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

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.

SUBMITTER: Chatterjee M

PROVIDER: S-EPMC11186765 | biostudies-literature | 2024 Jun

REPOSITORIES: biostudies-literature

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

Chatterjee Madhurima M Özdemir Selcuk S Fritz Christian C Möbius Wiebke W Kleineidam Luca L Mandelkow Eckhard E Biernat Jacek J Doğdu Cem C Peters Oliver O Cosma Nicoleta Carmen NC Wang Xiao X Schneider Luisa-Sophia LS Priller Josef J Spruth Eike E Kühn Andrea A AA Krause Patricia P Klockgether Thomas T Vogt Ina R IR Kimmich Okka O Spottke Annika A Hoffmann Daniel C DC Fliessbach Klaus K Miklitz Carolin C McCormick Cornelia C Weydt Patrick P Falkenburger Björn B Brandt Moritz M Guenther René R Dinter Elisabeth E Wiltfang Jens J Hansen Niels N Bähr Mathias M Zerr Inga I Flöel Agnes A Nestor Peter J PJ Düzel Emrah E Glanz Wenzel W Incesoy Enise E Bürger Katharina K Janowitz Daniel D Perneczky Robert R Rauchmann Boris S BS Hopfner Franziska F Wagemann Olivia O Levin Johannes J Teipel Stefan S Kilimann Ingo I Goerss Doreen D Prudlo Johannes J Gasser Thomas T Brockmann Kathrin K Mengel David D Zimmermann Milan M Synofzik Matthis M Wilke Carlo C Selma-González Judit J Turon-Sans Janina J Santos-Santos Miguel Angel MA Alcolea Daniel D Rubio-Guerra Sara S Fortea Juan J Carbayo Álvaro Á Lleó Alberto A Rojas-García Ricardo R Illán-Gala Ignacio I Wagner Michael M Frommann Ingo I Roeske Sandra S Bertram Lucas L Heneka Michael T MT Brosseron Frederic F Ramirez Alfredo A Schmid Matthias M Beschorner Rudi R Halle Annett A Herms Jochen J Neumann Manuela M Barthélemy Nicolas R NR Bateman Randall J RJ Rizzu Patrizia P Heutink Peter P Dols-Icardo Oriol O Höglinger Günter G Hermann Andreas A Schneider Anja A

Nature medicine 20240618 6

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 ...[more]

PMID: 38890531

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Project description:ImportanceBiomarkers are lacking that can discriminate frontotemporal lobar degeneration (FTLD) associated with tau (FTLD-tau) or TDP-43 (FTLD-TDP).ObjectiveTo test whether plasma biomarkers glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), or their ratio (GFAP/NfL) differ between FTLD-tau and FTLD-TDP.Design, setting, and participantsThis retrospective cross-sectional study included data from 2009 to 2020 from the University of Pennsylvania Integrated Neurodegenerative Disease Database, with a median (IQR) follow-up duration of 2 (0.3-4.2) years. The training sample was composed of patients with autopsy-confirmed and familial FTLD; nonimpaired controls were included as a reference group. The independent validation sample included patients with FTD with a clinical diagnosis of progressive supranuclear palsy syndrome (PSPS) associated with tau (PSPS-tau) or amytrophic lateral sclerosis (ALS) associated with TDP-43 (ALS-TDP). In patients with FTLD with autopsy-confirmed or variant-confirmed pathology, receiver operating characteristic (ROC) curves tested the GFAP/NfL ratio and established a pathology-confirmed cut point. The cut point was validated in an independent sample of patients with clinical frontotemporal dementia (FTD). Data were analyzed from February to July 2022.ExposuresClinical, postmortem histopathological assessments, and plasma collection.Main outcomes and measuresROC and area under the ROC curve (AUC) with 90% CIs evaluated discrimination of pure FTLD-tau from pure FTLD-TDP using plasma GFAP/NfL ratio; the Youden index established optimal cut points. Sensitivity and specificity of cut points were assessed in an independent validation sample.ResultsOf 349 participants with available plasma data, 234 met inclusion criteria (31 controls, 141 in the training sample, and 62 in the validation sample). In the training sample, patients with FTLD-tau were older than patients with FTLD-TDP (FTLD-tau: n = 46; mean [SD] age, 65.8 [8.29] years; FTLD-TDP: n = 95; mean [SD] age, 62.3 [7.82] years; t84.6 = 2.45; mean difference, 3.57; 95% CI, 0.67-6.48; P = .02) but with similar sex distribution (FTLD-tau: 27 of 46 [59%] were male; FTLD-TDP: 51 of 95 [54%] were male; χ21 = 0.14; P = .70). In the validation sample, patients with PSPS-tau were older than those with ALS-TDP (PSPS-tau: n = 31; mean [SD] age, 69.3 [7.35] years; ALS-TDP: n = 31; mean [SD] age, 54.6 [10.17] years; t54.6 = 6.53; mean difference, 14.71; 95% CI, 10.19-19.23; P < .001) and had fewer patients who were male (PSPS-tau: 9 of 31 [29%] were male; ALS-TDP: 22 of 31 [71%] were male; χ21 = 9.3; P = .002). ROC revealed excellent discrimination of FTLD-tau from FTLD-TDP by plasma GFAP/NfL ratio (AUC = 0.89; 90% CI, 0.82-0.95; sensitivity = 0.73; 90% CI, 0.65-0.89; specificity = 0.89; 90% CI, 0.78-0.98), which was higher than either GFAP level alone (AUC = 0.65; 90% CI, 0.54-0.76) or NfL levels alone (AUC = 0.75; 90% CI, 0.64-0.85). In the validation sample, there was sensitivity of 0.84 (90% CI, 0.66-0.94) and specificity of 0.81 (90% CI, 0.62-0.91) when applying the autopsy-derived plasma GFAP/NfL threshold.Conclusions and relevanceThe plasma ratio of GFAP/NfL may discriminate FTLD-tau from FTLD-TDP.

Dataset Information

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

Publications

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

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