{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T04:46:43Z","timestamp":1791434803796,"version":"4.3.3"},"reference-count":77,"publisher":"Oxford University Press (OUP)","issue":"5","funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["NIA F30 AG074524"],"award-info":[{"award-number":["NIA F30 AG074524"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["NIA R01 AG072796"],"award-info":[{"award-number":["NIA R01 AG072796"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R01 AG069474"],"award-info":[{"award-number":["R01 AG069474"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University of Pennsylvania Alzheimer\u2019s Disease Core Center","award":["NIA P30 AG072979"],"award-info":[{"award-number":["NIA P30 AG072979"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,5,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Polypathology is a major driver of heterogeneity in the clinical presentation and extent of neurodegeneration (N) in patients with Alzheimer\u2019s disease (AD). Beyond amyloid (A) and tau (T) pathologies, over half of patients with AD have concomitant pathology such as \u03b1-synuclein (S) in mixed AD with Lewy body disease (LBD). Patients with multiple aetiology dementia such as AD + LBD have faster progression and potentially differential responses to targeted treatments, although the diagnosis of AD + LBD can be challenging given the overlapping clinical and imaging features. Development and validation of improved in vivo biomarkers are required to study relationships between N and S and identify imaging patterns reflecting mixed AD + LBD pathologies.<\/jats:p>\n                  <jats:p>We hypothesized that individual proteinopathies, such as T and S, are associated with commensurate levels of N. Thus, we assessed biomarkers of A, T, N and S with PET, MRI and CSF seeding amplification assay (SAA) data to determine molecular presentations of mixed A+S+ versus A+S\u2013 cognitively impaired patients from the Alzheimer\u2019s Disease Neuroimaging Initiative (ADNI).<\/jats:p>\n                  <jats:p>Strikingly, A+S+ patients had parieto-occipital 18F-fluorodeoxyglucose hypometabolism (a measure of N) disproportionate to the degree of regional atrophy or T burden, highlighting worse hypometabolism associated with S+ status on SAA. Following up on this hypometabolic mismatch with CSF metabolite and proteome analyses, we found that A+S+ patients exhibited lower CSF levels of dopamine metabolites and synaptic markers like neuronal pentraxin-2 (NPTX2), suggesting that altered neurotransmission and neuron integrity contribute to this dissociation between metabolic PET and MRI. Potential confounders exist when studying relations between N, AD and LBD pathologies, including neuroinflammation and other non-Alzheimer\u2019s pathologies in mixed dementia, although our findings imply posterior hypometabolic mismatch is related more to S than vascular or TDP-43 pathology.<\/jats:p>\n                  <jats:p>Overall, A+S+ patients had posterior mismatch with excessive 18F-fluorodeoxyglucose hypometabolism relative to atrophy or T load, possibly reflecting impaired neuronal integrity. Further research must disentangle the impact of multiple proteinopathies and clinicopathologic factors on hypometabolism and atrophy. Cumulatively, patients with mixed AD + LBD aetiologies harbour a unique metabolic PET mismatch signature.<\/jats:p>","DOI":"10.1093\/brain\/awae352","type":"journal-article","created":{"date-parts":[[2024,11,13]],"date-time":"2024-11-13T15:21:12Z","timestamp":1731511272000},"page":"1577-1587","source":"Crossref","is-referenced-by-count":20,"title":["Hypometabolic mismatch with atrophy and tau pathology in mixed Alzheimer\u2019s and Lewy body disease"],"prefix":"10.1093","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0312-5530","authenticated-orcid":false,"given":"Michael Tran","family":"Duong","sequence":"first","affiliation":[{"name":"Department of Radiology, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]},{"name":"Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania , Philadelphia, PA 19104 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,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueying","family":"Lyu","sequence":"additional","affiliation":[{"name":"Department of Radiology, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]},{"name":"Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Long","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Radiology, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]},{"name":"Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"McGrew","sequence":"additional","affiliation":[{"name":"Department of Radiology, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Dehghani","sequence":"additional","affiliation":[{"name":"Department of Neurology, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corey T","family":"McMillan","sequence":"additional","affiliation":[{"name":"Department of Neurology, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]},{"name":"Alzheimer\u2019s Disease Research Center, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4589-1180","authenticated-orcid":false,"given":"Edward B","family":"Lee","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Disease Research Center, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]},{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie M","family":"Shaw","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Disease Research Center, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]},{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8543-4016","authenticated-orcid":false,"given":"Paul 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Medicine, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilya M","family":"Nasrallah","sequence":"additional","affiliation":[{"name":"Department of Radiology, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]},{"name":"Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]},{"name":"Alzheimer\u2019s Disease Research Center, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,11,22]]},"reference":[{"key":"2025052317032705800_awae352-B1","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s00401-022-02444-1","article-title":"Frequency of LATE neuropathologic change across the spectrum of 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