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Borwell Endowment Fund"},{"DOI":"10.13039\/501100004089","name":"Krembil Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004089","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,9,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Sleep fragmentation is common in older adults and is associated with cognitive impairment and dementia, as well as key histopathological correlates of dementia, including small vessel disease and cerebral infarcts. Vascular and blood\u2013brain barrier dysfunction are thought to contribute to cognitive decline and dementia. Pericytes, a key vascular cell type, may play a key role.<\/jats:p>\n                  <jats:p>In model organisms, sleep disruption is associated with pericyte dysfunction and blood\u2013brain barrier breakdown. Recent advances in single-nucleus RNA sequencing (snRNAseq) technology have identified two transcriptionally distinct subtypes of pericytes: extracellular matrix protein-expressing M-pericytes and solute carrier-expressing T-pericytes. However, the relationship between sleep, pericyte biology and cognition in humans remains unclear.<\/jats:p>\n                  <jats:p>We tested the hypothesis that differences in the composition of brain pericyte subpopulations, as inferred from marker gene expression, may link sleep fragmentation and cognitive decline. We leveraged two published human brain snRNAseq datasets to identify specific marker genes for M- and T-type pericytes. We then used post-mortem bulk RNAseq data from the dorsolateral prefrontal cortex (n = 1092) and lateral orbitofrontal cortex (n = 495) to quantify expression of these marker genes in older adults in two longitudinal cohort studies: the Religious Orders Study and Rush Memory and Aging Project. We derived trajectories of global cognitive function from participants\u2019 ante-mortem annual cognitive assessments, while sleep fragmentation was derived from ante-mortem wrist-actigraphy recordings from a subset of 572 participants. We used multivariate linear regression to relate pericyte marker gene expression to sleep fragmentation and cognitive decline in the decade preceding death.<\/jats:p>\n                  <jats:p>In the dorsolateral prefrontal cortex, greater average sleep fragmentation was associated with greater expression of M-pericyte marker genes [estimate = +3.65 \u00d7 10\u22121, standard error (SE) = 1.61 \u00d7 10\u22121, P = 0.024] but not T-pericyte marker genes. Dorsolateral prefrontal cortex expression of M-pericyte (estimate = \u22128.30 \u00d7 10\u22123, SE = 3.37 \u00d7 10\u22123, P = 0.014) but not T-pericyte marker genes was associated with more rapid cognitive decline in the 10 years prior to death. In the lateral orbitofrontal cortex, greater sleep fragmentation was also associated with greater composite M-pericyte gene expression (estimate = + 4.48 \u00d7 10\u22121, SE = 1.92 \u00d7 10\u22121, P = 0.02), which in turn was associated with faster cognitive decline in the decade preceding death (estimate = \u22121.30 \u00d7 10\u22122, SE = 4.55 \u00d7 10\u22123, P = 0.0044).<\/jats:p>\n                  <jats:p>These findings identify a potential role of M-pericytes in linking sleep fragmentation and cognitive trajectories in older adults. Additionally, our findings highlight the importance of vascular mechanisms in linking disrupted sleep to dementia.<\/jats:p>","DOI":"10.1093\/brain\/awaf161","type":"journal-article","created":{"date-parts":[[2025,5,4]],"date-time":"2025-05-04T07:58:17Z","timestamp":1746345497000},"page":"3379-3391","source":"Crossref","is-referenced-by-count":6,"title":["Sleep, pericyte subtypes and cognitive decline in adults with and without Alzheimer\u2019s disease"],"prefix":"10.1093","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-6446-9115","authenticated-orcid":false,"given":"Mahnoor","family":"Hamid","sequence":"first","affiliation":[{"name":"Division of Neurology, Department of Medicine, Hurvitz Brain Sciences Program, Sunnybrook Health Sciences Centre, University of Toronto , Toronto, ON , M4N 3M5","place":["Canada"]},{"name":"Institute of Medical Sciences, University of Toronto , Toronto, ON , M5S 3K3","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trishna","family":"Saha Detroja","sequence":"additional","affiliation":[{"name":"Division of Neurology, Department of Medicine, Hurvitz Brain Sciences Program, Sunnybrook Health Sciences Centre, University of Toronto , Toronto, ON , M4N 3M5","place":["Canada"]},{"name":"Institute of Medical Sciences, University of Toronto , Toronto, ON , M5S 3K3","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shreejoy J","family":"Tripathy","sequence":"additional","affiliation":[{"name":"Institute of Medical Sciences, University of Toronto , Toronto, ON , M5S 3K3","place":["Canada"]},{"name":"Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health , Toronto, ON , M5T 2S8","place":["Canada"]},{"name":"Department of Psychiatry, University of Toronto , Toronto, ON , M5T 1R8","place":["Canada"]},{"name":"Department of Physiology, University of Toronto , Toronto, ON , M5S 1A8","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vilas","family":"Menon","sequence":"additional","affiliation":[{"name":"Rush Alzheimer Disease Center, Rush University Medical Center , Chicago, IL 60612 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jishu","family":"Xu","sequence":"additional","affiliation":[{"name":"Rush Alzheimer Disease Center, Rush University Medical Center , Chicago, IL 60612 ,","place":["USA"]},{"name":"Department of Neurological Sciences, Rush University , Chicago, IL 60612 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Yu","sequence":"additional","affiliation":[{"name":"Rush Alzheimer Disease Center, Rush University Medical Center , Chicago, IL 60612 ,","place":["USA"]},{"name":"Department of Neurological Sciences, Rush University , Chicago, IL 60612 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanling","family":"Wang","sequence":"additional","affiliation":[{"name":"Rush Alzheimer Disease Center, Rush University Medical Center , Chicago, IL 60612 ,","place":["USA"]},{"name":"Department of Neurological Sciences, Rush University , Chicago, IL 60612 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6426-2742","authenticated-orcid":false,"given":"Aron S","family":"Buchman","sequence":"additional","affiliation":[{"name":"Rush Alzheimer Disease Center, Rush University Medical Center , Chicago, IL 60612 ,","place":["USA"]},{"name":"Department of Neurological Sciences, Rush University , Chicago, IL 60612 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3689-554X","authenticated-orcid":false,"given":"David A","family":"Bennett","sequence":"additional","affiliation":[{"name":"Rush Alzheimer Disease Center, Rush University Medical Center , Chicago, IL 60612 ,","place":["USA"]},{"name":"Department of Neurological Sciences, Rush University , Chicago, IL 60612 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8057-2505","authenticated-orcid":false,"given":"Philip L","family":"De Jager","sequence":"additional","affiliation":[{"name":"Center for Translational & Computational Neuroimmunology, Columbia University Irving Medical Center , New York, NY 10032 ,","place":["USA"]},{"name":"Department of Neurology, Columbia University Irving Medical Center , New York, NY 10032 ,","place":["USA"]},{"name":"Department of Neurology, Taub Institute for Research on Alzheimer\u2019s Disease and the Aging Brain , NewYork, NY 10032 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew S P","family":"Lim","sequence":"additional","affiliation":[{"name":"Division of Neurology, Department of Medicine, Hurvitz Brain Sciences Program, Sunnybrook Health Sciences Centre, University of Toronto , Toronto, ON , M4N 3M5","place":["Canada"]},{"name":"Institute of Medical Sciences, University of Toronto , Toronto, ON , M5S 3K3","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,7,14]]},"reference":[{"key":"2025090219575708600_awaf161-B1","author":"WHO"},{"key":"2025090219575708600_awaf161-B2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cophys.2019.10.020","article-title":"Cleaning the sleeping brain\u2014The potential restorative function of the glymphatic system","volume":"15","author":"Hauglund","year":"2020","journal-title":"Curr Opin 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