Improved power for characterizing longitudinal amyloid-ß PET changes and evaluating amyloid-modifying treatments with a cerebral white matter reference region.

UNLABELLED: In this article, we describe an image analysis strategy with improved power for tracking longitudinal amyloid-ß (Aß) PET changes and evaluating Aß-modifying treatments. METHODS: Our aims were to compare the power of template-based cerebellar, pontine, and cerebral white matter reference regions to track 24-mo florbetapir standardized uptake value (SUV) ratio (SUVR) changes; to relate those changes to 24-mo clinical declines; and to evaluate Aß-modifying treatments in Aß-positive (Aß+) and Aß-negative (Aß-) patients with probable Alzheimer dementia (pAD), in patients with mild cognitive impairment (MCI), in cognitively normal controls (NCs), and in cognitively normal apolipoprotein E4 (APOE4) carriers and noncarriers. We used baseline and follow-up (∼24 mo) florbetapir PET scans from 332 Aß+ and Aß- subjects participating in the multicenter Alzheimer's Disease Neuroimaging Initiative. Each of the proposed analyses included 31 pAD patients, 187 MCI patients, and 114 NCs. Cerebral-to-white matter, cerebellar, and pontine SUVRs were characterized in terms of their longitudinal variability; their power to track longitudinal fibrillar Aß increases in Aß+ and Aß- subgroups and cognitively normal APOE4 carriers and noncarriers; the sample sizes needed to detect attenuated accumulation of or clearance of fibrillar Aß accumulation in randomized clinical trials; and their ability to relate 24-mo fibrillar Aß increases to clinical declines. RESULTS: As predicted, cerebral-to-white matter SUVR changes were significantly less variable and had significantly greater power to detect 24-mo fibrillar Aß increases and evaluate Aß-modifying treatment effects in Aß+ pAD, MCI, and NC subjects and cognitively normal APOE4 carriers. They were also distinguished by the ability to detect significant associations between 24-mo Aß increases and clinical declines. CONCLUSION: A cerebral white matter reference region may improve the power to track longitudinal fibrillar Aß increases, to characterize their relationship to longitudinal clinical declines, and to evaluate Aß-modifying treatments in randomized clinical trials.