Cumulative incidence of motor and cognitive features in the amyotrophic lateral sclerosis - frontotemporal degeneration spectrum

In frontotemporal degeneration and amyotrophic lateral sclerosis, subsequent motor or cognitive-behavioral features, respectively, are associated with shorter survival. However, factors influencing subsequent feature development remain largely unexplored. In this study, we examined whether the presence of a C9orf72 expansion or the initial clinical syndrome was associated with increased risk of subsequent feature development in individuals with amyotrophic lateral sclerosis and frontotemporal degeneration. We performed a retrospective evaluation of the entire disease course of individuals with an initial clinical syndrome of amyotrophic lateral sclerosis or frontotemporal degeneration who had neuropathological confirmation of TDP-43 proteinopathy at autopsy or a C9orf72 hexanucleotide repeat expansion. We examined the odds and hazard of subsequent feature development and assessed whether each was modified by the presence of a C9orf72 expansion or initial clinical syndrome. At autopsy, we evaluated the association between TDP-43 pathology burden in characteristic brain regions and features across this disease spectrum. For individuals with amyotrophic lateral sclerosis (n=168) and frontotemporal degeneration (n=73), binary logistic regression revealed increased odds (odds ratio=3.49[95% confidence interval 1.64-7.80], p=0.002) and Cox proportional hazard analyses revealed an increased hazard (hazard ratio=3.78[95% confidence interval 1.86-7.65], p<0.001) for developing subsequent features in those with a C9orf72 expansion compared to those without. Beyond C9orf72 expansion status, binary logistic regression revealed decreased odds (odds ratio=0.25[95% confidence interval 0.12-0.53], p<0.001) and Cox proportional hazard analyses revealed a decreased hazard (hazard ratio=0.48[95% confidence interval 0.25-0.95], p=0.03) for developing subsequent features in those with an initial amyotrophic lateral sclerosis clinical syndrome compared to those with an initial frontotemporal degeneration clinical syndrome. We observed a 94-month difference in the time after symptom onset of the initial clinical syndrome that a given person without a C9orf72 expansion reached the highest probability of developing subsequent features (0.12[95% CI (0.03-0.19], 113.00 months) and a person with a C9orf72 expansion surpassed that probability (0.13[95% CI 0.06-0.19], 19.00 months). The distribution of TDP-43 pathology across characteristic brain regions reflected both the initial clinical syndrome and subsequent features, with relatively preserved spinal cord only in frontotemporal degeneration cases without subsequent motor features (p<0.0001) and relatively preserved neocortical regions only in amyotrophic lateral sclerosis cases without subsequent cognitive-behavioral features (p<0.0001). These data highlight the need for clinician vigilance to detect the onset of subsequent motor and cognitive-behavioral features in patients carrying a C9orf72 expansion, regardless of initial clinical syndrome. C9orf72 clinical care can be enhanced through coordination between cognitive and neuromuscular clinics.