{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T16:02:45Z","timestamp":1775318565810,"version":"3.50.1"},"reference-count":84,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2024,4,17]],"date-time":"2024-04-17T00:00:00Z","timestamp":1713312000000},"content-version":"vor","delay-in-days":107,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100003325","name":"Rossy Family Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100003325","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003136","name":"Edmond J Safra Philanthropic Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003136","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001805","name":"Canada Foundation for Innovation","doi-asserted-by":"publisher","award":["MSAC-2022-12-003"],"award-info":[{"award-number":["MSAC-2022-12-003"]}],"id":[{"id":"10.13039\/501100001805","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,5,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Multiple system atrophy is a neurodegenerative disease with \u03b1-synuclein pathology predominating in the striatonigral and olivopontocerebellar systems. Mixed pathologies are considered to be of low frequency and mostly comprise primary age-related tauopathy or low levels of Alzheimer\u2019s disease-related neuropathologic change. Therefore, the concomitant presence of different misfolded proteins in the same brain region is less likely in multiple system atrophy. During the neuropathological evaluation of 21 consecutive multiple system atrophy cases, we identified four cases exhibiting an unusual discrepancy between high Thal amyloid-\u03b2 phase and low transentorhinal Braak neurofibrillary tangle stage. We mapped \u03b1-synuclein pathology, measured the size and number of glial cytoplasmic inclusions and compared the amyloid-\u03b2 peptides between multiple system atrophy and Alzheimer\u2019s disease. In addition, we performed \u03b1-synuclein seeding assay from the affected putamen samples. We performed genetic testing for APOE, MAPT, PSEN1, PSEN2 and APP. We refer to the four multiple system atrophy cases with discrepancy between amyloid-\u03b2 and tau pathology as \u2018amyloid-\u03b2-predominant Alzheimer\u2019s disease neuropathologic change-multiple system atrophy\u2019 to distinguish these from multiple system atrophy with primary age-related tauopathy or multiple system atrophy with typical Alzheimer\u2019s disease neuropathologic change. As most multiple system atrophy cases with mixed pathologies reported in the literature, these cases did not show a peculiar clinical or MRI profile. Three amyloid-\u03b2-predominant Alzheimer\u2019s disease neuropathologic change-multiple system atrophy cases were available for genetic testing, and all carried the APOE \u025b4 allele. The extent and severity of neuronal loss and \u03b1-synuclein pathology were not different compared with typical multiple system atrophy cases. Analysis of amyloid-\u03b2 peptides revealed more premature amyloid-\u03b2 plaques in amyloid-\u03b2-predominant Alzheimer\u2019s disease neuropathologic change-multiple system atrophy compared with Alzheimer\u2019s disease. \u03b1-Synuclein seeding amplification assay showed differences in the kinetics in two cases. This study highlights a rare mixed pathology variant of multiple system atrophy in which there is an anatomical meeting point of amyloid-\u03b2 and \u03b1-synuclein, i.e. the striatum or cerebellum. Since biomarkers are entering clinical practice, these cases will be recognized, and the clinicians have to be informed that the prognosis is not necessarily different than in pure multiple system atrophy cases but that the effect of potential \u03b1-synuclein-based therapies might be influenced by the co-presence of amyloid-\u03b2 in regions where \u03b1-synuclein also aggregates. We propose that mixed pathologies should be interpreted not only based on differences in the clinical phenotype but also on whether protein depositions regionally overlap, potentially leading to a different response to \u03b1-synuclein-targeted therapies.<\/jats:p>","DOI":"10.1093\/braincomms\/fcae141","type":"journal-article","created":{"date-parts":[[2024,4,17]],"date-time":"2024-04-17T20:02:13Z","timestamp":1713384133000},"source":"Crossref","is-referenced-by-count":12,"title":["Multiple system atrophy with amyloid-\u03b2-predominant Alzheimer\u2019s disease neuropathologic change"],"prefix":"10.1093","volume":"6","author":[{"given":"Tomoya","family":"Kon","sequence":"first","affiliation":[{"name":"Tanz Centre for Research in Neurodegenerative Disease, University of Toronto , Toronto, ON M5T 0S8 , Canada"},{"name":"Department of Neurology, Hirosaki University Graduate School of Medicine , Hirosaki 036-8562 , 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L","family":"Forrest","sequence":"additional","affiliation":[{"name":"Tanz Centre for Research in Neurodegenerative Disease, University of Toronto , Toronto, ON M5T 0S8 , Canada"},{"name":"Laboratory Medicine Program & Krembil Brain Institute, University Health Network , Toronto, ON M5T 0S8 , Canada"},{"name":"Faculty of Medicine, Health and Human Sciences, Dementia Research Centre, Macquarie Medical School, Macquarie University , Sydney, NSW 2109 , Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine","family":"Sato","sequence":"additional","affiliation":[{"name":"Tanz Centre for Research in Neurodegenerative Disease, University of Toronto , Toronto, ON M5T 0S8 , Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ekaterina","family":"Rogaeva","sequence":"additional","affiliation":[{"name":"Tanz Centre for Research in Neurodegenerative Disease, University of Toronto , Toronto, ON M5T 0S8 , Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan H","family":"Fox","sequence":"additional","affiliation":[{"name":"Edmund J Safra Program in Parkinson\u2019s Disease and Rossy Program in Progressive Supranuclear Palsy, Toronto Western Hospital , Toronto, ON M5T 2S8 , Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony E","family":"Lang","sequence":"additional","affiliation":[{"name":"Tanz Centre for Research in Neurodegenerative Disease, University of Toronto , Toronto, ON M5T 0S8 , Canada"},{"name":"Division of Neurology, Department of Medicine, University of Toronto , Toronto, ON M5S 1A1 , Canada"},{"name":"Edmund J Safra Program in Parkinson\u2019s Disease and Rossy Program in Progressive Supranuclear Palsy, Toronto Western Hospital , Toronto, ON M5T 2S8 , Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3841-5511","authenticated-orcid":false,"given":"Gabor 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