Background and Aims:

The presymptomatic brain changes of granulin (GRN) disease, preceding by years frontotemporal dementia, need to be still fully characterized. Dynamic functional network connectivity (dFNC) allows to capture both spatial networks configurations and their dynamic changes over time.

Aim of the study is to investigate the dFNC in 141 presymptomatic GRN mutation carriers and 282 non-carriers from the Genetic Frontotemporal dementia research Initiative (GENFI) cohort.

Methods:

We considered time-varying patterns of the default mode network, the language network and the salience network, each presenting in four distinct recurring spatial states. Dwell time (DT), i.e., the time each individual spends in each spatial state of each network, was considered. Correlations between DTs and estimated years from expected symptom onset (EYO) and clinical performances were assessed.

Results:

Presymptomatic GRN mutation carriers spent significantly more time in those spatial states characterised by greater activation of the insula and the parietal cortices, as compared to non-carriers (p<0.05, FDR-corrected). A significant correlation between DTs of these spatial states and EYO was found, the longer the time spent in the spatial states, the closer the EYO. DTs significantly correlated with performances at tests tapping processing speed, with worse scores associated with increased spatial states’ DTs.

Conclusions:

Our results demonstrated that presymptomatic GRN disease presents a complex dynamic re-organization of brain connectivity. dFNC, evaluating both the spatial and temporal changes of brain network connectivity, provides a unique glimpse into brain function and allows a more sophisticated evaluation of the earliest disease changes and the understanding of possible compensative mechanisms in GRN disease.