In vivo staging of regional amyloid progression in healthy middle-aged to older people at risk of Alzheimer\u2019s disease

Fedor Levin,Ozioma Okonkwo,Stefan J. Teipel,Sterling C. Johnson,Irina Jelistratova,Michel J. Grothe,Tobey J. Betthauser

doi:10.1186/s13195-021-00918-0

Abstract

BackgroundWe investigated regional amyloid staging characteristics in 11C-PiB-PET data from middle-aged to older participants at elevated risk for AD enrolled in the Wisconsin Registry for Alzheimer’s Prevention.MethodsWe analyzed partial volume effect-corrected 11C-PiB-PET distribution volume ratio maps from 220 participants (mean age = 61.4 years, range 46.9–76.8 years). Regional amyloid positivity was established using region-specific thresholds. We used four stages from the frequency-based staging of amyloid positivity to characterize individual amyloid deposition. Longitudinal PET data was used to assess the temporal progression of stages and to evaluate the emergence of regional amyloid positivity in participants who were amyloid-negative at baseline. We also assessed the effect of amyloid stage on longitudinal cognitive trajectories.ResultsThe staging model suggested progressive accumulation of amyloid from associative to primary neocortex and gradually involving subcortical regions. Longitudinal PET measurements supported the cross-sectionally estimated amyloid progression. In mixed-effects longitudinal analysis of cognitive follow-up data obtained over an average period of 6.5 years following the baseline PET measurement, amyloid stage II showed a faster decline in executive function, and advanced amyloid stages (III and IV) showed a faster decline across multiple cognitive domains compared to stage 0.ConclusionsOverall, the 11C-PiB-PET-based staging model was generally consistent with previously derived models from 18F-labeled amyloid PET scans and a longitudinal course of amyloid accumulation. Differences in longitudinal cognitive decline support the potential clinical utility of in vivo amyloid staging for risk stratification of the preclinical phase of AD even in middle-aged to older individuals at risk for AD.

Highlights

Aggregates of amyloid-β (Aβ) protein are an important early histopathological hallmark of Alzheimer’s disease (AD)
In contrast to the established neuropathological staging schemes of regionally progressing amyloid pathology [4, 9], clinical positron emission tomography (PET)-based in vivo assessment of amyloid pathology is most commonly limited to a binary classification into positive or negative categories based on the global amyloid PET signal
We developed a data-driven in vivo staging model of regional amyloid progression which was based on the frequency of regional amyloid positivity in 18F-florbetapir PET scans of cognitively unimpaired older adults [10]

Summary

Introduction

Aggregates of amyloid-β (Aβ) protein are an important early histopathological hallmark of Alzheimer’s disease (AD). We developed a data-driven in vivo staging model of regional amyloid progression which was based on the frequency of regional amyloid positivity in 18F-florbetapir PET scans of cognitively unimpaired older adults [10]. The staging model was validated in an independent cohort of participants with subjective cognitive decline [11] In both studies, amyloid staging identified early stages of amyloid accumulation that were not detected by the conventional binary classification approach based on global PET signal. A stage-proportional risk for clinical disease progression could be demonstrated across cohorts [13] Taken together, these findings indicate the potential usefulness of in vivo amyloid staging for a pathologic stratification of preclinical AD. We investigated regional amyloid staging characteristics in 11C-PiB-PET data from middle-aged to older participants at elevated risk for AD enrolled in the Wisconsin Registry for Alzheimer’s Prevention

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Results

Conclusion