease. Previous neuroimaging studies have suggested loss of hippocampal volume is a pathway for cognitive impairment in CADASIL. We used unbiased stereological methods to estimate SMI32-positive and total numbers and volumes of neurons in the hippocampal formation of 12 patients with CADASIL and similar age controls (young controls) and older controls. We found densities of SMI32-positive neurons in the entorhinal cortex, layer V, and cornu ammonis CA2 regions were reduced by 26%–50% in patients with CADASIL compared with young controls (p < 0.01), with a decreasing trend observed in older controls in the order of young controls> older controls ≥ CADASIL. These changes were not explained by any hippocampal infarct or vascular pathology or glial changes. Our results suggest notable loss of subsets of projection neurons within the hippocampal formation that may contribute to certain memory deficits in CADASIL, which is purely a vascular disease. It is likely that the severe arteriopathy leads to white matter damage which disconnects cortico-cortical and subcortical-cortical networks including the hippocampal formation.
Highlights
Loss of neurons and subsequent atrophy of the hippocampal formation within the cornu ammonis (CA) fields, subiculum and entorhinal cortex (EC), are common pathological changes observed in different stages of cognitive impairment including mild cognitive impairment (Pennanen et al, 2004), Alzheimer's disease (AD) (Gomez-Isla et al, 1996; Kril et al, 2002a), and dementia with Lewy body (Harding et al, 2002)
Compared with the young controls, we found SMI32-positive neurons to be lower in old control participants, but differences in mean densities and percentage of SMI32-positive neurons were significant only in the CA1 (p 1⁄4 0.019 and p 1⁄4 0.037) and only trend was observed in EC layer V (ECV) (p 1⁄4 0.075 and p 1⁄4 0.094)
There was no significant correlation in any of the regions in CADASIL cases. These results indicated that while only the expression of SMI32 was reduced in older controls, small numbers of large pyramidal neurons were lost in the hippocampus of CADASIL
Summary
Loss of neurons and subsequent atrophy of the hippocampal formation within the cornu ammonis (CA) fields, subiculum and entorhinal cortex (EC), are common pathological changes observed in different stages of cognitive impairment including mild cognitive impairment (Pennanen et al, 2004), Alzheimer's disease (AD) (Gomez-Isla et al, 1996; Kril et al, 2002a), and dementia with Lewy body (Harding et al, 2002). Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common form of hereditary small vessel disease (SVD) caused by mutations in the NOTCH3 gene (Chabriat et al, 2009).
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