In vivo staging of regional amyloid deposition

Abstract

Objectives: To estimate a regional progression pattern of amyloid deposition from cross-sectional amyloid-sensitive PET data and evaluate its potential for in vivo staging of an individual's amyloid pathology.

Methods: Multiregional analysis of florbetapir (¹⁸F-AV45)-PET data was used to determine individual amyloid distribution profiles in a sample of 667 participants from the Alzheimer's Disease Neuroimaging Initiative cohort, including cognitively normal older individuals (CN) as well as patients with mild cognitive impairment and Alzheimer disease (AD) dementia. The frequency of regional amyloid positivity across CN individuals was used to construct a 4-stage model of progressing amyloid pathology, and individual distribution profiles were used to evaluate the consistency of this hierarchical stage model across the full cohort.

Results: According to a 4-stage model, amyloid deposition begins in temporobasal and frontomedial areas, and successively affects the remaining associative neocortex, primary sensory-motor areas and the medial temporal lobe, and finally the striatum. Amyloid deposition in these brain regions showed a highly consistent hierarchical nesting across participants, where only 2% exhibited distribution profiles that deviated from the staging scheme. The earliest in vivo amyloid stages were mostly missed by conventional dichotomous classification approaches based on global florbetapir-PET signal, but were associated with significantly reduced CSF Aβ42 levels. Advanced in vivo amyloid stages were most frequent in patients with AD and correlated with cognitive impairment in individuals without dementia.

Conclusions: The highly consistent regional hierarchy of PET-evidenced amyloid deposition across participants resembles neuropathologic observations and suggests a predictable regional sequence that may be used to stage an individual's progress of amyloid pathology in vivo.

Figure 1. Model of regional amyloid progression and staging scheme

Brain renderings on the left illustrate the frequency of regional amyloid positivity across individuals on a color scale from black/blue (lowest) to yellow/red (highest). The 52 brain regions are merged into 4 larger anatomic divisions based on equal partitions of the frequency range (1–4). In the resulting 4-stage model of regional amyloid progression (I–IV), incremental stages are defined by involvement of higher numbered anatomic divisions (in red), in addition to the affected areas of the previous stage (blue).

Figure 2. Staging of individual amyloid burden

Each row of the matrix corresponds to a study participant and each column to one of the 4 anatomic divisions (1–4). Absence or presence of amyloid is denoted by gray and red, respectively. Amyloid deposition in the 4 anatomic divisions shows a consistent hierarchical nesting across participants, allowing us to stage 98% of the participants with detectable regional amyloid deposits into one of the 4 amyloid stages predicted by the regional progression model (blue boxes, I–IV). Only 8 participants showed distribution profiles that did not conform to the model (yellow arrows; 2 individuals [1 cognitively normal (CN), 1 Alzheimer disease] with deposition profiles of 1-1-0-1; 5 individuals [2 CN, 3 mild cognitive impairment (MCI)] with 0-1-0-0; and 1 individual [MCI] with 0-0-0-1).

Figure 3. Proportions of in vivo amyloid stages by clinical diagnosis

The relative proportions of in vivo amyloid stages were plotted for each diagnostic group separately and across all participants. Among participants exhibiting stageable amyloid deposition, there is a shift from lower to higher in vivo amyloid stages across the cognitively normal (CN) over the mild cognitive impairment (MCI) to the Alzheimer disease (AD) group. Unstageable cases were relatively rare across all diagnostic categories.