Biomarkers of tau phosphorylation state are associated with the clinical course of multiple sclerosis.

Autor: Emeršič A; Department of Neurology, University Medical Centre Ljubljana, Ljubljana 1000, Slovenia; Faculty of Pharmacy, University of Ljubljana, Ljubljana 1000, Slovenia. Electronic address: andreja.emersic@kclj.si., Karikari TK; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg 413 45, Sweden; Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15215, USA., Kac PR; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg 413 45, Sweden., Gonzalez-Ortiz F; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg 413 45, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal 431 80, Sweden., Dulewicz M; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg 413 45, Sweden., Ashton NJ; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg 413 45, Sweden; Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg 405 30, Sweden; Department of Old Age Psychiatry, Maurice Wohl Clinical Neuroscience Institute, King's College London, London SE5 8AF, UK; NIHR Biomedical Research Centre for Mental Health & Biomedical Research Unit for Dementia at South London & Maudsley NHS Foundation, London SE5 8AF, UK., Brecl Jakob G; Department of Neurology, University Medical Centre Ljubljana, Ljubljana 1000, Slovenia; Faculty of Medicine, University of Ljubljana, Ljubljana 1000, Slovenia., Horvat Ledinek A; Department of Neurology, University Medical Centre Ljubljana, Ljubljana 1000, Slovenia., Hanrieder J; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg 413 45, Sweden; Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK., Zetterberg H; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg 413 45, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal 431 80, Sweden; Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; UK Dementia Research Institute at UCL, London WC1N 3AR, UK; Hong Kong Center for Neurodegenerative Diseases, Hong Kong 518172, China; School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA., Rot U; Department of Neurology, University Medical Centre Ljubljana, Ljubljana 1000, Slovenia; Faculty of Medicine, University of Ljubljana, Ljubljana 1000, Slovenia., Čučnik S; Department of Neurology, University Medical Centre Ljubljana, Ljubljana 1000, Slovenia; Faculty of Pharmacy, University of Ljubljana, Ljubljana 1000, Slovenia; Department of Rheumatology, University Medical Centre Ljubljana, Ljubljana 1000, Slovenia., Blennow K; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg 413 45, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal 431 80, Sweden; Paris Brain Institute, ICM, Pitié-Salpêtrière Hospital, Sorbonne University, Paris 75013, 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 230001, PR China.
Jazyk: angličtina
Zdroj: Multiple sclerosis and related disorders [Mult Scler Relat Disord] 2024 Oct; Vol. 90, pp. 105801. Date of Electronic Publication: 2024 Aug 05.
DOI: 10.1016/j.msard.2024.105801
Abstrakt: Background: Mechanisms underlying neurodegeneration in multiple sclerosis (MS) remain poorly understood but mostly implicate molecular pathways that are not unique to MS. Recently detected tau seeding activity in MS brain tissues corroborates previous neuropathological reports of hyperphosphorylated tau (p-tau) accumulation in secondary and primary progressive MS (PPMS). We aimed to investigate whether aberrant tau phosphorylation can be detected in the cerebrospinal fluid (CSF) of MS patients by using novel ultrasensitive immunoassays for different p-tau biomarkers.
Methods: CSF samples of patients with MS (n = 55) and non-inflammatory neurological disorders (NIND, n = 31) were analysed with in-house Single molecule array (Simoa) assays targeting different tau phosphorylation sites (p-tau181, p-tau212, p-tau217 and p-tau231). Additionally, neurofilament light (NFL) and glial fibrillary acidic protein (GFAP) were measured with a multiplexed Simoa assay. Patients were diagnosed with clinically isolated syndrome (CIS, n = 10), relapsing-remitting MS (RRMS, n = 21) and PPMS (n = 24) according to the 2017 McDonald criteria and had MRI, EDSS and basic CSF analysis performed at the time of diagnosis.
Results: Patients with progressive disease course had between 1.4-fold (p-tau217) and 2.2-fold (p-tau212) higher p-tau levels than relapsing MS patients (PPMS compared with CIS + RRMS, p < 0.001 for p-tau181, p-tau212, p-tau231 and p = 0.042 for p-tau217). P-tau biomarkers were associated with disease duration (ρ=0.466-0.622, p < 0.0001), age (ρ=0.318-0.485, p < 0.02, all but p-tau217) and EDSS at diagnosis and follow-up (ρ=0.309-0.440, p < 0.02). In addition, p-tau biomarkers correlated with GFAP (ρ=0.517-0.719, p ≤ 0.0001) but not with the albumin quotient, CSF cell count or NFL. Patients with higher MRI lesion load also had higher p-tau levels p ≤ 0.01 (<10 vs. ≥ 10 lesions, all p ≤ 0.01).
Conclusion: CSF concentrations of novel p-tau biomarkers point to a higher degree of tau phosphorylation in PPMS than in RRMS. Associations with age, disease duration and EDSS suggest this process increases with disease severity; however, replication of these results in larger cohorts is needed to further clarify the relevance of altered tau phosphorylation throughout the disease course in MS.
Competing Interests: Declaration of competing interest AE has participated in meetings sponsored by Novartis and received travel grants or research support from Novartis. GBJ participated as a clinical investigator and/or received consultation and/or speaker fees from Biogen, Janssen, Lek, Merck, Novartis, Pliva/Teva, Roche, Sanofi Genzyme and Swixx. UR participated as a clinical investigator and/or received consultation and/or speaker fees from Bayer, Biogen, Sanofi Genzyme, Merck, Novartis, Pliva/Teva, Roche. AHL participated as a clinical investigator and/or received consultation and/or speaker fees from Bayer, Biogen, Sanofi Genzyme, Merck, Novartis, Pliva/Teva, Roche. 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, 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 and at advisory boards for AC Immune, Acumen, ALZPath, AriBio, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; has served at data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics. HZ and KB are co-founders of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. The other authors declare no competing interest.
(Copyright © 2024. Published by Elsevier B.V.)
Databáze: MEDLINE
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