In-Vivo Staging of Regional Amyloid Progression In Healthy Middle Aged To Older People At Risk of Alzheimer’s Disease

Abstract

Background 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. Methods We analyzed partial volume effect-corrected 11C-PiB-PET distribution volume ratio maps from 220 participants (mean age = 61.4y, range: 46.9-76.8y). Regional amyloid-positivity was established using region-specific thresholds. We used four stages from frequency-based staging of amyloid-positivity to characterize individual amyloid deposition. Longitudinal PET data was used to assess temporal progression of stages and to evaluate 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.Results The 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.Conclusions Overall, the 11C-PiB-PET-based staging model was generally consistent with previously derived models from 18F-labled 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.

The foundation and architecture of precision medicine in neurology and psychiatry

“…Molecular imaging methods, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT), use radio-ligands that bind to distinct molecular targets implicated in disease-relevant biological pathways. Molecular imaging can directly detect disease-associated molecular and cellular process(es), such as protein misfolding and accumulation (e.g., measured by amyloid and tau PET) [69,70], changes in neuronal metabolism (e.g., measured by fluorodeoxyglucose PET), microglial activation (e.g., detected by translocator protein [TSPO] imaging) [71], and neurochemical dysfunction (e.g., measured using cholinergic, glutamatergic, or dopaminergic system radiotracers) [72,73].…”

“…The tight association between the uptake of certain radiotracers and corresponding neuropathological findings has generated core/supportive diagnostic biomarkers for different neurodegenerative diseases [73,74]. Moreover, recent quantitative approaches, leveraging automatic analysis pipelines, allow the in vivo tracking of neurobiological pathways, resembling the traditional neuropathological staging and potentially supporting stage-driven therapeutic approaches [69].…”