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

Abstract

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: We investigated brain network predictors of dementia symptom onset Frontotemporal dementia results in characteristic dynamic network patterns Alterations in network dynamics are associated with neuropsychological impairment Network dynamic changes predict symptomatic conversion in presymptomatic carriers Network dynamic changes are associated with longitudinal cognitive decline.

Keywords: disease progression; frontotemporal dementia; functional magnetic resonance imaging (fMRI); network dynamics; presymptomatic.

FIGURE 1

Network dynamics in the Genetic Frontotemporal Initiative. (A) Mean activation maps for the six modelled states. (B) Fractional occupancy by state, with increased occupancy in states 2 and 4, and decreased occupancy in states 3 and 5. (C) Altered transition and persistence probabilities in frontotemporal dementia (FTD) using a permutation test. Blue lines represent significantly decreased transitions in FTD, and red lines significantly increased transitions. The figures show the absolute percentage increase or decrease in probability in FTD

FIGURE 2

Changes in network dynamics occurring in the late presymptomatic phase. (A) Component loadings from a principal component analysis (PCA) on state occupancies. (B) Component scores showing a significant increase in converters (at their latest presymptomatic scan) in contrast to those who have not converted to the symptomatic phase during longitudinal follow‐up. (C) Fractional occupancy by state, showing an increase for converters in state 2 (salience) occupancy. (D) State 2 occupancy in all carriers. (E) State 2 occupancy in presymptomatic mutation carriers (PSC) showing evidence of a non‐linear relationship with age, in contrast to non‐carriers (NC). GENFI, Genetic Frontotemporal Initiative; HMM, hidden Markov model

FIGURE 3

Cognitive decline in symptomatic participants. (A) Baseline component scores predict subsequent cognitive decline in symptomatic participants in the Mini‐Mental State Examination (MMSE), with an uncorrected association with Digit Span and Trail Making Test B (TMTB). Annualized rates of change in cognitive scores are derived from a mixed linear effect model, and taken to a second model to compare with component scores while partialing out covariates. (B) Baseline state 2 occupancy predicts subsequent cognitive decline in symptomatic patients in a range of clinical and neuropsychological tests. CBI‐R, Cambridge Behavioral Inventory‐Revised