Big tau and brain-derived tau reveal peripheral and central nervous system involvement in neuropathies
- 1Neurological Diseases, IR SANT PAU, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, 08041, Barcelona, Spain
Abstract
INTRODUCTIONBiomarkers 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), Alzheimers disease (AD), and healthy controls (HC).
METHODSUltra-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-Barre 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).
RESULTSSerum 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).
CONCLUSIONSHigher 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.
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BibTeX
@misc{martinaguilar2026brainderived,
title = {{Big tau and brain-derived tau reveal peripheral and central nervous system involvement in neuropathies}},
author = {L. Martin-Aguilar and F. Gonzalez-Ortiz and H. Zetterberg and T. K. Karikari and M. Suarez-Calvet and C. Casasnovas and G. Gutierrez-Gutierrez and M. J. Sedano-Tous and J. Pardo-Fernandez and C. Marquez-Infante and I. Rojas-Marcos and I. Jerico-Pascual and E. Martinez-Hernandez and G. Moris de la Tassa and C. Dominguez-Gonzalez and T. Sevilla and A. L. Pelayo and R. Rojas-Garcia and R. Collet-Vidiella and H. Codes-Mendez and M. Caballero-Avila and C. Tejada-Illa and C. Lleixa and G. Riesco-Navarro and N. Blanco-Sanroman and T. Mederer-Fernandez and L. Panicot-Buj and E. Pascual-Goni and A. Vidal-Jordana and K. Blennow and H. Kvartsberg and L. Querol},
howpublished = {medRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.27.26361202},
url = {https://www.medrxiv.org/content/10.64898/2026.08.27.26361202v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Big tau and brain-derived tau reveal peripheral and central nervous system involvement in neuropathies
AU - L. Martin-Aguilar
AU - F. Gonzalez-Ortiz
AU - H. Zetterberg
AU - T. K. Karikari
AU - M. Suarez-Calvet
AU - C. Casasnovas
AU - G. Gutierrez-Gutierrez
AU - M. J. Sedano-Tous
AU - J. Pardo-Fernandez
AU - C. Marquez-Infante
AU - I. Rojas-Marcos
AU - I. Jerico-Pascual
AU - E. Martinez-Hernandez
AU - G. Moris de la Tassa
AU - C. Dominguez-Gonzalez
AU - T. Sevilla
AU - A. L. Pelayo
AU - R. Rojas-Garcia
AU - R. Collet-Vidiella
AU - H. Codes-Mendez
AU - M. Caballero-Avila
AU - C. Tejada-Illa
AU - C. Lleixa
AU - G. Riesco-Navarro
AU - N. Blanco-Sanroman
AU - T. Mederer-Fernandez
AU - L. Panicot-Buj
AU - E. Pascual-Goni
AU - A. Vidal-Jordana
AU - K. Blennow
AU - H. Kvartsberg
AU - L. Querol
PY - 2026
DA - 2026/08/27
PB - medRxiv
DO - 10.64898/2026.08.27.26361202
UR - https://www.medrxiv.org/content/10.64898/2026.08.27.26361202v1
AB - INTRODUCTIONBiomarkers 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), Alzheimers disease (AD), and healthy controls (HC). METHODSUltra-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-Barre 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). RESULTSSerum 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). CONCLUSIONSHigher 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.
ER -