Pseudo‐longitudinal trajectories of cerebrovascular disease biomarkers in adults with Down syndrome across the lifespan

Abstract

AbstractBackgroundAdults with Down syndrome (DS) overproduce amyloid precursor protein, develop amyloid plaques at an early age, and are diagnosed with Alzheimer’s disease (AD) dementia at a high frequency. There is emerging evidence that cerebrovascular disease is elevated across the AD continuum in older adults with DS, independent of age and vascular risk, but it is unknown when cerebrovascular disease emerges across the lifespan.MethodAdults with DS from the multisite Alzheimer’s Biomarker Consortium‐Down Syndrome study (ABC‐DS; n = 241; age = 25‐72, 44±10; 45% women; 77/11/12% Cognitively‐Stable/MCI‐DS/AD dementia) underwent harmonized MRI and received a cognitive diagnosis at a consensus conference. Cross‐sectional white matter hyperintensity volume (WMH; ischemic small vessel disease), enlarged perivascular space score (PVS; impaired toxin clearance), chronic infarcts (large vessel disease), and microbleeds (hemorrhagic small vessel disease/cerebral amyloid angiopathy) were fit against piece‐wise, left null regression models with age to estimate the age inflection point at which these cerebrovascular markers emerged. The residuals for each biomarker (i.e., more than expected for their age) were then regressed on diagnosis.ResultTotal WMH volume (0.01‐31.7, 4±4.6 cm3), enlarged PVS score (0‐26, 8±5), infarcts (15% have at least one), and microbleeds (12% have at least one) were present in this lifespan sample of adults with DS. There was a significant inflection point in the fourth decade of life for total WMH (37±6, p = 7E‐3), enlarged PVS (31±6, p = 3E‐6), and infarcts (31±9, p = 2E‐3), but not microbleeds (36±21, p = 0.7). Regionally, there were significant inflection points for frontal (36±6, p = 3E‐3), parietal (36±7, p = 0.02), and occipital (42±6, p = 0.02), but not temporal WMH (33±14, p = 0.3). AD dementia was associated with higher residuals in parietal (0.5±0.2, p = 0.02) and occipital WMH (0.6±0.3, p = 0.02).ConclusionIn adults with DS, there is cerebrovascular pathology on MRI that emerges around the same age as what has been reported for amyloid PET positivity and tau PET accumulation in this population. More posterior small vessel disease for a given age may arise with a diagnosis of AD, suggesting a cerebrovascular process in AD pathogenesis. Longitudinal assessment in relation to AD biomarkers, including amyloid and tau PET, will provide additional insight.