. 2024 Mar 13;95(4):356-359.

doi: 10.1136/jnnp-2023-331854.

Alzheimer's disease marker phospho-tau181 is not elevated in the first year after moderate-to-severe TBI

Neil Graham^{1

2}, Karl Zimmerman^{1

2}, Amanda J Heslegrave³, Ashvini Keshavan⁴, Federico Moro^{5

6}, Samia Abed-Maillard⁷, Adriano Bernini⁸, Vincent Dunet⁹, Elena Garbero¹⁰, Giovanni Nattino¹⁰, Arturo Chieregato¹¹, Enrico Fainardi¹², Camelia Baciu¹¹, Primoz Gradisek¹³, Sandra Magnoni¹⁴, Mauro Oddo^{7

15}, Guido Bertolini¹⁰, Jonathan M Schott^{3

16}, Henrik Zetterberg^{3

17}, David Sharp^{18

2}

Affiliations

¹ Brain Sciences, Imperial College London, London, UK.
² UK Dementia Research Institute Centre for Care Research and Technology, Imperial College London, London, UK.
³ UK Dementia Research Institute, University College London, London, UK.
⁴ Dementia Research Centre, UCL Queen Square Institute of Neurology, London, UK.
⁵ Laboratory of Acute Brain Injury and Neuroprotection, Department of Acute Brain and Cardiovascular Injury, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
⁶ Dipartimento di Anestesia e Rianimazione, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
⁷ Neuroscience Critical Care Research Group, Department of Intensive Care Medicine, CHUV Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
⁸ Department of Clinical Neurosciences, CHUV Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
⁹ Department of Medical Radiology, CHUV Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
¹⁰ Laboratory of Clinical Epidemiology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Ranica, Italy.
¹¹ Terapia Intensiva ad indirizzo Neurologico & Neurochirurgico, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy.
¹² Department of Experimental and Clinical Sciences, Careggi University Hospital and University of Firenze, Florence, Italy.
¹³ Clinical Department of Anaesthesiology and Intensive Therapy, University Medical Center, Ljubljana, Slovenia.
¹⁴ Department of Anesthesia and Intensive Care, Santa Chiara Hospital, Trento, Italy.
¹⁵ Directorate for Innovation and Clinical Research, CHUV Lausanne University Hospital, Lausanne, Switzerland.
¹⁶ Dementia Research Centre and Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
¹⁷ Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
¹⁸ Brain Sciences, Imperial College London, London, UK david.sharp@imperial.ac.uk.

PMID: 37833041
PMCID: PMC10958285
DOI: 10.1136/jnnp-2023-331854

Alzheimer's disease marker phospho-tau181 is not elevated in the first year after moderate-to-severe TBI

Neil Graham et al. J Neurol Neurosurg Psychiatry. 2024.

. 2024 Mar 13;95(4):356-359.

doi: 10.1136/jnnp-2023-331854.

Authors

Affiliations

¹ Brain Sciences, Imperial College London, London, UK.
² UK Dementia Research Institute Centre for Care Research and Technology, Imperial College London, London, UK.
³ UK Dementia Research Institute, University College London, London, UK.
⁴ Dementia Research Centre, UCL Queen Square Institute of Neurology, London, UK.
⁵ Laboratory of Acute Brain Injury and Neuroprotection, Department of Acute Brain and Cardiovascular Injury, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
⁶ Dipartimento di Anestesia e Rianimazione, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
⁷ Neuroscience Critical Care Research Group, Department of Intensive Care Medicine, CHUV Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
⁸ Department of Clinical Neurosciences, CHUV Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
⁹ Department of Medical Radiology, CHUV Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
¹⁰ Laboratory of Clinical Epidemiology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Ranica, Italy.
¹¹ Terapia Intensiva ad indirizzo Neurologico & Neurochirurgico, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy.
¹² Department of Experimental and Clinical Sciences, Careggi University Hospital and University of Firenze, Florence, Italy.
¹³ Clinical Department of Anaesthesiology and Intensive Therapy, University Medical Center, Ljubljana, Slovenia.
¹⁴ Department of Anesthesia and Intensive Care, Santa Chiara Hospital, Trento, Italy.
¹⁵ Directorate for Innovation and Clinical Research, CHUV Lausanne University Hospital, Lausanne, Switzerland.
¹⁶ Dementia Research Centre and Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
¹⁷ Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
¹⁸ Brain Sciences, Imperial College London, London, UK david.sharp@imperial.ac.uk.

PMID: 37833041
PMCID: PMC10958285
DOI: 10.1136/jnnp-2023-331854

Abstract

Background: Traumatic brain injury (TBI) is associated with the tauopathies Alzheimer's disease and chronic traumatic encephalopathy. Advanced immunoassays show significant elevations in plasma total tau (t-tau) early post-TBI, but concentrations subsequently normalise rapidly. Tau phosphorylated at serine-181 (p-tau181) is a well-validated Alzheimer's disease marker that could potentially seed progressive neurodegeneration. We tested whether post-traumatic p-tau181 concentrations are elevated and relate to progressive brain atrophy.

Methods: Plasma p-tau181 and other post-traumatic biomarkers, including total-tau (t-tau), neurofilament light (NfL), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP), were assessed after moderate-to-severe TBI in the BIO-AX-TBI cohort (first sample mean 2.7 days, second sample within 10 days, then 6 weeks, 6 months and 12 months, n=42). Brain atrophy rates were assessed in aligned serial MRI (n=40). Concentrations were compared patients with and without Alzheimer's disease, with healthy controls.

Results: Plasma p-tau181 concentrations were significantly raised in patients with Alzheimer's disease but not after TBI, where concentrations were non-elevated, and remained stable over one year. P-tau181 after TBI was not predictive of brain atrophy rates in either grey or white matter. In contrast, substantial trauma-associated elevations in t-tau, NfL, GFAP and UCH-L1 were seen, with concentrations of NfL and t-tau predictive of brain atrophy rates.

Conclusions: Plasma p-tau181 is not significantly elevated during the first year after moderate-to-severe TBI and levels do not relate to neuroimaging measures of neurodegeneration.

Keywords: DEMENTIA; TRAUMATIC BRAIN INJURY.

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Conflict of interest statement

Competing interests: HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). MO received research support and speaker fees from Neuroptics, USA, unrelated to the present work, and is member of the Scientific Advisory Board of Neuroptics. DS serves on the concussion advisory board of the UK Rugby Football Union, and undertakes clinical private practice including medicolegal assessments.

Figures

**Figure 1**
Longitudinal fluid biomarker trajectories after moderate-to-severe TBI, healthy volunteers and Alzheimer’s disease. Fluid biomarkers in healthy volunteers, longitudinally in patients following TBI, people with AD and non-AD healthy controls (non-AD controls). Boxplots show median and quartiles (hinges), with whiskers extending upto 1.5 times the IQR. Individual data points are shown and connected by lines indicating within-subject trajectories. (A) shows p-tau₁₈₁; (B) shows total τ (t-tau), neurofilament light (NfL), ubiquitin c-terminal hydrolase L1 (UCH-L1) and glial fibrillar acidic protein (GFAP). AD, Alzheimer’s disease; TBI, traumatic brain injury.

See this image and copyright information in PMC

References

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Alzheimer's disease marker phospho-tau181 is not elevated in the first year after moderate-to-severe TBI

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Alzheimer's disease marker phospho-tau181 is not elevated in the first year after moderate-to-severe TBI

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Conflict of interest statement

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