Plasma extracellular vesicle tau and TDP-43 as diagnostic biomarkers in FTD and ALS

Abstract

Minimally invasive biomarkers are urgently needed to detect molecular pathology in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Here, we show that plasma extracellular vesicles (EVs) contain quantifiable amounts of TDP-43 and full-length tau, which allow the quantification of 3-repeat (3R) and 4-repeat (4R) tau isoforms. Plasma EV TDP-43 levels and EV 3R/4R tau ratios were determined in a cohort of 704 patients, including 37 genetically and 31 neuropathologically proven cases. Diagnostic groups comprised patients with TDP-43 proteinopathy ALS, 4R tauopathy progressive supranuclear palsy, behavior variant FTD (bvFTD) as a group with either tau or TDP-43 pathology, and healthy controls. EV tau ratios were low in progressive supranuclear palsy and high in bvFTD with tau pathology. EV TDP-43 levels were high in ALS and in bvFTD with TDP-43 pathology. Both markers discriminated between the diagnostic groups with area under the curve values >0.9, and between TDP-43 and tau pathology in bvFTD. Both markers strongly correlated with neurodegeneration, and clinical and neuropsychological markers of disease severity. Findings were replicated in an independent validation cohort of 292 patients including 34 genetically confirmed cases. Taken together, the combination of EV TDP-43 levels and EV 3R/4R tau ratios may aid the molecular diagnosis of FTD, FTD spectrum disorders and ALS, providing a potential biomarker to monitor disease progression and target engagement in clinical trials.

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Item Type:	Article
Authors/Creators:	Chatterjee, M. Özdemir, S. Fritz, C. Möbius, W. https://orcid.org/0000-0002-2902-7165 Kleineidam, L. Mandelkow, E. https://orcid.org/0000-0003-4655-4829 Biernat, J. Doğdu, C. Peters, O. Cosma, N.C. https://orcid.org/0000-0002-2656-8046 Wang, X. Schneider, L.-S. Priller, J. https://orcid.org/0000-0001-7596-0979 Spruth, E. Kühn, A.A. https://orcid.org/0000-0002-4134-9060 Krause, P. Klockgether, T. Vogt, I.R. Kimmich, O. Spottke, A. Hoffmann, D.C. Fliessbach, K. Miklitz, C. McCormick, C. Weydt, P. Falkenburger, B. Brandt, M. Guenther, R. Dinter, E. Wiltfang, J. Hansen, N. Bähr, M. Zerr, I. Flöel, A. Nestor, P.J. Düzel, E. Glanz, W. Incesoy, E. Bürger, K. Janowitz, D. Perneczky, R. https://orcid.org/0000-0003-1981-7435 Rauchmann, B.S. Hopfner, F. Wagemann, O. Levin, J. Teipel, S. Kilimann, I. Goerss, D. Prudlo, J. Gasser, T. Brockmann, K. https://orcid.org/0000-0002-7515-8596 Mengel, D. Zimmermann, M. Synofzik, M. Wilke, C. Selma-González, J. Turon-Sans, J. Santos-Santos, M.A. Alcolea, D. https://orcid.org/0000-0002-3819-3245 Rubio-Guerra, S. https://orcid.org/0000-0001-7652-8029 Fortea, J. https://orcid.org/0000-0002-1340-638X Carbayo, Á https://orcid.org/0000-0001-9282-8603 Lleó, A. https://orcid.org/0000-0002-2568-5478 Rojas-García, R. Illán-Gala, I. Wagner, M. Frommann, I. https://orcid.org/0000-0002-7244-2014 Roeske, S. https://orcid.org/0000-0002-8262-4356 Bertram, L. https://orcid.org/0009-0005-3594-6925 Heneka, M.T. https://orcid.org/0000-0003-4996-1630 Brosseron, F. Ramirez, A. https://orcid.org/0000-0003-4991-763X Schmid, M. Beschorner, R. https://orcid.org/0000-0003-1109-915X Halle, A. Herms, J. Neumann, M. Barthélemy, N.R. Bateman, R.J. https://orcid.org/0000-0002-7729-1702 Rizzu, P. Heutink, P. Dols-Icardo, O. https://orcid.org/0000-0003-2656-8748 Höglinger, G. https://orcid.org/0000-0001-7587-6187 Hermann, A. https://orcid.org/0000-0002-7364-7791 Schneider, A. https://orcid.org/0000-0001-9540-8700
Copyright, Publisher and Additional Information:	© The Author(s) 2024. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Keywords:	Humans; Amyotrophic Lateral Sclerosis; tau Proteins; Extracellular Vesicles; Frontotemporal Dementia; Biomarkers; DNA-Binding Proteins; Female; Male; Aged; Middle Aged; Supranuclear Palsy, Progressive; Protein Isoforms
Dates:	Published: June 2024 Published (online): 18 June 2024 Accepted: 21 March 2024
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health
Depositing User:	Symplectic Sheffield
Date Deposited:	02 Jul 2024 15:16
Last Modified:	02 Jul 2024 15:16
Published Version:	http://dx.doi.org/10.1038/s41591-024-02937-4
Status:	Published
Publisher:	Springer Science and Business Media LLC
Refereed:	Yes
Identification Number:	10.1038/s41591-024-02937-4
Related URLs:	PubMed URL
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:214245

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Plasma extracellular vesicle tau and TDP-43 as diagnostic biomarkers in FTD and ALS

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