Fluctuations in blood biomarkers of head trauma in NCAA football athletes over the course of a season

OBJECTIVERepetitive subconcussive head trauma is a consequence of participation in contact sports and may be linked to neurodegenerative diseases. The degree of neurological injury caused by subconcussive head trauma is not easily detectible, and this injury does not induce readily identifiable clinical signs or symptoms. Recent advancements in immunoassays make possible the detection and quantification of blood biomarkers linked to head trauma. Identification of a blood biomarker that can identify the extent of neurological injury associated with subconcussive head trauma may provide an objective measure for informed decisions concerning cumulative exposure to subconcussive head trauma. The purpose of the current study was to examine changes in the blood biomarkers of subconcussive head trauma over the course of an American football season.METHODSThirty-five National Collegiate Athletic Association (NCAA) American football athletes underwent blood sampling throughout the course of a football season. Serial samples were obtained throughout the 2016 season, during which the number and magnitude of head impacts changed. Blood samples were analyzed for plasma concentrations of tau and serum concentrations of neurofilament light polypeptide (NF-L). Athletes were grouped based on their starter status, because athletes identified as starters are known to sustain a greater number of impacts. Between-group differences and time-course differences were assessed.RESULTSIn nonstarters, plasma concentrations of tau decreased over the course of the season, with lower values observed in starters; this resulted in a lower area under the curve (AUC) (starters: 416.78 ± 129.17 pg/ml/day; nonstarters: 520.84 ± 163.19 pg/ml/day; p = 0.050). Plasma concentrations of tau could not be used to discern between starters and nonstarters. In contrast, serum concentrations of NF-L increased throughout the season as head impacts accumulated, specifically in those athletes categorized as starters. The higher serum concentrations of NF-L observed in starters resulted in a larger AUC (starters: 1605.03 ± 655.09 pg/ml/day; nonstarters: 1067.29 ± 272.33 pg/ml/day; p = 0.007). The AUC of the receiver operating characteristic curve analyses displayed fair to modest accuracy to identify athletes who were starters with the use of serum NF-L following periods of repetitive impacts.CONCLUSIONSThe different patterns observed in serum NF-L and plasma tau concentrations provide preliminary evidence for the use of blood biomarkers to detect the neurological injury associated with repetitive subconcussive head trauma. Although further investigation is necessary, such findings might lay the foundation for the further development of an objective measure for the detection of neurological injury caused by subconcussive head trauma.

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The Neuropathology of Chronic Traumatic Encephalopathy: The Status of the Literature

Seminars in Neurology ◽

10.1055/s-0040-1713632 ◽

2020 ◽

Vol 40 (04) ◽

pp. 359-369

Author(s):

Ann C. McKee

Keyword(s):

White Matter ◽

Head Trauma ◽

Chronic Traumatic Encephalopathy ◽

The Elderly ◽

Brain Regions ◽

American Football ◽

Cumulative Exposure ◽

Football Players ◽

Tau Pathology ◽

The Status

AbstractChronic traumatic encephalopathy (CTE) is a tauopathy associated with repetitive mild head trauma, including concussion and asymptomatic subconcussive impacts. CTE was first recognized in boxers almost a century ago and has been identified more recently in contact sports athletes, military veterans exposed to blast, and victims of domestic violence. Like most neurodegenerative diseases, CTE is diagnosed conclusively by a neuropathological examination of brain tissue. CTE is characterized by the buildup of hyperphosphorylated tau (p-tau) in neurofibrillary tangles (NFTs), neurites, and, sometimes, astrocytes, surrounding small blood vessels in a patchy distribution at the sulcal depths of the cerebral cortex. In 2015, using the McKee proposed criteria for the neuropathological diagnosis of CTE, a consensus panel of expert neuropathologists confirmed CTE as a unique neurodegenerative disease with a pathognomonic lesion and published the preliminary NINDS (National Institute of Neurological Disorders and Stroke) criteria for CTE. Since that time, the NINDS criteria for CTE have been implemented and validated in multiple international publications. Using the NINDS criteria, the largest clinicopathological series of CTE to date was reported that included 177 former American football players, including 110 (99%) of 111 former National Football League players, 48 (91%) of 53 former college football players, and 3 (21%) of 14 former high school players. Studies have also shown a significant association between cumulative exposure to repetitive head trauma, as judged by the length of American football playing career, and risk for and severity of CTE. There is also a significant relationship of the length of football playing career with p-tau pathology, inflammation, white matter rarefaction, and age at death in CTE. While p-tau pathology, inflammation, white matter rarefaction, and arteriolosclerosis contribute to dementia in CTE, whether they also influence the behavioral and mood symptoms in CTE has yet to be determined. There have been several instances of aging-related tau astrogliopathy (ARTAG), a common astrocytic pathology in the elderly, misdiagnosed as CTE in the recent literature, provoking claims that CTE pathology is present in people not known to have experienced repetitive head trauma. Although ARTAG is often found in CTE, the pathognomonic lesion of CTE is a neuronal lesion consisting of NFTs and neurites, with or without p-tau immunoreactive astrocytes. Some authors consider β-amyloid (Aβ) to be a primary feature of CTE, yet the data indicate that CTE is a primary tauopathy, with Aβ deposition a function of age and inheritance of the ApoEe4 allele. Some authors also question the progressive nature of CTE pathology, although there is clear evidence in most individuals that p-tau pathology increases in density and affects more brain regions with survival. This review is intended to outline the status of the evidence-based literature regarding CTE neuropathology and to address the misrepresentations and confusions that have arisen in recent reviews and a letter of correspondence.

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The Effect of Bilateral Nephrectomy on Renalase and Catecholamines in Hemodialysis Patients

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18126282 ◽

2021 ◽

Vol 18 (12) ◽

pp. 6282

Author(s):

Magda Wiśniewska ◽

Natalia Serwin ◽

Violetta Dziedziejko ◽

Małgorzata Marchelek-Myśliwiec ◽

Barbara Dołęgowska ◽

...

Keyword(s):

Healthy Subjects ◽

Plasma Concentrations ◽

Serum Levels ◽

Hemodialysis Patients ◽

Pressure Regulation ◽

Serum Concentrations ◽

Monoamine Oxidase Activity ◽

Normal Kidney ◽

Bilateral Nephrectomy ◽

Arterial Blood

Background/Aims: Renalase is an enzyme with monoamine oxidase activity that metabolizes catecholamines; therefore, it has a significant influence on arterial blood pressure regulation and the development of cardiovascular diseases. Renalase is mainly produced in the kidneys. Nephrectomy and hemodialysis (HD) may alter the production and metabolism of renalase. The aim of this study was to examine the effect of bilateral nephrectomy on renalase levels in the serum and erythrocytes of hemodialysis patients. Methods: This study included 27 hemodialysis patients post-bilateral nephrectomy, 46 hemodialysis patients without nephrectomy but with chronic kidney disease and anuria and 30 healthy subjects with normal kidney function. Renalase levels in the serum and erythrocytes were measured using an ELISA kit. Results: Serum concentrations of renalase were significantly higher in post-bilateral nephrectomy patients when compared with those of control subjects (101.1 ± 65.5 vs. 19.6 ± 5.0; p < 0.01). Additionally, renalase concentrations, calculated per gram of hemoglobin, were significantly higher in patients after bilateral nephrectomy in comparison with those of healthy subjects (994.9 ± 345.5 vs. 697.6 ± 273.4, p = 0.015). There were no statistically significant differences in plasma concentrations of noradrenaline or adrenaline. In contrast, the concentration of dopamine was significantly lower in post-nephrectomy patients when compared with those of healthy subjects (116.8 ± 147.7 vs. 440.9 ± 343.2, p < 0.01). Conclusions: Increased serum levels of renalase in post-bilateral nephrectomy hemodialysis patients are likely related to production in extra-renal organs as a result of changes in the cardiovascular system and hypertension.

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Blood neurofilament light concentration at admittance: a potential prognostic marker in COVID-19

Journal of Neurology ◽

10.1007/s00415-021-10517-6 ◽

2021 ◽

Author(s):

Anne Hege Aamodt ◽

Einar August Høgestøl ◽

Trine Haug Popperud ◽

Jan Cato Holter ◽

Anne Ma Dyrhol-Riise ◽

...

Keyword(s):

Nervous System ◽

Single Molecule ◽

Linear Models ◽

Clinical Signs ◽

Repeated Measurements ◽

Cns Injury ◽

Serum Concentrations ◽

Blood Biomarkers ◽

Neurofilament Light Chain ◽

Neurofilament Light

Abstract Objective To test the hypotheses that blood biomarkers for nervous system injury, serum concentrations of neurofilament light chain protein (NfL) and glial fibrillary acidic protein (GFAp) can serve as biomarkers for disease severity in COVID-19 patients. Methods Forty-seven inpatients with confirmed COVID-19 had blood samples drawn on admission for assessing serum biomarkers of CNS injury by Single molecule array (Simoa), NfL and GFAp. Concentrations of NfL and GFAp were analyzed in relation to symptoms, clinical signs, inflammatory biomarkers and clinical outcomes. We used multivariate linear models to test for differences in biomarker concentrations in the subgroups, accounting for confounding effects. Results In total, 21% (n = 10) of the patients were admitted to an intensive care unit, and the overall mortality rate was 13% (n = 6). Non-survivors had higher serum concentrations of NfL (p < 0.001) upon admission than patients who were discharged alive both in adjusted analyses (p = 2.6 × 10–7) and unadjusted analyses (p = 0.001). The concentrations of NfL in non-survivors increased over repeated measurements; whereas, the concentrations in survivors were stable. The GFAp concentration was also significantly higher in non-survivors than survivors (p = 0.02). Conclusion Increased concentrations of NfL and GFAp in COVID-19 patients on admission may indicate increased mortality risk. Measurement of blood biomarkers for nervous system injury can be useful to detect and monitor CNS injury in COVID-19.

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Gastrin and the Moderate Hypergastrinemias

International Journal of Molecular Sciences ◽

10.3390/ijms22136977 ◽

2021 ◽

Vol 22 (13) ◽

pp. 6977

Author(s):

Jens F. Rehfeld

Keyword(s):

Helicobacter Pylori ◽

Plasma Concentrations ◽

Antral Mucosa ◽

Serum Concentrations ◽

Health Issues ◽

Gastrin Secretion ◽

Mucosal Growth ◽

Early Phases ◽

Molecular Nature ◽

Concentration Levels

The antral hormone gastrin potently regulates gastric acid secretion and fundic mucosal growth. Consequently, appropriate gastrin secretion and plasma concentrations are important for the early phases of digestion. This review describes as the first premise the normal biogenesis of gastrin in the antral mucosa, but also mentions the extraantral expression. Subsequently, the molecular nature and concentration levels of gastrin in serum or plasma are overviewed. Third, assays for accurate measurements of plasma or serum concentrations are commented. Finally, the problem of moderate hypergastrinemia due to Helicobacter pylori infections and/or treatment with proton-pump inhibitors (PPI) is discussed. The review concludes that accurate measurement of the true concentrations of bioactive gastrins in plasma is important. Moreover, it suggests that moderate hypergastrinemias are also essential health issues that require serious attention.

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Identifying degenerative effects of repetitive head trauma with neuroimaging: a clinically-oriented review

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01197-4 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Breton M. Asken ◽

Gil D. Rabinovici

Keyword(s):

Head Trauma ◽

Pet Imaging ◽

Fdg Pet ◽

Chronic Traumatic Encephalopathy ◽

Structural Mri ◽

Disease Diagnosis ◽

Underlying Disease ◽

American Football ◽

Cavum Septum Pellucidum ◽

Tau Pet

Abstract Background and Scope of Review Varying severities and frequencies of head trauma may result in dynamic acute and chronic pathophysiologic responses in the brain. Heightened attention to long-term effects of head trauma, particularly repetitive head trauma, has sparked recent efforts to identify neuroimaging biomarkers of underlying disease processes. Imaging modalities like structural magnetic resonance imaging (MRI) and positron emission tomography (PET) are the most clinically applicable given their use in neurodegenerative disease diagnosis and differentiation. In recent years, researchers have targeted repetitive head trauma cohorts in hopes of identifying in vivo biomarkers for underlying biologic changes that might ultimately improve diagnosis of chronic traumatic encephalopathy (CTE) in living persons. These populations most often include collision sport athletes (e.g., American football, boxing) and military veterans with repetitive low-level blast exposure. We provide a clinically-oriented review of neuroimaging data from repetitive head trauma cohorts based on structural MRI, FDG-PET, Aβ-PET, and tau-PET. We supplement the review with two patient reports of neuropathology-confirmed, clinically impaired adults with prior repetitive head trauma who underwent structural MRI, FDG-PET, Aβ-PET, and tau-PET in addition to comprehensive clinical examinations before death. Review Conclusions Group-level comparisons to controls without known head trauma have revealed inconsistent regional volume differences, with possible propensity for medial temporal, limbic, and subcortical (thalamus, corpus callosum) structures. Greater frequency and severity (i.e., length) of cavum septum pellucidum (CSP) is observed in repetitive head trauma cohorts compared to unexposed controls. It remains unclear whether CSP predicts a particular neurodegenerative process, but CSP presence should increase suspicion that clinical impairment is at least partly attributable to the individual’s head trauma exposure (regardless of underlying disease). PET imaging similarly has not revealed a prototypical metabolic or molecular pattern associated with repetitive head trauma or predictive of CTE based on the most widely studied radiotracers. Given the range of clinical syndromes and neurodegenerative pathologies observed in a subset of adults with prior repetitive head trauma, structural MRI and PET imaging may still be useful for differential diagnosis (e.g., assessing suspected Alzheimer’s disease).

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Head Trauma in a Community-Based Sample of Victims of Intimate Partner Violence: Prevalence, Mechanisms of Injury and Symptom Presentation

Journal of Interpersonal Violence ◽

10.1177/08862605211016362 ◽

2021 ◽

pp. 088626052110163

Author(s):

Jessica E. Meyer ◽

Varna Jammula ◽

Peter A. Arnett

Keyword(s):

Intimate Partner Violence ◽

Brain Injury ◽

Head Trauma ◽

Partner Violence ◽

Physical Violence ◽

Structured Interview ◽

Intimate Partner ◽

Difficulty Breathing ◽

History Of ◽

Subconcussive Head Trauma

Objective. The present study aimed to explore the prevalence of subconcussive head trauma, traumatic brain injury (TBI), potential hypoxic events, and hypoxic brain injury (HBI) in victims of physical intimate partner violence (IPV). The study also aimed to characterize the injury presentation and mechanisms of injury in this population. Method. A group of 47 female participants with a history of at least one relationship that included physical violence completed a structured interview assessing for subconcussive hits, TBI, and HBI. Participants ranged in age from 19 to 55, and had an average of 15.3 years of education. Forty-four participants completed the structured interview in person and three participants completed the interview over the phone. Results. The majority of participants reported sustaining at least one impact to the head and approximately half of the participants sustained at least one impact that resulted in a mild TBI. Approximately half of the participants experienced at least one incident of having difficulty breathing due to a violent act from their partner, and approximately one-third of participants reported symptoms consistent with mild HBI. The most common mechanisms of injury were being hit with a closed fist and being strangled. Conclusions. The high levels of head trauma observed in this study highlight the need for clinical and community providers to screen victims of physical IPV for head trauma. The unique characteristics of this population (female sex, high frequency of injuries, and presence of HBIs) indicate that research evaluating the cognitive effects of injuries in this population is needed.

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On-Field Performance of an Instrumented Mouthguard for Detecting Head Impacts in American Football

Annals of Biomedical Engineering ◽

10.1007/s10439-020-02654-2 ◽

2020 ◽

Vol 48 (11) ◽

pp. 2599-2612

Author(s):

Lee F. Gabler ◽

Samuel H. Huddleston ◽

Nathan Z. Dau ◽

David J. Lessley ◽

Kristy B. Arbogast ◽

...

Keyword(s):

Field Performance ◽

American Football ◽

Head Impacts

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Concussion BASICS II

Neurology ◽

10.1212/wnl.0000000000006616 ◽

2018 ◽

Vol 91 (23) ◽

pp. e2123-e2132 ◽

Cited By ~ 10

Author(s):

Breton M. Asken ◽

Russell M. Bauer ◽

Steven T. DeKosky ◽

Zachary M. Houck ◽

Charles C. Moreno ◽

...

Keyword(s):

Collegiate Athletes ◽

Head Impact ◽

Amyloid Peptide ◽

Serum Biomarker ◽

Cumulative Exposure ◽

Head Impacts ◽

Clinical Assessments ◽

Recent Exposure ◽

Impact Index ◽

Concussion History

ObjectiveTo examine the effect of concussion history and cumulative exposure to collision sports on baseline serum biomarker concentrations, as well as associations between biomarker concentrations and clinical assessments.MethodsIn this observational cohort study, β-amyloid peptide 42 (Aβ42), total tau, S100 calcium binding protein B (S100B), ubiquitin carboxy-terminal hydrolyzing enzyme L1 (UCH-L1), glial fibrillary acidic protein, microtubule associated protein 2, and 2′,3′-cyclic-nucleotide 3′-phosphodiesterase serum concentrations were measured in 415 (61% male, 40% white, aged 19.0 ± 1.2 years) nonconcussed collegiate athletes without recent exposure to head impacts. Regression analyses were used to evaluate the relationship between self-reported history of concussion(s), cumulative years playing collision sports, clinical assessments, and baseline biomarker concentrations. Football-specific analyses were performed using a modified Cumulative Head Impact Index. Clinical assessments included symptom, cognitive, balance, and oculomotor tests.ResultsAthletes with a greater number of concussions had a higher baseline Aβ42 concentration only (ρ = 0.140, p = 0.005, small effect size). No biomarker concentrations correlated with cumulative exposure to collision sports. Race status fully mediated the correlations of S100B, UCH-L1, and Aβ42 with cognitive scores. Football exposure, specifically, was not associated with serum biomarker concentrations or clinical assessment scores based on the modified Cumulative Head Impact Index.ConclusionConcussion-related serum biomarkers showed no consistent association with concussion history, cumulative exposure to collision sports, or clinical assessments in a sample of healthy collegiate athletes. Serum Aβ42 concentrations could increase following multiple previous concussions. Considering race status is essential when investigating links between biomarkers and cognition. The biomarkers studied may not detect residual effects of concussion or repetitive head impact exposure in otherwise asymptomatic collegiate athletes without recent exposure to head impacts. Much more research is needed for identifying reliable and valid blood biomarkers of brain trauma history.

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Association Between Antemortem FLAIR White Matter Hyperintensities and Neuropathology in Brain Donors Exposed to Repetitive Head Impacts

Neurology ◽

10.1212/wnl.0000000000013012 ◽

2021 ◽

pp. 10.1212/WNL.0000000000013012

Author(s):

Madeline Uretsky ◽

Sylvain Bouix ◽

Ronald J. Killiany ◽

Yorghos Tripodis ◽

Brett Martin ◽

...

Keyword(s):

White Matter ◽

White Matter Hyperintensities ◽

Microvascular Disease ◽

Head Impact ◽

American Football ◽

Football Players ◽

Head Impacts ◽

Repetitive Head Impacts ◽

Pathological Correlation ◽

Daily Function

Background and Objectives:Late neuropathologies of repetitive head impacts from contact sports can include chronic traumatic encephalopathy (CTE) and white matter degeneration. White matter hyperintensities (WMH) on fluid attenuated inversion recovery (FLAIR) MRI scans are often viewed as microvascular disease from vascular risk, but might have unique underlying pathologies and risk factors in the setting of repetitive head impacts. We investigated the neuropathological correlates of antemortem WMH in brain donors exposed to repetitive head impacts. The association between WMH, and repetitive head impact exposure and informant-reported cognitive and daily function were tested.Methods:This imaging-pathological correlation study included symptomatic deceased men exposed to repetitive head impacts. Donors had antemortem FLAIR scans from medical records and were without evidence of CNS neoplasm, large vessel infarcts, hemorrhage, and/or encephalomalacia. WMH were quantified using log-transformed values for total lesion volume (TLV), calculated using the lesion prediction algorithm from the Lesion Segmentation Toolbox. Neuropathological assessments included semi-quantitative ratings of white matter rarefaction, cerebrovascular disease, p-tau severity (CTE stage, dorsolateral frontal cortex), and Aβ. Among football players, years of play was a proxy for repetitive head impact exposure. Retrospective informant-reported cognitive and daily function were assessed using the Cognitive Difficulties Scale (CDS) and Functional Activities Questionnaire (FAQ). Regression models controlled for demographics, diabetes, hypertension, and MRI resolution. Statistical significance was defined as p<0.05.Results:The sample included 75 donors: 67 football players and 8 non-football contact sport athletes and/or military veterans. Dementia was the most common MRI indication (64%). Fifty-three (70.7%) had CTE at autopsy. Log-TLV was associated with white matter rarefaction (OR=2.32, 95% CI=1.03,5.24, p=0.04), arteriolosclerosis (OR=2.38, 95% CI=1.02,5.52, p=0.04), CTE stage (OR=2.58, 95% CI=1.17,5.71, p=0.02), and dorsolateral frontal p-tau severity (OR=3.03, 95% CI=1.32,6.97, p=0.01). There was no association with Aβ. More years of football play was associated with log-TLV (b=0.04, 95% CI=0.01,0.06, p=0.01). Greater log-TLV correlated with higher FAQ (unstandardized beta=4.94, 95% CI=0.42,8.57, p=0.03) and CDS scores (unstandardized beta=15.35, 95% CI=-0.27,30.97, p=0.05).Discussion:WMH might capture long-term white matter pathologies from repetitive head impacts, including those from white matter rarefaction and p-tau, in addition to microvascular disease. Prospective imaging-pathological correlation studies are needed.Classification of Evidence:This study provides Class IV evidence of associations between FLAIR white matter hyperintensities, and neuropathological changes (white matter rarefaction, arteriolosclerosis, p-tau accumulation), years of American football play, and reported cognitive symptoms in symptomatic brain donors exposed to repetitive head impacts.

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Cost-reducing traits for agonistic head collisions: a case for neurophysiology

Integrative and Comparative Biology ◽

10.1093/icb/icab034 ◽

2021 ◽

Author(s):

Daniel J Tobiansky ◽

Kira M Long ◽

Jordan E Hamden ◽

Jeffrey D Brawn ◽

Matthew J Fuxjager

Keyword(s):

Head Trauma ◽

Animal Species ◽

High Impact ◽

Computational Studies ◽

Independent Manner ◽

Head Impacts ◽

Impact Forces ◽

Selection For ◽

The Cost ◽

Impact Head

Abstract Many animal species have evolved extreme behaviors requiring them to engage in repeated high-impact collisions. These behaviors include mating displays like headbutting in sheep and drumming in woodpeckers. To our knowledge, these taxa do not experience any notable acute head trauma, even though the deceleration forces would cause traumatic brain injury in most animals. Previous research has focused on skeletomuscular morphology, biomechanics, and material properties in an attempt to explain how animals moderate these high-impact forces. However, many of these behaviors are understudied, and most morphological or computational studies make assumptions about the behavior without accounting for the physiology of an organism. Studying neurophysiological and immune adaptations that co-vary with these behaviors can highlight unique or synergistic solutions to seemingly deleterious behavioral displays. Here, we argue that selection for repeated, high-impact head collisions may rely on a suite of coadaptations in intracranial physiology as a cost-reducing mechanism. We propose that there are three physiological systems that could mitigate the effects of repeated head trauma: (i) the innate neuroimmune response, (ii) the glymphatic system, and (iii) the choroid plexus. These systems are interconnected yet can evolve in an independent manner. We then briefly describe the function of these systems, their role in head trauma, and research that has examined how these systems may evolve to help reduce the cost of repeated, forceful head impacts. Ultimately, we note that little is known about cost-reducing intracranial mechanisms making it a novel field of comparative study that is ripe for exploration.

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