The down syndrome biomarker initiative (DSBI) pilot: proof of concept for deep phenotyping of Alzheimer's disease biomarkers in down syndrome

Abstract

To gain further knowledge on the preclinical phase of Alzheimer's disease (AD), we sought to characterize cognitive performance, neuroimaging and plasma-based AD biomarkers in a cohort of non-demented adults with down syndrome (DS). The goal of the down syndrome biomarker Initiative (DSBI) pilot is to test feasibility of this approach for future multicenter studies. We enrolled 12 non-demented participants with DS between the ages of 30-60 years old. Participants underwent extensive cognitive testing, volumetric MRI, amyloid positron emission tomography (PET; 18F-florbetapir), fluorodeoxyglucose (FDG) PET (18F-fluorodeoxyglucose) and retinal amyloid imaging. In addition, plasma beta-amyloid (Aβ) species were measured and Apolipoprotein E (ApoE) genotyping was performed. Results from our multimodal analysis suggest greater hippocampal atrophy with amyloid load. Additionally, we identified an inverse relationship between amyloid load and regional glucose metabolism. Cognitive and functional measures did not correlate with amyloid load in DS but did correlate with regional FDG PET measures. Biomarkers of AD can be readily studied in adults with DS as in other preclinical AD populations. Importantly, all subjects in this feasibility study were able to complete all test procedures. The data indicate that a large, multicenter longitudinal study is feasible to better understand the trajectories of AD biomarkers in this enriched population. This trial is registered with ClinicalTrials.gov, number NCT02141971.

Keywords: Alzheimer’s disease; MRI; PET; amyloid; biomarkers; down syndrome; plasma; retinal.

Figure 1

Left: multimodal comparisons can be made in native space within individual subjects longitudinally. Right: Amyloid PET, FDG PET, and volumetric MRI were successfully performed in adults with down syndrome (DS) to capture important structure-function relationships.

Figure 2

Correlations between cognitive and neuroimaging measures. The bold text indicates Spearman rank correlations (r) that are significant at the 0.05 level after false discovery rate adjustment. AV45 = ¹⁸F-florbetapir.

Figure 3

Correlations between cognitive measures, retinal amyloid and plasma biomarkers. None of the Spearman rank correlations (r) are significant at the 0.05 level after false discovery rate adjustment.

Figure 4

Correlations between PET and hippocampal occupancy (HOC). None of the Spearman rank correlations (r) are significant at the 0.05 level after false discovery rate adjustment. AV45 = ¹⁸F-florbetapir.

Figure 5

Representative retinal images from an adult with DS demonstrating positive amyloid plaques in DS. Note the orange-colored puncta. The distribution in the vicinity of blood vessels is striking, pointing to a retinal manifestation of congophilic angiopathy.