{"doi":"10.1093/braincomms/fcaf405","title":"Cumulative incidence of motor and cognitive features in the amyotrophic lateral sclerosis—frontotemporal degeneration spectrum","abstract":"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.","journal":"Brain Communications","year":2025,"id":577986,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9519,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":227428,"name":"Sharon X. Xie","orcid":"0000-0002-7886-4103","position":1,"is_corresponding":false},{"id":642220,"name":"Daniel T. Ohm","orcid":"0000-0002-7930-5434","position":2,"is_corresponding":false},{"id":495593,"name":"Lauren Elman","orcid":"0000-0003-4706-950X","position":3,"is_corresponding":false},{"id":226514,"name":"Colin Quinn","orcid":"0000-0003-0618-5854","position":4,"is_corresponding":false},{"id":625500,"name":"Defne A. Amado","orcid":"0000-0001-6202-3900","position":5,"is_corresponding":false},{"id":1067629,"name":"Michael Baer","orcid":"0009-0001-3739-4344","position":6,"is_corresponding":false},{"id":107087,"name":"Edward B. Lee","orcid":"0000-0002-4589-1180","position":7,"is_corresponding":false},{"id":27603,"name":"Vivianna M. Van Deerlin","orcid":"0000-0002-7400-9097","position":8,"is_corresponding":false},{"id":990235,"name":"Laynie Dratch","orcid":"0000-0002-2179-3199","position":9,"is_corresponding":false},{"id":260095,"name":"Lauren Massimo","orcid":"0000-0002-3407-7335","position":10,"is_corresponding":false},{"id":227417,"name":"David J. Irwin","orcid":"0000-0002-5599-5098","position":11,"is_corresponding":false},{"id":227422,"name":"Corey T. McMillan","orcid":"0000-0002-7581-6405","position":12,"is_corresponding":false},{"id":434086,"name":"Barbara E. Spencer","orcid":"0000-0002-1685-2967","position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":null,"created_at":"2026-07-19T02:58:16.148027Z","pmid":"41216140","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}