Temporal dynamics predict symptom onset and cognitive decline in familial frontotemporal dementia

Abstract

Copyright © 2022 The Authors. Introduction We tested whether changes in functional networks predict cognitive decline and conversion from the presymptomatic prodrome to symptomatic disease in familial frontotemporal dementia (FTD). Methods For hypothesis generation, 36 participants with behavioral variant FTD (bvFTD) and 34 controls were recruited from one site. For hypothesis testing, we studied 198 symptomatic FTD mutation carriers, 341 presymptomatic mutation carriers, and 329 family members without mutations. We compared functional network dynamics between groups, with clinical severity and with longitudinal clinical progression. Results: We identified a characteristic pattern of dynamic network changes in FTD, which correlated with neuropsychological impairment. Among presymptomatic mutation carriers, this pattern of network dynamics was found to a greater extent in those who subsequently converted to the symptomatic phase. Baseline network dynamic changes predicted future cognitive decline in symptomatic participants and older presymptomatic participants. Discussion: Dynamic network abnormalities in FTD predict cognitive decline and symptomatic conversion. Highlights: 1. We investigated brain network predictors of dementia symptom onset. 2. Frontotemporal dementia results in characteristic dynamic network patterns. 3. Alterations in network dynamics are associated with neuropsychological impairment. 4. Network dynamic changes predict symptomatic conversion in presymptomatic carriers. 5. Network dynamic changes are associated with longitudinal cognitive decline.Medical Research Council UK. Grant Numbers: MR/M023664/1, SUAG/092116768 JPND GENFI-PROX. Grant Number: DLR/BMBF 2019-02248 Munich Cluster for Systems Neurology. Grant Number: 390857198 National Institute for Health Research (NIHR) Biomedical Research Centre at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge. Grant Number: BRC-1215-20014 Cambridge Centre for Parkinson-plus. Grant Number: RG95450 Wellcome Trust. Grant Number: 22025