Microbleeds and Cerebral Amyloid Angiopathy in the Brains of People with Down Syndrome with Alzheimer's Disease

Abstract

Cerebrovascular pathology is a significant mediator in Alzheimer's disease (AD) in the general population. In people with Down syndrome (DS), the contribution of vascular pathology to dementia may play a similar role in age of onset and/or the rate of progression of AD. In the current study, we explored the extent of microbleeds (MBs) and the link between cerebral amyloid angiopathy (CAA) and MBs in the frontal cortex (FCTX) and occipital cortex (OCTX) in an autopsy series from individuals with DS (<40 years), DS with AD pathology (DSAD), sporadic AD, and control cases (2-83 years). Sections were immunostained against Aβ1 - 40 and an adjacent section stained using Prussian blue for MBs. MBs were both counted and averaged in each case and CAA was scored based on previously published methods. MBs were more frequent in DS cases relative to controls but present to a similar extent as sporadic AD. This aligned with CAA scores, with more extensive CAA in DS relative to controls in both brain regions. CAA was also more frequent in DSAD cases relative to sporadic AD. We found CAA to be associated with MBs and that MBs increased with age in DS after 30 years of age in the OCTX and after 40 years of age in the FCTX. MB and CAA appear to be a significant contributors to the development of dementia in people with DS and are important targets for future clinical trials.

Keywords: Cerebral amyloid angiopathy; Prussian blue; microhemorrhages; trisomy 21.

Figure 1:. CAA was scored on a scale of 0–4 in the FCTX and OCTX

, where 0=no deposition (not pictured), 1=scattered segmental deposition of amyloid (B), 2=circumferential deposition in up to 10 vessels (B), 3=widespread, strong, circumferential deposition in up to 75% of vessels (C) 4= deposition in over 75% of region (includes dyshoric changes) (D). Sections are from the frontal cortex and immunostained with anti-Aβ1–40 and arrows indicate CAA pathology in each classification. The scale bar represents 120 µm.

Figure 2:. DSAD and AD individuals have more severe CAA than age-matched controls.

(A-D) Aβ_1–40 (1:500) immunohistochemistry stain; all images taken at 20x magnification and in the OCTX (A) MC (age=51), (B) DSAD (age=51), (C) OC (age=78), (D) AD (age=78). In the FCTX (E), The DSAD group did not have significantly higher CAA scores than the AD group (p=0.097), all individuals with DS (DS+DSAD) had higher CAA scores than age matched controls. In the OCTX (F), individuals in the DSAD and AD groups had high counts of CAA, although these groups were not significantly different from each other (OR = 9.0, 95% CI 2.3–35.4). Overall, we found that based on an unadjusted ordinal regression model, people with DS across all ages have more severe CAA scores than their age-matched controls in the OCTX (OR=57.5, 95% CI 6.5–509.7). The scale bar represents 120 µm.

Figure 3:. Microbleeds increase with age in the FCTX and OCTX.

Prussian blue staining in our control (A-C) and non-control (D-F) groups, with positive MB labeling marked with arrows; all scale bars represent 120 µm. (A) YC (Age=39), (B) MC (age=56), (C) OC (age=76), (D) DS (age=2), (E) DSAD (age=57), (F) AD (age=76). MB counts were highest in the AD and DSAD group for both the FCTX (G) and OCTX (H). Arrows highlight areas where there are MBs.

Figure 4:. Microbleeds increase with age in individuals with Down syndrome.

In the FCTX (A), the number of MB increases with age, starting around 40 years old, whereas the number of MB in control cases stays fairly consistent. In the OCTX (B), MB start increasing in individuals with DS in their 30s, which is about a decade earlier than in the FCTX. In addition, control cases also appear to have a slight increase in number of MB with age, although not as severely and at a much later age (in cases that are 80 years or older).