Abstract
Traumatic brain injury (TBI) is a leading cause of long-term disability across the world. Evidence for the usefulness of imaging and fluid biomarkers to predict outcomes and screen for the need to monitor complications in the acute stage is steadily increasing. Still, many people experience symptoms such as fatigue and cognitive and motor dysfunction in the chronic phase of TBI, where objective assessments for brain injury are lacking. Consensus criteria for traumatic encephalopathy syndrome, a clinical syndrome possibly associated with the neurodegenerative disease chronic traumatic encephalopathy, which is commonly associated with sports concussion, have been defined only recently. However, these criteria do not fit all individuals living with chronic consequences of TBI. The pathophysiology of chronic TBI shares many similarities with other neurodegenerative and neuroinflammatory conditions, such as Alzheimer disease. As with Alzheimer disease, advancements in fluid biomarkers represent one of the most promising paths for unravelling the chain of pathophysiological events to enable discrimination between these conditions and, with time, provide prediction modelling and therapeutic end points. This Review summarizes fluid biomarker findings in the chronic phase of TBI (≥6 months after injury) that demonstrate the involvement of inflammation, glial biology and neurodegeneration in the long-term complications of TBI. We explore how the biomarkers associate with outcome and imaging findings and aim to establish mechanistic differences in biomarker patterns between types of chronic TBI and other neurodegenerative conditions. Finally, current limitations and areas of priority for future fluid biomarker research are highlighted.
Key points
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Many people live with chronic symptoms following traumatic brain injury (TBI), with an increased risk of developing neurodegenerative conditions.
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The current definitions of chronic TBI do not cover all aspects of the disease, and biomarkers of neurodegeneration and neuroinflammation have not been included in the diagnostic criteria.
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Neurofilament light and glial fibrillary acidic protein remain elevated in blood years after brain injury, and elevated tau protein is seen in people with chronic TBI who are developing neurodegenerative conditions.
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Autoantibodies towards brain-enriched proteins are elevated in blood in both the acute and chronic phases of TBI and are associated with levels of neurodegenerative proteins.
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Considering the heterogeneity of the existing literature, improved grading of chronic TBI symptomatology and better biomarker sampling strategies are warranted to advance current criteria and guidelines.
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References
Maas, A. I. R. et al. Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research. Lancet Neurol. 16, 987–1048 (2017).
Dewan, M. C. et al. Estimating the global incidence of traumatic brain injury. J. Neurosurg. 130, 1080–1097 (2018).
Brazinova, A. et al. Epidemiology of traumatic brain injury in Europe: a living systematic review. J. Neurotrauma 38, 1411–1440 (2021).
Rubiano, A. M., Carney, N., Chesnut, R. & Puyana, J. C. Global neurotrauma research challenges and opportunities. Nature 527, S193–S197 (2015).
Li, Y. et al. Head injury as a risk factor for dementia and Alzheimer’s disease: a systematic review and meta-analysis of 32 observational studies. PLoS ONE 12, e0169650 (2017).
Balabandian, M., Noori, M., Lak, B., Karimizadeh, Z. & Nabizadeh, F. Traumatic brain injury and risk of Parkinson’s disease: a meta-analysis. Acta Neurol. Belg. 123, 1225–1239 (2023).
Watanabe, Y. & Watanabe, T. Meta-analytic evaluation of the association between head injury and risk of amyotrophic lateral sclerosis. Eur. J. Epidemiol. 32, 867–879 (2017).
Lunny, C. A., Fraser, S. N. & Knopp-Sihota, J. A. Physical trauma and risk of multiple sclerosis: a systematic review and meta-analysis of observational studies. J. Neurol. Sci. 336, 13–23 (2014).
Wang, K. K. et al. An update on diagnostic and prognostic biomarkers for traumatic brain injury. Expert Rev. Mol. Diagn. 18, 165–180 (2018).
Edalatfar, M. et al. Biofluid biomarkers in traumatic brain injury: a systematic scoping review. Neurocrit. Care 35, 559–572 (2021).
Tabor, J. B. et al. Role of biomarkers and emerging technologies in defining and assessing neurobiological recovery after sport-related concussion: a systematic review. Br. J. Sports Med. 57, 789–797 (2023).
Hossain, I., Marklund, N., Czeiter, E., Hutchinson, P. & Buki, A. Blood biomarkers for traumatic brain injury: a narrative review of current evidence. Brain Spine 4, 102735 (2024).
Pierre, K. et al. Chronic traumatic encephalopathy: diagnostic updates and advances. AIMS Neurosci. 9, 519–535 (2022).
McKee, A. C. et al. The spectrum of disease in chronic traumatic encephalopathy. Brain 136, 43–64 (2013).
McKee, A. C. et al. Chronic traumatic encephalopathy (CTE): criteria for neuropathological diagnosis and relationship to repetitive head impacts. Acta Neuropathol. 145, 371–394 (2023).
Katz, D. I. et al. National Institute of Neurological Disorders and Stroke Consensus Diagnostic Criteria for traumatic encephalopathy syndrome. Neurology 96, 848–863 (2021).
Cullum, C. M. & LoBue, C. Defining traumatic encephalopathy syndrome — advances and challenges. Nat. Rev. Neurol. 17, 331–332 (2021).
Iverson, G. L., Keene, C. D., Perry, G. & Castellani, R. J. The need to separate chronic traumatic encephalopathy neuropathology from clinical features. J. Alzheimers Dis. 61, 17–28 (2018).
Stern, R. A. et al. Tau positron-emission tomography in former national football league players. N. Engl. J. Med. 380, 1716–1725 (2019).
Bieniek, K. F. et al. Chronic traumatic encephalopathy pathology in a neurodegenerative disorders brain bank. Acta Neuropathol. 130, 877–889 (2015).
Shively, S., Scher, A. I., Perl, D. P. & Diaz-Arrastia, R. Dementia resulting from traumatic brain injury: what is the pathology? Arch. Neurol. 69, 1245–1251 (2012).
McKee, A. C. et al. Neuropathologic and clinical findings in young contact sport athletes exposed to repetitive head impacts. JAMA Neurol. 80, 1037–1050 (2023).
Fesharaki-Zadeh, A. Chronic traumatic encephalopathy: a brief overview. Front. Neurol. 10, 713 (2019).
Jankovic, T. & Pilipovic, K. Single versus repetitive traumatic brain injury: current knowledge on the chronic outcomes, neuropathology and the role of TDP-43 proteinopathy. Exp. Neurobiol. 32, 195–215 (2023).
Postolache, T. T. et al. Inflammation in traumatic brain injury. J. Alzheimers Dis. 74, 1–28 (2020).
Randolph, C. Chronic traumatic encephalopathy is not a real disease. Arch. Clin. Neuropsychol. 33, 644–648 (2018).
Iverson, G. L. & Gardner, A. J. Symptoms of traumatic encephalopathy syndrome are common in the US general population. Brain Commun. 3, fcab001 (2021).
Iverson, G. L. Retired national football league players are not at greater risk for suicide. Arch. Clin. Neuropsychol. 35, 332–341 (2020).
Graham, N. S. & Sharp, D. J. Understanding neurodegeneration after traumatic brain injury: from mechanisms to clinical trials in dementia. J. Neurol. Neurosurg. Psychiatry 90, 1221–1233 (2019).
Gilbert, M. et al. The association of traumatic brain injury with rate of progression of cognitive and functional impairment in a population-based cohort of Alzheimer’s disease: the Cache County Dementia Progression Study. Int. Psychogeriatr. 26, 1593–1601 (2014).
Fann, J. R. et al. Long-term risk of dementia among people with traumatic brain injury in Denmark: a population-based observational cohort study. Lancet Psychiatry 5, 424–431 (2018).
Mackay, D. F. et al. Neurodegenerative disease mortality among former professional soccer players. N. Engl. J. Med. 381, 1801–1808 (2019).
Russell, E. R. et al. Neurodegenerative disease risk among former international rugby union players. J. Neurol. Neurosurg. Psychiatry 93, 1262–1268 (2022).
Johnson, V. E., Stewart, W., Trojanowski, J. Q. & Smith, D. H. Acute and chronically increased immunoreactivity to phosphorylation-independent but not pathological TDP-43 after a single traumatic brain injury in humans. Acta Neuropathol. 122, 715–726 (2011).
Hay, J. R., Johnson, V. E., Young, A. M., Smith, D. H. & Stewart, W. Blood–brain barrier disruption is an early event that may persist for many years after traumatic brain injury in humans. J. Neuropathol. Exp. Neurol. 74, 1147–1157 (2015).
Johnson, V. E., Stewart, W. & Smith, D. H. Traumatic brain injury and amyloid-beta pathology: a link to Alzheimer’s disease? Nat. Rev. Neurosci. 11, 361–370 (2010).
Chen, X. H., Johnson, V. E., Uryu, K., Trojanowski, J. Q. & Smith, D. H. A lack of amyloid beta plaques despite persistent accumulation of amyloid beta in axons of long-term survivors of traumatic brain injury. Brain Pathol. 19, 214–223 (2009).
Bazarian, J. J. et al. Serum GFAP and UCH-L1 for prediction of absence of intracranial injuries on head CT (ALERT-TBI): a multicentre observational study. Lancet Neurol. 17, 782–789 (2018).
Lindblad, C. et al. Fluid proteomics of CSF and serum reveal important neuroinflammatory proteins in blood–brain barrier disruption and outcome prediction following severe traumatic brain injury: a prospective, observational study. Crit. Care 25, 103 (2021).
Zetterberg, H., Smith, D. H. & Blennow, K. Biomarkers of mild traumatic brain injury in cerebrospinal fluid and blood. Nat. Rev. Neurol. 9, 201–210 (2013).
Khalil, M. et al. Neurofilaments as biomarkers in neurological disorders — towards clinical application. Nat. Rev. Neurol. 20, 269–287 (2024).
Cooper, J. G. et al. Age specific reference intervals for plasma biomarkers of neurodegeneration and neurotrauma in a Canadian population. Clin. Biochem. 121–122, 110680 (2023).
Wang, K. K. W. et al. Parallel cerebrospinal fluid and serum temporal profile assessment of axonal injury biomarkers neurofilament-light chain and phosphorylated neurofilament-heavy chain: associations with patient outcome in moderate-severe traumatic brain injury. J. Neurotrauma 41, 1609–1627 (2024).
Graham, N. S. N. et al. Axonal marker neurofilament light predicts long-term outcomes and progressive neurodegeneration after traumatic brain injury. Sci. Transl. Med. 13, eabg9922 (2021).
Needham, E. J. et al. Complex autoantibody responses occur following moderate to severe traumatic brain injury. J. Immunol. 207, 90–100 (2021).
Newcombe, V. F. J. et al. Post-acute blood biomarkers and disease progression in traumatic brain injury. Brain 145, 2064–2076 (2022).
Taghdiri, F. et al. Neurofilament-light in former athletes: a potential biomarker of neurodegeneration and progression. Eur. J. Neurol. 27, 1170–1177 (2020).
Shahim, P. et al. Neurochemical aftermath of repetitive mild traumatic brain injury. JAMA Neurol. 73, 1308–1315 (2016).
Preische, O. et al. Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer’s disease. Nat. Med. 25, 277–283 (2019).
Guedes, V. A. et al. Exosomal neurofilament light: a prognostic biomarker for remote symptoms after mild traumatic brain injury? Neurology 94, e2412–e2423 (2020).
Guedes, V. A. et al. Extracellular vesicle proteins and microRNAs are linked to chronic post-traumatic stress disorder symptoms in service members and veterans with mild traumatic brain injury. Front. Pharmacol. 12, 745348 (2021).
Flynn, S. et al. Extracellular vesicle concentrations of glial fibrillary acidic protein and neurofilament light measured 1 year after traumatic brain injury. Sci. Rep. 11, 3896 (2021).
Schraen-Maschke, S. et al. Tau as a biomarker of neurodegenerative diseases. Biomark. Med. 2, 363–384 (2008).
Alonso, A. D., Grundke-Iqbal, I., Barra, H. S. & Iqbal, K. Abnormal phosphorylation of tau and the mechanism of Alzheimer neurofibrillary degeneration: sequestration of microtubule-associated proteins 1 and 2 and the disassembly of microtubules by the abnormal tau. Proc. Natl Acad. Sci. USA 94, 298–303 (1997).
Mielke, M. M. et al. Plasma phospho-tau181 increases with Alzheimer’s disease clinical severity and is associated with tau- and amyloid-positron emission tomography. Alzheimers Dement. 14, 989–997 (2018).
Palmqvist, S. et al. Discriminative accuracy of plasma phospho-tau217 for Alzheimer disease vs other neurodegenerative disorders. JAMA 324, 772–781, (2020).
Ashton, N. J. et al. Plasma p-tau231: a new biomarker for incipient Alzheimer’s disease pathology. Acta Neuropathol. 141, 709–724 (2021).
Blennow, K. et al. Tau protein in cerebrospinal fluid: a biochemical marker for axonal degeneration in Alzheimer disease? Mol. Chem. Neuropathol. 26, 231–245 (1995).
Coban, H., Nadella, P., Tu, D., Shinohara, R. & Berger, J. R. Total tau level in cerebrospinal fluid as a predictor of survival in Creutzfeldt–Jakob disease: a retrospective analysis. Neurol. Clin. Pract. 13, e200161 (2023).
McKee, A. C., Stein, T. D., Kiernan, P. T. & Alvarez, V. E. The neuropathology of chronic traumatic encephalopathy. Brain Pathol. 25, 350–364 (2015).
Turk, K. W. et al. A comparison between tau and amyloid-beta cerebrospinal fluid biomarkers in chronic traumatic encephalopathy and Alzheimer disease. Alzheimers Res. Ther. 14, 28 (2022).
Asken, B. M. et al. Plasma P-tau181 and P-tau217 in patients with traumatic encephalopathy syndrome with and without evidence of Alzheimer disease pathology. Neurology 99, e594–e604 (2022).
Vasilevskaya, A. et al. Investigating the use of plasma pTau181 in retired contact sports athletes. J. Neurol. 269, 5582–5595 (2022).
Goetzl, E. J., Peltz, C. B., Mustapic, M., Kapogiannis, D. & Yaffe, K. Neuron-derived plasma exosome proteins after remote traumatic brain injury. J. Neurotrauma 37, 382–388 (2020).
Pattinson, C. L. et al. Elevated tau in military personnel relates to chronic symptoms following traumatic brain injury. J. Head Trauma Rehabil. 35, 66–73 (2020).
Fischer, I. & Baas, P. W. Resurrecting the mysteries of big tau. Trends Neurosci. 43, 493–504 (2020).
Laverse, E. et al. Plasma glial fibrillary acidic protein and neurofilament light chain, but not tau, are biomarkers of sports-related mild traumatic brain injury. Brain Commun. 2, fcaa137 (2020).
Gonzalez-Ortiz, F. et al. Association of serum brain-derived tau with clinical outcome and longitudinal change in patients with severe traumatic brain injury. JAMA Netw. Open 6, e2321554 (2023).
Stern, R. A. et al. Preliminary study of plasma exosomal tau as a potential biomarker for chronic traumatic encephalopathy. J. Alzheimers Dis. 51, 1099–1109 (2016).
Peltz, C. B. et al. Blood biomarkers of traumatic brain injury and cognitive impairment in older veterans. Neurology 95, e1126–e1133 (2020).
Ramos-Cejudo, J. et al. Traumatic brain injury and Alzheimer’s disease: the cerebrovascular link. eBioMedicine 28, 21–30 (2018).
Rostowsky, K. A., Irimia, A. & Alzheimer’s Disease Neuroimaging Initiative. Acute cognitive impairment after traumatic brain injury predicts the occurrence of brain atrophy patterns similar to those observed in Alzheimer’s disease. Geroscience 43, 2015–2039 (2021).
Blennow, K. A review of fluid biomarkers for Alzheimer’s disease: moving from CSF to blood. Neurol. Ther. 6, 15–24 (2017).
Xu, C., Zhao, L. & Dong, C. A review of application of Aβ42/40 ratio in diagnosis and prognosis of Alzheimer’s disease. J. Alzheimers Dis. 90, 495–512 (2022).
Eng, L. F., Ghirnikar, R. S. & Lee, Y. L. Glial fibrillary acidic protein: GFAP-thirty-one years (1969–2000). Neurochem. Res. 25, 1439–1451 (2000).
Liedtke, W. et al. GFAP is necessary for the integrity of CNS white matter architecture and long-term maintenance of myelination. Neuron 17, 607–615 (1996).
Munoz-Ballester, C. & Robel, S. Astrocyte-mediated mechanisms contribute to traumatic brain injury pathology. WIREs Mech. Dis. 15, e1622 (2023).
Benedet, A. L. et al. Differences between plasma and cerebrospinal fluid glial fibrillary acidic protein levels across the Alzheimer disease continuum. JAMA Neurol. 78, 1471–1483 (2021).
Meier, S. et al. Serum glial fibrillary acidic protein compared with neurofilament light chain as a biomarker for disease progression in multiple sclerosis. JAMA Neurol. 80, 287–297 (2023).
Lippa, S. M., Gill, J., Brickell, T. A., French, L. M. & Lange, R. T. Blood biomarkers relate to cognitive performance years after traumatic brain injury in service members and veterans. J. Int. Neuropsychol. Soc. 27, 508–514 (2021).
Lange, R. T., Lippa, S., Brickell, T. A., Gill, J. & French, L. M. 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. J. Neurotrauma 40, 482–492 (2023).
Pierce, M. E. et al. Plasma biomarkers associated with deployment trauma and its consequences in post-9/11 era veterans: initial findings from the TRACTS longitudinal cohort. Transl. Psychiatry 12, 80 (2022).
Sandroni, C. et al. Prediction of good neurological outcome in comatose survivors of cardiac arrest: a systematic review. Intensive Care Med. 48, 389–413 (2022).
Bagnato, S. et al. Reduced neuron-specific enolase levels in chronic severe traumatic brain injury. J. Neurotrauma 37, 423–427 (2020).
Powell, J. R. et al. Neuroinflammatory biomarkers associated with mild traumatic brain injury history in special operations forces combat soldiers. J. Head Trauma Rehabil. 35, 300–307 (2020).
Svingos, A. M. et al. Predicting clinical outcomes 7–10 years after severe traumatic brain injury: exploring the prognostic utility of the IMPACT lab model and cerebrospinal fluid UCH-L1 and MAP-2. Neurocrit. Care 37, 172–183 (2022).
Thelin, E. et al. A serum protein biomarker panel improves outcome prediction in human traumatic brain injury. J. Neurotrauma 36, 2850–2862 (2019).
Shahim, P. et al. Time course and diagnostic utility of NfL, tau, GFAP, and UCH-L1 in subacute and chronic TBI. Neurology 95, e623–e636 (2020).
Hinson, H. E., Rowell, S. & Schreiber, M. Clinical evidence of inflammation driving secondary brain injury: a systematic review. J. Trauma Acute Care Surg. 78, 184–191 (2015).
Shi, K., Zhang, J., Dong, J. F. & Shi, F. D. Dissemination of brain inflammation in traumatic brain injury. Cell. Mol. Immunol. 16, 523–530 (2019).
Ramlackhansingh, A. F. et al. Inflammation after trauma: microglial activation and traumatic brain injury. Ann. Neurol. 70, 374–383 (2011).
Johnson, V. E. et al. Inflammation and white matter degeneration persist for years after a single traumatic brain injury. Brain 136, 28–42 (2013).
Loane, D. J. & Byrnes, K. R. Role of microglia in neurotrauma. Neurotherapeutics 7, 366–377 (2010).
Yong, V. W. Microglia in multiple sclerosis: protectors turn destroyers. Neuron 110, 3534–3548 (2022).
Alam, A. et al. Cellular infiltration in traumatic brain injury. J. Neuroinflamm. 17, 328 (2020).
Cash, A. & Theus, M. H. Mechanisms of blood–brain barrier dysfunction in traumatic brain injury. Int. J. Mol. Sci. https://doi.org/10.3390/ijms21093344 (2020).
Jassam, Y. N., Izzy, S., Whalen, M., McGavern, D. B. & El Khoury, J. Neuroimmunology of traumatic brain injury: time for a paradigm shift. Neuron 95, 1246–1265 (2017).
Edwards, P. et al. Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury-outcomes at 6 months. Lancet 365, 1957–1959 (2005).
McConeghy, K. W., Hatton, J., Hughes, L. & Cook, A. M. A review of neuroprotection pharmacology and therapies in patients with acute traumatic brain injury. CNS Drugs 26, 613–636 (2012).
Wright, D. W. et al. Very early administration of progesterone for acute traumatic brain injury. N. Engl. J. Med. 371, 2457–2466 (2014).
Masel, B. E. & DeWitt, D. S. Traumatic brain injury: a disease process, not an event. J. Neurotrauma 27, 1529–1540 (2010).
Faden, A. I. & Loane, D. J. Chronic neurodegeneration after traumatic brain injury: Alzheimer disease, chronic traumatic encephalopathy, or persistent neuroinflammation? Neurotherapeutics 12, 143–150 (2015).
Scott, G. et al. Minocycline reduces chronic microglial activation after brain trauma but increases neurodegeneration. Brain 141, 459–471 (2018).
Hernandez-Ontiveros, D. G. et al. Microglia activation as a biomarker for traumatic brain injury. Front. Neurol. 4, 30 (2013).
Zeiler, F. A. et al. Cerebrospinal fluid and microdialysis cytokines in severe traumatic brain injury: a scoping systematic review. Front. Neurol. 8, 331 (2017).
Li, G. et al. Neurological symptoms and their associations with inflammatory biomarkers in the chronic phase following traumatic brain injuries. Front. Psychiatry 13, 895852 (2022).
Chaban, V. et al. Systemic inflammation persists the first year after mild traumatic brain injury: results from the prospective Trondheim mild traumatic brain injury study. J. Neurotrauma 37, 2120–2130 (2020).
Elkon, K. & Casali, P. Nature and functions of autoantibodies. Nat. Clin. Pract. Rheumatol. 4, 491–498 (2008).
Wu, J. & Li, L. Autoantibodies in Alzheimer’s disease: potential biomarkers, pathogenic roles, and therapeutic implications. J. Biomed. Res. 30, 361–372 (2016).
Kocurova, G., Ricny, J. & Ovsepian, S. V. Autoantibodies targeting neuronal proteins as biomarkers for neurodegenerative diseases. Theranostics 12, 3045–3056 (2022).
Raad, M. et al. Autoantibodies in traumatic brain injury and central nervous system trauma. Neuroscience 281, 16–23 (2014).
Wang, K. K. et al. Plasma anti-glial fibrillary acidic protein autoantibody levels during the acute and chronic phases of traumatic brain injury: a transforming research and clinical knowledge in traumatic brain injury pilot study. J. Neurotrauma 33, 1270–1277 (2016).
Marchi, N. et al. Consequences of repeated blood–brain barrier disruption in football players. PLoS ONE 8, e56805 (2013).
Thelin, E. P., Nelson, D. W. & Bellander, B. M. A review of the clinical utility of serum S100B protein levels in the assessment of traumatic brain injury. Acta Neurochir. 159, 209–225 (2017).
Lindblad, C. et al. Influence of blood–brain barrier integrity on brain protein biomarker clearance in severe traumatic brain injury: a longitudinal prospective study. J. Neurotrauma 37, 1381–1391 (2020).
Thelin, E. P. et al. Serial sampling of serum protein biomarkers for monitoring human traumatic brain injury dynamics: a systematic review. Front. Neurol. 8, 300 (2017).
Castell, J. V. et al. Plasma clearance, organ distribution and target cells of interleukin-6/hepatocyte-stimulating factor in the rat. Eur. J. Biochem. 177, 357–361 (1988).
Werner, C. & Engelhard, K. Pathophysiology of traumatic brain injury. Br. J. Anaesth. 99, 4–9 (2007).
Eide, P. K. et al. Plasma neurodegeneration biomarker concentrations associate with glymphatic and meningeal lymphatic measures in neurological disorders. Nat. Commun. 14, 2084 (2023).
Plog, B. A. et al. Biomarkers of traumatic injury are transported from brain to blood via the glymphatic system. J. Neurosci. 35, 518–526 (2015).
Baiardi, S. et al. Diagnostic value of plasma p-tau181, NfL, and GFAP in a clinical setting cohort of prevalent neurodegenerative dementias. Alzheimers Res. Ther. 14, 153 (2022).
Park, Y., Kc, N., Paneque, A. & Cole, P. D. Tau, glial fibrillary acidic protein, and neurofilament light chain as brain protein biomarkers in cerebrospinal fluid and blood for diagnosis of neurobiological diseases. Int. J. Mol. Sci. https://doi.org/10.3390/ijms25126295 (2024).
Varlow, C., Knight, A. C., McQuade, P. & Vasdev, N. Characterization of neuroinflammatory positron emission tomography biomarkers in chronic traumatic encephalopathy. Brain Commun. 4, fcac019 (2022).
Coughlin, J. M. et al. Neuroinflammation and brain atrophy in former NFL players: an in vivo multimodal imaging pilot study. Neurobiol. Dis. 74, 58–65 (2015).
Simon, D. W. et al. The far-reaching scope of neuroinflammation after traumatic brain injury. Nat. Rev. Neurol. 13, 171–191 (2017).
Heppner, F. L., Ransohoff, R. M. & Becher, B. Immune attack: the role of inflammation in Alzheimer disease. Nat. Rev. Neurosci. 16, 358–372 (2015).
Wang, Q., Liu, Y. & Zhou, J. Neuroinflammation in Parkinson’s disease and its potential as therapeutic target. Transl. Neurodegener. 4, 19 (2015).
Kals, M. et al. A genome-wide association study of outcome from traumatic brain injury. eBioMedicine 77, 103933 (2022).
McFadyen, C. A. et al. Apolipoprotein E4 polymorphism and outcomes from traumatic brain injury: a living systematic review and meta-analysis. J. Neurotrauma 38, 1124–1136 (2021).
Toledo, J. B. et al. APOE effect on amyloid-β PET spatial distribution, deposition rate, and cut-points. J. Alzheimers Dis. 69, 783–793 (2019).
Stevenson-Hoare, J. et al. Plasma biomarkers and genetics in the diagnosis and prediction of Alzheimer’s disease. Brain 146, 690–699 (2023).
Ghai, V. et al. Alterations in plasma microRNA and protein levels in war veterans with chronic mild traumatic brain injury. J. Neurotrauma 37, 1418–1430 (2020).
van Amerongen, S. et al. Rationale and design of the ‘NEurodegeneration: Traumatic brain injury as Origin of the Neuropathology (NEwTON)’ study: a prospective cohort study of individuals at risk for chronic traumatic encephalopathy. Alzheimers Res. Ther. 14, 119 (2022).
Alosco, M. L. et al. Developing methods to detect and diagnose chronic traumatic encephalopathy during life: rationale, design, and methodology for the DIAGNOSE CTE Research Project. Alzheimers Res. Ther. 13, 136 (2021).
Brett, B. L. et al. Long-term multidomain patterns of change after traumatic brain injury: a TRACK-TBI LONG study. Neurology 101, e740–e753 (2023).
Zimmerman, K. A. et al. Prospective cohort study of long-term neurological outcomes in retired elite athletes: the advanced biomarker, advanced imaging and neurocognitive (BRAIN) health study protocol. BMJ Open 14, e082902 (2024).
Graham, N. S. N. et al. Multicentre longitudinal study of fluid and neuroimaging BIOmarkers of AXonal injury after traumatic brain injury: the BIO-AX-TBI study protocol. BMJ Open 10, e042093 (2020).
Koerbel, K. et al. Evaluating the utility of serum NfL, GFAP, UCHL1 and tTAU as estimates of CSF levels and diagnostic instrument in neuroinflammation and multiple sclerosis. Mult. Scler. Relat. Disord. 87, 105644 (2024).
The US Food and Drug Administration. FDA Authorizes Marketing of First Blood Test to Aid in the Evaluation of Concussion in Adults https://www.fda.gov/news-events/press-announcements/fda-authorizes-marketing-first-blood-test-aid-evaluation-concussion-adults (2018).
Benatar, M. et al. Validation of serum neurofilaments as prognostic and potential pharmacodynamic biomarkers for ALS. Neurology 95, e59–e69 (2020).
Santing, J. A. L. et al. Increasing incidence of ED-visits and admissions due to traumatic brain injury among elderly patients in the Netherlands, 2011–2020. Injury 54, 110902 (2023).
Kiwanuka, O. et al. Long-term health-related quality of life after trauma with and without traumatic brain injury: a prospective cohort study. Sci. Rep. 13, 2986 (2023).
Newcombe, V. F. et al. Dynamic changes in white matter abnormalities correlate with late improvement and deterioration following TBI: a diffusion tensor imaging study. Neurorehabil. Neural Repair. 30, 49–62 (2016).
Gonzalez, A. C. et al. Diffusion tensor imaging correlates of concussion related cognitive impairment. Front. Neurol. 12, 639179 (2021).
van Vliet, E. A. et al. Long-lasting blood–brain barrier dysfunction and neuroinflammation after traumatic brain injury. Neurobiol. Dis. 145, 105080 (2020).
Devoto, C. et al. Exosomal microRNAs in military personnel with mild traumatic brain injury: preliminary results from the chronic effects of neurotrauma consortium biomarker discovery project. J. Neurotrauma 37, 2482–2492 (2020).
Rubenstein, R. et al. Comparing plasma phospho tau, total tau, and phospho tau–total tau ratio as acute and chronic traumatic brain injury biomarkers. JAMA Neurol. 74, 1063–1072 (2017).
Schnakers, C. et al. Longitudinal changes in blood-based biomarkers in chronic moderate to severe traumatic brain injury: preliminary findings. Brain Inj. 35, 285–291 (2021).
Shahim, P. et al. Neurofilament light as a biomarker in traumatic brain injury. Neurology 95, e610–e622 (2020).
Shahim, P. et al. Serum NfL and GFAP as biomarkers of progressive neurodegeneration in TBI. Alzheimers Dement. 20, 4663–4676 (2024).
Acknowledgements
C.L. is supported through Uppsala Region ALF together with Uppsala University and Uppsala University Hospital through the Research Residency Program in Neurosurgery and has received travelling grants from the Swedish Society of Medicine and Karolinska Institute. F.A.Z. is supported through the Natural Sciences and Engineering Research Council of Canada (NSERC) (DGECR-2022-00260, RGPIN-2022-03621, ALLRP-576386-22, ALLRP-576386-22, I2IPJ 586104-23 and ALLRP 586244-23), the University of Manitoba Endowed Manitoba Public Insurance (MPI) Chair in Neuroscience, the Canadian Institutes of Health Research (CIHR) (472286 and 432061), the Health Sciences Centre Foundation Winnipeg, the Pan Am Clinic Foundation, the Canada Foundation for Innovation (CFI) (38583), Research Manitoba (3906 and 5529) and the University of Manitoba VPRI Research Investment Fund (RIF). H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (2018-02532), the European Union’s Horizon Europe research and innovation programme (101053962), Swedish State Support for Clinical Research (ALFGBG-71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (201809-2016862), the AD Strategic Fund and the Alzheimer’s Association (ADSF-21-831376-C, ADSF-21-831381-C and ADSF-21-831377-C), the Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (FO2022-0270), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement (860197, MIRIADE), the European Union Joint Programme — Neurodegenerative Disease Research (JPND2021-00694), and the UK Dementia Research Institute at UCL (UKDRI-1003). T.G. is a recipient of the Grant for Multiple Sclerosis Innovation award and supported by grants from Region Stockholm and Karolinska Institute, the Swedish Research Council, the Swedish Society for Medical Research and Alzheimersfonden. P.S. is a Wallenberg Clinical Scholar (2020-0231) and supported by grants from the Swedish Research Council (2019-01422) and Region Stockholm (520183). F.P. is supported by the Swedish Research Council (2023-00533), the Region Stockholm (FoUI-987565), the Swedish Brain Fund (FO2021-0277) and the Horizon Europe Framework Programme (101136991). E.P.T. acknowledges funding support from Karolinska Institute Research Grants (2022-01576), Region Stockholm ALF (FoUI-962566), the Swedish Society of Medicine (SLS-985504), the Swedish Brain Foundation (Hjärnfonden, FO2023-0124), Region Stockholm Clinical Research Appointment (FoUI-981490) and the Erling-Persson Family Foundation.
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S.F., E.P.T., C.L. and F.P. contributed substantially to the idea and content throughout the Review. All authors wrote the article and reviewed the manuscript before submission.
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S.F., C.L., F.A.Z., T.G. and E.P.T. have nothing to disclose. H.Z. 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 Alzecure, Biogen, Cellectricon, Fujirebio 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). P.S. is serving in a DSMB for Lundbeck and in advisory boards for AbbVie and Takeda. F.P. has received research grants from Janssen, Merck KGaA and UCB and fees for serving on the data monitoring committee in clinical trials with Chugai, Lundbeck and Roche, has prepared an expert witness statement for Novartis and is steering committee member of the BioMS consortium.
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Nature Reviews Neurology thanks David Sharp; Firas Kobeissy; Ramon Diaz-Arrastia, who co-reviewed with Cillian Lynch; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Friberg, S., Lindblad, C., Zeiler, F.A. et al. Fluid biomarkers of chronic traumatic brain injury. Nat Rev Neurol 20, 671–684 (2024). https://doi.org/10.1038/s41582-024-01024-z
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DOI: https://doi.org/10.1038/s41582-024-01024-z
