{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T05:25:30Z","timestamp":1784093130257,"version":"3.55.0"},"posted":{"date-parts":[[2023,2,2]]},"group-title":"Pathology","reference-count":46,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,2,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>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\u2019s 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.<\/jats:p>","DOI":"10.1101\/2023.01.31.23285242","type":"posted-content","created":{"date-parts":[[2023,2,3]],"date-time":"2023-02-03T01:00:26Z","timestamp":1675386026000},"source":"Crossref","is-referenced-by-count":4,"title":["Data-driven neuropathological staging and subtyping of TDP-43 proteinopathies"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7772-781X","authenticated-orcid":false,"given":"Alexandra L","family":"Young","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob W","family":"Vogel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John L","family":"Robinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corey T","family":"McMillan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rik","family":"Ossenkoppele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Wolk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Irwin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren","family":"Elman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murray","family":"Grossman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia M-Y","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward B","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oskar","family":"Hansson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2023020420400604000_2023.01.31.23285242v1.1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awz099"},{"key":"2023020420400604000_2023.01.31.23285242v1.2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.23937"},{"key":"2023020420400604000_2023.01.31.23285242v1.3","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-013-1238-y"},{"key":"2023020420400604000_2023.01.31.23285242v1.4","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-013-1211-9"},{"key":"2023020420400604000_2023.01.31.23285242v1.5","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000003610"},{"key":"2023020420400604000_2023.01.31.23285242v1.6","doi-asserted-by":"crossref","unstructured":"Kim EJ , Vatsavayai S , Seeley WW . Neuropathology of dementia. In: The Behavioral Neurology of Dementia. Cambridge University Press; 2016:94\u2013122.","DOI":"10.1017\/9781139924771.008"},{"key":"2023020420400604000_2023.01.31.23285242v1.7","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a024117"},{"key":"2023020420400604000_2023.01.31.23285242v1.8","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.f4827"},{"key":"2023020420400604000_2023.01.31.23285242v1.9","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-017-1679-9"},{"key":"2023020420400604000_2023.01.31.23285242v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)31287-4"},{"key":"2023020420400604000_2023.01.31.23285242v1.11","doi-asserted-by":"crossref","unstructured":"McMillan CT , Wuu J , Rascovsky K , et al. Defining cognitive impairment in amyotrophic lateral sclerosis: an evaluation of empirical approaches. Amyotroph Lateral Scler Frontotemporal Degener. 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