Staging β-Amyloid Pathology With Amyloid Positron Emission Tomography

Abstract

Importance: Different brain regions appear to be involved during β-amyloid (Aβ) accumulation in Alzheimer disease (AD), but a longitudinally valid system to track Aβ stages in vivo using positron emission tomography (PET) is lacking.

Objective: To construct a longitudinally valid in vivo staging system for AD using amyloid PET.

Design, setting, and participants: Longitudinal multicenter cohort study using data accessed on August 20, 2018, from the Alzheimer's Disease Neuroimaging Initiative database of scans performed from June 9, 2010, to July 12, 2018, from 741 persons: 304 without cognitive impairment, 384 with mild cognitive impairment, and 53 with AD dementia. Cerebrospinal fluid (CSF) Aβ42 and fluorine 18-labeled florbetapir (18F-florbetapir) data were used to determine early, intermediate, and late regions of Aβ accumulation. β-Amyloid stages ranging from 0 to 3 were constructed using these composites. Each subsequent stage required involvement of more advanced regions. Patients were followed up at 2, 4, and 6 years. Replication and validation were conducted using an independent cohort (Swedish BioFINDER) and gene expression information from the Allen Human Brain Atlas database. Analyses were conducted August 21, 2018, to May 24, 2019.

Main outcomes and measures: The main outcome was change in stage. Stages were compared for diagnosis, CSF biomarkers of tau, and longitudinal atrophy, cognitive measures, and regional gene expression. Transitions between stages were tested using longitudinal 18F-florbetapir data.

Results: Among 641 participants with CSF Aβ42 data and at least two 18F-florbetapir scans, 335 (52.3%) were male. The early region of Aβ accumulation included the precuneus, posterior cingulate, isthmus cingulate, insula, and medial and lateral orbitofrontal cortices. The late region included the lingual, pericalcarine, paracentral, precentral, and postcentral cortices. The intermediate region included remaining brain regions with increased accumulation rates. In 2072 PET scans from 741 participants, 2039 (98.4%) were unambiguously staged. At baseline, participants with stage 0 (n = 402) had a 14.7% (95% CI, 11.2%-18.1%) probability of progression to a higher stage; stage 1 (n = 21), 71.4% (95% CI, 50.0%-90.9%); and stage 2 (n = 79), 53.1% (95% CI, 42.2%-64.0%). Seven of the 741 participants (0.9%) reverted to a lower stage. Higher stages were associated with lower CSF Aβ42 concentrations (from stage 1 at baseline), greater CSF P-tau (from stage 1) and CSF T-tau (from stage 2), and accelerated cognitive decline (from stage 2) and atrophy (from stage 3), even when adjusting for clinical diagnosis. Key findings were replicated in the BioFINDER cohort (N = 474). The regions of different stages differed by gene expression profiles when using the transcriptome from the Allen Human Brain Atlas, especially involving genes associated with voltage-gated ion channel activity especially involving genes associated with voltage-gated ion channel activity, but also blood circulation, axon guidance, and lipid transportation.

Conclusions and relevance: Results of this study suggest that this robust staging system of Aβ accumulation may be useful for monitoring patients throughout the course of AD. Progression through stages may depend on underlying selective vulnerability in different brain regions.

Figure 1.. β-Amyloid (Aβ) Stages of Alzheimer Disease by Longitudinal Fluorine 18–Labeled Florbetapir (¹⁸F-Florbetapir) Positron Emission Tomography (PET)

A, Early (positive in stage 1), intermediate (positive in stage 2), and late (positive in stage 3) composites (eTables 2-4 in the Supplement). B, Baseline global neocortical ¹⁸F-florbetapir by Aβ stage. C, shows the rates of global neocortical ¹⁸F-florbetapir by Aβ stage. Baseline and rates are participant-specific intercepts and slopes from a linear mixed effects model with all available longitudinal data (Table 2 provides numerical details, including statistical comparisons). D, Intraindividual Aβ stage transitions from baseline to follow-up, using the last available scan for each participant for follow-up. For each baseline stage, data are expressed as proportion of participants for each of the possible follow-up stages. The 12 participants who were unstageable at baseline are not shown in the figure. Table 3 shows numerical details, including 95% CIs for the proportions. SUVR indicates standardized uptake value ratio; U, unstageable.

Figure 2.. Predicting Amyloid Stage by Regional Gene Expression

A, Surface rendering of Allen Human Brain Atlas tissue samples from the training set, colored by their observed (top row) and predicted (bottom row) labels. B, Observed and predicted labels for tissue samples from the testing set. C, Confusion matrices summarizing correct and incorrect predictions for training (left) and test (right) data. D, The primary cluster summarizing relationships between enriched (false discovery rate < 0.1) gene sets. Nodes represent individual gene sets, with node size indicating enrichment effect size based on gene set enrichment analysis leading-edge analysis. Edges represent overlapping genes within each set. Annotations represent summaries of terms composing each cluster.