Basic Science and Pathogenesis

Background: In amyotrophic lateral sclerosis and behavioral-variant frontotemporal degeneration, the presence of secondary cognitive-behavioral or motor symptoms, respectively, is associated with shorter survival. However, factors influencing the risk of secondary symptom development remain largely unexplored and time-to-event characterization for developing secondary symptoms is important for prognostic clinical decision-making.

Method: We performed a retrospective evaluation of the entire disease course of individuals in the Penn Integrated Neurodegenerative Disease Database with a primary clinical phenotype of amyotrophic lateral sclerosis (n = 173) or behavioral-variant frontotemporal degeneration (n = 69). All individuals were evaluated for C9orf72 expansions (>30 repeats). Only individuals who had neuropathological confirmation of a TDP-43 proteinopathy at autopsy or had a C9orf72 repeat expansion were included for analysis. We examined the odds and hazard of secondary symptom development and assessed whether they were modified by the presence of a C9orf72 repeat expansion or primary clinical phenotype.

Result: Binary logistic regression and Cox proportional hazard analyses revealed increased odds (odds ratio = 4.26 [1.98-9.18]; p<0.001) and an increased hazard (hazard ratio = 4.79 [2.33- 9.82], p<0.001) for developing secondary symptoms in C9orf72 expansion carriers compared to noncarriers. Primary phenotype, age at symptom onset, and sex were not associated with risk for secondary symptom development.

Conclusion: These findings highlight the need for clinician vigilance to detect the onset of secondary cognitive-behavioral and motor symptoms in patients carrying a C9orf72 repeat expansion, regardless of primary phenotype, and may warrant dual referrals between cognitive and neuromuscular clinics in these cases.