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Although ALS typically leads to death within 3 to 5\u00a0years after initial symptom onset, approximately 10% of patients with ALS live more than 10\u00a0years after symptom onset. We set out to determine similarities and differences in clinical presentation and neuropathology in persons with ALS with long vs. those with standard duration. Participants were United States military Veterans with a pathologically confirmed diagnosis of ALS (n\u00a0=\u00a0179), dichotomized into standard duration (&lt;10\u00a0years) and long\u2010duration (\u226510\u00a0years). The ALS Functional Rating Scale\u2010Revised (ALSFRS\u2010R) was administered at study entry and semi\u2010annually thereafter until death. Microglial density was determined in a subset of participants. long\u2010duration ALS occurred in 76 participants (42%) with a mean disease duration of 16.3\u00a0years (min\/max\u00a0=\u00a010.1\/42.2). Participants with long\u2010duration ALS were younger at disease onset (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.002), had a slower initial ALS symptom progression on the ALSFRS\u2010R (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) and took longer to diagnose (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.002) than standard duration ALS. Pathologically, long\u2010duration ALS was associated with less frequent TDP\u201043 pathology (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001). Upper motor neuron degeneration was similar; however, long\u2010duration ALS participants had less severe lower motor neuron degeneration at death (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001). In addition, the density of microglia was decreased in the corticospinal tract (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.017) and spinal cord anterior horn (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.009) in long\u2010duration ALS. Notably, many neuropathological markers of ALS were similar between the standard and long\u2010duration groups and there was no difference in the frequency of known ALS genetic mutations. These findings suggest that the lower motor neuron system is relatively spared in long\u2010duration ALS and that pathological progression is likely slowed by as yet unknown genetic and environmental modifiers.<\/jats:p>","DOI":"10.1111\/bpa.12876","type":"journal-article","created":{"date-parts":[[2020,7,7]],"date-time":"2020-07-07T12:50:30Z","timestamp":1594126230000},"page":"1028-1040","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Neuropathological profile of long\u2010duration amyotrophic lateral sclerosis in military Veterans"],"prefix":"10.1111","volume":"30","author":[{"given":"Keith R.","family":"Spencer","sequence":"first","affiliation":[{"name":"VA Boston Healthcare System  Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachariah W.","family":"Foster","sequence":"additional","affiliation":[{"name":"VA Boston Healthcare System  Boston 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Boston University School of Medicine  Boston MA"},{"name":"Department of Veterans Affairs Medical Center  Bedford MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bertrand R.","family":"Huber","sequence":"additional","affiliation":[{"name":"VA Boston Healthcare System  Boston MA"},{"name":"Boston University Alzheimer's Disease and CTE Center, Boston University School of Medicine  Boston MA"},{"name":"Department of Veterans Affairs Medical Center  Bedford MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann C.","family":"McKee","sequence":"additional","affiliation":[{"name":"VA Boston Healthcare System  Boston MA"},{"name":"Boston University Alzheimer's Disease and CTE Center, Boston University School of Medicine  Boston MA"},{"name":"Department of Neurology Boston University School of Medicine  Boston MA"},{"name":"Department of Veterans Affairs Medical Center  Bedford MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil 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