Abstract
OBJECTIVE: To determine autosomal dominant genetic predictors of survival in individuals with behavioral variant frontotemporal degeneration (bvFTD). METHODS: A retrospective chart review of 174 cases with a clinical phenotype of bvFTD but no associated elementary neurologic features was performed, with diagnosis either autopsy-confirmed (n = 57) or supported by CSF evidence of non-Alzheimer pathology (n = 117). Genetic analysis of the 3 most common genes with pathogenic autosomal dominant mutations associated with frontotemporal degeneration was performed in all patients, which identified cases with C9orf72 expansion (n = 28), progranulin (GRN) mutation (n = 12), and microtubule-associated protein tau (MAPT) mutation (n = 10). Cox proportional hazards regressions were used to test for associations between survival and mutation status, sex, age at symptom onset, and education. RESULTS: Across all patients with bvFTD, the presence of a disease-associated pathogenic mutation was associated with shortened survival (hazard ratio [HR] 2.164, 95% confidence interval [CI] 1.391, 3.368). In separate models, a GRN mutation (HR 2.423, 95% CI 1.237, 4.744), MAPT mutation (HR 8.056, 95% CI 2.938, 22.092), and C9orf72 expansion (HR 1.832, 95% CI 1.034, 3.244) were each individually associated with shorter survival relative to sporadic bvFTD. A mutation on the MAPT gene results in an earlier age at onset than a C9orf72 expansion or mutation on the GRN gene (p = 0.016). CONCLUSIONS: Our findings suggest that autosomal dominantly inherited mutations, modulated by age at symptom onset, associate with shorter survival among patients with bvFTD. We suggest that clinical trials and clinical management should consider mutation status and age at onset when evaluating disease progression.