PET measurement of longitudinal amyloid load identifies the earliest stages of amyloid-beta accumulation during Alzheimer’s disease progression in Down syndrome

Abstract

Introduction:

Adults with Down syndrome (DS) are predisposed to Alzheimer’s disease (AD) and reveal early amyloid beta (A β) pathology in the brain. Positron emission tomography (PET) provides an in vivo measure of A β throughout the AD continuum. Due to the high prevalence of AD in DS, there is need for longitudinal imaging studies of A β to better characterize the natural history of A β accumulation, which will aid in the staging of this population for clinical trials aimed at AD treatment and prevention.

Methods:

Adults with DS ( N = 79; Mean age (SD) = 42.7 (7.28) years) underwent longitudinal [C-11]Pittsburgh compound B (PiB) PET. Global A β burden was quantified using the amyloid load metric (A β _L). Modeled PiB images were generated from the longitudinal A β _L data to visualize which regions are most susceptible to A β accumulation in DS. A β _L change was evaluated across A β(−), A β-converter, and A β(+) groups to assess longitudinal A β trajectories during different stages of AD-pathology progression. A β _L change values were used to identify A β-accumulators within the A β(−) group prior to reaching the A β(+) threshold (previously reported as 20 A β _L) which would have resulted in an A β-converter classification. With knowledge of trajectories of A β(−) accumulators, a new cutoff of A β(+) was derived to better identify subthreshold A β accumulation in DS. Estimated sample sizes necessary to detect a 25% reduction in annual A β change with 80% power (alpha 0.01) were determined for different groups of A β-status.

Results:

Modeled PiB images revealed the striatum, parietal cortex and precuneus as the regions with earliest detected A β accumulation in DS. The A β(−) group had a mean A β _L change of 0.38 (0.58) A β _L/year, while the A β-converter and A β(+) groups had change of 2.26 (0.66) and 3.16 (1.34) A β _L/year, respectively. Within the A β(−) group, A β-accumulators showed no significant difference in A β _L change values when compared to A β-converter and A β(+) groups. An A β(+) cutoff for subthreshold A β accumulation was derived as 13.3 A β _L. The estimated sample size necessary to detect a 25% reduction in A β was 79 for A β(−) accumulators and 59 for the A β-converter/A β(+) group in DS.

Conclusion:

Longitudinal A β _L changes were capable of distinguishing A β accumulators from non-accumulators in DS. Longitudinal imaging allowed for identification of subthreshold A β accumulation in DS during the earliest stages of AD-pathology progression. Detection of active A β deposition evidenced by subthreshold accumulation with longitudinal imaging can identify DS individuals at risk for AD development at an earlier stage.