2.Cerebrovascular neuropathology in the brains of people with Down syndrome

Abstract

AbstractBackgroundPeople with Down syndrome (DS) are at genetic risk of developing early‐onset Alzheimer’s disease (AD). By age 40 years, virtually all people with DS develop beta amyloid plaques and tau neurofibrillary tangles, typically followed by the development of AD dementia over a decade later. Despite having a low frequency of vascular risk factors (i.e., hypertension, atherosclerosis), people with DS show an age‐related progression of cerebral amyloid angiopathy (CAA), white matter hyperintensities, microbleeds, micro infarcts, and enlarged perivascular spaces by neuroimaging. Interestingly, the incidence of CAA at autopsy is significantly higher in people with DS than patients with late onset AD. Our main objective is to investigate the cerebrovascular pathology in DS autopsy cases.MethodFree floating 30 µm thick sections from the occipital cortex of DS cases with or without AD pathology (DSAD and DS, respectively, n = 5/group) were compared to age matched cognitively normal controls (n = 5). Sections were immunostained for collagen IV (basement membranes) and for fibrinogen (protein extravasation).ResultPreliminary results show that compared to controls, DSAD brains have impaired vascular integrity, observed as reduced collagen IV basement membrane labeling and evidence of protein extravasation which may reflect microbleeds observed using in vivo neuroimaging.ConclusionOur preliminary data suggest a disruption of blood vessel basement membranes observed as losses in collagen IV immunostaining in DSAD brains. Moreover, fibrinogen extravasation was consistently observed in DSAD brains. We are currently characterizing the age of onset of collagen IV disruption/losses and fibrinogen leakage into the brain parenchyma in the context of an AT(N) framework to understand when in AD progression, cerebrovascular pathology evolves in DS.