Higher exosomal phosphorylated tau and total tau among veterans with combat-related repetitive chronic mild traumatic brain injury

Kenney, Kimbra; Qu, Bao-Xi; Lai, Chen; Devoto, Christina; Motamedi, Vida; Walker, William C.; Levin, Harvey S.; Nolen, Tracy; Wilde, Elisabeth A.; Diaz-Arrastia, Ramon; Gill, Jessica; the CENC Multisite Observational Study Investigators

doi:10.1080/02699052.2018.1483530

Cited by 94Traumatic Brain Injury ResearchExtracellular vesicles in diseaseTraumatic Brain Injury and Neurovascular Disturbances

Higher exosomal phosphorylated tau and total tau among veterans with combat-related repetitive chronic mild traumatic brain injury

Kenney, Kimbra, Qu, Bao-Xi, Lai, Chen, Devoto, Christina, Motamedi, Vida, Walker, William C., Levin, Harvey S., Nolen, Tracy +4 more·2018·Brain Injury

DOI 10.1080/02699052.2018.1483530

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Abstract

OBJECTIVE: The objective of the study is to measure plasma and exosomal levels of tau, phosphorylated tau (p-tau), and amyloid beta (Aβ) in Veterans with historical mild traumatic brain injury (mTBI) and chronic neuropsychological symptoms. METHODS: Tau, p-tau, Aβ40, and Aβ42 were measured by ultrasensitive immunoassay in plasma and exosomes from 195 Veterans enrolled in the Chronic Effects of Neurotrauma Consortium Multicenter Observational Study. Protein biomarkers were compared among groups with and without mTBI with loss of consciousness (LOC) or post-traumatic amnesia (PTA), and also in those with and without repetitive (≥3) mTBI (rTBI) compared to those with 0 (TBI-neg) and 1-2 mTBI. RESULTS: There were no differences in measures of plasma and exosomal protein levels among mTBI with LOC or PTA, mTBI with alteration of consciousness only or TBI-neg. Exosomal tau and exosomal p-tau were elevated in rTBI compared to those with 2 or fewer mTBIs and TBI-neg (p < 0.05). Elevations of exosomal tau and p-tau significantly correlated with post-traumatic and post-concussive symptoms, with exosomal tau also relating specifically to cognitive, affective, and somatic post-concussive symptoms (p < 0.05). CONCLUSION: rTBI is associated with elevations of exosomal p-tau and exosomal tau, suggesting that blood-based exosomes may provide a peripheral source of informative, centrally derived biomarkers in remote mTBI and that rTBI may contribute to chronic neuropsychological symptoms.

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Recent findings show elevated p-Tau within neuronally enriched EVs in TBI subjects.
“Recent findings of elevated p-Tau within neuronally enriched EVs in TBI subjects highlight the dynamic processes and time-dependent mechanisms at play in TBI [185, 187, 188].”
From Extracellular vesicles as nanotheranostic platforms for targeted neurological disorder interventions (2024) · cites this paper as [185]
Efforts to identify EV-based biomarkers for TBI have largely centered on well-characterized proteins like UCHL1, Tau, and Aβ.
“Efforts to identify EV-based biomarkers for TBI have largely centered on well-characterized proteins like UCHL1, Tau, and Aβ [184–186].”
From Extracellular vesicles as nanotheranostic platforms for targeted neurological disorder interventions (2024) · cites this paper as [185]

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Assessment of Long-Term Effects of Sports-Related Concussions: Biological Mechanisms and Exosomal Biomarkers
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Perspectives on Primary Blast Injury of the Brain: Translational Insights Into Non-inertial Low-Intensity Blast Injury
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Clinical Applications of Extracellular Vesicles in the Diagnosis and Treatment of Traumatic Brain Injury
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Blood-based traumatic brain injury biomarkers – Clinical utilities and regulatory pathways in the United States, Europe and Canada
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Neurological Effects of Repeated Blast Exposure in Special Operations Personnel
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Cell-Derived Exosomes as Therapeutic Strategies and Exosome-Derived microRNAs as Biomarkers for Traumatic Brain Injury
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Mesenchymal stem cell-derived extracellular vesicles as a cell-free therapy for traumatic brain injury via neuroprotection and neurorestoration
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Extracellular vesicles as mediators and markers of acute organ injury: current concepts
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Extracellular Vesicle Proteins and MicroRNAs Are Linked to Chronic Post-Traumatic Stress Disorder Symptoms in Service Members and Veterans With Mild Traumatic Brain Injury
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Sex Differences in Behavioral Symptoms and the Levels of Circulating GFAP, Tau, and NfL in Patients With Traumatic Brain Injury
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Extracellular vesicle concentrations of glial fibrillary acidic protein and neurofilament light measured 1 year after traumatic brain injury
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Assessment of Blood Biomarker Profile After Acute Concussion During Combative Training Among US Military Cadets
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Neurochemical Markers of Traumatic Brain Injury: Relevance to Acute Diagnostics, Disease Monitoring, and Neuropsychiatric Outcome Prediction
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Plasma Tau and Amyloid Are Not Reliably Related to Injury Characteristics, Neuropsychological Performance, or White Matter Integrity in Service Members with a History of Traumatic Brain Injury
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Long-Term Effects of SARS-CoV-2 in the Brain: Clinical Consequences and Molecular Mechanisms
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Clinical research findings from the long-term impact of military-relevant brain injury consortium-Chronic Effects of Neurotrauma Consortium (LIMBIC-CENC) 2013-2021
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Proposed mechanisms of tau: relationships to traumatic brain injury, Alzheimer’s disease, and epilepsy
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Serum Tau, Neurofilament Light Chain, Glial Fibrillary Acidic Protein, and Ubiquitin Carboxyl-Terminal Hydrolase L1 Are Associated with the Chronic Deterioration of Neurobehavioral Symptoms after Traumatic Brain Injury
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Temporal Profiles of P-Tau, T-Tau, and P-Tau:Tau Ratios in Cerebrospinal Fluid and Blood from Moderate-Severe Traumatic Brain Injury Patients and Relationship to 6–12 Month Global Outcomes
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Extracellular vesicles as nanotheranostic platforms for targeted neurological disorder interventions
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Developing Biomarkers of Mild Traumatic Brain Injury: Promise and Progress of CNS-Derived Exosomes
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Diverse changes in microglia morphology and axonal pathology during the course of 1 year after mild traumatic brain injury in pigs
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Fluid Biomarkers for Chronic Traumatic Encephalopathy
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REMOVED: Mild traumatic brain injury exacerbates Parkinson's disease induced hemeoxygenase-2 expression and brain pathology: Neuroprotective effects of co-administration of TiO2 nanowired mesenchymal stem cells and cerebrolysin
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Can mild traumatic brain injury alter cognition chronically? A LIMBIC-CENC multicenter study.
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Small Neuron-Derived Extracellular Vesicles from Individuals with Down Syndrome Propagate Tau Pathology in the Wildtype Mouse Brain
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Neuronally-derived tau is increased in experienced breachers and is associated with neurobehavioral symptoms
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Neuroimaging of traumatic brain injury in military personnel: An overview
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The Role of Inflammation and Infection in Age-Related Neurodegenerative Diseases: Lessons From Bacterial Meningitis Applied to Alzheimer Disease and Age-Related Macular Degeneration
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Early preclinical plasma protein biomarkers of brain trauma are influenced by early seizures and levetiracetam
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The Neurological Consequences of Engaging in Australian Collision Sports
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Implication of the cooking oil-peroxidation product “hydroxynonenal” for Alzheimer’s disease
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Serum amyloid A and mitochondrial DNA in extracellular vesicles are novel markers for detecting traumatic brain injury in a mouse model
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Poor Sleep Quality is Linked to Elevated Extracellular Vesicle-Associated Inflammatory Cytokines in Warfighters With Chronic Mild Traumatic Brain Injuries
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Regenerative Medicine and Traumatic Brain Injury: From Stem Cell to Cell-Free Therapeutic Strategies
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Elevations in Tumor Necrosis Factor Alpha and Interleukin 6 From Neuronal-Derived Extracellular Vesicles in Repeated Low-Level Blast Exposed Personnel
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Neurovascular Unit-Derived Extracellular Vesicles: From Their Physiopathological Roles to Their Clinical Applications in Acute Brain Injuries
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Blood-Based Biomarkers in the Diagnosis of Chronic Traumatic Encephalopathy: Research to Date and Future Directions
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Plasma phosphorylated tau181 as a biomarker of mild traumatic brain injury: findings from THINC and NCAA-DoD CARE Consortium prospective cohorts
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Chronic elevation of plasma vascular endothelial growth factor-A (VEGF-A) is associated with a history of blast exposure
Meabon, J. S., Cook, D. G., Yagi, M., Terry, G. E., Cross, D. J., Muzi, M., Pagulayan, K. F., Logsdon, A. F., Schindler, A. G., Ghai, V., et al. (2020) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2020.117049 · Cited by 17 · see citing works
Laterality and region-specific tau phosphorylation correlate with PTSD-related behavioral traits in rats exposed to repetitive low-level blast
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Elevated Axonal Protein Markers Following Repetitive Blast Exposure in Military Personnel
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Recent Advances in Blood-Based Biomarkers of Remote Combat-Related Traumatic Brain Injury
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Long Noncoding RNA VLDLR-AS1 Levels in Serum Correlate with Combat-Related Chronic Mild Traumatic Brain Injury and Depression Symptoms in US Veterans
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Molecular and Diffusion Tensor Imaging Biomarkers of Traumatic Brain Injury: Principles for Investigation and Integration
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Connecting cellular mechanisms and extracellular vesicle cargo in traumatic brain injury
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Exploring the Potential of Exosomal Biomarkers in Mild Traumatic Brain Injury and Post-Concussion Syndrome: A Systematic Review
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Biofluid, Imaging, Physiological, and Functional Biomarkers of Mild Traumatic Brain Injury and Subconcussive Head Impacts
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Extracellular Vesicle MicroRNAs as Predictive Biomarkers in Postoperative Delirium After Spine Surgery: Preliminary Study
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Fluid biomarkers and risk of neurodegenerative disease in retired athletes with multiple concussions: results from the International Concussion and Head Injury Research Foundation Brain health in Retired athletes Study of Ageing and Impact-Related Neurodegenerative Disease (ICHIRF-BRAIN study)
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Auditory evoked brain potentials as markers of chronic effects of mild traumatic brain injury in mid-life
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A Narrative Review of Existing and Developing Biomarkers in Acute Traumatic Brain Injury for Potential Military Deployed Use
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Blood Biomarkers Predict Future Cognitive Decline after Military-Related Traumatic Brain Injury
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Elevated Serum Tau and UCHL-1 Concentrations Within 12 Months of Injury Predict Neurobehavioral Functioning 2 or More Years Following Traumatic Brain Injury: A Longitudinal Study
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Efficacy of biomarkers and imaging techniques for the diagnosis of traumatic brain injury: challenges and opportunities
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Extracellular Vesicle Glial Fibrillary Acidic Protein as a Circulating Biomarker of Traumatic Brain Injury Severity
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Evaluating Targeted Therapeutic Response With Predictive Blood-Based Biomarkers in Patients With Chronic Mild Traumatic Brain Injury
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Biofluid-based predictors of post-concussion symptoms: a narrative review of mild traumatic brain injury biomarkers
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Tissue-Derived Small Extracellular Vesicles: Emerging Regulators of Inter-Organ Crosstalk in Health and Disease
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Lipidomic Analysis Reveals Systemic Alterations in Servicemen Exposed to Repeated Occupational Low-Level Blast Waves
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Biomarkers in Brain Traumatic Injury
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APOE4 and age affect the brain entorhinal cortex structure and blood arachidonic acid and docosahexaenoic acid levels after mild TBI
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From seed to flower: blossoming of microglia in development and brain repair
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Biomarkers of Acute Brain Injury
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Sensitive immunoassay testing platforms
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Author Response: Exosomal Neurofilament Light: A Prognostic Biomarker for Remote Symptoms After Mild Traumatic Brain Injury?
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Reader Response: Exosomal Neurofilament Light: A Prognostic Biomarker for Remote Symptoms After Mild Traumatic Brain Injury?
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Transcranial Doppler (TCD): Role for Patients After Concussion
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Extracellular Vesicle Biomarkers for Neurological Diseases
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Mild Traumatic Brain Injury Biomarkers: Current Status and Future Directions
Fink, E., Causey, M. W., Peitz, G. W., & Hamburger, A. (2026) · International Journal of Translational Medicine · doi:10.3390/ijtm6020016
Associations between posttraumatic stress and comorbidities of traumatic brain injury and substance use disorders with Alzheimer’s disease in older veterans: A narrative review
Reddy-Mazzitello, R. M., Alexander, J., Skawratananond, S., Sehar, U., Mukherjee, U., Brownell, M., Ballada, S., & Reddy, P. H. (2026) · Ageing Research Reviews · doi:10.1016/j.arr.2026.103188
Differentially Methylated Gene Expression in Professional Fighters with Repetitive Mild Traumatic Brain Injury Is Distinct from Alzheimer’s Disease and Associated with Brain Volume
Weber, G. E., Khrestian, M., Formica, S. V., Tuason, E. D., Rao, S., Pillai, J., Ritter, A., Bernick, C. B., Leverenz, J. B., & Bekris, L. M. (2026) · Neurotrauma Reports · doi:10.1177/2689288x261462083

Exosomal and Plasma Protein Biomarkers of Neuronal Injury and Inflammation in Chronic Mild TBI: A Chronic Effects of Neurotrauma Consortium (CENC) Biomarker Discovery Project (P2.9-046)
Kenney, K., Shahim, P.-P., Lai, C., Qu, B., Devoto, C., Walker, W. C., Diaz-Arrastia, R. R., & Gill, J. (2019) · Neurology · doi:10.1212/wnl.92.15_supplement.p2.9-046
Self-citation
Higher exosomal tau, amyloid-beta 42 and IL-10 are associated with mild TBIs and chronic symptoms in military personnel
Gill, J., Mustapić, M., Diaz-Arrastia, R. R., Lange, R. T., Gulyani, S., Diehl, T., Motamedi, V., Osier, N. D., Stern, R. A., & Kapogiannis, D. (2018) · Brain Injury · doi:10.1080/02699052.2018.1471738 · Cited by 152 · see citing works
Self-citation
Exosomal neurofilament light
Guedes, V. A., Kenney, K., Shahim, P., Qu, B., Lai, C., Devoto, C., Walker, W. C., Nolen, T. L., Diaz-Arrastia, R. R., Gill, J., et al. (2020) · Neurology · doi:10.1212/wnl.0000000000009577 · Cited by 112 · see citing works
Self-citation
Elevated exosomal total and phosphorylated tau among veterans with chronic repetitive mild tbi; a cenc study interim analysis
Kenney, K., Qu, B., Lai, C., Devoto, C., Motamedi, V., Walker, W. C., Levin, H. S., Nolen, T. L., Wilde, E. A., Diaz-Arrastia, R. R., et al. (2018) · Journal of Neurotrauma
Self-citation
Assessing Neuronal and Astrocyte Derived Exosomes From Individuals With Mild Traumatic Brain Injury for Markers of Neurodegeneration and Cytotoxic Activity
Winston, C. N., Romero, H. K., Ellisman, M., Nauss, S. N., Julovich, D. A., Conger, T., Hall, J. R., Campana, W. M., O’Bryant, S. E., Nievergelt, C. M., et al. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.01005 · Cited by 111 · see citing works

Authors: Kenney, K., Qu, B.-X., Lai, C., Devoto, C., Motamedi, V., Walker, W. C., Levin, H. S., Nolen, T., Wilde, E. A., Diaz-Arrastia, R., Gill, J., & the CENC Multisite Observational Study Investigators
Affiliations: Uniformed Services University of the Health Sciences (US)
National Institutes of Health (US)
Virginia Commonwealth University (US)
Michael E. DeBakey VA Medical Center (US)
RTI International (US)
University of Pennsylvania (US)
Corresponding author: Kenney, Kimbra
ORCID: Kenney, Kimbra
Qu, Bao-Xi
Lai, Chen
Motamedi, Vida
Walker, William C.
Levin, Harvey S.
Nolen, Tracy
Wilde, Elisabeth A.
Diaz-Arrastia, Ramon
Gill, Jessica
Venue: Brain Injury
Publisher: Informa UK Limited
Published: 2018-06-11
Volume: 32
Issue: 10
Pages: 1276-1284
ISSN: 0269-9052 (ISSN-L)
1362-301X
DOI: 10.1080/02699052.2018.1483530
OpenAlex: W2808596369
Cited by: 94
References: 58
Citations by year: 2026: 4 · 2025: 4 · 2024: 11 · 2023: 14 · 2022: 16 · 2021: 23 · 2020: 12 · 2019: 8 · 2018: 2
FWCI: 8.82
Type: journal article
Language: en
Open access: closed
Locations: Brain Injury (publishedVersion)
PubMed (publishedVersion)
Funders: U.S. Department of Defense (CENC W81XWH-13-2-0095)
U.S. Department of Veterans Affairs (CENC Award I01 CX001135)
Topics: Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
Keywords: repetitive mild traumatic brain injury, phosphorylated tau, amyloid-beta, plasma biomarkers, exosomes, combat-related brain injury, veterans, post-concussion symptoms, post-traumatic amnesia, loss of consciousness, blood-based biomarkers
MeSH terms: Adult, Brain Concussion, Cognition Disorders, Cross-Sectional Studies, Female, Humans, Male, Middle Aged, Peptide Fragments, Phosphorylation, Surveys and Questionnaires, Veterans, Amyloid beta-Peptides, tau Proteins, Mood Disorders, Brain Injury, Chronic

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Higher exosomal phosphorylated tau and total tau among veterans with combat-related repetitive chronic mild traumatic brain injury

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