Plasma p-tau212 as a biomarker of sporadic and Down Syndrome Alzheimer's disease.

Autor:	Kac PR; Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden., Alcolea D; Sant Pau Memory Unit, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.; Center for Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid, Spain., Montoliu-Gaya L; Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden., Fernández S; Barcelona Down Medical Center, Fundació Catalana Síndrome de Down, Barcelona, Spain., Rodriguez JL; Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden., Maure L; Sant Pau Memory Unit, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.; Center for Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid, Spain.; Barcelona Down Medical Center, Fundació Catalana Síndrome de Down, Barcelona, Spain., González-Ortiz F; Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden., Benejam B; Sant Pau Memory Unit, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.; Barcelona Down Medical Center, Fundació Catalana Síndrome de Down, Barcelona, Spain., Turton M; Bioventix Plc, Farnham, GU9 7SX, United Kingdom., Barroeta I; Sant Pau Memory Unit, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.; Center for Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid, Spain.; Barcelona Down Medical Center, Fundació Catalana Síndrome de Down, Barcelona, Spain., Harrison P; Bioventix Plc, Farnham, GU9 7SX, United Kingdom., Videla L; Sant Pau Memory Unit, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.; Center for Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid, Spain.; Barcelona Down Medical Center, Fundació Catalana Síndrome de Down, Barcelona, Spain., Ashton NJ; Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.; Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.; NIHR Biomedical Research Centre for Mental Health & Biomedical Research Unit for Dementia at South London & Maudsley NHS Foundation, London, United Kingdom.; Department of Old Age Psychiatry, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, London, United Kingdom., Lleó A; Sant Pau Memory Unit, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.; Center for Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid, Spain., Zetterberg H; Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.; Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.; Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China.; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.; UK Dementia Research Institute at UCL, London, United Kingdom., Carmona-Iragui M; Sant Pau Memory Unit, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.; Center for Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid, Spain.; Barcelona Down Medical Center, Fundació Catalana Síndrome de Down, Barcelona, Spain., Karikari TK; Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.; Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA., Fortea J; Sant Pau Memory Unit, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.; Center for Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid, Spain.; Barcelona Down Medical Center, Fundació Catalana Síndrome de Down, Barcelona, Spain., Blennow K; Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.; Paris Brain Institute, ICM, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.; Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, and Department of Neurology, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC, Hefei, P.R. China.
Jazyk:	angličtina
Zdroj:	MedRxiv : the preprint server for health sciences [medRxiv] 2024 Nov 02. Date of Electronic Publication: 2024 Nov 02.
DOI:	10.1101/2024.10.31.24316469
Abstrakt:	Background: All individuals with Down Syndrome (DS) will develop full-blown Alzheimeŕs disease (AD) pathology by age 40, decades before the occurrence of sporadic late-onset AD. Understanding this strong biological relation between age and AD pathology risk in DS is important to accelerate diagnostics, disease monitoring, and treatment. Several genes encoded in chromosome 21 including dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) have been proven to contribute to the pathology. A recently validated plasma immunoassay to measure tau phosphorylation at threonine-212 (p-tau212) has very high diagnostic accuracy in detecting AD. P-tau212 is also very sensitive to DYRK1A phosphorylation and is increased in DSAD brain lysates. Here, we assessed the potential of this biomarker in DSAD and sporadic AD. Methods: Using Simoa technology, we tested p-tau212 and p-tau181 (n=245 for plasma, n=114 matching cerebrospinal fluid (CSF) samples). We used AUC-ROC to examine diagnostic performance and the DeLong test to compare the AUC-ROC differences between methods. Spearman correlation is used to examine correlations. Fold changes relative to median levels were calculated for their respective asymptomatic groups. ANCOVA followed by Tukey posthoc test was used to calculate differences across groups. LOESS was used to determine the temporality of plasma biomarker changes. Results: We have confirmed that p-tau212 has extremely high accuracy in detecting AD-related changes in euploid controls. For the DS population, we observed a strong correlation between plasma and CSF p-tau212 (r=0.867; p<0.001). In prodromal DS (pDS) and dementia DS (dDS), we observed significantly elevated levels of p-tau212 in reference to asymptomatic DS (aDS). The diagnostic accuracy to differentiate between aDS and dDS was AUC=0.91 and AUC = 0.86 in discriminating between DS amyloid positive and amyloid negative participants. Plasma p-tau212 started increasing approximately when people became amyloid PET-positive. Conclusions: We have confirmed that the levels of plasma p-tau212 are increased in the DS population and sporadic AD cases including prodromal and MCI states. Plasma p-tau212 might have utility for theragnostic, monitoring therapy efficacy, and as a target engagement biomarker in clinical trials both in sporadic and DSAD. Competing Interests: MT and PH are employees of Bioventix Plc. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). KB has served as a consultant or at advisory boards for Abcam, Axon, BioArctic, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Ono Pharma, Pharmatrophix, Prothena, Roche Diagnostics, and Siemens Healthineers. HZ and KB are co-founders of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. D.A. participated in advisory boards from Fujirebio-Europe, Roche Diagnostics, Grifols S.A. and Lilly, and received speaker honoraria from Fujirebio-Europe, Roche Diagnostics, Nutricia, Krka Farmacéutica S.L., Zambon S.A.U. and Esteve Pharmaceuticals S.A. D.A. and JF declare a filed patent application (licensed to Adx, EPI8382175 J.F. reported receiving personal fees for service on the advisory boards, adjudication committees or speaker honoraria from AC Immune, Adamed, Alzheon, Biogen, Eisai, Esteve, Eisai, Fujirebio, Ionis, Laboratorios Carnot, Lilly, Life Molecular Imaging, Lundbeck, Perha, Roche, and, outside the submitted work.The other authors declare no competing interest.
Databáze:	MEDLINE
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