TY  - JOUR
AU  - Chatterjee, Madhurima
AU  - Oezdemir, Selcuk
AU  - Fritz, Christian
AU  - Möbius, Wiebke
AU  - Kleineidam, Luca
AU  - Mandelkow, Eckhard
AU  - Biernat, Jacek
AU  - Doğdu, Cem
AU  - Peters, Oliver
AU  - Cosma, Nicoleta-Carmen
AU  - Wang, Xiao
AU  - Schneider, Luisa-Sophia
AU  - Priller, Josef
AU  - Spruth, Eike
AU  - Kühn, Andrea A
AU  - Krause, Patricia
AU  - Klockgether, Thomas
AU  - Vogt, Ina R
AU  - Kimmich, Okka
AU  - Spottke, Annika
AU  - Hoffmann, Daniel C
AU  - Fliessbach, Klaus
AU  - Miklitz, Carolin
AU  - McCormick, Cornelia
AU  - Weydt, Patrick
AU  - Falkenburger, Björn
AU  - Brandt, Moritz
AU  - Guenther, René
AU  - Dinter, Elisabeth
AU  - Wiltfang, Jens
AU  - Hansen, Niels
AU  - Bähr, Mathias
AU  - Zerr, Inga
AU  - Flöel, Agnes
AU  - Nestor, Peter John
AU  - Düzel, Emrah
AU  - Glanz, Wenzel
AU  - Incesoy, Enise
AU  - Bürger, Katharina
AU  - Janowitz, Daniel
AU  - Perneczky, Robert
AU  - Rauchmann, Boris Stephan
AU  - Hopfner, Franziska
AU  - Wagemann, Olivia
AU  - Levin, Johannes
AU  - Teipel, Stefan
AU  - Kilimann, Ingo
AU  - Goerss, Doreen
AU  - Prudlo, Johannes
AU  - Gasser, Thomas
AU  - Brockmann, Kathrin
AU  - Mengel, David
AU  - Zimmermann, Milan
AU  - Synofzik, Matthis
AU  - Wilke, Carlo
AU  - Selma-González, Judit
AU  - Turon-Sans, Janina
AU  - Santos-Santos, Miguel Angel
AU  - Alcolea, Daniel
AU  - Rubio-Guerra, Sara
AU  - Fortea, Juan
AU  - Carbayo, Álvaro
AU  - Lleó, Alberto
AU  - Rojas-García, Ricardo
AU  - Illán-Gala, Ignacio
AU  - Wagner, Michael
AU  - Frommann, Ingo
AU  - Röske, Sandra
AU  - Bertram, Lucas
AU  - Heneka, Michael T
AU  - Brosseron, Frederic
AU  - Ramirez, Alfredo
AU  - Schmid, Matthias
AU  - Beschorner, Rudi
AU  - Halle, Annett
AU  - Herms, Jochen
AU  - Neumann, Manuela
AU  - Barthélemy, Nicolas R
AU  - Bateman, Randall J
AU  - Rizzu, Patrizia
AU  - Heutink, Peter
AU  - Dols-Icardo, Oriol
AU  - Höglinger, Günter
AU  - Hermann, Andreas
AU  - Schneider, Anja
TI  - Plasma extracellular vesicle tau and TDP-43 as diagnostic biomarkers in FTD and ALS.
JO  - Nature medicine
VL  - 30
IS  - 6
SN  - 1078-8956
CY  - New York, NY
PB  - Nature America Inc.
M1  - DZNE-2024-00791
SP  - 1771 - 1783
PY  - 2024
AB  - 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.
KW  - Humans
KW  - Amyotrophic Lateral Sclerosis: blood
KW  - Amyotrophic Lateral Sclerosis: diagnosis
KW  - Amyotrophic Lateral Sclerosis: pathology
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - tau Proteins: blood
KW  - tau Proteins: metabolism
KW  - Extracellular Vesicles: metabolism
KW  - Frontotemporal Dementia: blood
KW  - Frontotemporal Dementia: diagnosis
KW  - Frontotemporal Dementia: genetics
KW  - Frontotemporal Dementia: pathology
KW  - Biomarkers: blood
KW  - DNA-Binding Proteins: blood
KW  - DNA-Binding Proteins: genetics
KW  - Female
KW  - Male
KW  - Aged
KW  - Middle Aged
KW  - Supranuclear Palsy, Progressive: blood
KW  - Supranuclear Palsy, Progressive: diagnosis
KW  - Protein Isoforms: blood
KW  - tau Proteins (NLM Chemicals)
KW  - Biomarkers (NLM Chemicals)
KW  - DNA-Binding Proteins (NLM Chemicals)
KW  - TARDBP protein, human (NLM Chemicals)
KW  - MAPT protein, human (NLM Chemicals)
KW  - Protein Isoforms (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:38890531
C2  - pmc:PMC11186765
DO  - DOI:10.1038/s41591-024-02937-4
UR  - https://pub.dzne.de/record/270411
ER  -