Basic Science and Pathogenesis

Area of Science:

• Neuroscience
• Genetics
• Pathology

Background:

• Behavioral variant frontotemporal dementia (bvFTD) is a common FTD presentation with diverse underlying causes.
• Understanding bvFTD's genetic and pathological landscape is crucial for diagnosis and treatment.

Purpose of the Study:

• To investigate the genetic and neuropathological features of a large bvFTD cohort.
• To identify patterns of familial risk and co-pathologies in bvFTD.

Main Methods:

• Characterized 410 bvFTD cases using Rascovsky criteria, excluding other dementia types.
• Assessed familial risk via pedigrees and performed gene burden analysis.
• Examined neuropathological features in 88 cases, including FTLD-TDP, FTLD-Tau, and co-pathologies like ADNC.

Main Results:

• Identified 107 monogenic cases, suggesting a higher familial burden than previously thought.
• Found FTLD-TDP in 59.1% and FTLD-Tau in 39.8% of neuropathologically examined cases.
• Observed high rates of co-pathology, with ADNC present in 50% of FTLD-TDP and 37% of FTLD-Tau cases.

Conclusions:

• bvFTD exhibits significant genetic enrichment and high rates of co-pathology, especially ADNC.
• Findings on ADNC co-pathology have implications for emerging disease-modifying therapies.
• Further gene burden analysis is needed to identify rare variants contributing to bvFTD.