{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,28]],"date-time":"2025-12-28T09:02:03Z","timestamp":1766912523669,"version":"build-2065373602"},"reference-count":59,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,5,21]],"date-time":"2024-05-21T00:00:00Z","timestamp":1716249600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Chang Gung Memorial Hospital, Taiwan","award":["CORPG8N0041","CMRPG8J0524","CMRPG8J0843","CMRPG8K1533","NSTC 112-2321-B-182A-004"],"award-info":[{"award-number":["CORPG8N0041","CMRPG8J0524","CMRPG8J0843","CMRPG8K1533","NSTC 112-2321-B-182A-004"]}]},{"name":"National Science and Technology Council, Taiwan","award":["CORPG8N0041","CMRPG8J0524","CMRPG8J0843","CMRPG8K1533","NSTC 112-2321-B-182A-004"],"award-info":[{"award-number":["CORPG8N0041","CMRPG8J0524","CMRPG8J0843","CMRPG8K1533","NSTC 112-2321-B-182A-004"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The purpose of this study was to investigate whether plasma biomarkers can help to diagnose, differentiate from Alzheimer disease (AD), and stage cognitive performance in patients with positron emission tomography (PET)-confirmed primary age-related tauopathy, termed tau-first cognitive proteinopathy (TCP) in this study. In this multi-center study, we enrolled 285 subjects with young-onset AD (YOAD; n = 55), late-onset AD (LOAD; n = 96), TCP (n = 44), and cognitively unimpaired controls (CTL; n = 90) and analyzed plasma A\u03b242\/A\u03b240, pTau181, neurofilament light (NFL), and total-tau using single-molecule assays. Amyloid and tau centiloids reflected pathological burden, and hippocampal volume reflected structural integrity. Receiver operating characteristic curves and areas under the curves (AUCs) were used to determine the diagnostic accuracy of plasma biomarkers compared to hippocampal volume and amyloid and tau centiloids. The Mini-Mental State Examination score (MMSE) served as the major cognitive outcome. Logistic stepwise regression was used to assess the overall diagnostic accuracy, combining fluid and structural biomarkers and a stepwise linear regression model for the significant variables for MMSE. For TCP, tau centiloid reached the highest AUC for diagnosis (0.79), while pTau181 could differentiate TCP from YOAD (accuracy 0.775) and LOAD (accuracy 0.806). NFL reflected the clinical dementia rating in TCP, while pTau181 (rho = 0.3487, p = 0.03) and A\u03b242\/A\u03b240 (rho = \u22120.36, p = 0.02) were significantly correlated with tau centiloid. Hippocampal volume (unstandardized \u03b2 = 4.99, p = 0.01) outperformed all of the fluid biomarkers in predicting MMSE scores in the TCP group. Our results support the superiority of tau PET to diagnose TCP, pTau181 to differentiate TCP from YOAD or LOAD, and NFL for functional staging.<\/jats:p>","DOI":"10.3390\/ijms25115607","type":"journal-article","created":{"date-parts":[[2024,5,22]],"date-time":"2024-05-22T07:56:11Z","timestamp":1716364571000},"page":"5607","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Clinical Significance of the Plasma Biomarker Panels in Amyloid-Negative and Tau PET-Positive Amnestic Patients: Comparisons with Alzheimer\u2019s Disease and Unimpaired Cognitive Controls"],"prefix":"10.3390","volume":"25","author":[{"given":"Hsin-I","family":"Chang","sequence":"first","affiliation":[{"name":"Department of Neurology, Cognition and Aging Center, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan"},{"name":"Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kuo-Lun","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Linkou Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333423, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0598-5684","authenticated-orcid":false,"given":"Chung-Gue","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory, Linkou Chang Gung Memorial Hospital, Department of Medical Bio-Technology and Laboratory Science, Chang Gung University, Taoyuan 333423, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chi-Wei","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Cognition and Aging Center, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shu-Hua","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1933-4564","authenticated-orcid":false,"given":"Kun-Ju","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Linkou Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333423, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6721-2556","authenticated-orcid":false,"given":"Chiung-Chih","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Cognition and Aging Center, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan"},{"name":"Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan"},{"name":"School of Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung 80404, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.jalz.2018.02.018","article-title":"NIA-AA Research Framework: Toward a biological definition of Alzheimer\u2019s disease","volume":"14","author":"Jack","year":"2018","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"183","DOI":"10.3233\/JAD-140771","article-title":"Amyloid-beta 42\/40 cerebrospinal fluid concentration ratio in the diagnostics of Alzheimer\u2019s disease: Validation of two novel assays","volume":"43","author":"Lewczuk","year":"2015","journal-title":"J. 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