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However, few studies since Charcot\u2019s original descriptions in the nineteenth century have directly correlated clinical UMN phenotypes with corresponding neuropathological findings. We examined the pathology of the lateral CST at the cervical, thoracic, and lumbar levels of the spinal cord from ALS patients with predominantly UMN (UMN-p) phenotypes and compared it with that in patients with predominantly LMN (LMN-p) phenotypes. We assessed myelin loss, axonal degeneration, neuroinflammation, and TDP-43 pathology. Spinal cords from UMN-p ALS cases exhibited pronounced myelin loss in the lateral CST compared to LMN-p cases and controls, consistent with clinical phenotyping. Quantitative analysis revealed significant axonal loss across all axon diameter ranges in UMN-p ALS, which was more severe than in LMN-p ALS. Importantly, axonal loss was more pronounced in the lumbar than in the cervical spinal cord. We identified a distinct population of foamy, inflammatory microglia localized to regions of severe myelin and axonal loss in UMN-p ALS. TDP-43 was measurably increased in the UMN axons of the lateral and ventral CSTs. In summary, \u201clateral sclerosis\u201d of ALS correlates to clinically imputed UMN degeneration. It consists of a combination of myelin loss, distal greater than proximal axonal degeneration, inflammatory microglial activation within the CSTs, and abnormally increased axonal TDP-43. The length-dependent gradient of motor axonal loss supports a \"dying-back\" process. A detailed comparison of \u201cdying-forward\u201d and \u201cdying-forward\u201d is provided in the Discussion. The association of loss of axons and myelin with abnormal microglial activity shows glio-axonal interactions in UMN axon degeneration, the latter CST (lateral sclerosis) across all three spinal cord levels in the ALS UMN-p samples but does not establish a causal relationship.<\/jats:p>","DOI":"10.1007\/s00401-026-03072-9","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T08:44:19Z","timestamp":1791535459000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Lateral sclerosis in amyotrophic lateral sclerosis is an upper motor neuron distal axonopathy (\u201cdying back\u201d): a clinical-neuropathological study"],"prefix":"10.1007","volume":"152","author":[{"given":"Jianguo","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kailee","family":"Ong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gorazd B.","family":"Stokin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey A.","family":"Loeb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6521-4649","authenticated-orcid":false,"given":"John","family":"Ravits","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1705-1686","authenticated-orcid":false,"given":"Fei","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,9]]},"reference":[{"key":"3072_CR1","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1007\/s00401-018-01955-0","volume":"137","author":"O Aladesuyi Arogundade","year":"2019","unstructured":"Aladesuyi Arogundade O, Stauffer JE, Saberi S, Diaz-Garcia S, Malik S, Basilim H et al (2019) Antisense RNA foci are associated with nucleoli and TDP-43 mislocalization in C9orf72-ALS\/FTD: a quantitative study. 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