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

## TL;DR

This study shows that people with a C9orf72 gene expansion are more likely to develop additional motor or cognitive symptoms in ALS or FTD, and highlights the need for close monitoring in these patients.

## Contribution

The study identifies C9orf72 expansion and initial clinical syndrome as key modifiers of subsequent feature development in ALS-FTD spectrum disorders.

## Key findings

- Individuals with a C9orf72 expansion had significantly increased odds and hazard of developing subsequent features.
- Those with an initial ALS clinical syndrome had decreased odds and hazard of developing subsequent features compared to FTD cases.
- TDP-43 pathology distribution in brain regions reflected initial syndrome and subsequent features.

## Abstract

In frontotemporal degeneration and amyotrophic lateral sclerosis, subsequent motor or cognitive-behavioural 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-behavioural features (P < 0.0001). These data highlight the need for clinician vigilance to detect the onset of subsequent motor and cognitive-behavioural 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.

Spencer et al. demonstrated both the presence of a C9orf72 expansion and the initial clinical syndrome modify risk of subsequent feature development in frontotemporal degeneration and amyotrophic lateral sclerosis, highlighting the need for clinician vigilance to detect the onset of subsequent motor and cognitive-behavioural features in this disease spectrum.

Graphical Abstract