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

Area of Science:

• Neuroscience
• Genetics
• Neurology

Background:

• Frontotemporal dementia (FTD) is a heritable neurodegenerative disorder with diverse clinical and pathological presentations.
• The role of the TARDBP gene in right and left temporal variant FTD (tvFTD) remains unclear.
• Existing FTD classifications may not fully capture the spectrum of tvFTD phenotypes.

Purpose of the Study:

• To reclassify a Sardinian FTD cohort using proposed semantic behavioral variant FTD (sbvFTD) criteria.
• To investigate the association between TARDBP gene mutations and tvFTD.
• To review existing literature on TARDBP mutations in FTD.

Main Methods:

• Reclassification of 94 FTD patients based on sbvFTD criteria.
• Analysis of TARDBP mutations, focusing on the p.A382T missense mutation.
• Comparison of clinical features between TARDBP mutation carriers, C9orf72 carriers, and non-mutated patients.

Main Results:

• Ten patients met the criteria for sbvFTD.
• Four new cases of tvFTD (two sbvFTD, two svPPA) with the TARDBP p.A382T mutation were identified, showing distinct temporal lobe involvement.
• TARDBP mutation carriers exhibited an earlier age of onset, higher prevalence of tvFTD (especially sbvFTD), and increased motor neuron disease compared to other groups.

Conclusions:

• TARDBP mutations are associated with sbvFTD and semantic dementia, suggesting a genetic contribution to temporal variants of FTD.
• Screening for TARDBP mutations is recommended for patients with tvFTD, particularly sbvFTD and semantic dementia.
• Reclassifying FTD cohorts using refined criteria aids in defining the tvFTD spectrum and guiding differential diagnosis.