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Abstract
Objectives Obesity is associated with chronic inflammation, which may impact recovery from mild traumatic brain injury (mTBI). The objective was to assess the role of obesity in recovery of symptoms, functional outcome and inflammatory blood biomarkers after mTBI.
Methods TRACK-TBI is a prospective study of patients with acute mTBI (Glasgow Coma Scale=13–15) who were enrolled ≤24 hours of injury at an emergency department of level 1 trauma centres and followed for 12 months. A total of 770 hospitalised patients who were either obese (body mass index (BMI) >30.0) or healthy mass (BMI=18.5–24.9) were enrolled. Blood concentrations of high-sensitivity C reactive protein (hsCRP), interleukin (IL) 6, IL-10, tumour necrosis factor alpha; Rivermead Post-Concussion Symptoms Questionnaire (RPQ), Quality of Life After Brain Injury and Glasgow Outcome Score-Extended reflecting injury-related functional limitations at 6 and 12 months were collected.
Results After adjusting for age and gender, obese participants had higher concentrations of hsCRP 1 day after injury (mean difference (MD)=0.65; 95% CI: 0.44 to 0.87, p<0.001), at 2 weeks (MD=0.99; 95% CI: 0.74 to 1.25, p<0.001) and at 6 months (MD=1.08; 95% CI: 0.79 to 1.37, p<0.001) compared with healthy mass participants. Obese participants had higher concentrations of IL-6 at 2 weeks (MD=0.37; 95% CI: 0.11 to 0.64, p=0.006) and 6 months (MD=0.42; 95% CI: 0.12 to 0.72, p=0.006). Obese participants had higher RPQ total score at 6 months (MD=2.79; p=0.02) and 12 months (MD=2.37; p=0.049).
Conclusions Obesity is associated with higher symptomatology at 6 and 12 months and higher concentrations of blood inflammatory markers throughout recovery following mTBI.
- TRAUMATIC BRAIN INJURY
- BLOOD-BRAIN BARRIER
Data availability statement
Data are available in a public, open access repository. Data are available in FITBIR.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Obesity and mild traumatic brain injury (mTBI) are associated with inflammation, but little is known about whether obesity moderates the relationship between mTBI and inflammatory response.
WHAT THIS STUDY ADDS
Obese participants had elevated markers of systemic inflammation up to 6 months post-mTBI and higher symptomatology up to 1 year post-mTBI.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Obese body mass may be an important risk factor for inflammatory response to mTBI and long-term clinical outcomes.
Introduction
Approximately 2.5 million people present to emergency departments (EDs) for traumatic brain injury (TBI) annually in the USA,1 with the vast majority of TBIs (~75%) classified as ‘mild’ (mTBI; Glasgow Coma Score (GCS)=13–15).2 Approximately 87% of patients with mTBI have functional limitations at 2 weeks post-injury, and 53% have functional limitations at 12 months post-injury.3 Neuroinflammation has long been proposed as a key mechanism responsible for worse outcomes following mTBI.4 Specifically, patients with mTBI and higher acute inflammation have poorer functional outcome at 3 and 6 months post-injury.5 C reactive protein (CRP), a sensitive biomarker of systemic inflammation, was prognostic of 6-month disability secondary to mTBI when measured within 2 weeks of injury.6 Interleukin (IL) 6 can be chronically elevated and associated with poor outcomes at 6 months following mTBI.7 Inflammation may even mediate the degree of secondary effects of brain injury following the primary insult.5
Chronic inflammation underlies many disease states, such as obesity and metabolic syndrome.8 Obesity is an American public health crisis: the Centers for Disease Control and Prevention reports that 42.4% of adults in the USA are obese.9 The prevalence of TBI and TBI-related disability suggests ~900 000 Americans seen for mTBI at a hospital, and ~1.1 million people with functional limitations up to 1 year after TBI may be obese. Obesity is known to result in chronic, low-grade inflammation which supports the pathogenesis of a myriad of metabolic diseases, including diabetes, cardiovascular disease and cancer.10 Higher levels of white adipose tissue are linked to macrophage proliferation and higher concentrations of proinflammatory cytokines in obese people, which in turn are associated with cognitive deficits in executive function, memory and learning.11 Obesity is also highly related to other known sequelae of mTBI, such as sleep apnoea, migraines, vestibular dysfunction and mood issues.12–17 Recent research using murine models demonstrates a relationship between obesity and worse outcomes following brain injury.18 However, the role of obesity and its promotion of a chronic inflammatory state following mTBI has not been adequately explored in humans.
We assessed associations between obesity, inflammatory blood biomarkers, symptoms, health-related quality of life and functional outcomes in persons who presented to a level 1 hospital ED with an mTBI. Our hypothesis was that obese patients would experience higher and more prolonged symptom burden and inflammatory biomarker responses after mTBI compared with participants with healthy body mass.
Methods
This is a retrospective cohort analysis of subjects enrolled in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Study (2013–2019). TRACK-TBI is a prospective, longitudinal, observational study of patients with TBI who presented to the (ED of 18 level 1 trauma centres in the USA.
Procedures
Participants or their legally authorised representatives provided written informed consent to participate after being approached by a member of the research team in the ED. The Galveston Orientation and Amnesia Test was used to determine competency to self-consent. Enrolled patients provided blood samples within 24 hours of injury (D1), and at 2 weeks (W2) and 6 months (M6) post-injury. Clinical outcomes were obtained at W2, 3 months (M3), M6 and 12 months (M12) post-injury. The Strengthening the Reporting of Observational Studies in Epidemiology reporting guideline was followed.
Equity, diversity and inclusion statement
This research study enrolled all identified cases of mTBI who presented to participating sites based on inclusion/exclusion criteria and willingness to participate in research. We did not discriminate on enrolment based on sex, gender, race/ethnicity or any other demographic variable. The author group is balanced in terms of included race/ethnicities, biological sexes and experience. Two authors on the byline are considered junior. The author group is multidisciplinary, with subject matter experts in neurosurgery, biostatistics, clinical outcome assessment, neurology and osteopathic medicine. The results are only generalisable to those with access to a level 1 trauma centre in the USA.
Participants were included in the study if presenting to the ED within 24 hours of an apparent head injury, sufficient for the treating ED physician to order a CT scan. Exclusion criteria included pregnancy, incarceration, non-survivable physical trauma, debilitating mental health disorders or neurological disease, and MRI contraindications (eg, cardiac pacemakers, aneurysm clips, insulin pumps). Because this analysis focused on mTBI, we restricted the sample to patients with a GCS score of 13–15 on arrival at the ED. Participants were categorised into body mass groups from height and weight data taken at hospital intake according to body mass index (BMI) guidelines.19 Participants who were underweight (BMI <18.5) or overweight (BMI=25.0–29.9) by BMI standards were excluded from analysis. Obese participants (BMI >30.0) and normal weight participants (BMI=18.5–24.9) at the time of their injury were retained for analysis (see figure 1: Consolidated Standards of Reporting Trials diagram). Participants were included in each longitudinal model if they had at least one of the longitudinal outcome scores.
CONSORT diagram. BMI, body mass index; CONSORT, Consolidated Standards of Reporting Trials; GCS, Glasgow Coma Scale; GOSE, Glasgow Outcome Scale-Extended; hsCRP, high-sensitivity C reactive protein; IL, interleukin; TBI, traumatic brain injury; TNFα, tumour necrosis factor alpha.
Clinical outcomes
Participants completed a standardised set of outcome assessments at W2, M3, M6 and M12, including the Rivermead Post-Concussion Symptoms Questionnaire (RPQ), Brief Symptom Inventory-18 (BSI-18) and the Quality of Life after Brain Injury (QOLIBRI) Overall Scale. The RPQ measures severity of headaches, dizziness and nausea, as well as cognitive, mood, and sleep disturbances and other physical symptoms associated with concussion. Each item is rated on a scale of 0–4, with 0 indicating the symptom was not experienced at all and 4 indicating the symptom was a severe problem within the past 7 days, as compared with pre-injury status.20 The BSI-18 provides an assessment of psychological distress by measuring depression, anxiety and somatisation symptom domains.21 This study used T-scores, calculated from the summed responses in each domain and normalised across sex. The QOLIBRI scale is a health-related quality of life instrument used for patients with TBI with six domains and an overall score.22 The overall score was analysed in this study, with scores ranging from 0 to 100. Lower scores indicate a worse quality of life. The Glasgow Outcome Scale-Extended (GOSE) was used to assess functional outcome specific to TBI at W2, M3, M6 and M12 after injury. Good recovery was defined as a GOSE score of 7 or 8; incomplete recovery was defined as GOSE <7.
Blood biomarkers
Blood samples were collected at D1, W2 and M6. All samples were dated and time-stamped to compare with time of injury. Samples were processed and stored according to the Traumatic Brain Injury Common Data Elements Biospecimens and Biomarkers Working Group consensus recommendations for plasma and serum preparation.23 Plasma and serum aliquots were prepared for each subject and frozen at −80°C for future analysis. All samples were deidentified using a unique study ID, specific to site and subject, and batch-shipped in temperature-controlled overnight express freight containers to the TRACK-TBI Biospecimens Repository at the BLINDED FOR REVIEW.
Blinded sample analysis of high-sensitivity CRP (hsCRP) was carried out by a single laboratory (University College Dublin) using the Abbott Architect c8000, MULTIGENT CRP Vario assay with the high-sensitivity method (CRP16). Serum samples were thawed in batches at room temperature and centrifuged at 10 000 rfc for 10 min at 4°C before testing. Assays were performed in duplicate with a lower limit of quantification of 0.1 mg/L and a reportable range of 0.1–160.0 mg/L. Circulating plasma concentrations (pg/mL) of the cytokines IL-6, IL-10 and tumour necrosis factor alpha (TNFα) were measured by SiMoA (Quanterix, Billerica, Massachusetts, USA) using the Cytokine 3-plex A kit at University College Dublin. Temporal trends of these biomarkers were analysed and reported.
Statistical analysis
Patient characteristics were summarised for the study cohorts. Group comparisons used Wilcoxon rank-sum test for the continuous variables and Fisher’s exact test for the categorical variables. Linear mixed-effects models were used to compare the biomarker levels (in log scale) at D1, W2 and M6 between the obese and healthy mass groups, adjusting for age and sex. Each model included biomarker levels (in log scale) as the dependent variable; fixed effects included BMI group (obese vs healthy), time point (W2, M6 vs D1), BMI group-by-time point interaction, age and gender; random effects included random intercept. Similar models were used to compare the self-report measures at W2, M3, M6 and M12 between the obese and healthy weight groups, adjusting for age, sex, race, years of education, prior TBI and psychiatric history at baseline. Model-estimated mean group differences with 95% CIs were reported at each follow-up visit. Generalised estimating equation models were used to compare the group difference in incomplete recovery (GOSE <7 vs 7–8), adjusting for age, sex, race, years of education, prior TBI and psychiatric history. Model-estimated ORs with 95% CIs were reported at each follow-up visit. Participants were excluded from the model if missing ≥1 covariates. Statistical significance was set to p<0.05. All analyses were conducted in R V.4.1.2.
Results
Study cohort
Patient characteristics are presented in table 1. The obese cohort was approximately 5 years older than the healthy mass cohort and had a higher proportion (+5.4%) of black patients. There were no statistically significant differences in years of education, female sex, Hispanic ethnicity, psychiatric history, TBI history or CT scan status (ie, positive or negative).
Patient characteristics (mean±SD or number (percentage))
Blood biomarkers
Table 2 presents the linear mixed-effects model results comparing the blood-based biomarker levels at D1, W2 and M6 between the obese and healthy mass groups. After adjusting for age and gender, obese participants had higher concentrations of hsCRP (log scale) at D1 (mean difference=0.65; 95% CI: 0.44 to 0.87, p<0.001), W2 (mean difference=0.99; 95% CI: 0.74 to 1.25, p<0.001) and M6 (mean difference=1.08; 95% CI: 0.79 to 1.37, p<0.001) compared with healthy mass participants. Obese participants had higher concentrations of IL-6 (log scale) at W2 (mean difference=0.37; 95% CI: 0.11 to 0.64, p=0.006) and M6 (mean difference=0.42; 95% CI: 0.12 to 0.72, p=0.006). There were no differences between groups in IL-10 or TNFα concentrations over time.
Linear mixed-effects models for biomarkers in log scale adjusted for age and sex
Symptom outcomes
Table 3 presents the linear mixed-effects model results comparing the symptoms and quality of life scores at W2, M3, M6 and M12 between the obese and healthy mass groups. After adjusting for age, gender, race, years of education, psychiatric history and prior TBI, obese participants had higher prolonged symptom burdens in overall mTBI symptoms (ie, RPQ) at M6 (mean difference=2.79; 95% CI: 0.44 to 5.14, p=0.02) and M12 (mean difference=2.37; 95% CI: 0.01 to 4.73, p=0.049). There were no differences over time in QOLIBRI and BSI T-score.
Linear mixed-effects models for symptoms and quality of life adjusted for age, sex, race, years of education, psychiatric history and prior TBI (n=649)
Functional outcome
The obese group had a higher proportion of incomplete functional recovery (GOSE <7) at 6 months compared with the healthy mass group (39.4% vs 30.6%, p=0.04). However, after adjusting for age, gender, race, years of education, psychiatric history and prior TBI, there were no significant group differences at any time point (table 4).
Generalised estimating equation model for incomplete recovery (GOSE <7 vs 7–8) adjusted for age, gender, race, years of education, psychiatric history and prior TBI (n=605)
Discussion
In patients who presented to a level 1 ED with an mTBI, there was an association between obesity and higher symptom burden at M6 and M12 and higher concentrations of blood inflammatory markers up to M6 post-injury. Specifically, obese participants had higher concentrations of serum hsCRP at D1, W2 and M6 and serum IL-6 at W2 and M6 post-injury compared with participants with healthy body mass. Obese participants experienced a higher rate of incomplete recovery (GOSE <7) at M6 post-injury, but this result did not reach statistical significance after controlling for other risk factors. Obesity at the time of mTBI may be clinically relevant for recovery over the first year post-injury, as longitudinal differences in symptomatology and serum inflammatory markers were observed in comparison with healthy body mass participants after controlling for risk factors of prolonged recovery from mTBI.
Obesity is associated with higher levels of circulatory inflammation compared with healthy weight people. Higher body fat percentage is associated with higher circulating hsCRP, which is a sensitive blood biomarker of low-level circulating inflammation.24–26 Another study found that hsCRP is more sensitive than IL-6 and TNFα for differentiating obesity.27 This result may explain why hsCRP was consistently elevated across time points in the present study, while IL-6 was only elevated at later time points and TNFα showed no group differences (table 2). The lack of acute differences in IL-6 and longitudinal differences in TNFα requires further investigation, as IL-6 has been shown to regulate hsCRP in response to inflammation and TNFα stimulates IL-6.28 29 IL-6 and TNFα are proinflammatory cytokines which have all been repeatedly associated with obesity, so we expected similar responses for both throughout mTBI recovery.30
IL-10 is an anti-inflammatory cytokine which attenuates the inflammatory process associated with TNFα and IL-6.31 IL-10 is negatively correlated with BMI and per cent fat mass.31 Obese people typically have lower levels of IL-10, which can be magnified by comorbidities such as the metabolic syndrome and type II diabetes.31 No statistically significant differences were observed between groups in the present study. This result could be clinically relevant, because IL-10 plays a critical role in resolution of inflammatory cascades after brain injury.32 The combination of higher concentrations of circulating proinflammatory cytokines and insufficient anti-inflammatory cytokines pre-injury may create a biomolecular environment which predisposes the obese patient with mTBI to higher odds of worse clinical outcomes.
Clinical implications
There was no statistical difference between global mTBI symptoms (ie, RPQ), mood symptoms (ie, BSI-18) and quality of life scores (ie, QOLIBRI) between groups in the acute-to-subacute recovery window (table 3). At chronic recovery time points (ie, M6 and M12), global symptoms remained significantly elevated compared with healthy mass participants. Previous findings in patients with mTBI that did not consider body mass suggest that prolonged symptoms can be debilitating.33 34 It is unclear why obese participants have higher burden of prolonged symptoms at M6 and M12 after mTBI. Limited research exists regarding obesity’s potential effect on clinical recovery from mTBI. Lee et al 35 reported longer symptom resolution and overall recovery time in obese adolescent athletes compared with normal weight athletes following mTBI. Understanding specific symptoms or symptom clusters which may differ between BMI groups is an important subject for future research. Excessive weight gain is a concern for many patients after TBI. For example, Izzy et al 36 reported an HR of 1.7 for increased odds of becoming obese after mTBI compared with healthy controls. The authors also reported similar HRs for comorbidities highly related to obesity, such as diabetes mellitus (HR=1.8) or cardiovascular disease (HR=1.7). Unfortunately, documentation of these comorbidities was not well curated in the present dataset.
Limitations
This study has limitations. Obesity and healthy mass were defined by BMI, which is an imperfect measure of obesity due to no direct measure of adiposity.19 Per cent fat mass was not obtained as part of the TRACK-TBI Study and was not available for this analysis. The present analysis was restricted to hospitalised patients with mTBI, as measured height and weight were not documented in non-hospitalised patients. Missing data were observed throughout the study. However, our rate of missing data was comparable with the broader TBI literature.37 Clinical assessments were limited to symptom or quality of life reports for this analysis, but future work would benefit from assessment of neurocognition. Previous work has shown that obese patients have poorer neurocognition than healthy weight patients, both when healthy and after mTBI.38 Documentation of comorbidities which are highly associated with obesity, such as diabetes mellitus, cardiovascular disease, insulin resistance and metabolic syndrome, was not available in the present study and could have altered the outcomes. Future work should extend these analyses by investigating the potentially causal role of inflammation in clinical outcomes in this population.
Conclusion
In patients with mTBI from the TRACK-TBI Study, obesity was associated with higher symptomatology and higher blood inflammatory profiles. Obesity was operationally defined using BMI; future studies should consider per cent fat mass and other comorbidities associated with obesity. The results of this study suggest that obese body mass at time of injury may be a clinical risk factor for worse clinical outcomes after mTBI, in comparison with patients with healthy body mass. The design of the present study does not allow a causal determination whether obesity itself is the primary condition contributing to higher symptom burden after mTBI or if the myriad associated chronic diseases are the primary factors. Future longitudinal studies will be required to understand the temporal relationship between disease states and how it impacts mTBI recovery.
Data availability statement
Data are available in a public, open access repository. Data are available in FITBIR.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and was approved by Baylor College of Medicine, Massachusetts General Hospital/Spaulding Rehabilitation Hospital, University of California San Francisco, University of Cincinnati, University of Maryland, University of Miami, University of Pittsburgh (STUDY19070435), University of Texas, Austin, University of Texas Southwestern, University of Washington, Virginia Commonwealth University, University of Pennsylvania, Emory University, Medical College of Wisconsin, University of Utah, Indiana University, Hennepin County Medical Center and Denver Health Medical Center-Craig Hospital. Participants gave informed consent to participate in the study before taking part.
References
Footnotes
Twitter @shawn_eagle
Collaborators Adam R. Ferguson, Department of Neurological Surgery, University of California San Francisco, San Francisco, CA; Shankar Gopinath, Department of Neurosurgery, Baylor College of Medicine, Houston, TX; Ramesh Grandhi, Department of Neurosurgery, University of Utah, Salt Lake City, UT; C. Dirk Keene, Department of Pathology, University of Washington, Seattle, WA; Randall Merchant, Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA; Claudia Robertson, Department of Neurosurgery, Baylor College of Medicine, Houston, TX; David Schnyer, Department of Psychology, University of Texas at Austin, Austin, TX; Nancy Temkin, Department of Pathology, University of Washington, Seattle, WA; John K. Yue, Department of Neurological Surgery, University of California San Francisco, San Francisco, CA; Ross Zafonte, Physical Medicine and Rehabilitation, Harvard University, Cambridge, MA, USA.
Contributors SE conceived of the study, wrote the initial draft, revised the draft and approved the final draft. AMP, LDN, MM, JG, RD-A, GM, DOO and TRACK-TBI investigators contributed to study design, data collection and oversight for the original study, reviewed the draft and approved the final version. WC contributed to study conceptualisation, revised the draft and approved the final version. SJ and XS contributed to study design and analytical plan, conducted the statistical analyses and approved the final version.
Funding This study was funded by the National Institutes of Health (award number: 1U01NS086090-01).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.