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Here, we investigated the relationships between 24\u2010hour rest\u2010activity rhythms, cognitive trajectories, and autopsy\u2010derived LC integrity in older adults with and without cortical AD neuropathology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This retrospective study leveraged multi\u2010modal data from participants of the longitudinal clinical\u2010pathological Rush Memory and Aging Project. Indices of 24\u2010hour rest\u2010activity rhythm fragmentation (intradaily variability) and stability (interdaily stability) were extracted from annual actigraphic recordings, and cognitive trajectories were computed from annual cognitive evaluations. At autopsy, LC neurodegeneration was determined by the presence of hypopigmentation, and cortical AD neuropathology was assessed. Contributions of comorbid pathologies (Lewy bodies, cerebrovascular pathology) were evaluated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Among the 388 cases included in the study sample (age at death\u2009=\u200992.1\u2009\u00b1\u20095.9\u2009years; 273 women), 98 (25.3%) displayed LC hypopigmentation, and 251 (64.7%) exhibited cortical AD neuropathology. Logistic regression models showed that higher rest\u2010activity rhythm fragmentation, measured up to ~7.1\u2009years before death, was associated with increased risk to display LC neurodegeneration at autopsy (odds ratio [OR]\u2009=\u20091.46, 95% confidence interval [CI\n                      <jats:sub>95%<\/jats:sub>\n                      ]: 1.16\u20131.84,\n                      <jats:italic>p<\/jats:italic>\n                      <jats:sub>BONF<\/jats:sub>\n                      \u2009=\u20090.004), particularly in individuals with cortical AD neuropathology (OR\u2009=\u20091.56, CI\n                      <jats:sub>95%<\/jats:sub>\n                      : 1.15\u20132.15,\n                      <jats:italic>p<\/jats:italic>\n                      <jats:sub>BONF<\/jats:sub>\n                      \u2009=\u20090.03) and independently of comorbid pathologies. In addition, longitudinal increases in rest\u2010activity rhythm fragmentation partially mediated the association between LC neurodegeneration and cognitive decline (estimate\u2009=\u2009\u20100.011, CI\n                      <jats:sub>95%<\/jats:sub>\n                      : \u20100.023\u2013\u20100.002,\n                      <jats:italic>p<\/jats:italic>\n                      <jats:sub>BONF<\/jats:sub>\n                      \u2009=\u20090.03).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>These findings highlight the LC as a neurobiological correlate of sleep\u2013wake dysregulation in AD, and further underscore the clinical relevance of monitoring rest\u2010activity patterns for improved detection of at\u2010risk individuals. ANN NEUROL 2024;95:653\u2013664<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.26880","type":"journal-article","created":{"date-parts":[[2024,2,26]],"date-time":"2024-02-26T09:05:46Z","timestamp":1708938346000},"page":"653-664","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Associations of 24\u2010Hour Rest\u2010Activity Rhythm Fragmentation, Cognitive Decline, and Postmortem Locus Coeruleus Hypopigmentation in Alzheimer's Disease"],"prefix":"10.1002","volume":"95","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3142-2623","authenticated-orcid":false,"given":"Maxime","family":"Van Egroo","sequence":"first","affiliation":[{"name":"Faculty of Health, Medicine and Life Sciences, School for Mental Health and Neuroscience Alzheimer Centre Limburg, Maastricht University  Maastricht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eus J.W.","family":"van 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