Plasma extracellular vesicle tau and TDP-43 as diagnostic biomarkers in FTD and ALS
Por:
Chatterjee, M, Özdemir, S, Fritz, C, Möbius, W, Kleineidam, L, Mandelkow, E, Biernat, J, Dogdu, C, Peters, O, Cosma, NC, Wang, X, Schneider, LS, Priller, J, Spruth, E, Kühn, AA, Krause, P, Klockgether, T, Vogt, IR, Kimmich, O, Spottke, A, Hoffmann, DC, 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, PJ, Düzel, E, Glanz, W, Incesoy, E, Bürger, K, Janowitz, D, Perneczky, R, Rauchmann, BS, Hopfner, F, Wagemann, O, Levin, J, Teipel, S, Kilimann, I, Goerss, D, Prudlo, J, Gasser, T, Brockmann, K, Mengel, D, Zimmermann, M, Synofzik, M, Wilke, C, Selma-Gonzáalez, J, Turon-Sans, J, Santos-Santos, MA, Alcolea, D, Rubio-Guerra, S, Fortea, J, Carbayo, A, Lleó, A, Rojas-García, R, Illán-Gala, I, Wagner, M, Frommann, I, Roeske, S, Bertram, L, Heneka, MT, Brosseron, F, Ramirez, A, Schmid, M, Beschorner, R, Halle, A, Herms, J, Neumann, M, Barthélemy, NR, Bateman, RJ, Rizzu, P, Heutink, P, Dols-Icardo, O, Höglinger, G, Hermann, A, Schneider, A
Publicada:
1 jun 2024
Resumen:
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.
Filiaciones:
Chatterjee, M:
German Ctr Neurodegenerat Dis DZNE, Bonn, Germany
Özdemir, S:
German Ctr Neurodegenerat Dis DZNE, Bonn, Germany
Ataturk Univ, Dept Genet, Erzurum, Turkiye
Fritz, C:
German Ctr Neurodegenerat Dis DZNE, Bonn, Germany
Möbius, W:
Max Planck Inst Multidisciplinary Sci, Dept Neurogenet, Gottingen, Germany
Univ Gottingen, Cluster Excellence Multiscale Bioimaging Mol Ma, Gottingen, Germany
Kleineidam, L:
German Ctr Neurodegenerat Dis DZNE, Bonn, Germany
Univ Bonn, Univ Hosp Bonn, Dept Old Age Psychiat & Cognit Disorders, Bonn, Germany
Mandelkow, E:
Univ Bonn, Univ Hosp Bonn, Dept Old Age Psychiat & Cognit Disorders, Bonn, Germany
Biernat, J:
Univ Bonn, Univ Hosp Bonn, Dept Old Age Psychiat & Cognit Disorders, Bonn, Germany
Dogdu, C:
German Ctr Neurodegenerat Dis DZNE, Bonn, Germany
Peters, O:
German Ctr Neurodegenerat Dis DZNE, Berlin, Germany
Charite Univ Med Berlin, Berlin, Germany
Free Univ Berlin, Berlin, Germany
Humboldt Univ, Inst Psychiat & Psychotherapy, Berlin, Germany
Cosma, NC:
German Ctr Neurodegenerat Dis DZNE, Berlin, Germany
Wang, X:
German Ctr Neurodegenerat Dis DZNE, Berlin, Germany
Schneider, LS:
German Ctr Neurodegenerat Dis DZNE, Berlin, Germany
Priller, J:
German Ctr Neurodegenerat Dis DZNE, Berlin, Germany
Charite Univ Med Berlin, Dept Psychiat & Psychotherapy, Berlin, Germany
Tech Univ Munich, Dept Psychiat & Psychotherapy, Sch Med, Munich, Germany
Univ Edinburgh, Edinburgh, Midlothian, Scotland
UK DRI, Edinburgh, Midlothian, Scotland
Spruth, E:
Charite Univ Med Berlin, Dept Psychiat & Psychotherapy, Berlin, Germany
Kühn, AA:
German Ctr Neurodegenerat Dis DZNE, Berlin, Germany
Charite Univ Med Berlin, Dept Neurol, Movement Disorder & Neuromodulat Unit, Berlin, Germany
Krause, P:
Charite Univ Med Berlin, Dept Neurol, Movement Disorder & Neuromodulat Unit, Berlin, Germany
Klockgether, T:
Univ Bonn, Dept Neurol, Bonn, Germany
Vogt, IR:
German Ctr Neurodegenerat Dis DZNE, Bonn, Germany
Kimmich, O:
German Ctr Neurodegenerat Dis DZNE, Bonn, Germany
Spottke, A:
German Ctr Neurodegenerat Dis DZNE, Bonn, Germany
Univ Bonn, Dept Neurol, Bonn, Germany
Hoffmann, DC:
German Ctr Neurodegenerat Dis DZNE, Bonn, Germany
Fliessbach, K:
German Ctr Neurodegenerat Dis DZNE, Bonn, Germany
Univ Bonn, Univ Hosp Bonn, Dept Old Age Psychiat & Cognit Disorders, Bonn, Germany
Miklitz, C:
German Ctr Neurodegenerat Dis DZNE, Bonn, Germany
Univ Bonn, Univ Hosp Bonn, Dept Old Age Psychiat & Cognit Disorders, Bonn, Germany
McCormick, C:
German Ctr Neurodegenerat Dis DZNE, Bonn, Germany
Univ Bonn, Univ Hosp Bonn, Dept Old Age Psychiat & Cognit Disorders, Bonn, Germany
Weydt, P:
German Ctr Neurodegenerat Dis DZNE, Bonn, Germany
Falkenburger, B:
German Ctr Neurodegenerat Dis DZNE, Dresden, Germany
Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dept Neurol, Dresden, Germany
Brandt, M:
German Ctr Neurodegenerat Dis DZNE, Dresden, Germany
Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dept Neurol, Dresden, Germany
Guenther, R:
German Ctr Neurodegenerat Dis DZNE, Dresden, Germany
Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dept Neurol, Dresden, Germany
Dinter, E:
German Ctr Neurodegenerat Dis DZNE, Dresden, Germany
Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dept Neurol, Dresden, Germany
Wiltfang, J:
German Ctr Neurodegenerat Dis DZNE, Gottingen, Germany
Univ Gottingen, Univ Med Ctr Gottingen, Dept Psychiat & Psychotherapy, Gottingen, Germany
Univ Aveiro, Inst Biomed iBiMED, Dept Med Sci, Neurosci & Signaling Grp, Aveiro, Portugal
Hansen, N:
German Ctr Neurodegenerat Dis DZNE, Gottingen, Germany
Univ Gottingen, Univ Med Ctr Gottingen, Dept Psychiat & Psychotherapy, Gottingen, Germany
Bähr, M:
German Ctr Neurodegenerat Dis DZNE, Gottingen, Germany
Univ Med Ctr, Georg August Univ, Dept Neurol, Gottingen, Germany
Univ Med Greifswald, Dept Neurol, Greifswald, Germany
Zerr, I:
German Ctr Neurodegenerat Dis DZNE, Gottingen, Germany
Univ Med Ctr, Georg August Univ, Dept Neurol, Gottingen, Germany
Flöel, A:
Univ Med Greifswald, Dept Neurol, Greifswald, Germany
German Ctr Neurodegenerat Dis DZNE, Rostock, Germany
Nestor, PJ:
German Ctr Neurodegenerat Dis DZNE, Magdeburg, Germany
Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia
Mater Publ Hosp, Brisbane, Qld, Australia
Düzel, E:
German Ctr Neurodegenerat Dis DZNE, Magdeburg, Germany
Otto von Guericke Univ, Inst Cognit Neurol & Dementia Res, Magdeburg, Germany
UCL, Inst Cognit Neurosci, London, England
Glanz, W:
German Ctr Neurodegenerat Dis DZNE, Magdeburg, Germany
Otto von Guericke Univ, Inst Cognit Neurol & Dementia Res, Magdeburg, Germany
Univ Hosp Magdeburg, Clin Neurol, Magdeburg, Germany
Incesoy, E:
German Ctr Neurodegenerat Dis DZNE, Magdeburg, Germany
Otto von Guericke Univ, Inst Cognit Neurol & Dementia Res, Magdeburg, Germany
Univ Hosp Magdeburg, Dept Psychiat & Psychotherapy, Magdeburg, Germany
Bürger, K:
German Ctr Neurodegenerat Dis DZNE, Munich, Germany
Ludwig Maximilians Univ Munchen, Univ Hosp, Inst Stroke & Dementia Res, Munich, Germany
Janowitz, D:
Ludwig Maximilians Univ Munchen, Univ Hosp, Inst Stroke & Dementia Res, Munich, Germany
Perneczky, R:
German Ctr Neurodegenerat Dis DZNE, Munich, Germany
Ludwig Maximilians Univ Munchen, Univ Hosp, Dept Psychiat & Psychotherapy, Munich, Germany
Munich Cluster Syst Neurol SyNergy Munich, Munich, Germany
Imperial Coll London, Sch Publ Hlth, Ageing Epidemiol Res Unit, London, England
Rauchmann, BS:
Ludwig Maximilians Univ Munchen, Univ Hosp, Dept Psychiat & Psychotherapy, Munich, Germany
Univ Hosp LMU, Dept Neuroradiol, Munich, Germany
Univ Sheffield, Sheffield Inst Translat Neurosci SITraN, Sheffield, England
Hopfner, F:
Ludwig Maximilians Univ LMU Munich, Univ Hosp Munich, Dept Neurol, Munich, Germany
Wagemann, O:
German Ctr Neurodegenerat Dis DZNE, Munich, Germany
Ludwig Maximilians Univ LMU Munich, Univ Hosp Munich, Dept Neurol, Munich, Germany
Levin, J:
German Ctr Neurodegenerat Dis DZNE, Munich, Germany
Munich Cluster Syst Neurol SyNergy Munich, Munich, Germany
Ludwig Maximilians Univ LMU Munich, Univ Hosp Munich, Dept Neurol, Munich, Germany
Teipel, S:
Rostock Univ, Dept Psychosomat Med, Med Ctr, Rostock, Germany
Kilimann, I:
Rostock Univ, Dept Psychosomat Med, Med Ctr, Rostock, Germany
Prudlo, J:
Rostock Univ, Dept Neurol, Med Ctr, Rostock, Germany
Gasser, T:
Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, Tubingen, Germany
Brockmann, K:
Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, Tubingen, Germany
Mengel, D:
Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, Tubingen, Germany
Zimmermann, M:
Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, Tubingen, Germany
Synofzik, M:
Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, Tubingen, Germany
Wilke, C:
Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, Tubingen, Germany
Selma-Gonzáalez, J:
Univ Autonoma Barcelona, Inst Recerca Sant Pau,Dept Neurol, Hosp Santa Creu i Sant Pau, Sant Pau Memory Unit,Dept Neurol, Barcelona, Spain
Turon-Sans, J:
Univ Autonoma Barcelona, Inst Recerca Sant Pau,Dept Neurol, Hosp Santa Creu i Sant Pau, Sant Pau Memory Unit,Dept Neurol, Barcelona, Spain
Lleó, A:
Univ Autonoma Barcelona, Inst Recerca Sant Pau,Dept Neurol, Hosp Santa Creu i Sant Pau, Sant Pau Memory Unit,Dept Neurol, Barcelona, Spain
Rojas-García, R:
Univ Autonoma Barcelona, Inst Recerca Sant Pau, Hosp Santa Creu i Sant Pau,Neuromuscular Dis Unit, Motor Neuron Dis Clin,Neuromuscular Dis Unit, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid, Spain
Illán-Gala, I:
Univ Autonoma Barcelona, Inst Recerca Sant Pau,Dept Neurol, Hosp Santa Creu i Sant Pau, Sant Pau Memory Unit,Dept Neurol, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurogenerat C, Madrid, Spain
Wagner, M:
German Ctr Neurodegenerat Dis DZNE, Bonn, Germany
Univ Luxembourg, Luxembourg Ctr Syst Biomed LCSB, Belvaux, Luxembourg
Frommann, I:
German Ctr Neurodegenerat Dis DZNE, Bonn, Germany
Roeske, S:
German Ctr Neurodegenerat Dis DZNE, Bonn, Germany
Bertram, L:
German Ctr Neurodegenerat Dis DZNE, Bonn, Germany
Heneka, MT:
Univ Massachussetss, Dept Infect Dis & Immunol, Med Sch, North Worcester, MA USA
Brosseron, F:
German Ctr Neurodegenerat Dis DZNE, Bonn, Germany
Ramirez, A:
German Ctr Neurodegenerat Dis DZNE, Bonn, Germany
Univ Bonn, Univ Hosp Bonn, Dept Old Age Psychiat & Cognit Disorders, Bonn, Germany
Univ Cologne, Excellence Cluster Cellular Stress Responses Agin, Cologne, Germany
Univ Cologne, Dept Psychiat, Div Neurogenet & Mol Psychiat, Cologne, Germany
UT Hlth San Antonio, Dept Psychiat, Glenn Biggs Inst Alzheimers & Neurodegenerat Dis, San Antonio, TX USA
Schmid, M:
German Ctr Neurodegenerat Dis DZNE, Bonn, Germany
Univ Hosp Bonn, Inst Med Biometry Informat & Epidemiol, Bonn, Germany
Beschorner, R:
Univ Tubingen, Dept Neuropathol, Tubingen, Germany
Halle, A:
German Ctr Neurodegenerat Dis DZNE, Bonn, Germany
Univ Hosp Bonn, Dept Neuropathol, Bonn, Germany
Herms, J:
German Ctr Neurodegenerat Dis DZNE, Munich, Germany
Munich Cluster Syst Neurol SyNergy Munich, Munich, Germany
Ludwig Maximilians Univ Munchen, Ctr Neuropathol & Prion Res, Munich, Germany
Neumann, M:
Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, Tubingen, Germany
Univ Tubingen, Dept Neuropathol, Tubingen, Germany
Barthélemy, NR:
Washington Univ, Dept Neurol, Sch Med, St Louis, MO USA
Tracy Family SILQ Ctr Neurodegenerat Biol, St Louis, MO USA
Bateman, RJ:
Washington Univ, Dept Neurol, Sch Med, St Louis, MO USA
Tracy Family SILQ Ctr Neurodegenerat Biol, St Louis, MO USA
Rizzu, P:
Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, Tubingen, Germany
Heutink, P:
Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, Tubingen, Germany
Dols-Icardo, O:
Univ Autonoma Barcelona, Inst Recerca Sant Pau,Dept Neurol, Hosp Santa Creu i Sant Pau, Sant Pau Memory Unit,Dept Neurol, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurogenerat C, Madrid, Spain
Höglinger, G:
German Ctr Neurodegenerat Dis DZNE, Munich, Germany
Munich Cluster Syst Neurol SyNergy Munich, Munich, Germany
Ludwig Maximilians Univ LMU Munich, Univ Hosp Munich, Dept Neurol, Munich, Germany
Hermann, A:
German Ctr Neurodegenerat Dis DZNE, Rostock, Germany
Univ Med Ctr Rostock, Translat Neurodegenerat Sect Albrecht Kossel, Rostock, Germany
Univ Med Ctr Rostock, Ctr Transdisciplinary Neurosci, Rostock, Germany
Schneider, A:
German Ctr Neurodegenerat Dis DZNE, Bonn, Germany
Univ Bonn, Univ Hosp Bonn, Dept Old Age Psychiat & Cognit Disorders, Bonn, Germany
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