Intracerebral haemorrhage in Down syndrome: protected or predisposed?

Abstract

Down syndrome (DS), which arises from trisomy of chromosome 21, is associated with deposition of large amounts of amyloid within the central nervous system. Amyloid accumulates in two compartments: as plaques within the brain parenchyma and in vessel walls of the cerebral microvasculature. The parenchymal plaque amyloid is thought to result in an early onset Alzheimer's disease (AD) dementia, a phenomenon so common amongst people with DS that it could be considered a defining feature of the condition. The amyloid precursor protein ( APP) gene lies on chromosome 21 and its presence in three copies in DS is thought to largely drive the early onset AD. In contrast, intracerebral haemorrhage (ICH), the main clinical consequence of vascular amyloidosis, is a more poorly defined feature of DS. We review recent epidemiological data on stroke (including haemorrhagic stroke) in order to make comparisons with a rare form of familial AD due to duplication (i.e. having three copies) of the APP region on chromosome 21, here called 'dup-APP', which is associated with more frequent and severe ICH. We conclude that although people with DS are at increased risk of ICH, this is less common than in dup-APP, suggesting the presence of mechanisms that act protectively. We review these mechanisms and consider comparative research into DS and dup-APP that may yield further pathophysiological insight.

Keywords: Alzheimer’s disease; Cerebral amyloid angiopathy; Down syndrome; Intracerebral haemorrhage; trisomy.

Figure 1.. Summary of kindreds harbouring duplication (i.e. having three copies) of the amyloid precursor protein region on chromosome 21 (dup-APP).

Phenotype with respect to dementia (black crescent) and intracerebral haemorrhage (ICH) (red crescent) is shown. Genotype is reported as APP duplication present (dup), absent (-), or not determined (ND). The French kindreds (Wallon et al. ) are not shown, as there are insufficient data provided for this purpose. Owing to limitations of the original article, it was not possible to report the genotypes for the Finnish kindred: nine of the affected individuals carry dup-APP, but it is not reported which of the family members this applies to.

Figure 2.. Histological severity of cerebral amyloid angiopathy (system of Vonsattel et al. ) seen in post mortem studies of people with Down syndrome in different age groups.

Age ranges are indicated above charts. Data are reproduced from .