Hereditary vascular cognitive decline

Abstract

A number of monogenic forms of cerebral small vessel disease (SVD) cause early onset lacunar stroke and dementia. By far the most common of these is CADASIL due to NOTCH3 mutations, although other underlying genes causing similar diseases include HTRA1 and COL4A1/2. Characteristic MRI features include white matter hyperintensities, lacunar infarcts, and cerebral microbleeds. The pattern of cognitive impairment usually shows prominent executive dysfunction and information processing speed. Diagnosis depends on family history, characteristic clinical features, and characterised MRI markers, and is confirmed by genetic testing, made much simpler with newer gene arrays. Although there is little evidence based management, recent European Neurological Association guidelines provide a useful management framework. Increasing evidence has implicated a key role of disruption in the matrisome and extracellular matrix (ECM) of the small perforating arteries within the brain in disease pathogenesis, with disruption in different genes converging on shared pathways. Recent evidence suggests that more common variants in the same genes can predispose to sporadic younger onset stroke and dementia. Interestingly study of community cohorts has demonstrated that the mutations causing familial SVD are much commoner in the general population than would be expected from familial SVD prevalence. Why mutations sometimes result in early onset disease and on other occasions do not is still being investigated. However these population variants have also been associated with an increased risk of sporadic stroke and sporadic vascular dementia.