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

2024; Nature Portfolio; Volume: 30; Issue: 6 Linguagem: Inglês

10.1038/s41591-024-02937-4

1546-170X

Madhurima Chatterjee, Selcuk Özdemir, Christian Fritz, Wiebke Möbius, Luca Kleineidam, Eckhard Mandelkow�, Jacek Biernat, Cem Doğdu, Oliver Peters, Nicoleta Carmen Cosma, Xiao Wang, Luisa‐Sophie Schneider, Josef Priller, Eike Jakob Spruth, Andrea A. Kühn, Patricia Krause, Thomas Klockgether, Ina R. Vogt, Okka Kimmich, Annika Spottke, Daniel C. Hoffmann, Klaus Fließbach, Carolin Miklitz, Cornelia McCormick, Patrick Weydt, Björn Falkenburger, Moritz Brandt, René Guenther, Elisabeth Dinter, Jens Wiltfang, Niels Hansen, Mathias Bähr, Inga Zerr, Agnes Flöel, Peter J. Nestor, Emrah Düzel, Wenzel Glanz, Enise I. Incesoy, Katharina Bürger, Daniel Janowitz, Robert Perneczky, Boris‐Stephan Rauchmann, Franziska Hopfner, Olivia Wagemann, Johannes Levin, Stefan Teipel, Ingo Kilimann, Doreen Göerß, Johannes Prudlo, Thomas Gasser, Kathrin Brockmann, David Mengel, Milan Zimmermann, Matthis Synofzik, Carlo Wilke, Judit Selma‐González, Janina Turón‐Sans, Miguel A. Santos‐Santos, Daniel Alcolea, Sara Rubio‐Guerra, Juan Fortea, Álvaro Carbayo, Alberto Lleó, Ricardo Rojas‐García, Ignacio Illán‐Gala, Michael Wagner, Ingo Frommann, Sandra Roeske, L Bertram, Michael T. Heneka, Frederic Brosseron, Alfredo Ramı́rez, Matthias Schmid, Rudi Beschorner, Annett Halle, Jochen Herms, Manuela Neumann, Nicolas R. Barthélemy, Randall J. Bateman, Patrizia Rizzu, Peter Heutink, Oriol Dols‐Icardo, Günter U. Höglinger, Andreas Hermann, Anja Schneider,

Neuroinflammation and Neurodegeneration Mechanisms

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.