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The genetic basis of inter-individual variation in recovery from traumatic brain injury.

ABSTRACT: Traumatic brain injury (TBI) is one of the leading causes of death among young people, and is increasingly prevalent in the aging population. Survivors of TBI face a spectrum of outcomes from short-term non-incapacitating injuries to long-lasting serious and deteriorating sequelae. TBI is a highly complex condition to treat; many variables can account for the observed heterogeneity in patient outcome. The limited success of neuroprotection strategies in the clinic has led to a new emphasis on neurorestorative approaches. In TBI, it is well recognized clinically that patients with similar lesions, age, and health status often display differences in recovery of function after injury. Despite this heterogeneity of outcomes in TBI, restorative treatment has remained generic. There is now a new emphasis on developing a personalized medicine approach in TBI, and this will require an improved understanding of how genetics impacts on long-term outcomes. Studies in animal model systems indicate clearly that the genetic background plays a role in determining the extent of recovery following an insult. A candidate gene approach in human studies has led to the identification of factors that can influence recovery. Here we review studies of the genetic basis for individual differences in functional recovery in the CNS in animals and man. The application of in vitro modeling with human cells and organoid cultures, along with whole-organism studies, will help to identify genes and networks that account for individual variation in recovery from brain injury, and will point the way towards the development of new therapeutic approaches.

SUBMITTER: Cortes D

PROVIDER: S-EPMC7820607 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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The genetic basis of inter-individual variation in recovery from traumatic brain injury.

Cortes Daniel D Pera Martin F MF

NPJ Regenerative medicine 20210121 1

Traumatic brain injury (TBI) is one of the leading causes of death among young people, and is increasingly prevalent in the aging population. Survivors of TBI face a spectrum of outcomes from short-term non-incapacitating injuries to long-lasting serious and deteriorating sequelae. TBI is a highly complex condition to treat; many variables can account for the observed heterogeneity in patient outcome. The limited success of neuroprotection strategies in the clinic has led to a new emphasis on ne ...[more]

PMID: 33479258

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Project description:ImportanceOne traumatic brain injury (TBI) increases the risk of subsequent TBIs. Research on longitudinal outcomes of civilian repetitive TBIs is limited.ObjectiveTo investigate associations between sustaining 1 or more TBIs (ie, postindex TBIs) after study enrollment (ie, index TBIs) and multidimensional outcomes at 1 year and 3 to 7 years.Design, setting, and participantsThis cohort study included participants presenting to emergency departments enrolled within 24 hours of TBI in the prospective, 18-center Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study (enrollment years, February 2014 to July 2020). Participants who completed outcome assessments at 1 year and 3 to 7 years were included. Data were analyzed from September 2022 to August 2023.ExposuresPostindex TBI(s).Main outcomes and measuresDemographic and clinical factors, prior TBI (ie, preindex TBI), and functional (Glasgow Outcome Scale-Extended [GOSE]), postconcussive (Rivermead Post-Concussion Symptoms Questionnaire [RPQ]), psychological distress (Brief Symptom Inventory-18 [BSI-18]), depressive (Patient Health Questionnaire-9 [PHQ-9]), posttraumatic stress disorder (PTSD; PTSD Checklist for DSM-5 [PCL-5]), and health-related quality-of-life (Quality of Life After Brain Injury-Overall Scale [QOLIBRI-OS]) outcomes were assessed. Adjusted mean differences (aMDs) and adjusted relative risks are reported with 95% CIs.ResultsOf 2417 TRACK-TBI participants, 1572 completed the outcomes assessment at 1 year (1049 [66.7%] male; mean [SD] age, 41.6 [17.5] years) and 1084 completed the outcomes assessment at 3 to 7 years (714 [65.9%] male; mean [SD] age, 40.6 [17.0] years). At 1 year, a total of 60 participants (4%) were Asian, 255 (16%) were Black, 1213 (77%) were White, 39 (2%) were another race, and 5 (0.3%) had unknown race. At 3 to 7 years, 39 (4%) were Asian, 149 (14%) were Black, 868 (80%) were White, 26 (2%) had another race, and 2 (0.2%) had unknown race. A total of 50 (3.2%) and 132 (12.2%) reported 1 or more postindex TBIs at 1 year and 3 to 7 years, respectively. Risk factors for postindex TBI were psychiatric history, preindex TBI, and extracranial injury severity. At 1 year, compared with those without postindex TBI, participants with postindex TBI had worse functional recovery (GOSE score of 8: adjusted relative risk, 0.57; 95% CI, 0.34-0.96) and health-related quality of life (QOLIBRI-OS: aMD, -15.9; 95% CI, -22.6 to -9.1), and greater postconcussive symptoms (RPQ: aMD, 8.1; 95% CI, 4.2-11.9), psychological distress symptoms (BSI-18: aMD, 5.3; 95% CI, 2.1-8.6), depression symptoms (PHQ-9: aMD, 3.0; 95% CI, 1.5-4.4), and PTSD symptoms (PCL-5: aMD, 7.8; 95% CI, 3.2-12.4). At 3 to 7 years, these associations remained statistically significant. Multiple (2 or more) postindex TBIs were associated with poorer outcomes across all domains.Conclusions and relevanceIn this cohort study of patients with acute TBI, postindex TBI was associated with worse symptomatology across outcome domains at 1 year and 3 to 7 years postinjury, and there was a dose-dependent response with multiple postindex TBIs. These results underscore the critical need to provide TBI prevention, education, counseling, and follow-up care to at-risk patients.

Project description:Interactions between microglia and neuronal components are important for normal CNS function. They are also associated with neuroinflammation and many pathological processes and several studies have explored these interactions in terms of phagocytic engulfment. Much progress has also been made in understanding the consequences of chronic neuroinflammatory changes following trauma. However, little is known about acute alterations to these physical non-phagocytic microglial-neuronal interactions following traumatic brain injury (TBI), and particularly to what degree these post-injury interactions may be influenced by the animal species utilized in pre-clinical models of TBI. To investigate these problems, we evaluated the physical interactions between microglia and injured axons acutely (6 h and 1 day) following central fluid percussion injury (cFPI) in both rats and micro pigs. The physical interactions between Iba-1+ microglia and either normal MBP+ myelinated fibers or APP+ injured axonal swellings in the thalamus were assessed following injury or sham via quantitative image analysis of 3D confocal micrographs. The results indicated that the physical interactions between microglia and injured axonal swellings decreased by nearly half in rats 6 h following cFPI but was consistent with sham control at 1 day post-cFPI. This reduction was also observed in non-injured intact fibers at both timepoints following TBI in the rat. Microglial process interactions with injured axons in the micro pig, however, increased nearly 2-fold compared to interactions with intact axonal segments 1 day post-cFPI. This study shows that the species utilized for in vivo pre-clinical studies influences the manner in which microglial-axonal interactions change following TBI. These species differences can be leveraged to further our understanding of the mechanisms involved in microglial process convergence and how these neuro-immune interactions alter the progression of axonal injury following TBI.

Project description:Poor outcomes after traumatic brain injury (TBI) are common yet remain difficult to predict. Diffuse axonal injury is important for outcomes, but its assessment remains limited in the clinical setting. Currently, axonal injury is diagnosed based on clinical presentation, visible damage to the white matter or via surrogate markers of axonal injury such as microbleeds. These do not accurately quantify axonal injury leading to misdiagnosis in a proportion of patients. Diffusion tensor imaging provides a quantitative measure of axonal injury in vivo, with fractional anisotropy often used as a proxy for white matter damage. Diffusion imaging has been widely used in TBI but is not routinely applied clinically. This is in part because robust analysis methods to diagnose axonal injury at the individual level have not yet been developed. Here, we present a pipeline for diffusion imaging analysis designed to accurately assess the presence of axonal injury in large white matter tracts in individuals. Average fractional anisotropy is calculated from tracts selected on the basis of high test-retest reliability, good anatomical coverage and their association to cognitive and clinical impairments after TBI. We test our pipeline for common methodological issues such as the impact of varying control sample sizes, focal lesions and age-related changes to demonstrate high specificity, sensitivity and test-retest reliability. We assess 92 patients with moderate-severe TBI in the chronic phase (≥6 months post-injury), 25 patients in the subacute phase (10 days to 6 weeks post-injury) with 6-month follow-up and a large control cohort (n = 103). Evidence of axonal injury is identified in 52% of chronic and 28% of subacute patients. Those classified with axonal injury had significantly poorer cognitive and functional outcomes than those without, a difference not seen for focal lesions or microbleeds. Almost a third of patients with unremarkable standard MRIs had evidence of axonal injury, whilst 40% of patients with visible microbleeds had no diffusion evidence of axonal injury. More diffusion abnormality was seen with greater time since injury, across individuals at various chronic injury times and within individuals between subacute and 6-month scans. We provide evidence that this pipeline can be used to diagnose axonal injury in individual patients at subacute and chronic time points, and that diffusion MRI provides a sensitive and complementary measure when compared to susceptibility weighted imaging, which measures diffuse vascular injury. Guidelines for the implementation of this pipeline in a clinical setting are discussed.

Project description:Study hypothesis: CRC risk is affected by diet and by genetic polymorphisms leading to inter-individual variation in the metabolism of environmental carcinogens. Our first hypothesis is that these effects may combine to place certain individuals at greatly enhanced risk according to their diet. We shall examine how dietary factors known to affect CRC risk (including meats, fat, fruit and vegetables, cooking methods, dietary supplements and drugs) and genetic polymorphisms implicated in CRC (Glutathione S-transferase: GSTM1, GSTM3, GSTT1; N-acetyl transferase: NAT1, NAT2; and Cytochrome P450: CYP1A1, CYP2D6) combine to affect the prevalence of colorectal polyps, both adenomatous (the precursor lesion of CRC) and metaplastic. Our second hypothesis is that diets associated with increased risk (high red meat, low vegetable and low fibre consumption) may affect DNA damage markers which may be elevated in people with colorectal adenomas. We shall therefore examine the effect of diet on adduct rates (cross sectional) and adduct rates in people with and without colorectal adenomas. We shall examine malondialdehyde adduct rates in relation to anti-oxidant status and carboxymethyl adduct rates and k-ras mutation frequency in relation to meat consumption; and examine the effect of DNA repair enzyme (ATase) activity on any relationship found. In summary the aim of this population based study is to link dietary factors thought to be important in the genesis of colorectal polyps and cancer with genetic polymorphisms and DNA damage markers in rectal mucosa and in blood. Primary outcome(s): We shall perform cross-sectional and case-control analyses of the effect of diet and genetic polymorphisms on the prevalence of adenomatous and metaplastic polyps. Genetic polymorphisms will be examined in isolation and paired combinations and in groups stratified according to diet. We shall examine the effect of diet on MDA adduct rates (concentrating on foods relating to anti-oxidant status) and CBM adduct rates and k-ras mutations (concentrating on meat consumption and cooking methods) by categorical variables; and MDA and CBM adducts and k-ras mutation frequency in people with adenomatous polyps and polyp free controls (case-control). We shall examine the affect of ATase activity on any relationship found and ATase activity in people with adenomatous polyps and polyp free controls (case control). DNA will be stored for future analysis of as yet unrecognised polymorphisms which may be recognised as having a role in CRC. Samples taken from EPIC participants for adduct, ATase and k-ras measurement whose polyps are found to be metaplastic will be stored for possible future analysis: we shall investigate people with adenomatous polyps in the first instance as these are the precursors of colorectal cancer.

Project description:Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality worldwide. It is linked with a number of medical, neurological, cognitive, and behavioral sequelae. The influence of genetic factors on the biology and related recovery after TBI is poorly understood. Studies that seek to elucidate the impact of genetic influences on neurorecovery after TBI will lead to better individualization of prognosis and inform development of novel treatments, which are considerably lacking. Current genetic studies related to TBI have focused on specific candidate genes. The objectives of this study were to use a system biology-based approach to identify biologic processes over-represented with genetic variants previously implicated in clinical outcomes after TBI and identify unique genes potentially related to recovery after TBI. After performing a systematic review to identify genes in the literature associated with clinical outcomes, we used the genes identified to perform a systems biology-based integrative computational analysis to ascertain the interactions between molecular components and to develop models for regulation and function of genes involved in TBI recovery. The analysis identified over-representation of genetic variants primarily in two biologic processes: response to injury (cell proliferation, cell death, inflammatory response, and cellular metabolism) and neurocognitive and behavioral reserve (brain development, cognition, and behavior). Overall, this study demonstrates the use of a systems biology-based approach to identify unique/novel genes or sets of genes important to the recovery process. Findings from this systems biology-based approach provide additional insight into the potential impact of genetic variants on the underlying complex biological processes important to TBI recovery and may inform the development of empirical genetic-related studies for TBI. Future studies that combine systems biology methodology and genomic, proteomic, and epigenetic approaches are needed in TBI.

Dataset Information

The genetic basis of inter-individual variation in recovery from traumatic brain injury.

Publications

The genetic basis of inter-individual variation in recovery from traumatic brain injury.

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