Subcortical atrophy imaging biomarker performance across the sporadic and genetic frontotemporal dementias

Abstract

AbstractBackgroundFrontotemporal dementia (FTD) is a common cause of young‐onset dementia, with promising disease‐modifying candidates. Cortical signatures are well established; however, comprehensive longitudinal investigations of subcortical atrophy are limited and sample size estimates to inform imaging biomarker choice are lacking. Therefore, the current study investigated the relative utility of automated subcortical atrophy measures to detect putative disease‐modifying treatment effects in clinical, genetic and pathologically‐confirmed FTD.MethodLongitudinal registration and segmentation algorithms were applied to a cohort of 262 people, 184 of whom were diagnosed with FTD, to measure atrophy in the amygdala, hippocampus, caudate and thalamus. Clinical diagnoses were behavioural variant FTD (n = 66) and primary progressive aphasia (PPA, n = 118), comprising semantic variant PPA (n = 45), non‐fluent variant PPA (n = 45), logopenic variant PPA (n = 21), and PPA‐not otherwise specified (n = 7). Fifty‐three patients had either a known pathogenic mutation (in the MAPT, C9orf72 or GRN genes) and/or underlying tau or TDP‐43 pathology confirmed at post‐mortem. Seventy‐eight cognitively normal controls were included for comparison. Sample size estimates were computed to explore the relative feasibility of subcortical atrophy measures to track disease progression and detect treatment‐related effects across the different subgroups.ResultRelatively distinct patterns of significantly increased atrophy across the amygdala, hippocampus, caudate and/or thalamus were detected (p < 0.001) for all sporadic, genetic, and pathology‐confirmed FTD subgroups, with a strong left‐dominant pattern evident for PPA‐NOS and GRN patients. The best performing marker (as determined by lowest sample size required to detect a treatment effect) varied by subgroup supporting the importance of informed regional biomarker choice based on the population enrolled. Measures of the caudate and thalamus performed particularly well across all the subgroups, producing estimates well below 100 patients per treatment arm. The left hippocampal BSI (boundary shift integral) measure produced the lowest estimate overall in PPA‐NOS, with 12 individuals required to detect a 30% reduction in atrophy.ConclusionThis work confirms the relative utility of subcortical atrophy measures across the FTD spectrum and provides valuable sample size information to inform non‐invasive biomarker choice for sporadic and genetic FTD trials.