Plasma extracellular vesicle Tau isoform ratios and TDP-43 inform about molecular pathology in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis
Authors: Chatterjee Madhurima , Özdemir Selcuk , Fritz Christian , Möbius Wiebke , Kleineidam Luca , Mandelkow Eckhard , Biernat Jacek , Dogdu Cem , Peters Oliver , Cosma Nicoleta Carmen , Wang Xiao , Schneider Luisa-Sophia , Priller Josef , Spruth Eicke , Kühn Andrea , Krause Patricia , Klockgether Thomas , Vogt Ina , Kimmich Okka , Spottke Annika , Hoffmann Daniel , Fliessbach Klaus , Miklitz Carolin , McCormick Cornelia , Falkenburger Björn , Brandt Moritz , Günther Rene , Dinter Elisabeth , Wiltfang Jens , Hansen Niels , Baehr Mathias , Zerr Inga , Flöel Agnes , Nestor Peter , Düzel Emrah , Glanz Wenzel , Incesoy Enise , Buerger Katharina , Janowitz Daniel , Perneczky Robert , Rauchmann Boris-Stephan , Hopfner Franziska , Levin Johannes , Teipel Stefan , Kilimann Ingo , Goerss Doreen , Prudlo Johannes , Gasser Thomas , Brockmann Kathrin , Synofzik Matthis , Wilke Carlo , Wagner Michael , Frommann Ingo , Roeske Sandra , Betram Lucas , Heneka Michael , Brosseron Frederic , Ramirez Alfredo , Schmid Matthias , Beschorner Rudi , Halle Annett , Herms Jochen , Neuman Manuela , Barthelemy Nicolas , Bateman Randall , Rizzu Patrizia , Heutink Peter , Höglinger Günter , Hermann Andreas , Schneider Anja 
Published: July 2023

Low-invasive biomarkers are urgently needed for the detection of molecular pathology in Frontotemporal Dementia (FTD), FTD spectrum disorders and Amyotrophic Lateral Sclerosis (ALS). This is particularly true in behavior variant FTD (bvFTD), in which premortem biomarkers are missing to distinguish underlying Tau from TAR DNA binding protein (TDP-43) pathology. This lack of biomarkers prevents the stratification of patients for intervention trials and constitutes a major obstacle for the development of disease-modifying therapies. Extracellular vesicles (EVs) have been implicated in neurodegenerative disease pathology, contributing to the release and potentially to intercellular transmission of pathologically aggregated proteins. Here, we show that plasma EVs contain quantifiable amounts of TDP-43 and full-length Tau, which allows 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 pilot and validation study of 704 patients, including 37 genetic and 31 neuropathologically proven cases. Diagnostic groups comprised patients with the TDP-43 proteinopathy ALS, the 4R tauopathy Progressive Supranuclear Palsy (PSP), bvFTD as a group with either Tau or TDP-43 pathology, and healthy controls (HC). Compared to HC, plasma EV 3R/4R Tau ratios were decreased in PSP, unchanged in ALS, and increased in a subset of bvFTD patients, consistent with Tau pathology in approximately 40% of cases with bvFTD. EV Tau ratio discriminated between PSP and bvFTD, ALS and healthy controls (AUC 0.96-0.99), and between bvFTD and ALS (AUC 0.90) as well as HC (AUC 0.91). Plasma EV TDP-43 levels were increased in ALS and in those bvFTD patients who did not display high EV Tau ratios. Plasma EV TDP-43 discriminated patients with ALS from HC (AUC 0.99), bvFTD (AUC 0.91) and PSP (AUC 0.99). The combination of EV Tau ratio and EV TDP-43 was reliably able to discriminate between TDP-43 and Tau pathology in bvFTD. This blood-based classification was confirmed in genetic and autopsy proven cases. Both markers strongly correlated with the neurodegeneration marker neurofilament light chain (NfL) as well as with clinical and neuropsychological markers of disease severity in ALS (TDP-43 with ECAS, ALS-FRS-R), bvFTD (TDP-43 and Tau ratio with CDR-SB, CDR plus NACC FTLD) and PSP (Tau ratio with PSP-RS). Taken together, the combination of both markers may aid the molecular diagnosis of FTD, FTD spectrum disorders and ALS, the stratification of patients for therapeutic trials and bears the potential of a biomarker to monitor disease progression and target engagement.