Abstract Recent studies have suggested that cerebellar and subcortical structures are impacted early in the disease progression of genetic frontotemporal dementia (FTD) due to microtubule-associated protein tau ( MAPT ), progranulin ( GRN ) and chromosome 9 open reading frame 72 ( C9orf72 ). However, the clinical contribution of the structures involved in the cerebello-subcortical circuitry has been understudied in FTD given their potentially central role in cognition and behaviour processes. The present study aims to investigate whether there is an association between the atrophy of the cerebellar and subcortical structures, and neuropsychiatric symptoms (using the revised version of the Cambridge Behavioral Inventory, CBI-R) across genetic mutations and whether this association starts during the preclinical phase of the disease. Our study included 983 participants from the Genetic Frontotemporal dementia Initiative (GENFI) including mutation carriers (n=608) and non-carrier first-degree relatives of known symptomatic carriers (n= 375). Voxel-wise analysis of the thalamus, striatum, globus pallidus, amygdala, and the cerebellum was performed using deformation based morphometry (DBM) and partial least squares analyses (PLS) were used to link morphometry and behavioural symptoms. Our univariate results suggest that in this group of primarily presymptomatic subjects, volume loss in subcortical and cerebellar structure was primarily a function of aging, with only the C9orf72 group showing more pronounced volume loss in the thalamus compared to the non-carrier individuals. PLS analyses demonstrated that the cerebello-subcortical circuitry is related to all neuropsychiatric symptoms from the CBI-R, with significant overlap in brain/behaviour patterns, but also specificity for each genetic group. The biggest differences were in the extent of the cerebellar involvement (larger extent in C9orf72 group) and more prominent amygdalar contribution in the MAPT group. Finally, our findings demonstrated that C9orf72 and MAPT brain scores were related to estimated years before the age of symptom onset (EYO) in a second order relationship highlighting a steeper brain score decline 20 years before expected symptom onset, while GRN brain scores were related to age and not EYO. Overall, these results demonstrated the important role of the subcortical structures and especially of the cerebellum in genetic FTD symptom expression.

Cerebellar and subcortical atrophy contribute to psychiatric symptoms in frontotemporal dementia