scholarly journals A Levee to the Flood: Pre-injury Neuroinflammation and Immune Stress Influence Traumatic Brain Injury Outcome

2022 ◽  
Vol 13 ◽  
Author(s):  
Samuel Houle ◽  
Olga N. Kokiko-Cochran
Keyword(s):  
Risk Factors ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Inflammatory Response ◽  
Genetic Risk ◽  
Traumatic Injury ◽  
Genetic Risk Factors ◽  
Post Injury ◽  
Immune Stress ◽  
Age Related

Increasing evidence demonstrates that aging influences the brain's response to traumatic brain injury (TBI), setting the stage for neurodegenerative pathology like Alzheimer's disease (AD). This topic is often dominated by discussions of post-injury aging and inflammation, which can diminish the consideration of those same factors before TBI. In fact, pre-TBI aging and inflammation may be just as critical in mediating outcomes. For example, elderly individuals suffer from the highest rates of TBI of all severities. Additionally, pre-injury immune challenges or stressors may alter pathology and outcome independent of age. The inflammatory response to TBI is malleable and influenced by previous, coincident, and subsequent immune insults. Therefore, pre-existing conditions that elicit or include an inflammatory response could substantially influence the brain's ability to respond to traumatic injury and ultimately affect chronic outcome. The purpose of this review is to detail how age-related cellular and molecular changes, as well as genetic risk variants for AD affect the neuroinflammatory response to TBI. First, we will review the sources and pathology of neuroinflammation following TBI. Then, we will highlight the significance of age-related, endogenous sources of inflammation, including changes in cytokine expression, reactive oxygen species processing, and mitochondrial function. Heightened focus is placed on the mitochondria as an integral link between inflammation and various genetic risk factors for AD. Together, this review will compile current clinical and experimental research to highlight how pre-existing inflammatory changes associated with infection and stress, aging, and genetic risk factors can alter response to TBI.

Systematic Review of Genetic Risk Factors for Sustaining a Mild Traumatic Brain Injury

2017 ◽  
Vol 34 (13) ◽  
pp. 2093-2099 ◽  
Author(s):  
William J. Panenka ◽  
Andrew J. Gardner ◽  
Michael N. Dretsch ◽  
Gogce C. Crynen ◽  
Fiona C. Crawford ◽  
...  
Keyword(s):  
Risk Factors ◽  
Systematic Review ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Mild Traumatic Brain Injury ◽  
Genetic Risk ◽  
Genetic Risk Factors

scholarly journals A-126 Clinical Utility of Risk Factors to Predict Self-reported Neurobehavioral Outcome Following Traumatic Brain Injury: PTSD, Sleep, Resilience, and Lifetime Blast Exposure

2020 ◽  
Vol 35 (6) ◽  
pp. 919-919
Author(s):  
Lange R ◽  
Lippa S ◽  
Hungerford L ◽  
Bailie J ◽  
French L ◽  
...  
Keyword(s):  
Risk Factors ◽  
Traumatic Brain Injury ◽  
Risk Factor ◽  
Brain Injury ◽  
Clinical Utility ◽  
Poor Sleep ◽  
Post Injury ◽  
Poor Outcome ◽  
Blast Exposure ◽  
Neurobehavioral Outcome

Abstract Objective To examine the clinical utility of PTSD, Sleep, Resilience, and Lifetime Blast Exposure as ‘Risk Factors’ for predicting poor neurobehavioral outcome following traumatic brain injury (TBI). Methods Participants were 993 service members/veterans evaluated following an uncomplicated mild TBI (MTBI), moderate–severe TBI (ModSevTBI), or injury without TBI (Injured Controls; IC); divided into three cohorts: (1) < 12 months post-injury, n = 237 [107 MTBI, 71 ModSevTBI, 59 IC]; (2) 3-years post-injury, n = 370 [162 MTBI, 80 ModSevTBI, 128 IC]; and (3) 10-years post-injury, n = 386 [182 MTBI, 85 ModSevTBI, 119 IC]. Participants completed a 2-hour neurobehavioral test battery. Odds Ratios (OR) were calculated to determine whether the ‘Risk Factors’ could predict ‘Poor Outcome’ in each cohort separately. Sixteen Risk Factors were examined using all possible combinations of the four risk factor variables. Poor Outcome was defined as three or more low scores (< 1SD) on five TBI-QOL scales (e.g., Fatigue, Depression). Results In all cohorts, the vast majority of risk factor combinations resulted in ORs that were ‘clinically meaningful’ (ORs > 3.00; range = 3.15 to 32.63, all p’s < .001). Risk factor combinations with the highest ORs in each cohort were PTSD (Cohort 1 & 2, ORs = 17.76 and 25.31), PTSD+Sleep (Cohort 1 & 2, ORs = 18.44 and 21.18), PTSD+Sleep+Resilience (Cohort 1, 2, & 3, ORs = 13.56, 14.04, and 20.08), Resilience (Cohort 3, OR = 32.63), and PTSD+Resilience (Cohort 3, OR = 24.74). Conclusions Singularly, or in combination, PTSD, Poor Sleep, and Low Resilience were strong predictors of poor outcome following TBI of all severities and injury without TBI. These variables may be valuable risk factors for targeted early interventions following injury.

Prevalence of age-related macular degeneration associated genetic risk factors and 4-year progression data in the Irish population

2018 ◽  
Vol 102 (12) ◽  
pp. 1691-1695 ◽  
Author(s):  
Emma Connolly ◽  
Maedbh Rhatigan ◽  
Aisling M O’Halloran ◽  
Katherine Alyson Muldrew ◽  
Usha Chakravarthy ◽  
...  
Keyword(s):  
Risk Factors ◽  
Macular Degeneration ◽  
Disease Progression ◽  
Genetic Risk ◽  
Risk Allele ◽  
Genetic Risk Factors ◽  
Age Related Macular Degeneration ◽  
Complement Factor ◽  
Age Related ◽  
Soft Drusen

Background/aimsAge-related macular degeneration (AMD) is estimated to affect 196 million people >50 years old globally. Prevalence of AMD-associated genetic risk factors and rate of disease progression are unknown in Ireland.MethodsPrevalence of AMD-associated genetic risk variants, complement factor H (CFH) rs1061170, age-related maculopathy susceptibility 2 (ARMS2) rs10490924, component 3 (C3) rs2230199, complement factor B (CFB) rs641153 and superkiller viralicidic activity 2-like (SKIV2L) rs429608 and 4-year progression data in a population-representative cohort (The Irish Longitudinal study on Ageing (TILDA)) were assessed. 4473 participants ≥50 years were assessed. 4173 had no disease n=1843; 44% male and n=2330; 56% female, mean age 60±9.0, 300 had AMD n=136; 45% male and n=164; 55% female, mean age 64±9.0. A 4-year follow-up was undertaken with 66% of AMD cases attending. Progression and regression from early to late AMD were measured. Genetic association as indicators of disease and as predictors of progression were assessed by multinomial logistic regression.ResultsOlder age and the presence of CFH and ARMS2 risk alleles are two main risk factors associated with the prevalence of AMD in the TILDA cohort. 23% progressed to a higher grade of AMD. Carriers of CFH risk allele showed a strong association for disease progression. Heterozygosity for ARMS2 risk allele predicted progression to late AMD. 75% of those who progressed from early to late disease had soft drusen and hyperpigmentation at baseline.ConclusionsThe prevalence of risk-associated genes and 4-year progression rates of AMD in this Ireland cohort are comparable with other Caucasian populations. CFH Y402H is associated with disease progression, with soft drusen and hyperpigmentation as high-risk features.

scholarly journals Age-Related Differences in the Time Course of Coagulation and Fibrinolytic Parameters in Patients with Traumatic Brain Injury

2020 ◽  
Vol 21 (16) ◽  
pp. 5613
Author(s):  
Ryuta Nakae ◽  
Yu Fujiki ◽  
Yasuhiro Takayama ◽  
Takahiro Kanaya ◽  
Yutaka Igarashi ◽  
...  
Keyword(s):  
Risk Factors ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Propensity Score ◽  
Older Patients ◽  
Multivariate Logistic Regression Analysis ◽  
The Elderly ◽  
Elderly Group ◽  
Post Injury ◽  
D Dimer

Coagulopathy and older age are common and well-recognized risk factors for poorer outcomes in traumatic brain injury (TBI) patients; however, the relationships between coagulopathy and age remain unclear. We hypothesized that coagulation/fibrinolytic abnormalities are more pronounced in older patients and may be a factor in poorer outcomes. We retrospectively evaluated severe TBI cases in which fibrinogen and D-dimer were measured on arrival and 3–6 h after injury. Propensity score-matched analyses were performed to adjust baseline characteristics between older patients (the “elderly group,” aged ≥75 y) and younger patients (the “non-elderly group,” aged 16–74 y). A total of 1294 cases (elderly group: 395, non-elderly group: 899) were assessed, and propensity score matching created a matched cohort of 324 pairs. Fibrinogen on admission, the degree of reduction in fibrinogen between admission and 3–6 h post-injury, and D-dimer levels between admission and 3–6 h post-injury were significantly more abnormal in the elderly group than in the non-elderly group. On multivariate logistic regression analysis, independent risk factors for poor prognosis included low fibrinogen and high D-dimer levels on admission. Posttraumatic coagulation and fibrinolytic abnormalities are more severe in older patients, and fibrinogen and D-dimer abnormalities are negative predictive factors.

A prospective examination of Axis I psychiatric disorders in the first 5 years following moderate to severe traumatic brain injury

2016 ◽  
Vol 46 (6) ◽  
pp. 1331-1341 ◽  
Author(s):  
Y. Alway ◽  
K. R. Gould ◽  
L. Johnston ◽  
D. McKenzie ◽  
J. Ponsford
Keyword(s):  
Risk Factors ◽  
Traumatic Brain Injury ◽  
Substance Use ◽  
Brain Injury ◽  
Anxiety Disorders ◽  
Psychiatric Disorders ◽  
Substance Use Disorders ◽  
First Year ◽  
Post Injury ◽  
Over Time

BackgroundPsychiatric disorders commonly emerge during the first year following traumatic brain injury (TBI). However, it is not clear whether these disorders soon remit or persist for long periods post-injury. This study aimed to examine, prospectively: (1) the frequency, (2) patterns of co-morbidity, (3) trajectory, and (4) risk factors for psychiatric disorders during the first 5 years following TBI.MethodParticipants were 161 individuals (78.3% male) with moderate (31.2%) or severe (68.8%) TBI. Psychiatric disorders were diagnosed using the Structured Clinical Interview for DSM-IV, administered soon after injury and 3, 6 and 12 months, and 2, 3, 4 and 5 years post-injury. Disorder frequencies and generalized estimating equations were used to identify temporal relationships and risk factors.ResultsIn the first 5 years post-injury, 75.2% received a psychiatric diagnosis, commonly emerging within the first year (77.7%). Anxiety, mood and substance-use disorders were the most common diagnostic classes, often presenting co-morbidly. Many (56.5%) experienced a novel diagnostic class not present prior to injury. Disorder frequency ranged between 61.8 and 35.6% over time, decreasing by 27% [odds ratio (OR) 0.73, 95% confidence interval (CI) 0.65–0.83] with each year post-injury. Anxiety disorders declined significantly over time (OR 0.73, 95% CI 0.63–0.84), whilst mood and substance-use disorder rates remained stable. The strongest predictors of post-injury disorder were pre-injury disorder (OR 2.44, 95% CI 1.41–4.25) and accident-related limb injury (OR 1.78, 95% CI 1.03–3.07).ConclusionsFindings suggest the first year post-injury is a critical period for the emergence of psychiatric disorders. Disorder frequency declines thereafter, with anxiety disorders showing greater resolution than mood and substance-use disorders.

scholarly journals Longitudinal Analyses of the Reciprocity of Depression and Anxiety after Traumatic Brain Injury and Its Clinical Implications

2021 ◽  
Vol 10 (23) ◽  
pp. 5597
Author(s):  
Biyao Wang ◽  
Marina Zeldovich ◽  
Katrin Rauen ◽  
Yi-Jhen Wu ◽  
Amra Covic ◽  
...  
Keyword(s):  
Risk Factors ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
First Year ◽  
Depression And Anxiety ◽  
Post Injury ◽  
Related Factors ◽  
Cross Domain ◽  
Psychiatric Disturbances ◽  
Patient Reported

Depression and anxiety are common following traumatic brain injury (TBI). Understanding their prevalence and interplay within the first year after TBI with differing severities may improve patients’ outcomes after TBI. Individuals with a clinical diagnosis of TBI recruited for the large European collaborative longitudinal study CENTER-TBI were screened for patient-reported major depression (MD) and generalized anxiety disorder (GAD) at three, six, and twelve months post-injury (N = 1683). Data were analyzed using autoregressive cross-lagged models. Sociodemographic, premorbid and injury-related factors were examined as risk factors. 14.1–15.5% of TBI patients reported moderate to severe MD at three to twelve months after TBI, 7.9–9.5% reported GAD. Depression and anxiety after TBI presented high within-domain persistency and cross-domain concurrent associations. MD at three months post-TBI had a significant impact on GAD at six months post-TBI, while both acted bidirectionally at six to twelve months post-TBI. Being more severely disabled, having experienced major extracranial injuries, an intensive care unit stay, and being female were risk factors for more severe MD and GAD. Major trauma and the level of consciousness after TBI were additionally associated with more severe MD, whereas being younger was related to more severe GAD. Individuals after TBI should be screened and treated for MD and GAD early on, as both psychiatric disturbances are highly persistent and bi-directional in their impact. More severely disabled patients are particularly vulnerable, and thus warrant timely screening and intensive follow-up treatment.

Combined effects of genetic and non-genetic risk factors affect response to ranibizumab in exudative age-related macular degeneration

2014 ◽  
Vol 93 (6) ◽  
pp. e451-e457 ◽  
Author(s):  
Stefano Piermarocchi ◽  
Stefania Miotto ◽  
Davide Colavito ◽  
Alberta Leon ◽  
Tatiana Segato
Keyword(s):  
Risk Factors ◽  
Macular Degeneration ◽  
Genetic Risk ◽  
Genetic Risk Factors ◽  
Age Related Macular Degeneration ◽  
Combined Effects ◽  
Age Related

scholarly journals Determining the Role of ApoE4 in Age-Related Cerebrovascular Decline

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 118-119
Author(s):  
Kate Foley ◽  
Peter Borchian ◽  
Dylan Garceau ◽  
Kevin Kotredes ◽  
Paul Territo ◽  
...  
Keyword(s):  
Risk Factors ◽  
Genetic Risk ◽  
Transcriptional Profiling ◽  
Genetic Risk Factors ◽  
Expression Of Genes ◽  
Age Related ◽  
Age Dependent ◽  
Cerebrovascular Health ◽  
E4 Allele

Abstract Cerebrovascular decline occurs during aging and may be critical during prodromal phases of Alzheimer’s disease (AD). The E4 allele of apolipoprotein E (APOE4) is the greatest genetic risk factor for AD and decreased longevity and studies suggest APOE4 increases risk for age-dependent cerebrovascular damage. To study the relationship between APOE4 and age-related cerebrovascular decline, male and female C57BL/6J (B6) mice carrying combinations of APOE alleles including APOE4 (risk) and APOE3 (neutral), as well as B6 controls were assessed at a variety of ages from 4 to 24 mos for cognitive ability, biometrics and cerebrovascular health including i) PET/MRI using 64Cu-PTSM (perfusion) and 18F-FDG (metabolism), ii) transcriptional profiling and iii) immunofluorescence. Despite no cognitive decline, male APOE4 mice showed hypo-perfusion and hypo-metabolism by 12 mos, while female APOE4 mice showed an uncoupled hyper-perfusion and hypo-metabolism phenotype. Transcriptional profiling showed differential expression of genes involved in regulation of cerebral perfusion, glucose transportation and metabolism in APOE4 mice. An age-dependent blood brain barrier compromise was also apparent in the brains of female APOE4 mice. Physical activity reduces risk for human AD and our data shows exercise improves cerebrovascular health in mice. However, the effects to cerebrovascular health in individuals carrying genetic risk factors such as APOE4 are not known. To determine whether exercise can overcome APOE4-dependent cerebrovascular damage, APOE mice are being exercised from 2-4 and to 2-12 mos. Transcriptional profiling and immunofluorescence will determine whether the benefits of exercise to the cerebrovasculature are modulated by genetic risk factors such as APOE4.

scholarly journals Gut Microbiome Influences The Neuroinflammatory Response To Traumatic Brain Injury

2021 ◽  
Author(s):  
Akshita Jade Kumar ◽  
Supinder Singh Bedi ◽  
Naama Toledano-Furman ◽  
Louis Carrillo ◽  
Fanni Cardenas ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Inflammatory Response ◽  
Gut Microbiome ◽  
Central Component ◽  
Post Injury ◽  
Probiotic Treatment ◽  
Anti Inflammatory ◽  
Microglial Response ◽  
The Brain

Abstract Background: Traumatic brain injury (TBI) is a systemic injury that disrupts a complex arrangement of interacting cells in the brain and in the gastrointestinal tract (GI). Disruption in the brain results in neuroinflammation, in which microglia are a central component along with cytokines and other soluble factors [pro and anti-inflammatory microglia (M1:M2)]. Disruption in the GI due to TBI results in a systemic inflammation which is dependent upon the gut microbiome (GM). Gut microbiome can influence microglia in the brain via the gut-brain axis. In order to determine if the microbiome-microglia connections via the gut-brain axis can be modulated, we used probiotics and antibiotics in a rodent TBI model to evaluate the microbiome-microglial connections in acute and chronic experiments.Methods: The temporal effects of treatment (probiotics or antibiotics) were used to evaluate the gut-associated lymphoid tissue (GALT) influence on the microglial response at 72 hours or 21 days after a cortical contusion injury (CCI), a rodent model of TBI. Injured animals received daily probiotics, antibiotics, or no treatment. Sham-injured animals (controls) did not receive any treatment.Results: Twenty-one days of probiotic treatment attenuated the pro-inflammatory response of microglia (M1:M2) after CCI. The post-injury inflammatory response was heightened in the GALT with antibiotic-induced dysbiosis which resulted in amplification of the pro-inflammatory microglial response. Conclusions: Probiotic treatment after TBI is a potential therapeutic in attenuating microglial activation through anti-inflammatory signaling.

scholarly journals Traumatic Brain Injury Induces cGAS Activation and Type I Interferon Signaling in Aged Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
James P. Barrett ◽  
Susan M. Knoblach ◽  
Surajit Bhattacharya ◽  
Heather Gordish-Dressman ◽  
Bogdan A. Stoica ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Inflammatory Responses ◽  
Type I Interferons ◽  
Type I ◽  
Post Injury ◽  
Age Related ◽  
Inflammatory Processes ◽  
Sting Pathway ◽  
Induced Changes

Aging adversely affects inflammatory processes in the brain, which has important implications in the progression of neurodegenerative disease. Following traumatic brain injury (TBI), aged animals exhibit worsened neurological function and exacerbated microglial-associated neuroinflammation. Type I Interferons (IFN-I) contribute to the development of TBI neuropathology. Further, the Cyclic GMP-AMP Synthase (cGAS) and Stimulator of Interferon Genes (STING) pathway, a key inducer of IFN-I responses, has been implicated in neuroinflammatory activity in several age-related neurodegenerative diseases. Here, we set out to investigate the effects of TBI on cGAS/STING activation, IFN-I signaling and neuroinflammation in young and aged C57Bl/6 male mice. Using a controlled cortical impact model, we evaluated transcriptomic changes in the injured cortex at 24 hours post-injury, and confirmed activation of key neuroinflammatory pathways in biochemical studies. TBI induced changes were highly enriched for transcripts that were involved in inflammatory responses to stress and host defense. Deeper analysis revealed that TBI increased expression of IFN-I related genes (e.g. Ifnb1, Irf7, Ifi204, Isg15) and IFN-I signaling in the injured cortex of aged compared to young mice. There was also a significant age-related increase in the activation of the DNA-recognition pathway, cGAS, which is a key mechanism to propagate IFN-I responses. Finally, enhanced IFN-I signaling in the aged TBI brain was confirmed by increased phosphorylation of STAT1, an important IFN-I effector molecule. This age-related activation of cGAS and IFN-I signaling may prove to be a mechanistic link between microglial-associated neuroinflammation and neurodegeneration in the aged TBI brain.

Sign in / Sign up

Export Citation Format

Share Document