Regional amyloid accumulation predicts memory decline in initially cognitively unimpaired individuals

Abstract

Introduction: The value of quantitative longitudinal and regional amyloid beta (Aβ) measurements in predicting cognitive decline in initially cognitively unimpaired (CU) individuals remains to be determined.

Methods: We selected 133 CU individuals with two or more [11C]Pittsburgh compound B ([11C]PiB) scans and neuropsychological data from Open Access Series of Imaging Studies (OASIS-3). Baseline and annualized distribution volume ratios were computed for a global composite and four regional clusters. The predictive value of Aβ measurements (baseline, slope, and interaction) on longitudinal cognitive performance was examined.

Results: Global performance could only be predicted by Aβ burden in an early cluster (precuneus, lateral orbitofrontal, and insula) and the precuneus region of interest (ROI) by itself significantly improved the model. Precuneal Aβ burden was also predictive of immediate and delayed episodic memory performance. In Aβ subjects at baseline (N = 93), lateral orbitofrontal Aβ burden predicted working and semantic memory performance.

Discussion: Quantifying longitudinal and regional changes in Aβ can improve the prediction of cognitive functioning in initially CU individuals.

Keywords: Alzheimer's disease; amyloid beta; longitudinal; positron emission tomography; regional.

Conflict of interest statement

Lyduine E. Collij, Sophie E. Mastenbroek, Gemma Salvadó, Alle Meije Wink, and Isadora Lopes Alves report no disclosures relevant to this manuscript. Pieter Jelle Visser has served as member of the advisory board of Roche Diagnostics. Dr Visser received non‐financial support from GE Healthcare; research support from Biogen; and grants from Bristol‐Myers Squibb, EU/EFPIA Innovative Medicines Initiative Joint Undertaking, EU Joint Programme–Neurodegenerative Disease Research (JPND and ZonMw). Frederik Barkhof received payment and honoraria from Bayer Genzyme, Biogen‐Idec, TEVA, Merck, Novartis, Roche, IXICO Ltd, GeNeuro, and Apitope Ltd for consulting; payment from the IXICOLtd, and MedScape for educational presentations; and research support via grants from EU/EFPIA Innovative Medicines Initiative Joint Undertaking (AMYPAD consortium), EuroPOND (H2020), UK MS Society, Dutch MS Society, PICTURE (IMDI‐NWO), NIHR UCLH Biomedical Research Centre (BRC), and ECTRIMS‐MAGNIMS. Bart N.M. van Berckel received research support from ZON‐MW, AVID radiopharmaceuticals, CTMM, and Janssen Pharmaceuticals. BvB is a trainer for Piramal and GE; he receives no personal honoraria.

© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.

Figures

FIGURE 1

Quadratic relationship between baseline DVR and annualized rates of change. Scatterplot of the quadratic relationship between global baseline and annualized rates of change in distribution volume ratios (DVR). For the (A) AD template or global ROI; color‐coded for negative (dark green) and positive (dark red) baseline amyloid beta (Aβ) burden. The solid line represents the threshold at 1.12 DVR derived from Gaussian Mixture Modelling and taking the mean plus two SD from the normal population. (B) Representation of the multi‐tracer cortical amyloid staging model as published Collij et al., 2020 in Neurology. (C‐F) Scatterplots of the quadratic relationship between global baseline and annualized rates of change in DVR for stage 1 (blue), 2 (green), 3 (orange), and 4 (red), respectively

FIGURE 2

FI Relationship between Aβ pathology and decline in global cognition. Illustration of the association between continuous amyloid burden (baseline and longitudinal [11C]PiB PET DVR) and global cognitive functioning (MMSE) over time. The figure reflects the results of the linear mixed effect model including the precuneus ROI; baseline Aβ burden, Aβ slope, and interaction term (Aβprecuneus*∆Aβprecuneus). For illustrative purposes, these continuous measures were reduced to categorical groups, with baseline amyloid burden divided into three groups based on k‐mean clustering (low [green], gray‐zone [not shown], high [red]) and accumulator was defined as percentage change above 0.85% based on ([11C]PiB test‐retest data (see Supplemental Figure 3 and Supplemental materials). Colored bands representing the 95% confidence interval (CI). (A) Changes in MMSE score over time are provided for the subjects with a low Aβ burden (green) and high Aβ burden (red) at baseline. Although the differences in cognitive trajectories between the two groups is apparent, (B) the largest change in MMSE score is observed in those subjects with both high amyloid burden and low accumulation (red), illustrating the value of both cross‐sectional and longitudinal amyloid measures to identify subjects a high risk for decline

FIGURE 3

F Relationship between Aβ pathology and decline in specific memory tasks. Illustration of the association between continuous amyloid burden (baseline and longitudinal [11C]PiB PET DVR) and (A) immediate episode memory (Logical Memory IA) performance for the whole population and (B) working memory performance (DIGIB) in the at baseline Aβ− group. The figure reflects the results of the linear mixed‐effects model including the (A) precuneus ROI and (B) lateral orbitofrontal (LOFC) ROI; baseline Aβ burden, Aβ slope, and interaction term (AβROI*∆AβROI). For illustrative purposes, the continuous measure slope was reduced to categorical groups, with accumulator defined as percentage change above 0.85% based on [11C]PiB test‐retest data (see Supplemental materials). Colored bands represent 95% CI