Semantic behavioral variant frontotemporal dementia and semantic dementia associated with TARDBP mutations

Frontotemporal dementia (FTD) is a highly heritable group of neurodegenerative disorders, characterized by varying clinical and pathological features. TARDBP gene has been described worldwide within the FTD/ALS spectrum but its association with right and left temporal variant of FTD (tvFTD) is still unclear. This study aimed to reclassify a Sardinian FTD cohort according to proposed criteria for the semantic behavioral variant FTD (sbvFTD), explore TARDBP mutations' association with tvFTD, and review related literature. From our FTD cohort of 94 patients, ten fulfilled the criteria for sbvFTD. Therefore, in light of the diagnostic reclassification carried out, we describe the largest series of unrelated patients with TARDBP p.A382T missense mutation, including four new cases of tvFTD: two sbvFTD and two svPPA, exhibiting semantic and behavioral disorders and showing predominant right and left anterior temporal lobe involvement, respectively. We present for the first time two sbvFTD cases carrying the pA382T TARDBP mutation. Comparison with C9orf72 and non-mutated patients revealed lower age at onset (p = 0.006), and a higher prevalence of tvFTD, particularly sbvFTD (p < 0.001), and motor neuron disease in TARDBP carriers (p < 0.001). Our findings along with a review of the literature highlighted TARDBP mutations' association with sbvFTD and semantic dementia, suggesting a genetic role in temporal variants of FTD and emphasizing the need for TARDBP mutation screening in these cases. Reclassifying FTD cohorts, including the sbvFTD phenotype, could aid in better defining the clinical spectrum of tvFTD and guide differential diagnosis across different FTD populations with TARDBP or other FTD-related mutations.