Big tau and brain-derived tau reveal peripheral and central nervous system involvement in neuropathies
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: ABSTRACT INTRODUCTION Biomarkers for monitoring disease activity and treatment response in peripheral neuropathies remain limited. Big tau, a high-molecular-weight isoform of tau, is predominantly expressed in the peripheral nervous system (PNS). We investigated serum levels of big tau, brain-derived tau (BD-tau), and neurofilament light chain (NfL) in peripheral neuropathies, multiple sclerosis (MS), Alzheimer’s disease (AD), and healthy controls (HC). METHODS Ultra-sensitive blood-based assays run on an HD-X Single Molecule Array analyser (Quanterix) were used to measure big tau and BD-tau in serum from patients with Guillain–Barré syndrome (GBS, n=81), Miller Fisher syndrome (MFS, n=20), Charcot–Marie–Tooth disease (CMT, n=102), chronic inflammatory demyelinating polyneuropathy (CIDP, n=43), MS (n=159), AD (n=20), and HC (n=41). NfL was measured in patients with neuropathies using an SR-X Single Molecule Array analyser (Quanterix). RESULTS Serum big tau levels were higher in GBS than in AD (11.4 vs 2.4 pg/mL, p<0.0001) and MS (11.4 vs 9.0 pg/mL, p=0.01), and similar to CIDP and CMT. Contrarily, serum BD-tau levels in GBS were higher than in CIDP (3.0 vs 2.3 pg/mL, p=0.006) and MS (3.0 vs 1.7 pg/mL, p<0.0001), but similar to CMT, and lower than in AD (3.0 vs 9.8 pg/mL, p<0.0001). Serum NfL levels were higher in GBS than in CIDP (32.5 vs 13.0 pg/mL, p=0.0002), CMT (32.5 vs 12.3 pg/mL, p<0.0001), and HC (32.5 vs 7.6 pg/mL, p<0.0001). Compared with GBS, MFS patients showed higher BD-tau (12.7 vs 3.0 pg/mL, p=0.003), lower big tau (5.4 vs 11.4 pg/mL, p=0.002), and higher NfL levels, although the latter did not reach statistical significance (118.3 vs 32.5 pg/mL, p=0.16). The NfL/big tau ratio was significantly higher in MFS than in GBS, CIDP, and CMT. In GBS, BD-tau correlated with early clinical severity (MRC at 1 week; I-RODS at 4 weeks; maximum GBS-DS and GBS-DS at 4 weeks), whereas neither tau biomarker showed long-term clinical correlations. Higher BD-tau and big tau levels were associated with the need for mechanical ventilation (BD-tau: 8.6 vs 2.9 pg/mL, p=0.019; big tau: 19.7 vs 10.7 pg/mL, p=0.007), while higher BD-tau levels were associated with mortality (10.9 vs 2.9 pg/mL, p=0.003). CONCLUSIONS Higher big tau levels in peripheral neuropathies than in CNS diseases support its role as a PNS-specific biomarker. In MFS, increased serum BD-tau, reduced big tau, and an elevated NfL/big tau ratio suggest CNS involvement with relative preservation of the PNS.
Source: medRxiv
Authors: Lorena Martín-Aguilar, Fernando González-Ortiz, Henrik Zetterberg, Thomas K. Karikari, Marc Suárez-Calvet, Carlos Casasnovas, Gerardo Gutiérrez-Gutiérrez, Maria José Sedano-Tous, Julio Pardo-Fernandez, Celedonio Márquez-Infante, Iñigo Rojas-Marcos, Ivonne Jericó-Pascual, Eugenia Martínez-Hernández, Germán Morís de la Tassa, Cristina Domínguez-González, Teresa Sevilla, Ana Lara Pelayo, Ricard Rojas-García, Roger Collet-Vidiella, Helena Codes-Méndez, Marta Caballero-Ávila, Clara Tejada-Illa, Cinta Lleixà, Gemma Riesco-Navarro, Nerea Blanco-Sanroman, Tania Mederer-Fernández, Lara Panicot-Buj, Elba Pascual-Goñi, Angela Vidal-Jordana, Kaj Blennow, Hlin Kvartsberg, Luis Querol
Institutions: Universitat Autònoma de Barcelona, Hospital de Sant Pau, Institut de Recerca Sant Pau, Sahlgrenska University Hospital, University of Gothenburg, University of Wisconsin–Madison, UK Dementia Research Institute, UCL Queen Square Institute of Neurology, University College London, Pasqual Maragall Foundation, Barcelonaβeta Brain Research Center, Hospital Del Mar, Hospital del Mar Research Institute, Bellvitge University Hospital, Institut d'Investigació Biomédica de Bellvitge, Centre for Biomedical Network Research on Rare Diseases, Hospital Universitario Infanta Sofía, Universidad Europea de Madrid, Marqués de Valdecilla University Hospital, Complejo Hospitalario Universitario de Santiago, Hospital Universitario Virgen del Rocío, Hospital Universitario Reina Sofía, Complejo Hospitalario de Navarra, Hospital Clínic de Barcelona, Hospital Universitario Central de Asturias, Hospital Universitario 12 De Octubre, Universitat de València, Hospital Universitari i Politècnic La Fe, Universidad de Cantabria, Instituto de Investigación Marqués de Valdecilla
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Alzheimer's Association, Alzheimer's Drug Discovery Foundation, Familjen Erling-Perssons Stiftelse, Cure Alzheimer's Fund, Stiftelsen för Gamla Tjänarinnor, GBS/CIDP Foundation International, European Commission, Hjärnfonden, Vetenskapsrådet, Alzheimerfonden, Demensfonden, HORIZON EUROPE Framework Programme, Instituto de Salud Carlos III
Awards: G1057200632, G1451607819, G150733400, G1546555014, G1551449788, G1588116593, G1710774808, G1771944843, G1833008592, G185163580, G1928552717, G196098375, G201353144, G2057385626, G2081597990, G2224941001, G2256555670, G237833635, G2475953241, G292763017, G3241251457, Fluid biomarkers for neurodegenerative dementias, G3509189227, G3809224024, G3842727039, G3903502641, G4166693258, G4228906844, G4234328627, G4244943609, G4260843567, G4786159458, G4973243065, G506008078, G516766298, Fluid biomarkers for neurodegenerative dementias, G5576250680, G5712520100, MEDICINA DE PRECISIÓN EN NEUROPATÍAS AUTOINMUNES, CASCADE: CAuSe or Consequence in Alzheimer DiseasE?, RED ESPAÑOLA DE NEUROPATÍAS AUTOINMUNES, G6158734006, G6207287561, G6252389079, G6289970089, G6396693753, G6465255257, Multi-omics Interdisciplinary Research Integration to Address DEmentia diagnosis, G6701856265, G6745400708, G691317373, G7293611571, G7907773732, G8845388653
OpenAlex ID: W7204781596