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

Chatterjee, Madhurima; Özdemir, Selcuk; Fritz, Christian; Möbius, Wiebke ; Kleineidam, Luca; Mandelkow, Eckhard ; Biernat, Jacek; Doğdu, Cem; Peters, Oliver; Cosma, Nicoleta Carmen ; Wang, Xiao; Schneider, Luisa-Sophia; Priller, Josef ; Spruth, Eike; Kühn, Andrea A. ; Krause, Patricia; Klockgether, Thomas; Vogt, Ina R.; Kimmich, Okka; Spottke, Annika; Hoffmann, Daniel C.; Fliessbach, Klaus; Miklitz, Carolin; McCormick, Cornelia; Weydt, Patrick; Falkenburger, Björn; Brandt, Moritz; Guenther, René; Dinter, Elisabeth; Wiltfang, Jens; Hansen, Niels; Bähr, Mathias; Zerr, Inga; Flöel, Agnes; Nestor, Peter J.; Düzel, Emrah; Glanz, Wenzel; Incesoy, Enise; Bürger, Katharina; Janowitz, Daniel; Perneczky, Robert ; Rauchmann, Boris S.; Hopfner, Franziska ; Wagemann, Olivia; Levin, Johannes ; Teipel, Stefan; Kilimann, Ingo; Goerss, Doreen; Prudlo, Johannes; Gasser, Thomas; Brockmann, Kathrin ; Mengel, David; Zimmermann, Milan; Synofzik, Matthis; Wilke, Carlo; Selma-González, Judit; Turon-Sans, Janina; Santos-Santos, Miguel Angel; Alcolea, Daniel ; Rubio-Guerra, Sara ; Fortea, Juan ; Carbayo, Álvaro ; Lleó, Alberto ; Rojas-García, Ricardo; Illán-Gala, Ignacio; Wagner, Michael; Frommann, Ingo ; Roeske, Sandra ; Bertram, Lucas ; Heneka, Michael T. ; Brosseron, Frederic; Ramirez, Alfredo ; Schmid, Matthias; Beschorner, Rudi ; Halle, Annett; Herms, Jochen; Neumann, Manuela; Barthélemy, Nicolas R.; Bateman, Randall J. ; Rizzu, Patrizia; Heutink, Peter; Dols-Icardo, Oriol ; Höglinger, Günter ; Hermann, Andreas und Schneider, Anja (2024): Plasma extracellular vesicle tau and TDP-43 as diagnostic biomarkers in FTD and ALS. In: Nature Medicine, Bd. 30, Nr. 6: S. 1771-1783

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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy) ; Medizin > Institut für Schlaganfall- und Demenzforschung (ISD) ; Medizin > Klinikum der LMU München > Neurologische Klinik und Poliklinik mit Friedrich-Baur-Institut ; Medizin > Klinikum der LMU München > Klinik und Poliklink für Psychiatrie und Psychotherapie ; Medizin > Klinikum der LMU München > Klinik und Poliklinik für Radiologie
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1078-8956
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198