A TOPOGRAPHIC IMAGING BIOMARKER OF TDP43 PATHOLOGY IN AMNESTIC DEMENTIA BASED ON AUTOPSY-DERIVED FDG-PET PATTERNS

Abstract

Limbic TDP-43 pathology is a frequent neuropathologic finding in advanced age that associates with hippocampal sclerosis (HS) and can result in amnestic deficits mimicking Alzheimer's disease (AD) dementia. Recent imaging-pathologic association studies suggest that TDP-43/HS is linked to a distinct neurodegeneration pattern that may be used to detect the condition in-vivo. From the ADNI autopsy cohort we identified 41 patients with a clinical diagnosis of amnestic MCI or AD dementia at last clinical evaluation and availability of an FDG-PET scan. Six patients (15%) had limbic TDP-43 pathology but low AD pathology, two of whom also had HS. Seventeen patients showed typical AD pathology without co-morbid TDP-43/HS. “TDP-43-typical” and “AD-typical” hypometabolic patterns were estimated by contrasting FDG-PET data of the respective groups to normative data from healthy older controls (N=179). The pathology-specific patterns were used to classify individual FDG-PET patterns in larger samples of AD dementia (N=251) and aMCI (N=403) patients based on a spatial correlation approach that provides an “AD/TDP-43-index” of whether an individual scan is more “AD-like” or “TDP-43-like”. The respective patterns were tested for associations with clinical, molecular biomarker, and genetic features using dichotomous comparisons between classified patient groups as well as correlation analyses with the AD/TDP-43-index as a continuous variable. Compared to AD-typical hypometabolism, the TDP-43-typical pattern showed more pronounced involvement of temporolimbic and frontal areas and less involvement of posterior temporo-parietal areas (Fig.1). Clinically diagnosed AD dementia patients with a TDP-43-like hypometabolic pattern (N=26, 10%) did not differ significantly in global cognition or memory scores from patients with an AD-like pattern, but were less impaired in executive functions and showed less severe cognitive decline over follow-up (p<0.01). They were also significantly older, had lower levels of amyloid-β and tau biomarkers, lower APOE4 allele frequency, and higher frequency of the TMEM106B risk allele for TDP-43 pathology (all p<0.01) (Fig.2). aMCI patients with TDP-43-like hypometabolism showed similar disease characteristics, and all results remained significant when analyzing pattern expression on a continuous scale.