{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:31:36Z","timestamp":1790775096007,"version":"4.1.0"},"reference-count":93,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2023,8,17]],"date-time":"2023-08-17T00:00:00Z","timestamp":1692230400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100017510","name":"UK Dementia Research Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100017510","id-type":"DOI","asserted-by":"publisher"}]},{"name":"DRI Ltd."},{"DOI":"10.13039\/501100000265","name":"UK Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000320","name":"Alzheimer's Society","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000320","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002283","name":"Alzheimer's Research UK","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002283","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Wellcome Collaborative Award","award":["22308223082\/Z\/21\/Z"],"award-info":[{"award-number":["22308223082\/Z\/21\/Z"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,11,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Cortical cell loss is a core feature of Huntington\u2019s disease (HD), beginning many years before clinical motor diagnosis, during the premanifest stage. However, it is unclear how genetic topography relates to cortical cell loss. Here, we explore the biological processes and cell types underlying this relationship and validate these using cell-specific post-mortem data.<\/jats:p><jats:p>Eighty premanifest participants on average 15 years from disease onset and 71 controls were included. Using volumetric and diffusion MRI we extracted HD-specific whole brain maps where lower grey matter volume and higher grey matter mean diffusivity, relative to controls, were used as proxies of cortical cell loss. These maps were combined with gene expression data from the Allen Human Brain Atlas (AHBA) to investigate the biological processes relating genetic topography and cortical cell loss.<\/jats:p><jats:p>Cortical cell loss was positively correlated with the expression of developmental genes (i.e. higher expression correlated with greater atrophy and increased diffusivity) and negatively correlated with the expression of synaptic and metabolic genes that have been implicated in neurodegeneration. These findings were consistent for diffusion MRI and volumetric HD-specific brain maps.<\/jats:p><jats:p>As wild-type huntingtin is known to play a role in neurodevelopment, we explored the association between wild-type huntingtin (HTT) expression and developmental gene expression across the AHBA. Co-expression network analyses in 134 human brains free of neurodegenerative disorders were also performed. HTT expression was correlated with the expression of genes involved in neurodevelopment while co-expression network analyses also revealed that HTT expression was associated with developmental biological processes.<\/jats:p><jats:p>Expression weighted cell-type enrichment (EWCE) analyses were used to explore which specific cell types were associated with HD cortical cell loss and these associations were validated using cell specific single nucleus RNAseq (snRNAseq) data from post-mortem HD brains.<\/jats:p><jats:p>The developmental transcriptomic profile of cortical cell loss in preHD was enriched in astrocytes and endothelial cells, while the neurodegenerative transcriptomic profile was enriched for neuronal and microglial cells. Astrocyte-specific genes differentially expressed in HD post-mortem brains relative to controls using snRNAseq were enriched in the developmental transcriptomic profile, while neuronal and microglial-specific genes were enriched in the neurodegenerative transcriptomic profile.<\/jats:p><jats:p>Our findings suggest that cortical cell loss in preHD may arise from dual pathological processes, emerging as a consequence of neurodevelopmental changes, at the beginning of life, followed by neurodegeneration in adulthood, targeting areas with reduced expression of synaptic and metabolic genes. These events result in age-related cell death across multiple brain cell types.<\/jats:p>","DOI":"10.1093\/brain\/awad275","type":"journal-article","created":{"date-parts":[[2023,8,17]],"date-time":"2023-08-17T02:56:22Z","timestamp":1692240982000},"page":"4532-4546","source":"Crossref","is-referenced-by-count":41,"title":["Genetic topography and cortical cell loss in Huntington's disease link development and neurodegeneration"],"prefix":"10.1093","volume":"146","author":[{"given":"Carlos","family":"Estevez-Fraga","sequence":"first","affiliation":[{"name":"Department of Neurodegenerative Disease, University College London , London WC1B 5EH , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9265-2393","authenticated-orcid":false,"given":"Andre","family":"Altmann","sequence":"additional","affiliation":[{"name":"Centre for Medical Image Computing, University College London , London WC1V 6LJ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher S","family":"Parker","sequence":"additional","affiliation":[{"name":"Centre for Medical Image Computing, University College London , London WC1V 6LJ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael I","family":"Scahill","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease, University College London , London WC1B 5EH , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice","family":"Costa","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease, University College London , London WC1B 5EH , UK"},{"name":"Gladstone Institutes , San Francisco, CA 94158 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6668-7202","authenticated-orcid":false,"given":"Zhongbo","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease, University College London , London WC1B 5EH , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Manzoni","sequence":"additional","affiliation":[{"name":"School of Pharmacy, University College London , London WC1N 1AX , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2808-072X","authenticated-orcid":false,"given":"Angeliki","family":"Zarkali","sequence":"additional","affiliation":[{"name":"Dementia Research Centre, University College London , London WC1N 3AR , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8921-7104","authenticated-orcid":false,"given":"Alexandra","family":"Durr","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Paris Brain Institute (ICM), AP-HP, Inserm, CNRS , Paris 75013 , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymund A C","family":"Roos","sequence":"additional","affiliation":[{"name":"Department of Neurology, Leiden University Medical Centre , Leiden 2333 , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard","family":"Landwehrmeyer","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Ulm , Ulm 89081 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blair R","family":"Leavitt","sequence":"additional","affiliation":[{"name":"Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia , Vancouver BC V5Z 4H4 Canada"},{"name":"Division of Neurology, Department of Medicine, University of British Columbia Hospital , Vancouver BC V6T 2B5 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9623-7007","authenticated-orcid":false,"given":"Geraint","family":"Rees","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Human Neuroimaging, UCL Queen Square Institute of Neurology, University College London , London WC1N 3AR , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah J","family":"Tabrizi","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease, University College London , London WC1B 5EH , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"McColgan","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease, University College London , London WC1B 5EH , 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