AMNESTIC AND NON-AMNESTIC PHENOTYPES OF ALZHEIMER'S DISEASE: AN MRI-BASED PHASING ANALYSIS

Abstract

Typical amnestic Alzheimer's disease (AD) presents with memory difficulty, and pathology is first seen in the medial temporal lobe (MTL). Disease then spreads to cortex as language, visuospatial, and executive difficulties emerge. In contrast, these cognitive domains are the first impaired in non-amnestic AD. Pathologically, non-amnestic AD patients have relative sparing of MTL and selective distribution of pathology in the cortex. However, the temporal progression of disease is unclear. We used a novel MRI phasing algorithm, based on pathological staging studies, to test the hypothesis that non-amnestic AD has disease originating and spreading in neocortex. We inferred the anatomical origin and progression of disease in each AD variant based on the frequency of regional atrophy patterns in cross-sectional MRI from 131 patients with AD, confirmed through autopsy or CSF results. Disease progression models were computed separately for typical amnestic AD (aAD, 38 scans), logopenic variant primary progressive aphasia (lvPPA, 97 scans), posterior cortical atrophy (PCA, 54 scans), corticobasal syndrome (CBS, 31 scans), and behavioural/dysexecutive-variant AD (bvAD, 39 scans). For each AD variant, 4 phases of atrophy were defined in 120 anatomical regions-of-interest (ROIs) using a grey matter volume threshold of Z < -1.0 relative to elderly controls. The origin of disease (Phase 1) was inferred from the most frequently atrophied 10% of ROIs; similarly, Phases 2, 3, and 4 comprised ROIs in the 2nd, 3rd, and 4th deciles of atrophy frequency. We observed a unique distribution of atrophy for each phenotype. Phase 1 ROIs in our model represent the anatomical origin of disease, including: MTL for the aAD group (relatively spared in other phenotypes), left lateral temporal lobe for lvPPA, occipito-parietal cortex for PCA, temporo-parietal cortex for CBS, and fronto-temporal cortex for bvAD. Disease phase was significantly correlated with MMSE score and disease duration, independently of age.