Alzheimer-Related Cerebrovascular Disease in Down Syndrome

Abstract

Objective: Adults with Down syndrome (DS) develop Alzheimer disease (AD) pathology by their 5th decade. Compared with the general population, traditional vascular risks in adults with DS are rare, allowing examination of cerebrovascular disease in this population and insight into its role in AD without the confound of vascular risk factors. We examined in vivo magnetic resonance imaging (MRI)-based biomarkers of cerebrovascular pathology in adults with DS, and determined their cross-sectional relationship with age, beta-amyloid pathology, and mild cognitive impairment or clinical AD diagnostic status.

Methods: Participants from the Biomarkers of Alzheimer's Disease in Down Syndrome study (n = 138, 50 ± 7 years, 39% women) with MRI data and a subset (n = 90) with amyloid positron emission tomography (PET) were included. We derived MRI-based biomarkers of cerebrovascular pathology, including white matter hyperintensities (WMH), infarcts, cerebral microbleeds, and enlarged perivascular spaces (PVS), as well as PET-based biomarkers of amyloid burden. Participants were characterized as cognitively stable (CS), mild cognitive impairment-DS (MCI-DS), possible AD dementia, or definite AD dementia based on in-depth assessments of cognition, function, and health status.

Results: There were detectable WMH, enlarged PVS, infarcts, and microbleeds as early as the 5th decade of life. There was a monotonic increase in WMH volume, enlarged PVS, and presence of infarcts across diagnostic groups (CS < MCI-DS < possible AD dementia < definite AD dementia). Higher amyloid burden was associated with a higher likelihood of an infarct.

Interpretation: The findings highlight the prevalence of cerebrovascular disease in adults with DS and add to a growing body of evidence that implicates cerebrovascular disease as a core feature of AD and not simply a comorbidity. ANN NEUROL 2020;88:1165-1177.

FIGURE 1:

Examples of the cerebrovascular markers considered in the current study from typical study participants. (A) Distributed white matter hyperintensities displayed on T2-weighted fluid-attenuated inversion recovery (FLAIR) scan (left) labeled with in-house–developed software (right). (B) Widespread enlarged perivascular spaces throughout the white matter appreciated on T1-weighted scans in 2 participants displayed in axial (left) and coronal (right) orientations. (C) Lobar microbleeds in 2 study participants displayed on axial susceptibility-weighted images. (D) Cerebral infarcts in 2 participants displayed on axial T2-weighted FLAIR scans.

FIGURE 2:

Cerebrovascular markers and global amyloid standard uptake value ratio (SUVR) across diagnostic groups. Severity and presence of cerebrovascular markers and amyloid SUVR increased across diagnostic groups. Scatter points represent individual values, bars represent mean values, and errors bars represent 95% confidence intervals. AD = Alzheimer disease; MCI-DS = mild cognitive impairment–Down syndrome; PVC = partial volume correction; PVS = perivascular space; WMH = white matter hyperintensity.