Examining Traumatic Brain Injury as a Chronic Condition Proceedings of a Workshop (2025) / Chapter Skim
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2 Exploring the Evidence for Characterizing Traumatic Brain Injury as a Chronic Condition
2 Exploring the Evidence for Characterizing Traumatic Brain Injury as a Chronic Condition
Pages 9-52
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. • Research is needed to better understand such areas as comorbidity interactions, cognitive changes over time, sex differences in TBI injury and recovery, and developmental timing of injury (Corrigan, Sander, Schneider)
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. • Moderate to severe TBI can initiate systemic inflammation that evolves from acute immunosuppression to chronic immune dysfunc tion, increasing susceptibility to infections and comorbidities.
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EPIDEMIOLOGY OF TBI AS A CHRONIC CONDITION Kristen Dams-O'Connor, professor of rehabilitation and human performance and director of the Brain Injury Research Center of Mount Sinai, introduced and moderated the first of these sessions, which discussed data on the risks of increased mortality and long-term sequelae associated with TBI and what is known about biological and sociodemographic characteristics associated with an elevated risk of chronic TBI. TBI is increasingly being recognized not merely as an acute event but as a chronic condition with wide-ranging and long-lasting implications across cognitive, emotional, and physical domains, as well as an array of associated comorbidities, Dams-O'Connor said.
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Epidemiological Evidence of Long-Term TBI Sequelae Andrea Schneider, assistant professor at the University of Pennsylvania Perelman School of Medicine, discussed the growing body of evidence that TBI is a multisystem condition associated with long-term risks including functional disability, cognitive decline, dementia, epilepsy, cardiovascular disease, frailty, and increased mortality -- highlighting the need for longitudinal research and a comprehensive, life-course approach to care and prevention. TBI Prevalence and Mortality Trends Traumatic brain injury poses a major public health challenge, with prevalence estimates in the United States ranging from 15 percent to 30 percent, Schneider began.
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. Notably, individuals with both post-traumatic epilepsy and TBI had a threefold increased risk of developing dementia compared to those without either condition, underscoring the importance of examining the joint effect of comorbidities (Schneider et al., 2024a)
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. Additionally, individuals with TBI had a 1.7-fold increased risk of injurious falls requiring hospitalization over 23 years (Hunzinger et al., 2023)
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Evidence from the TBI Model Systems National Database Angelle Sander, professor at Baylor College of Medicine, presented findings from the Traumatic Brain Injury Model Systems (TBIMS) National Database, a 35-year longitudinal study tracking individuals with moderate to severe TBI who received Level 1 trauma care and specialized rehabilitation.
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• Mood: Risk factors for depression and other chronic psychiatric symp toms after traumatic brain injury included being middle age at the time of injury, experiencing post-traumatic epilepsy, unemployment, low income, and anxiety or depression one year post-injury, while protective factors included participation in religious services and resilience or strong coping ability. • Substance Use: Risk factors included pre-injury substance misuse; un employment; younger age; male sex; and lifetime history of two or more TBIs.
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. Substance use, particularly alcohol and illicit drugs, resurfaces postinjury as individuals regain mobility and community access, with 17 percent reporting problem alcohol use and 12 percent illicit drug use at year 2 In comparison, a study using data from the 2021 National Health Interview Survey of civilian noninstitutionalized adults found that approximately 5 percent reported life dissatisfaction, with those reporting poor physical health, psychological distress, very low food security, and some other physical, social, emotional, and financial characteristics reporting greater levels of life dissatisfaction (Miller et al., 2023)
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Ultimately, recognizing TBI as a chronic condition and expanding research beyond specialized cohorts will be essential to better address the long-term needs of all individuals affected by brain injury, she added. Discussion During discussion, Dams-O'Connor, Schneider, and Sander were joined by John Corrigan from the Ohio State University.
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Self-Report and Standardization Efforts Because many individuals with TBI never receive formal medical care, self-report remains essential, the panelists said. Sander noted findings from studies in which individuals with severe TBIs, including those with craniotomy scars, were unaware they had sustained a brain injury owing in part to a lack of postacute care and education.
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Dams-O'Connor reaffirmed the need for a complementary mix of medical, self-report, and community-sourced data for a more accurate and inclusive understanding of TBI. Schneider also emphasized that low- and middle-income countries are largely absent from global TBI research.
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Dams-O'Connor warned that focusing solely on "index injuries" (e.g. the initial brain injury that takes place in a given context)
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and peripheral systems in the context of systemic inflammation, associations between TBI and changes in the host immune response, and the risk those immune response changes pose in terms of secondary complications and mortality. Loane emphasized the complex and chronic nature of TBI, underscoring that both repetitive mild TBIs and single severe TBIs can lead to neurodegenerative diseases such as Alzheimer's disease (AD)
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These findings indicate that therapeutic interventions targeting microglial-mediated inflammation in the chronic postinjury period may restore brain function and halt further degeneration, he said, thereby expanding the window for effective treatment beyond the acute phase. TBI as a Systemic Disorder TBI affects not just the brain but also the peripheral immune system, Loane said, emphasizing the complex, bidirectional communication between the brain and organs such as the lungs, liver, gut, and bone marrow.
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Findings suggest that TBI induces a long-term shift in the host immune environment -- first towards immunosuppression and later toward hyperinflammation. This evidence underscores the critical importance of understanding how systemic inflammation interacts with and exacerbates chronic brain injury, especially when patients face new health challenges months or years after their initial TBI.
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Loane emphasized that rehabilitation and pharmacologic therapies should be developed to modify underlying mechanisms of dysfunction, highlighting the importance of timing and personalized treatment during the chronic phase of recovery. Chronic TBI-Associated Pathology in the Context of Health, Chronic Conditions, and Function Wagner echoed the need to consider TBI as a systemic condition, highlighting the importance of understanding the long-term effects of TBI on multiple body systems and the value of integrating biomarkers into this effort.
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Panel Discussion Insights from Preclinical TBI Research Wagner opened the discussion by asking about the limitations of rodent models in studying chronic TBI, specifically the challenge of translating rodent life spans to human conditions. Loane acknowledged these limitations but argued that rodent models offer unique opportunities to investigate genetic and inflammatory mechanisms over time that cannot be explored in humans.
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Loane challenged the idea there is only a narrow treatment window postinjury, emphasizing that TBI can be addressed as a lifelong condition with opportunities for intervention throughout the chronic phase. Sex Differences in Biological Responses After TBI Wagner raised the issue of sex differences in TBI-related outcomes and the underrepresentation of females in preclinical brain injury research.
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The dialogue highlighted how rodent models, when used thoughtfully and with clinically relevant markers, can inform the design of therapeutic interventions that address the full arc of TBI injury, recovery, and comorbidity. EVIDENCE ON HEALTH OUTCOMES AND COMORBIDITIES The third session explored outcomes and comorbidities linked to TBI, focusing on depression, post-traumatic epilepsy, endocrine dysfunction, cardiovascular disease, and dementia.
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Advisory Council cochair, stated she experiences multiple, varied long-term TBI symptoms. Despite trajectories such as hers, many people with TBI are told that their experi ences are "all in their head," said Starr.
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. Emphasizing that this study excluded participants with a prior history of depression or TBI, Bombardier underscored that approximately 20 percent of individuals with mild TBI and 15 percent of individuals with moderate to severe TBI experienced depression compared to 5 percent of people with no history of TBI.
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The rate of current major depression at 50 years postinjury was 11.2 percent for veterans with head injury and 8.5 for those with no head injury. Bombardier emphasized that the increased risk of depression in individuals with TBI lasts a lifetime.
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Recent studies have found that epilepsy and PTE are associated with the emergence of neurological and other chronic diseases, and that prior comorbidities play a role in this association, Pugh indicated. A study found that conditions including stroke, hypertension, cardiovascular disease, and diabetes emerged after epilepsy in a veteran cohort (Pugh et al., 2025)
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Evidence indicates that caregivers of relatives with epilepsy experience relationship strain, disruptions in work and daily routine, and mental health conditions such as anxiety, depression, and PTSD, Pugh continued. Emerging data from an ongoing study of the effects of PTE found that caregivers of people with PTE report higher levels of stress, sleep interference, and poorer health than caregivers of veterans with epilepsy or TBI alone.
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. Pituitary hormone deficiencies can develop after mild or severe TBI, said Wexler (Aimaretti et al., 2005; Alavi et al., 2016; Tanriverdi and Kelestimur, 2015; Yang et al., 2015; Yuen et al., 2022)
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Care providers may fail to conduct GHD evaluation in adults who have reached their full height, she noted, despite the multiple functions that growth hormone carries out throughout the body including a role in executive function, cardiovascular risk factors, bone strength, body composition, and energy and exercise capacity. Studies indicate that GHD may contribute to quality of life and neurocognitive sequalae after TBI and that individuals with TBI who have GHD fare more poorly than those with sufficient growth hormone levels (Kelly et al., 2014; Kreber et al., 2016)
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Furthermore, care providers should offer hormone replacement therapy to individuals diagnosed with PTHP via appropriate testing, said Wexler. Long-Term Risks of Cardiovascular Diseases After TBI Saef Izzy, associate professor at Brigham and Women's Hospital and Harvard Medical School, discussed the increased risk of developing longterm cardiovascular disease in individuals with TBI.
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These findings demonstrate an association between TBI and chronic cardiovascular disease, he said. Numerous factors affect cognitive impairment and cardiovascular dysfunction after TBI, Izzy continued, noting that cardiovascular disease may also play a role in chronic neurodegenerative disease, such as dementia (Izzy et al., 2023)
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Gardner, associate professor of neurology at Tel Aviv University School of Medicine and Sheba Medical Center, Israel, outlined the increased risk for dementia among individuals with TBI, along with modifiable risk factors, associated pathology, and areas for further research. TBI is a well-established risk factor for dementia, she said.
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A nationwide cohort study based on data from nearly 300,000 veterans in the Veterans Health Administration system explored whether reducing modifiable dementia risk factors, such as hypertension, diabetes, depression, and PTSD, could help prevent post-TBI dementia (Gardner et al., 2023b)
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These individuals may struggle with executive tasks, such as time management and self-expression, and are often forced to advocate for their needs despite these impairments, she said. Izzy added that cardiovascular problems in TBI patients are often overlooked or attributed solely to brain injury, leading to undertreatment.
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Age of Injury and Comorbidity Risk In response to questions about the influence of age at time of injury on comorbidities, Pugh explained that both PTE and epilepsy are more prevalent among the very young and the elderly. Her research on veterans found that individuals reporting moderate or severe TBIs at younger ages had increased risk of epilepsy even if their injury was not service related.
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Biomarkers and TBI Diagnosis Gardner emphasized the usefulness of implementing blood biomarker tests approved by the Food and Drug Administration (e.g., glial fibrillary acidic protein and ubiquitin C-terminal hydrolase) to diagnose mild TBI, especially when computed tomography imaging is negative.
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Suggestions for Improved Care With TBI affecting millions across the life span, a shift toward precision medicine, extended monitoring, and individualized care is essential to address the broad and complex effect of this condition, the panelists highlighted. Wexler noted that cognitive limitations in TBI patients can hinder their ability to self-advocate or even recognize the need for care.
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2010. Effect of recombinant growth hormone replacement in a growth hormone deficient subject recovering from mild traumatic brain injury: A case report.
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2004. Occurrence of pituitary dysfunction following traumatic brain injury.
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2023b. Medical and psychiatric risk factors for dementia in veterans with and without traumatic brain injury (TBI)
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2010. Effect of growth hormone replacement ther apy on cognition after traumatic brain injury.
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2016. Detection of growth hormone deficiency in adults with chronic traumatic brain injury.
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2005. Cognitive impairment associated with major depression following mild and moderate traumatic brain injury.
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2015. Pituitary dysfunction following traumatic brain injury: Clinical perspectives.
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2022. A consensus on optimization of care in patients with growth hormone deficiency and mild traumatic brain injury.
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PREPUBLICATION COPY -- Uncorrected Proofs
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