{"entity": "publication", "iuid": "d459d0955b8a43cb81dd82cb5a0b7884", "timestamp": "2026-09-08T10:05:22.761Z", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/d459d0955b8a43cb81dd82cb5a0b7884.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/d459d0955b8a43cb81dd82cb5a0b7884"}}, "title": "Data-driven neuropathological staging and subtyping of TDP-43 proteinopathies.", "authors": [{"family": "Young", "given": "Alexandra L", "initials": "AL"}, {"family": "Vogel", "given": "Jacob W", "initials": "JW"}, {"family": "Robinson", "given": "John L", "initials": "JL"}, {"family": "McMillan", "given": "Corey T", "initials": "CT"}, {"family": "Ossenkoppele", "given": "Rik", "initials": "R"}, {"family": "Wolk", "given": "David A", "initials": "DA"}, {"family": "Irwin", "given": "David J", "initials": "DJ"}, {"family": "Elman", "given": "Lauren", "initials": "L"}, {"family": "Grossman", "given": "Murray", "initials": "M"}, {"family": "Lee", "given": "Virginia M-Y", "initials": "VM"}, {"family": "Lee", "given": "Edward B", "initials": "EB"}, {"family": "Hansson", "given": "Oskar", "initials": "O"}], "type": "preprint", "published": "2023-02-02", "journal": {"title": "medRxiv", "issn-l": null}, "abstract": "TAR DNA-binding protein-43 (TDP-43) accumulation is the primary pathology underlying several neurodegenerative diseases. Charting the progression and heterogeneity of TDP-43 accumulation is necessary to better characterise TDP-43 proteinopathies, but current TDP-43 staging systems are heuristic and assume each syndrome is homogeneous. Here, we use data-driven disease progression modelling to derive a fine-grained empirical staging system for the classification and differentiation of frontotemporal lobar degeneration due to TDP-43 (FTLD-TDP, n=126), amyotrophic lateral sclerosis (ALS, n=141) and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) with and without Alzheimer\u00e2\u20ac\u2122s disease (n=304). The data-driven staging of ALS and FTLD-TDP complement and extend previously described human-defined staging schema for ALS and behavioural variant frontotemporal dementia. In LATE-NC individuals, progression along data-driven stages was positively associated with age, but negatively associated with age in individuals with FTLD-TDP. Using only regional TDP-43 severity, our data driven model distinguished individuals diagnosed with ALS, FTLD-TDP or LATE-NC with a cross-validated accuracy of 85.9%, with misclassifications associated with mixed pathological diagnosis, age and genetic mutations. Adding age and SuStaIn stage to this model increased accuracy to 92.3%. Our model differentiates LATE-NC from FTLD-TDP, though some overlap was observed between late-stage LATE-NC and early-stage FTLD-TDP. We further tested for the presence of subtypes with distinct regional TDP-43 progression patterns within each diagnostic group, identifying two distinct cortical-predominant and brainstem-predominant subtypes within FTLD-TDP and a further two subcortical-predominant and corticolimbic-predominant subtypes within ALS. The FTLD-TDP subtypes exhibited differing proportions of TDP-43 type, while there was a trend for age differing between ALS subtypes. Interestingly, a negative relationship between age and SuStaIn stage was seen in the brainstem/subcortical-predominant subtype of each proteinopathy. No subtypes were observed for the LATE-NC group, despite aggregating AD+ and AD-individuals and a larger sample size for this group. Overall, we provide an empirical pathological TDP-43 staging system for ALS, FTLD-TDP and LATE-NC, which yielded accurate classification. We further demonstrate that there is substantial heterogeneity amongst ALS and FTLD-TDP progression patterns that warrants further investigation in larger cross-cohort studies.", "doi": "10.1101/2023.01.31.23285242", "pmid": "36778217", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC9915837"}, {"db": "pii", "key": "2023.01.31.23285242"}], "notes": [], "created": "2026-08-20T10:43:35.438Z", "modified": "2026-08-20T10:43:35.463Z"}