Amyloid-PET imaging predicts functional decline in clinically normal individuals

Abstract

Background: There is good evidence that elevated amyloid-β (Aβ) positron emission tomography (PET) signal is associated with cognitive decline in clinically normal (CN) individuals. However, it is less well established whether there is an association between the Aβ burden and decline in daily living activities in this population. Moreover, Aβ-PET Centiloids (CL) thresholds that can optimally predict functional decline have not yet been established.

Methods: Cross-sectional and longitudinal analyses over a mean three-year timeframe were performed on the European amyloid-PET imaging AMYPAD-PNHS dataset that phenotypes 1260 individuals, including 1032 CN individuals and 228 participants with questionable functional impairment. Amyloid-PET was assessed continuously on the Centiloid (CL) scale and using Aβ groups (CL < 12 = Aβ-, 12 ≤ CL ≤ 50 = Aβ-intermediate/Aβ± , CL > 50 = Aβ+). Functional abilities were longitudinally assessed using the Clinical Dementia Rating (Global-CDR, CDR-SOB) and the Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q). The Global-CDR was available for the 1260 participants at baseline, while baseline CDR-SOB and A-IADL-Q scores and longitudinal functional data were available for different subsamples that had similar characteristics to those of the entire sample.

Results: Participants included 765 Aβ- (61%, Mdn_age = 66.0, IQR_age = 61.0-71.0; 59% women), 301 Aβ± (24%; Mdn_age = 69.0, IQR_age = 64.0-75.0; 53% women) and 194 Aβ+ individuals (15%, Mdn_age = 73.0, IQR_age = 68.0-78.0; 53% women). Cross-sectionally, CL values were associated with CDR outcomes. Longitudinally, baseline CL values predicted prospective changes in the CDR-SOB (b_CL*Time = 0.001/CL/year, 95% CI [0.0005,0.0024], p = .003) and A-IADL-Q (b_CL*Time = -0.010/CL/year, 95% CI [-0.016,-0.004], p = .002) scores in initially CN participants. Increased clinical progression (Global-CDR > 0) was mainly observed in Aβ+ CN individuals (HR_{Aβ+ vs Aβ-} = 2.55, 95% CI [1.16,5.60], p = .020). Optimal thresholds for predicting decline were found at 41 CL using the CDR-SOB (b_{Aβ+ vs Aβ-} = 0.137/year, 95% CI [0.069,0.206], p < .001) and 28 CL using the A-IADL-Q (b_{Aβ+ vs Aβ-} = -0.693/year, 95% CI [-1.179,-0.208], p = .005).

Conclusions: Amyloid-PET quantification supports the identification of CN individuals at risk of functional decline.

Trial registration: The AMYPAD PNHS is registered at www.clinicaltrialsregister.eu with the EudraCT Number: 2018-002277-22.

Keywords: Amyloid-PET; Centiloid; Functional decline; Instrumental activities of daily living; Preclinical Alzheimer.

Fig. 1

CDR-SOB and A-IADL-Q trajectories over time in CN individuals depending on the baseline CL group. A CDR-SOB trajectories in each amyloid group. Higher scores indicate greater functional impairment. B A-IADL-Q trajectories in each amyloid group. Lower scores indicate greater functional impairment

Fig. 2

Optimal data-driven thresholds for detecting functional decline on the CDR-SOB and the A-IADL-Q. A and C The Akaike information criterion (AIC) demonstrating the model fit depending on the tested cutoffs ranging from 15 to 50 CL for the CDR-SOB and the A-IADL-Q, respectively. B and D CDR-SOB and A-IADL-Q slopes, respectively, vs. Aβ- participants and their 95% CI for the Aβ+ and the Aβ± groups depending on the thresholds used for classifying participants as Aβ+ (participants were classified in the Aβ± group if their baseline CL value was between 12 CL and this cutoff)