Pub Date : 2024-08-22eCollection Date: 2024-01-01DOI: 10.1089/neur.2024.0048
Jena N Moody, Erica Howard, Kate E Nolan, Sarah Prieto, Mark W Logue, Jasmeet P Hayes
Traumatic brain injuries (TBIs) may increase the risk for Alzheimer's disease (AD) and its neuropathological correlates, although the mechanisms of this relationship are unclear. The current study examined the synergistic effects of TBI and genetic risk for AD on β-amyloid (Aβ) levels among Vietnam War Veterans. We hypothesized that the combination of TBI and higher polygenic risk score (PRS) for AD would be associated with lower cerebrospinal fluid (CSF) Aβ42/40. Data were obtained from the Department of Defense Alzheimer's Disease Neuroimaging Initiative. Participants included Vietnam War Veterans without dementia who identified as White non-Hispanic/Latino and had available demographic, clinical assessment, genetic, and CSF biomarker data. Lifetime TBI history was assessed using The Ohio State University TBI Identification Method. Participants were categorized into those with and without TBI. Among those with a prior TBI, injury severity was defined as either mild or moderate/severe. CSF Aβ42/40 ratios were calculated. Genetic propensity for AD was assessed using PRSs. Hierarchical linear regression models examined the interactive effects of TBI and PRS for AD on Aβ42/40. Exploratory analyses examined the interaction between TBI severity and PRS. The final sample included 88 male Vietnam War Veterans who identified as White non-Hispanic/Latino (Mage = 68.3 years), 49 of whom reported a prior TBI. There was a significant interaction between TBI and PRS, such that individuals with TBI and higher PRS for AD had lower Aβ42/40 (B = -0.45, 95% CI: -0.86 to -0.05, p = 0.03). This relationship may be stronger with increasing TBI severity (p = 0.05). Overall, TBI was associated with lower Aβ42/40, indicating greater amyloid deposition in the brain, in the context of greater polygenic risk for AD. These findings highlight who may be at increased risk for AD neuropathology following TBI.
{"title":"Traumatic Brain Injury and Genetic Risk for Alzheimer's Disease Impact Cerebrospinal Fluid β-Amyloid Levels in Vietnam War Veterans.","authors":"Jena N Moody, Erica Howard, Kate E Nolan, Sarah Prieto, Mark W Logue, Jasmeet P Hayes","doi":"10.1089/neur.2024.0048","DOIUrl":"10.1089/neur.2024.0048","url":null,"abstract":"<p><p>Traumatic brain injuries (TBIs) may increase the risk for Alzheimer's disease (AD) and its neuropathological correlates, although the mechanisms of this relationship are unclear. The current study examined the synergistic effects of TBI and genetic risk for AD on β-amyloid (Aβ) levels among Vietnam War Veterans. We hypothesized that the combination of TBI and higher polygenic risk score (PRS) for AD would be associated with lower cerebrospinal fluid (CSF) Aβ<sub>42/40</sub>. Data were obtained from the Department of Defense Alzheimer's Disease Neuroimaging Initiative. Participants included Vietnam War Veterans without dementia who identified as White non-Hispanic/Latino and had available demographic, clinical assessment, genetic, and CSF biomarker data. Lifetime TBI history was assessed using The Ohio State University TBI Identification Method. Participants were categorized into those with and without TBI. Among those with a prior TBI, injury severity was defined as either mild or moderate/severe. CSF Aβ<sub>42/40</sub> ratios were calculated. Genetic propensity for AD was assessed using PRSs. Hierarchical linear regression models examined the interactive effects of TBI and PRS for AD on Aβ<sub>42/40</sub>. Exploratory analyses examined the interaction between TBI severity and PRS. The final sample included 88 male Vietnam War Veterans who identified as White non-Hispanic/Latino (<i>M</i> <sub>age</sub> = 68.3 years), 49 of whom reported a prior TBI. There was a significant interaction between TBI and PRS, such that individuals with TBI and higher PRS for AD had lower Aβ<sub>42/40</sub> (<i>B</i> = -0.45, 95% CI: -0.86 to -0.05, <i>p</i> = 0.03). This relationship may be stronger with increasing TBI severity (<i>p</i> = 0.05). Overall, TBI was associated with lower Aβ<sub>42/40</sub>, indicating greater amyloid deposition in the brain, in the context of greater polygenic risk for AD. These findings highlight <i>who</i> may be at increased risk for AD neuropathology following TBI.</p>","PeriodicalId":74300,"journal":{"name":"Neurotrauma reports","volume":null,"pages":null},"PeriodicalIF":1.8,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11342050/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142057448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-08eCollection Date: 2024-01-01DOI: 10.1089/neur.2024.0071
Julie O'Reilly-Fong, Nick J Simpson, Zahra S Thirouin, Paolo A Bastone, Cristian Zaelzer, Anzala Murtaz, Charles W Bourque
Central autonomic and endocrine dysfunctions following traumatic brain injury (TBI) are believed to involve the hypothalamus; however, underlying mechanisms are unknown. Although chronic deficits might be caused by irreversible tissue damage, various neuroendocrine and autonomic symptoms are only observed transiently, suggesting they might result from a temporary alteration in the activity of hypothalamic neurons. We therefore examined if a mouse model of mild TBI could induce reversible autonomic phenotypes and cause acute changes in c-Fos expression within corresponding regions of the hypothalamus. Adult C57Bl/6 male mice were lightly anesthetized with isoflurane and subjected to TBI by lateral head impact using a Gothenburg impactor. Mice treated the same way, but without the head impact served as controls (shams). We monitored body weight and core body temperature by infrared thermography and performed immunohistochemistry against c-Fos in various regions of the hypothalamus. We determined that a projectile velocity of 9 m/s significantly delayed recovery from the anesthesia without inducing skull fractures and signs of discomfort disappeared within 3 h, as assessed by grimace scale. Compared with shams, TBI mice displayed a rapid decrease in core body temperature which resolved within 48 h. Daily body weight gain was also significantly lower in TBI mice on the day following injury but recovered thereafter. c-Fos analysis revealed a significantly higher density of c-Fos-positive cells in the paraventricular nucleus and a significantly lower density in the median preoptic nucleus and medial preoptic area. We conclude that mild TBI induced by a single lateral head impact in mice at 9 m/s produces acute and reversible symptoms associated with hypothalamic dysfunction accompanied by significant changes in c-Fos expression within relevant areas of the hypothalamus. These findings support the hypothesis that a temporary alteration of neuronal activity may underlie the expression of reversible central autonomic and neuroendocrine symptoms.
{"title":"Acute and Reversible Hypothalamic Symptoms in a Lateral Head Impact Mouse Model of Mild Traumatic Brain Injury.","authors":"Julie O'Reilly-Fong, Nick J Simpson, Zahra S Thirouin, Paolo A Bastone, Cristian Zaelzer, Anzala Murtaz, Charles W Bourque","doi":"10.1089/neur.2024.0071","DOIUrl":"10.1089/neur.2024.0071","url":null,"abstract":"<p><p>Central autonomic and endocrine dysfunctions following traumatic brain injury (TBI) are believed to involve the hypothalamus; however, underlying mechanisms are unknown. Although chronic deficits might be caused by irreversible tissue damage, various neuroendocrine and autonomic symptoms are only observed transiently, suggesting they might result from a temporary alteration in the activity of hypothalamic neurons. We therefore examined if a mouse model of mild TBI could induce reversible autonomic phenotypes and cause acute changes in c-Fos expression within corresponding regions of the hypothalamus. Adult C57Bl/6 male mice were lightly anesthetized with isoflurane and subjected to TBI by lateral head impact using a Gothenburg impactor. Mice treated the same way, but without the head impact served as controls (shams). We monitored body weight and core body temperature by infrared thermography and performed immunohistochemistry against c-Fos in various regions of the hypothalamus. We determined that a projectile velocity of 9 m/s significantly delayed recovery from the anesthesia without inducing skull fractures and signs of discomfort disappeared within 3 h, as assessed by grimace scale. Compared with shams, TBI mice displayed a rapid decrease in core body temperature which resolved within 48 h. Daily body weight gain was also significantly lower in TBI mice on the day following injury but recovered thereafter. c-Fos analysis revealed a significantly higher density of c-Fos-positive cells in the paraventricular nucleus and a significantly lower density in the median preoptic nucleus and medial preoptic area. We conclude that mild TBI induced by a single lateral head impact in mice at 9 m/s produces acute and reversible symptoms associated with hypothalamic dysfunction accompanied by significant changes in c-Fos expression within relevant areas of the hypothalamus. These findings support the hypothesis that a temporary alteration of neuronal activity may underlie the expression of reversible central autonomic and neuroendocrine symptoms.</p>","PeriodicalId":74300,"journal":{"name":"Neurotrauma reports","volume":null,"pages":null},"PeriodicalIF":1.8,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11342051/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142057515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-31eCollection Date: 2024-01-01DOI: 10.1089/neur.2024.0023
Anne Caroline Rodrigues Dos Santos, Renata Pereira Laurindo, Fernanda Marques Pestana, Luiza Dos Santos Heringer, Nathalie Henrique Silva Canedo, Ana Maria Blanco Martinez, Suelen Adriani Marques
Traumatic spinal cord injury (SCI) causes debilitating motor and sensory deficits that impair functional performance, and physical rehabilitation is currently the only established therapeutic reality in the clinical setting. In this study, we aimed to assess the effect of exercise of different volume and timing of intervention on functional recovery and neuromuscular regeneration in a mouse model of compressive SCI. Mice were assigned to one of four groups: laminectomy only (SHAM); injured, without treadmill training (SCI); injured, treadmill trained for 10 min until day 56 postinjury (TMT1); and injured, treadmill trained for two 10-min cycles with a 10-min pause between them until day 28 postinjury followed by the TMT1 protocol until day 56 postinjury (TMT3). On day 7 postinjury, animals started an eight-week treadmill-training exercise protocol and were trained three times a week. TMT3 mice had the best results in terms of neuroregeneration, functional recovery, and muscle plasticity as measured by functional and morphometric parameters. In conclusion, the volume of exercise can modulate the quality of the regenerative response to injury, when started in the acute phase and adjusted according to the inflammatory window.
{"title":"Exercise Volume Can Modulate the Regenerative Response to Spinal Cord Injury in Mice.","authors":"Anne Caroline Rodrigues Dos Santos, Renata Pereira Laurindo, Fernanda Marques Pestana, Luiza Dos Santos Heringer, Nathalie Henrique Silva Canedo, Ana Maria Blanco Martinez, Suelen Adriani Marques","doi":"10.1089/neur.2024.0023","DOIUrl":"10.1089/neur.2024.0023","url":null,"abstract":"<p><p>Traumatic spinal cord injury (SCI) causes debilitating motor and sensory deficits that impair functional performance, and physical rehabilitation is currently the only established therapeutic reality in the clinical setting. In this study, we aimed to assess the effect of exercise of different volume and timing of intervention on functional recovery and neuromuscular regeneration in a mouse model of compressive SCI. Mice were assigned to one of four groups: laminectomy only (SHAM); injured, without treadmill training (SCI); injured, treadmill trained for 10 min until day 56 postinjury (TMT1); and injured, treadmill trained for two 10-min cycles with a 10-min pause between them until day 28 postinjury followed by the TMT1 protocol until day 56 postinjury (TMT3). On day 7 postinjury, animals started an eight-week treadmill-training exercise protocol and were trained three times a week. TMT3 mice had the best results in terms of neuroregeneration, functional recovery, and muscle plasticity as measured by functional and morphometric parameters. In conclusion, the volume of exercise can modulate the quality of the regenerative response to injury, when started in the acute phase and adjusted according to the inflammatory window.</p>","PeriodicalId":74300,"journal":{"name":"Neurotrauma reports","volume":null,"pages":null},"PeriodicalIF":1.8,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141984132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-31eCollection Date: 2024-01-01DOI: 10.1089/neur.2024.0026
Alexa E Walter, Krupa Savalia, Jason Yoon, Justin Morrison, Andrea L C Schneider, Ramon Diaz-Arrastia, Danielle K Sandsmark
Enlarged perivascular spaces (EPVs) can be seen on magnetic resonance imaging (MRI) scans in various neurological diseases, including traumatic brain injury (TBI). EPVs have been associated with cognitive dysfunction and sleep disturbances; however, their clinical significance remains unclear. The goal of this study was to identify MRI burden of EPVs over time following TBI and to explore their relationship with postinjury outcomes. Individuals with TBI underwent postinjury data collection at Day 1 (blood), 2 weeks (blood, MRI, outcomes), and 6 months (blood, MRI, outcomes). EPV burden was assessed using T1 and FLAIR sequences on representative slices in the centrum semiovale, basal ganglia, and midbrain. Serum blood was assayed to measure concentrations of neurofilament light (NfL) and glial fibrillary acidic protein (GFAP). Thirty-two participants with TBI were included (mean age 36.8 years, 78% male, 50% White). Total EPVs count did not significantly change from 2 weeks (23.5 [95% confidence interval or CI = 22.0-32.0]) to 6 months (26.0 [95% CI = 22.0-30.0], p = 0.16). For self-reported measures of sleep, there were no significant associations between EPVs count and Insomnia Severity Index (2 weeks: β = -0.004; 95% CI = -0.094, 0.086; 6 months: β = 0.002; 95% CI = -0.122, 0.125) or the subset of sleep questions on the Rivermead Post-Concussion Symptoms Questionnaire (2 weeks: β = -0.005; 95% CI = -0.049, 0.039; 6 months: β = -0.019; 95% CI = -0.079, 0.042). Functional outcome, determined by 6 months incomplete recovery (Glasgow Outcome Scale-Extended [GOS-E < 8]) versus complete recovery (GOS-E = 8), was significantly associated with a higher number of EPVs at 2 weeks (odds ratio = 0.94, 95% CI = 0.88-0.99). Spearman correlations showed no significant relationship between EPVs count and GFAP or NfL. This study used commonly acquired MRI sequences to quantify EPVs and investigated their utility as a potential imaging biomarker in TBI. Given the minimal change in EPVs over time, this period may not be long enough for potential recovery or may indicate that EPVs are structural findings that do not significantly change over time.
{"title":"Change in Enlarged Perivascular Spaces over Time and Associations with Outcomes After Traumatic Brain Injury.","authors":"Alexa E Walter, Krupa Savalia, Jason Yoon, Justin Morrison, Andrea L C Schneider, Ramon Diaz-Arrastia, Danielle K Sandsmark","doi":"10.1089/neur.2024.0026","DOIUrl":"10.1089/neur.2024.0026","url":null,"abstract":"<p><p>Enlarged perivascular spaces (EPVs) can be seen on magnetic resonance imaging (MRI) scans in various neurological diseases, including traumatic brain injury (TBI). EPVs have been associated with cognitive dysfunction and sleep disturbances; however, their clinical significance remains unclear. The goal of this study was to identify MRI burden of EPVs over time following TBI and to explore their relationship with postinjury outcomes. Individuals with TBI underwent postinjury data collection at Day 1 (blood), 2 weeks (blood, MRI, outcomes), and 6 months (blood, MRI, outcomes). EPV burden was assessed using T1 and FLAIR sequences on representative slices in the centrum semiovale, basal ganglia, and midbrain. Serum blood was assayed to measure concentrations of neurofilament light (NfL) and glial fibrillary acidic protein (GFAP). Thirty-two participants with TBI were included (mean age 36.8 years, 78% male, 50% White). Total EPVs count did not significantly change from 2 weeks (23.5 [95% confidence interval or CI = 22.0-32.0]) to 6 months (26.0 [95% CI = 22.0-30.0], <i>p</i> = 0.16). For self-reported measures of sleep, there were no significant associations between EPVs count and Insomnia Severity Index (2 weeks: β = -0.004; 95% CI = -0.094, 0.086; 6 months: β = 0.002; 95% CI = -0.122, 0.125) or the subset of sleep questions on the Rivermead Post-Concussion Symptoms Questionnaire (2 weeks: β = -0.005; 95% CI = -0.049, 0.039; 6 months: β = -0.019; 95% CI = -0.079, 0.042). Functional outcome, determined by 6 months incomplete recovery (Glasgow Outcome Scale-Extended [GOS-E < 8]) versus complete recovery (GOS-E = 8), was significantly associated with a higher number of EPVs at 2 weeks (odds ratio = 0.94, 95% CI = 0.88-0.99). Spearman correlations showed no significant relationship between EPVs count and GFAP or NfL. This study used commonly acquired MRI sequences to quantify EPVs and investigated their utility as a potential imaging biomarker in TBI. Given the minimal change in EPVs over time, this period may not be long enough for potential recovery or may indicate that EPVs are structural findings that do not significantly change over time.</p>","PeriodicalId":74300,"journal":{"name":"Neurotrauma reports","volume":null,"pages":null},"PeriodicalIF":1.8,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141984131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-29eCollection Date: 2024-01-01DOI: 10.1089/neur.2024.0062
Dean M Cordingley, Izabella Marquez, Serena C L Buchwald, Frederick A Zeiler
The purpose of this study was to identify the response of biomolecules and biomarkers that are associated with the central nervous system to aerobic exercise in human and pre-clinical models of concussion or mild traumatic brain injury (TBI), and to highlight the knowledge gaps in the literature. A systematic scoping review was conducted following a search of EMBASE, MEDLINE, SCOPUS, BIOSIS, and Cochrane Libraries performed on September 8, 2023 (from data base inception). The scoping review was reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews. Duplicates were removed and article screening was performed using an online systematic review management system. The search resulted in a total of 2,449 articles being identified, with 14 articles meeting the inclusion/exclusion criteria and having their data extracted. One study was conducted in humans, while the remainder of identified studies utilized murine models. The current literature is limited and evaluated many different biomolecules and biomarkers with brain-derived neurotrophic factor being the most researched. Further studies on this topic are needed to better understand the biomarker response to exercise after concussion and mild TBI, especially in the human population.
{"title":"Response of Central Nervous System Biomolecules and Systemic Biomarkers to Aerobic Exercise Following Concussion: A Scoping Review of Human and Animal Research.","authors":"Dean M Cordingley, Izabella Marquez, Serena C L Buchwald, Frederick A Zeiler","doi":"10.1089/neur.2024.0062","DOIUrl":"10.1089/neur.2024.0062","url":null,"abstract":"<p><p>The purpose of this study was to identify the response of biomolecules and biomarkers that are associated with the central nervous system to aerobic exercise in human and pre-clinical models of concussion or mild traumatic brain injury (TBI), and to highlight the knowledge gaps in the literature. A systematic scoping review was conducted following a search of EMBASE, MEDLINE, SCOPUS, BIOSIS, and Cochrane Libraries performed on September 8, 2023 (from data base inception). The scoping review was reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews. Duplicates were removed and article screening was performed using an online systematic review management system. The search resulted in a total of 2,449 articles being identified, with 14 articles meeting the inclusion/exclusion criteria and having their data extracted. One study was conducted in humans, while the remainder of identified studies utilized murine models. The current literature is limited and evaluated many different biomolecules and biomarkers with brain-derived neurotrophic factor being the most researched. Further studies on this topic are needed to better understand the biomarker response to exercise after concussion and mild TBI, especially in the human population.</p>","PeriodicalId":74300,"journal":{"name":"Neurotrauma reports","volume":null,"pages":null},"PeriodicalIF":1.8,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11301856/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141903885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-16eCollection Date: 2024-01-01DOI: 10.1089/neur.2024.0028
Peyton M Mueller, Abel Torres-Espín, Cole Vonder Haar
The field of neurotrauma is grappling with the effects of the recently identified replication crisis. As such, care must be taken to identify and perform the most appropriate statistical analyses. This will prevent misuse of research resources and ensure that conclusions are reasonable and within the scope of the data. We anticipate that Bayesian statistical methods will see increasing use in the coming years. Bayesian methods integrate prior beliefs (or prior data) into a statistical model to merge historical information and current experimental data. These methods may improve the ability to detect differences between experimental groups (i.e., statistical power) when used appropriately. However, researchers need to be aware of the strengths and limitations of such approaches if they are to implement or evaluate these analyses. Ultimately, an approach using Bayesian methodologies may have substantial benefits to statistical power, but caution needs to be taken when identifying and defining prior beliefs.
{"title":"Bayesian Methods: A Means of Improving Statistical Power in Preclinical Neurotrauma?","authors":"Peyton M Mueller, Abel Torres-Espín, Cole Vonder Haar","doi":"10.1089/neur.2024.0028","DOIUrl":"10.1089/neur.2024.0028","url":null,"abstract":"<p><p>The field of neurotrauma is grappling with the effects of the recently identified replication crisis. As such, care must be taken to identify and perform the most appropriate statistical analyses. This will prevent misuse of research resources and ensure that conclusions are reasonable and within the scope of the data. We anticipate that Bayesian statistical methods will see increasing use in the coming years. Bayesian methods integrate prior beliefs (or prior data) into a statistical model to merge historical information and current experimental data. These methods may improve the ability to detect differences between experimental groups (i.e., statistical power) when used appropriately. However, researchers need to be aware of the strengths and limitations of such approaches if they are to implement or evaluate these analyses. Ultimately, an approach using Bayesian methodologies may have substantial benefits to statistical power, but caution needs to be taken when identifying and defining prior beliefs.</p>","PeriodicalId":74300,"journal":{"name":"Neurotrauma reports","volume":null,"pages":null},"PeriodicalIF":1.8,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11271152/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141790250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-16eCollection Date: 2024-01-01DOI: 10.1089/neur.2024.0039
Jawad Turfa, Ali Hijazi, Yasser Fadlallah, Melhem El-Harati, Hani Dimassi, Marwan El Najjar
Traumatic brain injury (TBI) is the leading cause of death among trauma patients. Identifying preoperative factors that predict postoperative outcomes in such patients can guide surgical decision-making. The aim of this study was to develop a predictive model using preoperative variables that predicts 30-day mortality and morbidity in patients undergoing neurosurgery following TBI. The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database was queried between 2005 and 2017 for patients aged 18 years or older who underwent TBI-specific surgery. The primary outcome was 30-day mortality, and the secondary outcome was a composite morbidity score. Significant variables on univariate analysis with Chi-squared test were used to compute multivariable logistic regression models for both outcomes, and Hosmer-Lemeshow test was used. A total of 1634 patients met the inclusion criteria. Most patients were elderly aged >60 years (74.48%), male (63.59%), of White race (73.62%), and non-Hispanic ethnicity (82.44%). The overall 30-day mortality rate was 20.3%. Using multivariate logistic regression, 11 preoperative variables were significantly associated with 30-day mortality, including (aOR, 95% CI) age 70-79 years (3.38, 2.03-5.62) and age >80 years (7.70, 4.74-12.51), ventilator dependency (6.04, 4.21-8.67), receiving dialysis (4.97, 2.43-10.18), disseminated cancer (4.42, 1.50-13.0), and coma >24 hours (3.30, 1.40-7.80), among others. Similarly, 12 preoperative variables were found to be significantly associated with 30-day morbidity, including acute renal failure (7.10, 1.91-26.32), return to OR (3.82, 2.77-5.27), sepsis (3.27, 1.11-9.66), prior operation within 30 days (2.55, 1.06-4.95), and insulin-dependent diabetes (1.60, 1.06-2.40), among others. After constructing receiver operating characteristic curve, the model for mortality had an area under the curve (AUC) of 0.843, whereas composite morbidity had an AUC of 0.716. This model can aid in clinical decision-making for triaging patients based on prognosis in cases of mass casualty events.
{"title":"Predictors of 30-Day Mortality and Morbidity Following Craniotomy for Traumatic Brain Injury: An ACS NSQIP Database Analysis.","authors":"Jawad Turfa, Ali Hijazi, Yasser Fadlallah, Melhem El-Harati, Hani Dimassi, Marwan El Najjar","doi":"10.1089/neur.2024.0039","DOIUrl":"10.1089/neur.2024.0039","url":null,"abstract":"<p><p>Traumatic brain injury (TBI) is the leading cause of death among trauma patients. Identifying preoperative factors that predict postoperative outcomes in such patients can guide surgical decision-making. The aim of this study was to develop a predictive model using preoperative variables that predicts 30-day mortality and morbidity in patients undergoing neurosurgery following TBI. The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database was queried between 2005 and 2017 for patients aged 18 years or older who underwent TBI-specific surgery. The primary outcome was 30-day mortality, and the secondary outcome was a composite morbidity score. Significant variables on univariate analysis with Chi-squared test were used to compute multivariable logistic regression models for both outcomes, and Hosmer-Lemeshow test was used. A total of 1634 patients met the inclusion criteria. Most patients were elderly aged >60 years (74.48%), male (63.59%), of White race (73.62%), and non-Hispanic ethnicity (82.44%). The overall 30-day mortality rate was 20.3%. Using multivariate logistic regression, 11 preoperative variables were significantly associated with 30-day mortality, including (aOR, 95% CI) age 70-79 years (3.38, 2.03-5.62) and age >80 years (7.70, 4.74-12.51), ventilator dependency (6.04, 4.21-8.67), receiving dialysis (4.97, 2.43-10.18), disseminated cancer (4.42, 1.50-13.0), and coma >24 hours (3.30, 1.40-7.80), among others. Similarly, 12 preoperative variables were found to be significantly associated with 30-day morbidity, including acute renal failure (7.10, 1.91-26.32), return to OR (3.82, 2.77-5.27), sepsis (3.27, 1.11-9.66), prior operation within 30 days (2.55, 1.06-4.95), and insulin-dependent diabetes (1.60, 1.06-2.40), among others. After constructing receiver operating characteristic curve, the model for mortality had an area under the curve (AUC) of 0.843, whereas composite morbidity had an AUC of 0.716. This model can aid in clinical decision-making for triaging patients based on prognosis in cases of mass casualty events.</p>","PeriodicalId":74300,"journal":{"name":"Neurotrauma reports","volume":null,"pages":null},"PeriodicalIF":1.8,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11271074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141790178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-16eCollection Date: 2024-01-01DOI: 10.1089/neur.2024.0025
Katherine O'Meara, Ava M Puccio, Dianxu Ren, Sandra Deslouches, Ruchira Jha, David O Okonkwo, Yvette P Conley
Management of severe traumatic brain injury (sTBI) typically involves the use of sedation, which inherently results in benefits and risks. The cytochrome P450 enzyme CYP2B6 is involved in the biotransformation of particular drug classes, including many intravenous sedatives. Variants of the CYP2B6 gene can lead to decreased systemic clearance of some sedatives, including propofol. This study aimed to investigate the relationship of CYP2B6 gene variation and patient outcomes after TBI while also considering propofol administration. Patients who sustained a non-penetrating sTBI and admitted to a single-center Level 1 trauma hospital were included in this study (n = 440). The *6 functional allele of CYP2B6 that leads to reduced enzyme expression and activity required genotyping two single nucleotide polymorphisms, rs3745274 and rs2279343. Patient outcomes were evaluated using the Glasgow Outcome Scale (GOS) and Disability Rating Scale (DRS) at 3 and 6 months post-injury. Data on sedative administration were abstracted from medical records. Individuals homozygous for the alleles coding for the reduced enzyme expression and activity were more likely to have worse outcomes. A relationship between propofol administration and 3-month GOS and 6-month DRS was noted when controlling for CYP2B6 genotype. These findings suggest that genetic variation in CYP2B6 may influence the impact of intravenous sedation on patient outcomes after TBI and warrants further investigation.
{"title":"The Influence of CYP2B6 Variants and Administration of Propofol on Patient Outcomes after Traumatic Brain Injury.","authors":"Katherine O'Meara, Ava M Puccio, Dianxu Ren, Sandra Deslouches, Ruchira Jha, David O Okonkwo, Yvette P Conley","doi":"10.1089/neur.2024.0025","DOIUrl":"10.1089/neur.2024.0025","url":null,"abstract":"<p><p>Management of severe traumatic brain injury (sTBI) typically involves the use of sedation, which inherently results in benefits and risks. The cytochrome P450 enzyme CYP2B6 is involved in the biotransformation of particular drug classes, including many intravenous sedatives. Variants of the <i>CYP2B6</i> gene can lead to decreased systemic clearance of some sedatives, including propofol. This study aimed to investigate the relationship of <i>CYP2B6</i> gene variation and patient outcomes after TBI while also considering propofol administration. Patients who sustained a non-penetrating sTBI and admitted to a single-center Level 1 trauma hospital were included in this study (<i>n</i> = 440). The *6 functional allele of <i>CYP2B6</i> that leads to reduced enzyme expression and activity required genotyping two single nucleotide polymorphisms, rs3745274 and rs2279343. Patient outcomes were evaluated using the Glasgow Outcome Scale (GOS) and Disability Rating Scale (DRS) at 3 and 6 months post-injury. Data on sedative administration were abstracted from medical records. Individuals homozygous for the alleles coding for the reduced enzyme expression and activity were more likely to have worse outcomes. A relationship between propofol administration and 3-month GOS and 6-month DRS was noted when controlling for <i>CYP2B6</i> genotype. These findings suggest that genetic variation in <i>CYP2B6</i> may influence the impact of intravenous sedation on patient outcomes after TBI and warrants further investigation.</p>","PeriodicalId":74300,"journal":{"name":"Neurotrauma reports","volume":null,"pages":null},"PeriodicalIF":1.8,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11271148/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141790179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-16eCollection Date: 2024-01-01DOI: 10.1089/neur.2024.0038
Emma G Iorio, Alireza Khanteymoori, Kenneth A Fond, Anastasia V Keller, Lex Maliga Davis, Jan M Schwab, Adam R Ferguson, Abel Torres-Espin, Ralf Watzlawick
Translation of spinal cord injury (SCI) therapeutics from pre-clinical animal studies into human studies is challenged by effect size variability, irreproducibility, and misalignment of evidence used by pre-clinical versus clinical literature. Clinical literature values reproducibility, with the highest grade evidence (class 1) consisting of meta-analysis demonstrating large therapeutic efficacy replicating across multiple studies. Conversely, pre-clinical literature values novelty over replication and lacks rigorous meta-analyses to assess reproducibility of effect sizes across multiple articles. Here, we applied modified clinical meta-analysis methods to pre-clinical studies, comparing effect sizes extracted from published literature to raw data on individual animals from these same studies. Literature-extracted data (LED) from numerical and graphical outcomes reported in publications were compared with individual animal data (IAD) deposited in a federally supported repository of SCI data. The animal groups from the IAD were matched with the same cohorts in the LED for a direct comparison. We applied random-effects meta-analysis to evaluate predictors of neuroconversion in LED versus IAD. We included publications with common injury models (contusive injuries) and standardized end-points (open field assessments). The extraction of data from 25 published articles yielded n = 1841 subjects, whereas IAD from these same articles included n = 2441 subjects. We observed differences in the number of experimental groups and animals per group, insufficient reporting of dropout animals, and missing information on experimental details. Meta-analysis revealed differences in effect sizes across LED versus IAD stratifications, for instance, severe injuries had the largest effect size in LED (standardized mean difference [SMD = 4.92]), but mild injuries had the largest effect size in IAD (SMD = 6.06). Publications with smaller sample sizes yielded larger effect sizes, while studies with larger sample sizes had smaller effects. The results demonstrate the feasibility of combining IAD analysis with traditional LED meta-analysis to assess effect size reproducibility in SCI.
脊髓损伤(SCI)疗法从临床前动物研究转化为人体研究面临着效应大小可变性、不可再现性以及临床前文献与临床文献所用证据不一致的挑战。临床文献重视可重复性,最高级别的证据(1 级)由荟萃分析组成,可在多项研究中重复显示巨大的疗效。相反,临床前文献重视新颖性而非重复性,缺乏严格的荟萃分析来评估多篇文章中效应大小的重复性。在此,我们将修改后的临床荟萃分析方法应用于临床前研究,比较了从已发表文献中提取的效应大小与这些相同研究中的动物个体原始数据。我们将从出版物中报告的数字和图表结果中提取的文献数据(LED)与存放在联邦政府支持的 SCI 数据库中的动物个体数据(IAD)进行了比较。IAD 中的动物组群与 LED 中的相同组群相匹配,以便进行直接比较。我们采用随机效应荟萃分析来评估 LED 与 IAD 中神经转换的预测因素。我们纳入了具有共同损伤模型(挫伤)和标准化终点(开放场地评估)的出版物。从 25 篇已发表的文章中提取的数据得出了 n = 1841 个受试者,而从这些相同的文章中提取的 IAD 数据则得出了 n = 2441 个受试者。我们观察到实验组和每组动物数量的差异、对辍学动物报告的不足以及实验细节信息的缺失。Meta 分析显示,LED 与 IAD 分层的效应大小存在差异,例如,重度损伤在 LED 中的效应大小最大(标准化平均差 [SMD = 4.92]),但轻度损伤在 IAD 中的效应大小最大(SMD = 6.06)。样本量较小的文献产生的效应大小较大,而样本量较大的研究产生的效应较小。结果表明,将IAD分析与传统的LED荟萃分析相结合来评估SCI的效应大小再现性是可行的。
{"title":"Effect-Size Discrepancies in Literature Versus Raw Datasets from Experimental Spinal Cord Injury Studies: A CLIMBER Meta-Analysis.","authors":"Emma G Iorio, Alireza Khanteymoori, Kenneth A Fond, Anastasia V Keller, Lex Maliga Davis, Jan M Schwab, Adam R Ferguson, Abel Torres-Espin, Ralf Watzlawick","doi":"10.1089/neur.2024.0038","DOIUrl":"10.1089/neur.2024.0038","url":null,"abstract":"<p><p>Translation of spinal cord injury (SCI) therapeutics from pre-clinical animal studies into human studies is challenged by effect size variability, irreproducibility, and misalignment of evidence used by pre-clinical versus clinical literature. Clinical literature values reproducibility, with the highest grade evidence (class 1) consisting of meta-analysis demonstrating large therapeutic efficacy replicating across multiple studies. Conversely, pre-clinical literature values novelty over replication and lacks rigorous meta-analyses to assess reproducibility of effect sizes across multiple articles. Here, we applied modified clinical meta-analysis methods to pre-clinical studies, comparing effect sizes extracted from published literature to raw data on individual animals from these same studies. Literature-extracted data (LED) from numerical and graphical outcomes reported in publications were compared with individual animal data (IAD) deposited in a federally supported repository of SCI data. The animal groups from the IAD were matched with the same cohorts in the LED for a direct comparison. We applied random-effects meta-analysis to evaluate predictors of neuroconversion in LED versus IAD. We included publications with common injury models (contusive injuries) and standardized end-points (open field assessments). The extraction of data from 25 published articles yielded <i>n</i> = 1841 subjects, whereas IAD from these same articles included <i>n</i> = 2441 subjects. We observed differences in the number of experimental groups and animals per group, insufficient reporting of dropout animals, and missing information on experimental details. Meta-analysis revealed differences in effect sizes across LED versus IAD stratifications, for instance, severe injuries had the largest effect size in LED (standardized mean difference [SMD = 4.92]), but mild injuries had the largest effect size in IAD (SMD = 6.06). Publications with smaller sample sizes yielded larger effect sizes, while studies with larger sample sizes had smaller effects. The results demonstrate the feasibility of combining IAD analysis with traditional LED meta-analysis to assess effect size reproducibility in SCI.</p>","PeriodicalId":74300,"journal":{"name":"Neurotrauma reports","volume":null,"pages":null},"PeriodicalIF":1.8,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11271150/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141790175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-16eCollection Date: 2024-01-01DOI: 10.1089/neur.2024.0040
Shawn R Eagle, Rebecca J Henry
A sizable proportion of patients with mild traumatic brain injury (mTBI) have persistent symptoms and functional impairments months to years following injury. This phenomenon is continually observed despite an explosion of research and interest in improving mTBI clinical outcomes over the last two decades. All pharmacological clinical trials to date have failed to demonstrate improved outcomes for mTBI. One possible explanation for these continued failures is an overly myopic approach to treating mTBI (i.e., testing the effect of a single drug with a specific mechanism on a group of people with highly heterogenous injuries). Clinical presentation and prognosis of mTBI vary considerably between patients, and yet we continue to assess group-level effects of a homogenized treatment. We need to utilize an equally complex treatment approach to match the extraordinary complexity of the human brain. Dynamical systems theory has been used to describe systems composed of multiple subsystems who function somewhat independently but are ultimately interconnected. This theory was popularized in the motor control literature as an overarching framework for how the mind and body connect to interact and move through the environment. However, the human body can be viewed as a dynamical system composed of multiple subsystems (i.e., organ systems) who have isolated functions, which are also codependent on the health and performance of other interconnected organ systems. In this perspective piece, we will use the example of mTBI in the obese patient to demonstrate how broadening our approach to treatment of the individual (and not necessarily the injury) may ultimately yield improved outcomes. Furthermore, we will explore clinical and pre-clinical evidence demonstrating multiple system interactions in the context of obesity and TBI and discuss how expanding our understanding of the mechanistic interplay between multiple organ systems may ultimately provide a more personalized treatment approach for this mTBI patient subpopulation.
{"title":"Applying Dynamical Systems Theory to Improve Personalized Medicine Following Mild Traumatic Brain Injury.","authors":"Shawn R Eagle, Rebecca J Henry","doi":"10.1089/neur.2024.0040","DOIUrl":"10.1089/neur.2024.0040","url":null,"abstract":"<p><p>A sizable proportion of patients with mild traumatic brain injury (mTBI) have persistent symptoms and functional impairments months to years following injury. This phenomenon is continually observed despite an explosion of research and interest in improving mTBI clinical outcomes over the last two decades. All pharmacological clinical trials to date have failed to demonstrate improved outcomes for mTBI. One possible explanation for these continued failures is an overly myopic approach to treating mTBI (i.e., testing the effect of a single drug with a specific mechanism on a group of people with highly heterogenous injuries). Clinical presentation and prognosis of mTBI vary considerably between patients, and yet we continue to assess group-level effects of a homogenized treatment. We need to utilize an equally complex treatment approach to match the extraordinary complexity of the human brain. Dynamical systems theory has been used to describe systems composed of multiple subsystems who function somewhat independently but are ultimately interconnected. This theory was popularized in the motor control literature as an overarching framework for how the mind and body connect to interact and move through the environment. However, the human body can be viewed as a dynamical system composed of multiple subsystems (i.e., organ systems) who have isolated functions, which are also codependent on the health and performance of other interconnected organ systems. In this perspective piece, we will use the example of mTBI in the obese patient to demonstrate how broadening our approach to treatment of the individual (and not necessarily the injury) may ultimately yield improved outcomes. Furthermore, we will explore clinical and pre-clinical evidence demonstrating multiple system interactions in the context of obesity and TBI and discuss how expanding our understanding of the mechanistic interplay between multiple organ systems may ultimately provide a more personalized treatment approach for this mTBI patient subpopulation.</p>","PeriodicalId":74300,"journal":{"name":"Neurotrauma reports","volume":null,"pages":null},"PeriodicalIF":1.8,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11271149/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141790249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}