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Fluctuations in blood biomarkers of head trauma in NCAA football athletes over the course of a season
Abstract
OBJECTIVE
Repetitive 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.
METHODS
Thirty-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.
RESULTS
In 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.
CONCLUSIONS
The 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.
... No other investigations are known that have examined the physiological stress associated with an acute game. However, more recently there have been several studies that have examined the effects of both a competitive football game (22,40,41) or competitive season (16,34,35) on markers of brain inflammation. These studies were likely motivated by investigations reporting cognitive dysfunction in former professional football players (10) and by the death of several former National Football League (NFL) players, whose postmortem examinations revealed significant brain disease (26). ...
... The injury risk associated with the game of football has been welldocumented (18). Although much effort has been made on examining the effect of football on brain health, most investigations have been epidemiological in nature examining long-term effects over a career (1,10) or have focused on the effects of a competitive season (34,35). Studies examining the acute effect of game participation on changes in inflammatory markers, BDNF and cognitive function are limited or nonexistent. ...
... However, these effects would reflect a playing career and not an acute game. Although Joseph et al. (16) reported tau protein elevations in players experiencing high head impact contact, most other studies have suggested that tau protein is a poor indicator of acute head trauma, even during a competitive football season (34,35). Interestingly, circulating total tau protein concentrations may not be elevated even after a sports-related concussion (45). ...
Hoffman, JR, Ostfeld, I, Zamir, A, Amedi, R, Fonville, TR, Horstemeyer, MF, and Gepner, Y. Examination of cognitive function, neurotrophin concentrations, and both brain and systemic inflammatory markers following a simulated game of American football. J Strength Cond Res 36(3): 686-694, 2022-This investigation examined the effect of a simulated American football game on cognitive function, neurotrophin concentrations, and markers of both systemic and brain inflammation. Members of the Israel national team (6 linemen and 9 skill position players) were examined 1 week before (PRE), immediately post (IP) and 24-hour post (24P) game. Blood was obtained, and cognitive function was measured at each assessment. No head injuries to any of the players participating in the study occurred. Significant (p < 0.001) decreases in acute memory, and a trend (p = 0.066) toward a decrease in delayed memory was noted at IP. Significant negative correlations were observed between playing time (number of plays) and concentration changes from PRE to IP (r = -0.801; p = 0.001) and from PRE to 24P (r = -0.549; p = 0.034). All cognitive function measures returned to PRE levels by 24P. Increases from PRE were noted in tumor necrosis factor-alpha (TNF-α) (p = 0.041) at IP and in brain-derived neurotrophic factor (p = 0.009) and C-reactive protein (CRP) (p = 0.019) concentrations at 24P. Circulating CRP concentrations and the cytokine markers, interleukin (IL)-4, IL-6, IL-10, and TNF-α, were significantly elevated in linemen compared with skill players. Brain inflammatory markers (S100B and glial fibrillary acidic protein) and total tau protein (a marker of brain injury) were not elevated from PRE. No change from PRE was noted in either myoglobin or creatine kinase-MM concentrations. In conclusion, muscle damage and inflammatory marker responses observed from the scrimmage game were consistent with muscle desensitization associated with football participation. In addition, the systemic inflammatory marker results observed in linemen were suggestive of chronic low-grade inflammation.
... Of the recently identified surrogate biomarkers of head trauma, serum neurofilament light (Nf-L) has been suggested to be sensitive and specific in regard to detecting neuroaxonal injury [41,42], a characteristic of TBI [43]. Recent work by our research group indicates that the quantification of serum Nf-L may be useful for detecting the neurological damage linked to RHI sustained during a season of collegiate ASF [44,45]. Additional work by our group demonstrated that daily supplementation with DHA exerts a neuroprotective effect in ASF athletes by attenuating elevations in serum Nf-L [46]. ...
... The available evidence has demonstrated that Nf-L increases progressively throughout a season, particularly in athletes categorized as starters [44,45]. Furthermore, Rubin et al. [61] reported that plasma Nf-L levels were influenced by the frequency and magnitude of head impact, as measured by an accelerometer-embedded mouth guard. ...
... Furthermore, Rubin et al. [61] reported that plasma Nf-L levels were influenced by the frequency and magnitude of head impact, as measured by an accelerometer-embedded mouth guard. We have previously reported that the accumulation of RHI over the course of an ASF season led to moderate to very large effect size increases in serum Nf-L levels in ASF starters [44][45][46]. In our current study, similar effect size increases of moderate to large were also observed in the starters of our control group. ...
Background
American-style football (ASF) athletes are at risk for cardiovascular disease (CVD) and exhibit elevated levels of serum neurofilament light (Nf-L), a biomarker of axonal injury that is associated with repetitive head impact exposure over the course of a season of competition. Supplementation with the w-3 fatty acid (FA) docosahexaenoic acid (DHA) attenuates serum Nf-L elevations and improves aspects of CVD, such as the omega-3 index (O3I). However, the effect of combining the w-3 FA eicosapentaenoic acid (EPA) and docosapentaenoic acid (DPA) with DHA on, specifically, serum Nf-L in ASF athletes is unknown. Therefore, this study assessed the effect of supplemental w-3 FA (EPA+DPA+DHA) on serum Nf-L, plasma w-3 FAs, the O3I, and surrogate markers of inflammation over the course of a season.
Methods
A multi-site, non-randomized design, utilizing two American football teams was employed. One team ( n = 3 1) received supplementation with a highly bioavailablew-3 FA formulation (2000mg DHA, 560mg EPA, 320mg DPA, Mindset®, Struct Nutrition, Missoula, MT) during pre-season and throughout the regular season, while the second team served as the control ( n = 35) and did not undergo supplementation. Blood was sampled at specific times throughout pre- and regular season coincident w ith changes in intensity, physical contact, and changes in the incidence and severity of head impacts. Group differences were determined via a mixed-model between-within subjects ANOVA. Effect sizes were calculated using Cohen’s d for all between-group differences. Significance was set a priori at p < .05.
Results
Compared to the control group, ASF athletes in the treatment group experienced large increases in plasma EPA ( p < .001, d = 1.71) and DHA ( p < .001, d = 2.10) which contributed to increases in the O3I ( p < .001, d = 2.16) and the EPA:AA ratio ( p = .001, d = 0.83) and a reduction in the w-6: w-3 ratio ( p < .001, d = 1.80). w-3 FA supplementation attenuated elevations in Nf-L ( p = .024). The control group experienced a significant increase in Nf-L compared to baseline at several measurement time points (T2, T3, and T4 [ p range < .001 – .005, d range = 0.59-0.85]).
Conclusions
These findings suggest a cardio- and neuroprotective effect of combined EPA+DPA+DHA w-3 FA supplementation in American-style football athletes.
Trial registration
This trial was registered with the ISRCTN registry ( ISRCTN90306741 ).
... This correlation has been attributed to the frequent exposure to head impacts, even without the presence of a diagnosed concussion. Three studies examined the role of NfL as a biomarker of neurological injury in athletes exposed to head impacts compared to non-concussive controls [38,40,41]. Sandmo et al. did not note any significant increase in serum NfL measured in pre-season, professional soccer athletes, and after sustaining head impacts [41]. ...
... Sandmo et al. did not note any significant increase in serum NfL measured in pre-season, professional soccer athletes, and after sustaining head impacts [41]. Conversely, both Oliver and Rubin et al. reported a statistically significant increase of serum NfL in American football athletes, indicative of subclinical acute brain damage [38,40]. Military personnel is prone to sub-concussive damage, especially those exposed to blast impacts. ...
... Nine studies explored the role of serum NfL as a potential biomarker in patients with head impacts [15,24,25,28,32,33,38,40,41]. Six studies were further metaanalyzed [15,24,25,28,32,33]. ...
Purpose
Traumatic brain injury is one of the leading causes of disability worldwide. Mild traumatic brain injury (TBI) is the most common and benign form of TBI, usually referred to by the medical term “concussion”. The purpose of our systematic review and meta-analysis was to explore the role of serum and CSF neurofilament light chain (NfL) as a potential biomarker in concussion.
Methods
We systematically searched PubMed, Web of Science, and Cochrane databases using specific keywords. As the primary outcome, we assessed CSF or serum NfL levels in patients with concussion and head impacts versus controls. The role of NfL in patients with concussion and head impacts compared to healthy controls was also assessed, as well as in sports-related and military-related conditions.
Results
From the initial 617 identified studies, we included 24 studies in our qualitative analysis and 14 studies in our meta-analysis. We found a statistically significant increase of serum NfL in patients suffering from a concussion or head impacts compared to controls (p = 0.0023), highlighting its potential role as a biomarker. From our sub-group analyses, sports-related concussion and mild TBI were mostly correlated with increased serum NfL values. Compared to controls, sports-related concussion was significantly associated with higher NfL levels (p = 0.0015), while no association was noted in patients suffering from head impacts or military-related TBI.
Conclusion
Serum NfL levels are higher in all patients suffering from concussion compared to healthy controls. The sports-related concussion was specifically associated with higher levels of NfL. Further studies exploring the use of NfL as a diagnostic and prognostic biomarker in mild TBI and head impacts are needed.
... 6 Neurological insult, such as sports-related concussion, results in alterations to critical components of the axon including microtubules and neurofilaments 7,8 ; as such, a number of axonal biomarkers have been identified. [9][10][11][12][13][14][15][16][17][18][19] Neurofilament light polypeptide (Nf-L), primarily found in axons, is integral to the structural support of the axonal cytoskeleton and functions to maintain axonal diameter. 8 Tau, a microtubule-associated protein, aids in microtubule assembly and stability, and it is necessary for axonal transport. ...
... 22 Moreover, the sensitivity of serum Nf-L as a biomarker of sports-related head trauma has recently been presented by our group. 13,18,32 Those data suggested that in the absence of a concussion diagnosis, routine subconcussive impacts sustained by football athletes result in some level of damage as measured by Nf-L. 13,18,32 In the current study, Nf-L was elevated after injury when compared with a 6-month follow-up sample. ...
... 13,18,32 Those data suggested that in the absence of a concussion diagnosis, routine subconcussive impacts sustained by football athletes result in some level of damage as measured by Nf-L. 13,18,32 In the current study, Nf-L was elevated after injury when compared with a 6-month follow-up sample. Higher concentrations were also observed in concussed athletes compared with control athletes, although nonsignificant. ...
Objective:
To examine changes in blood biomarkers, serum neurofilament light (Nf-L), and plasma tau, as well as the relationship between blood biomarkers and symptom reports, in athletes with a sports-related concussion.
Design:
Prospective cohort study.
Setting:
Private community-based concussion clinic.
Participants:
Athletes aged 13 to 18 years old with a diagnosed sports-related concussion presenting to a concussion clinic within 7 days of injury and noninjured athletes with no history of concussion aged 13 to 23 years old.
Assessment and main outcome measures:
Injured athletes provided a blood sample at the initial clinical evaluation and again at least 6 months after injury. Noninjured athletes provided a single blood sample. All participants completed symptom reports during each visit. Statistical comparisons of biomarker concentrations and symptom reports were conducted.
Results:
The mean rank for tau was significantly lower for concussed athletes compared with nonconcussed athletes. In contrast, the mean rank of Nf-L was higher for concussed athletes than for nonconcussed athletes, although the difference was nonsignificant. Plasma tau was significantly lower postinjury compared with 6 months after injury, whereas serum Nf-L was significantly higher postinjury. There was a weak but significant inverse relationship observed between tau and the number of symptoms reported, but no relationship was observed between Nf-L and the number of symptoms reported.
Conclusions:
These data indicate that in the days following a sports-related concussion, the blood biomarkers tau and Nf-L display contrasting patterns of change but may not be related to self-reported symptom scores.
... However, none have been accepted as a definitive blood biomarker of AD. From the few mTBI studies which have investigated blood based biomarkers, a significant role was identified for astrocyte, axonal and proteosomal proteins in the blood at relatively acute time points post-injury (DeKosky et al., 2013;Shen et al., 2014;Kulbe and Geddes, 2016;Zetterberg and Blennow, 2016;Meier et al., 2017;Mondello et al., 2017;Oliver et al., 2018;Shahim et al., 2018). Some studies have also shown a significant role for AD-related tau protein species (total tau, caspase cleaved tau fragments, phosphorylated tau) in the blood following mTBI in athletes and military personnel (Di Battista et al., 2013;Neselius et al., 2013b;Shahim et al., 2014Shahim et al., , 2016Olivera et al., 2015;Rubenstein et al., 2015;Gill et al., 2018). ...
... Because the cascade of secondary injury involves astrocytic/microglial activation, axonal degeneration, excitotoxicity, mitochondrial dysfunction, and lipid peroxidation, biomarker studies have focused primarily on identifying proteins related to these processes. For example those abundant in astroglia [S100B, Glial Fibrillary Acidic Protein (GFAP)], neurons [Neuron Specific Enolase (NSE), Ubiquitin C-Terminal Hydrolase-L1-(UCHL1)], oligodendrocytes (Myelin Basic Protein); neuronal cytoskeletal proteins (Spectrin Break Down Products, Tau, Neurofilament), inflammatory cytokines, metabolites, and oxidized lipids (Pineda et al., 2004;Kochanek et al., 2008;Svetlov et al., 2009;Dash et al., 2010;Sandler et al., 2010;Giacoppo et al., 2012;Yokobori et al., 2013;Papa et al., 2015aPapa et al., ,b, 2016Siman et al., 2015;Welch et al., 2016Welch et al., , 2017Gill et al., 2018;Oliver et al., 2018;Shahim et al., 2018). Specifically, S100B, UCHL1, NSE, GFAP and tau have been the most studied candidates. ...
... Specifically, S100B, UCHL1, NSE, GFAP and tau have been the most studied candidates. Investigators have shown good correlation with mTBI and neurological outcome at acute time points with some of these markers (de Kruijk et al., 2001;Papa et al., 2011aPapa et al., ,b, 2016Berger et al., 2012;Giacoppo et al., 2012;Neselius et al., 2013b;Shahim et al., 2014Shahim et al., , 2018Olivera et al., 2015;Rubenstein et al., 2015;Mondello et al., 2016;Welch et al., 2016Welch et al., , 2017Oliver et al., 2018). Likewise, preclinical biomarker studies in plasma samples that have focused on markers associated with the cascade of secondary injury from closed head TBI, weight drop, and blast models in rodents and pigs with a variety of frequency and injury severities have also revealed elevations in inflammatory/protease markers, astroglial, axonal, and vascular proteins (Gyorgy et al., 2011;Rostami et al., 2012;Ahmed et al., 2012;Chase, 2014;Sharma et al., 2017). ...
The relationship between repetitive mild traumatic brain injury (r-mTBI) and Alzheimer’s disease (AD) is well-recognized. However, the precise nature of how r-mTBI leads to or precipitates AD pathogenesis is currently not understood. Plasma biomarkers potentially provide non-invasive tools for detecting neurological changes in the brain, and can reveal overlaps between long-term consequences of r-mTBI and AD. In this study we address this by generating time-dependent molecular profiles of response to r-mTBI and AD pathogenesis in mouse models using unbiased proteomic analyses. To model AD, we used the well-validated hTau and PSAPP(APP/PS1) mouse models that develop age-related tau and amyloid pathological features, respectively, and our well-established model of r-mTBI in C57BL/6 mice. Plasma were collected at different ages (3, 9, and 15 months-old for hTau and PSAPP mice), encompassing pre-, peri- and post-“onset” of the cognitive and neuropathological phenotypes, or at different timepoints after r-mTBI (24 h, 3, 6, 9, and 12 months post-injury). Liquid chromatography/mass spectrometry (LC-MS) approaches coupled with Tandem Mass Tag labeling technology were applied to develop molecular profiles of protein species that were significantly differentially expressed as a consequence of mTBI or AD. Mixed model ANOVA after Benjamini–Hochberg correction, and a stringent cut-off identified 31 proteins significantly changing in r-mTBI groups over time and, when compared with changes over time in sham mice, 13 of these were unique to the injured mice. The canonical pathways predicted to be modulated by these changes were LXR/RXR activation, production of nitric oxide and reactive oxygen species and complement systems. We identified 18 proteins significantly changing in PSAPP mice and 19 proteins in hTau mice compared to their wild-type littermates with aging. Six proteins were found to be significantly regulated in all three models, i.e., r-mTBI, hTau, and PSAPP mice compared to their controls. The top canonical pathways coincidently changing in all three models were LXR/RXR activation, and production of nitric oxide and reactive oxygen species. This work suggests potential biomarkers for TBI and AD pathogenesis and for the overlap between these two, and warrant targeted investigation in human populations. Data are available via ProteomeXchange with identifier PXD010664.
... Identification of these biomarkers could benefit athletes by (a) helping to characterize pathophysiology and secondary injury after sport-related concussions (SRC) and (b) clinical application for early detection of concussions . Both groups could benefit from these biomarkers being used to detect the neurological injury associated with repetitive subconcussive head trauma (Oliver et al., 2018).. ...
... In athletes, other biomarkers such as brain derived neurotrophic factor (BDNF), choline, dehydroepiandrosterone sulfate (DHEA-S) interleukin IL-6, monocyte chemoattractant protein (MCP)-1 and (MCP)-4, myo-inositol, N-acetyl aspartate (NAA), peroxiredoxin-6 (PRDX-6), serum NF-L, and Willebrand factor (vWF), could be used to prognosis SRC and/or repetitive concussions (Battista et al., 2016Churchill et al., 2017;A. P. Di Battista et al., 2019;Oliver et al., 2018). ...
Background: There is no objective way of diagnosing or prognosticating acute traumatic brain injuries (TBIs). A systematic review conducted by Mondello et al. reviewed studies looking at blood based protein biomarkers in the context of acute mild traumatic brain injuries and correlation to results of computed tomography scanning. This paper provides a summary of this same literature using the SENSOR system.
Methods: An existing review written by Mondello et al. was selected to apply the previously described SENSOR system (Kamal et al.) that uses a systematic process made up of a Google Form for data intake, Google Drive for article access, and Google Sheets for the creation of the dashboard. The dashboard consisted of a map, bubble graphs, multiple score charts, and a pivot table to facilitate the presentation of data.
Results: A total of 29 entries were inputted by two team members. Sensitivities, specificities, positive predictive values (PPVs), negative predictive values (NPVs), demographics, cut-off levels, biomarker levels, and assay ranges were analyzed and presented in this study. S100B and GFAP biomarkers may provide good clinical utility, whereas UCH-L1, C-Tau, and NSE do not.
Discussion: This study determined the feasibility and reliability of multiple biomarkers (S100B, UCH-L1, GFAP, C-tau, and NSE) in predicting traumatic brain lesions on CT scans, in mTBI patients, using the SENSOR system. Many potential limitations exist for the existing literature including controlling for known confounders for mild traumatic brain injuries.
... Joseph et al. (2019) found increased levels of Tau postseason compared to preseason, whileOliver et al. (2019) found that ...
... at time points during the season but returned to baseline level after the season. Additionally, the study byJoseph et al. (2019) found non-significant increases in NF-L, GFAP, SBDP and a significant increase in UCH-L1, a multifunctional protein exclusively expressed in neurons in the brain, at postseason compared to preseason.Oliver et al. (2019) however, found increased levels of NF-L, involved in the axoskeleton and intracellular transport, throughout the season. ...
Examine the effect of subconcussive impact accumulation on cognitive/functional, imaging, and biomarker outcomes over the course of a single season, specifically in contact sport athletes at collegiate level or younger. Systematic review following PRISMA guidelines and using Oxford Center for Evidence-Based Medicine 2011 Levels of Evidence and Newcastle Ottawa Assessment Scale. PubMed MEDLINE, PsycInfo, SPORT-Discus, Web of Science. Original research in English that addressed the influence of subconcussive impacts on outcomes of interest with minimum preseason and postseason measurement in current youth, high school, or college-aged contact sport athletes. 796 articles were initially identified, and 48 articles were included in this review. The studies mostly involved male football athletes in high school or college and demonstrated an underrepresentation of female and youth studies. Additionally, operationalization of previous concussion history and concussion among studies was very inconsistent. Major methodological differences existed across studies, with ImPACT and diffusion tensor imaging being the most commonly used modalities. Biomarker studies generally showed negative effects, cognitive/functional studies mostly revealed no effects, and advanced imaging studies showed generally negative findings over the season; however, there was variability in the findings across all types of studies. This systematic review revealed growing literature on this topic, but inconsistent methodology and operationalization across studies makes it challenging to draw concrete conclusions. Overall, cognitive measures alone do not seem to detect changes across this timeframe while imaging and biomarker measures may be more sensitive to changes following subconcussive impacts.
... NfL levels were already significantly different between groups (control swimmers < non-starters < starters) at baseline measurement, indicating an effect of past exposure that had not normalized after a 9-week rest period. (27,28) Even during summer training camp, pre-to post-practice increases in plasma levels of NfL were associated with the frequency and magnitude of head impacts, measured using an accelerometerembedded mouth protection. (29) On the contrary, one study consisting of a mixed cohort (n = 11) of American football or ice hockey players failed to show any significant difference between serum NfL levels measured in the pre-season and those obtained at day 6 and 14 after suffering a SRC. ...
... We decided to give a sport-by-sport listing for reasons of comprehensiveness and specificity, and, as expected, most compelling evidence was present in boxers and American football players, where immediate exposure-associated increases were appreciable at the intra-individual level in exclusive cohorts. (13,(26)(27)(28)(29) The accuracy of NfL to discriminate boxers from controls after a bout was high, even separating out those with low exposure, with levels remaining elevated following a subsequent rest period of 3 months. ...
Objective
To evaluate whether participating in physical contact sports is associated with a release of neurofilaments and whether such release is related to future clinical neurological and/or psychiatric impairment.
Methods
We performed a systematic review of the PubMed, MEDLINE and Cochrane Library databases using a combination of the search terms neurofilament(s)/intermediate filament and sport(s)/athletes. Original studies, written in English, reporting on neurofilaments in cerebrospinal fluid and/or serum/plasma of contact sport athletes were included. This review was conducted following the Preferred Reporting Items for Systematic Review and Analyses guidelines.
Results
Eighteen studies in eight different contact sports (i.e. boxing, American football, ice hockey, soccer, mixed martial arts, lacrosse, rugby and wrestling) matched our criteria. Elevated light chain neurofilament (NfL) levels were described in 13/18 cohorts. Most compelling evidence was present in boxing and American football, where exposure-related increases were appreciable at the intra-individual level (up to 4.1- and 2.0-fold, respectively) in well-defined groups. Differences in exposure severity (including previous cumulative effects), sampling/measurement time points (with regard to expected peak values) and definitions of the baseline setting are considered as main contributors to the variability in findings. No studies were encountered that have investigated the relationship with the targeted clinical endpoints; therefore no NfL cut-offs exist that are associated with a poor outcome.
Conclusion
NfL release can be seen, as a potential marker of neuronal brain damage, in participants of physical contact sports, particularly boxing and American football. The exact significance regarding the risk for future clinical impairment remains to be elucidated.
... Currently, blood biomarkers and MRI volumetrics offer limited promise for determining the presence and progression of CTE-related degeneration [3,55,98]. It may be possible to monitor intraseasonal sport related brain trauma through the evaluation of serum levels of the neurofilament-light chain, but this has not demonstrated good long-term prognostic accuracy to date [76]. Despite the association between tau and mechanical trauma [56], plasma levels of tau are not altered in accord with trauma frequency or severity during the course of an American football season [76]. ...
... It may be possible to monitor intraseasonal sport related brain trauma through the evaluation of serum levels of the neurofilament-light chain, but this has not demonstrated good long-term prognostic accuracy to date [76]. Despite the association between tau and mechanical trauma [56], plasma levels of tau are not altered in accord with trauma frequency or severity during the course of an American football season [76]. The current and previous findings [72], suggest different forms of tau pathology provide a diverse set of markers to track CTE development and efficacy of tau-mediated treatments, especially in the pre-symptomatic stages of this disorder [7,58,72,87]. ...
Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative condition associated with repetitive traumatic brain injury (rTBI) seen in contact-sport athletes and military personnel. The medial temporal lobe (MTL; i.e., hippocampus, subiculum, and entorhinal and perirhinal cortices) memory circuit displays tau lesions during the pathological progression of CTE. We examined MTL tissue obtained from 40 male Caucasian and African American athletes who received a postmortem CTE neuropathological diagnosis defined as stage II, III, or IV. Sections were immunolabeled using an early (AT8) or a late (TauC3) marker for pathological tau and for amyloid beta (Aβ) species (6E10, Aβ1-42 and thioflavin S). Stereological analysis revealed that stage III had significantly less AT8-positive neurons and dystrophic neurites than stage IV in all MTL regions except hippocampal subfield CA3, whereas significantly more AT8-positive neurons, dystrophic neurites, and neurite clusters were found in the perirhinal cortex, entorhinal cortex, hippocampal CA1, and subiculum of CTE stage III compared with stage II. TauC3-positive pathology was significantly higher in the perirhinal and subicular cortex of stage IV compared to stage III and the perirhinal cortex of stage III compared to stage II. AT8-positive neurite clusters were observed in stages III and IV, but virtually absent in stage II. When observed, Aβ pathology appeared as amyloid precursor protein (APP)/Aβ (6E10)-positive diffuse plaques independent of region. Thioflavine S labeling, did not reveal evidence for fibril or neuritic pathology associated with plaques, confirming a diffuse, non-cored plaque phenotype in CTE. Total number of AT8-positive profiles correlated with age at death, age at symptom onset, and time from retirement to death. There was no association between AT8-positive tau pathology and age sport began, years played, or retirement age, and no difference between CTE stage and the highest level of sport played. In summary, our findings demonstrate different tau profiles in the MTL across CTE stages, proffering CA3 tau pathology and MTL dystrophic neurite clusters as possible markers for the transition between early (II) and late (III/IV) stages, while highlighting CTE as a progressive noncommunicative tauopathy.
... Oliver et al., 2018 [48] College football athletes (n = 35) ...
... However, there is a growing body of literature suggesting that the neurofilament light (NF-L) protein may be a biomarker of neuronal injury after TBI. NF-L has been found to be increased following a bout in boxers [46,47], concussion in professional hockey players [46], and a single season in collegiate football athletes [48,49]. However, similar to tau, NF-L levels appear to normalize at some point following injury. ...
Traumatic brain injuries (TBI) have received widespread media attention in recent years as being a risk factor for the development of dementia and chronic traumatic encephalopathy (CTE). This has sparked fears about the potential long-term effects of TBI of any severity on cognitive aging, leading to a public health concern. This article reviews the evidence surrounding TBI as a risk factor for the later development of changes in brain structure and function, and an increased risk of neurodegenerative disorders. A number of studies have shown evidence of long-term brain changes and accumulation of pathological biomarkers (e.g., amyloid and tau proteins) related to a history of moderate-to-severe TBI, and research has also demonstrated that individuals with moderate-to-severe injuries have an increased risk of dementia. While milder injuries have been found to be associated with an increased risk for dementia in some recent studies, reports on long-term brain changes have been mixed and often are complicated by factors related to injury exposure (i.e., number of injuries) and severity/complications, psychiatric conditions, and opioid use disorder. CTE, although often described as a neurodegenerative disorder, remains a neuropathological condition that is poorly understood. Future research is needed to clarify the significance of CTE pathology and determine whether that can explain any clinical symptoms. Overall, it is clear that most individuals who sustain a TBI (particularly milder injuries) do not experience worse outcomes with aging, as the incidence for dementia is found to be less than 7% across the literature.
... Contrary to prior research [23], our study suggests that the selected biomarkers for CTE do not change significantly during a single active season of AF in AFPs. However, when observed consistently over an extended period, they might indicate the development of CTE. ...
Background
Repetitive traumatic brain injuries in American football players (AFPs) can lead to the neurodegenerative disease chronic traumatic encephalopathy (CTE). Clinical symptoms of CTE range from mood and behavioral changes to cognitive impairment, depression, and suicidality. So far, CTE cannot be diagnosed in vivo and thus specific diagnostic parameters for CTE need to be found, to observe and treat exposed athletes as early as possible. Promising blood-based biomarkers for CTE include total tau (tTau), hyperphosphorylated tau (pTau), neurofilament light protein (NF-L), glial fibrillary acidic protein (GFAP), amyloid-β40 (Aβ40), amyloid-β42 (Aβ42) and calcium-binding protein B (S100-B). Previous studies have found elevated levels of these biomarkers in subjects exposed to TBIs, whereas cerebrospinal fluid (CSF) levels of Aβ40 and Aβ42 were decreased in CTE subjects. Here, we investigated whether young AFPs already exhibit changes of these biomarker candidates during the course of a single active season.
Methods
Blood samples were drawn from n = 18 American Football Players before and after a full season and n = 18 male age-matched control subjects. The plasma titers of tTau, pTau, NF-L, GFAP, Aβ40, Aβ42 and S100-B were determined. Additionally, Apathy, Depression, and Health status as well as the concussion history and medical care were assessed and analyzed for correlations.
Results
Here we show, that the selected biomarker candidates for CTE do not change significantly during the seven-month period of a single active season of American Football in blood samples of AFPs compared to healthy controls. But interestingly, they exhibit generally elevated pTau titers. Furthermore, we found correlations of depression, quality-of-life, career length, training participation and training continuation with headache after concussion with various titers.
Conclusion
Our data indicates, that changes of CTE marker candidates either occur slowly over several active seasons of American Football or are exclusively found in CSF. Nevertheless, our results underline the importance of a long-term assessment of these biomarker candidates, which might be possible through repeated blood biomarker monitoring in exposed athletes in the future.
Supplementary Information
The online version contains supplementary material available at 10.1186/s42466-024-00307-6.
... Recently, however, researchers have begun to measure molecular markers through non-invasive collection processes such as urine and saliva samples [18,19]. There are different types of molecular markers that have been studied as well, though they have been those that are predominantly expressed in neurons and localized in several areas of the neuronal infrastructure, including axonal localization (NF-L and Tau) [20], extracellular (BDNF) [21], and cytoplasmic (NSE and UCH-L1) [22]; acute inflammatory responses, such as C-reactive protein (CRP), IL-6, and IL-10 [23]; gene polymorphisms, including DNA methylation, SNP, and APEO gene [24]; and single-stranded non-coding RNA molecules, which have been found to be dysregulated in a variety of diseases and disorders, such as microRNAs [25]. GFAP and UCH-L1 tests have even been approved as biomarkers for mTBI by the US Food and Drug Administration [26]. ...
Reliable diagnostic methods for mild traumatic brain injury (mTBI) are lacking, and many researchers continue to search for objective biomarkers that can both define and detect mTBI. Although much research has been conducted in this field, there have not been many bibliometric studies. In this study, we aim to analyze the development over the last two decades in scientific output relating to the diagnosis of mTBI. To do this, we extracted documents from Web of Science, PubMed, and Embase and performed descriptive analysis (number of publications, primary journals, authors, and countries/regions), trend topics analysis, and citation analysis for papers across the globe, with a particular focus on molecular markers. One thousand twenty-three publications spanning 390 journals were identified on Web of Science, PubMed, and Embase for the period from 2000 to 2022. The number of publications increased every year (from 2 in 2000 to 137 in 2022). Of all the publications we analyzed, 58.7% had authors from the USA. Our analysis shows that molecular markers are the most studied markers in the field of mTBI diagnostics, accounting for 28.4% of all publications, and that the number of studies focused on this specific aspect has increased sharply in the past 5 years, indicating that molecular markers may become a research trend in the future.
... Noninvasive diagnosis of CTE remains problematic. Some current efforts have focused on dual and concomitant objectives: (i) explaining the underlying molecular mechanisms of diseases resulting from RHI and (ii) identifying molecular markers of disease progression [1,4,6,7]. For example, recent research has suggested persistent changes in DNA methylation with TBI. ...
Psychological and physical stress can induce dysregulation of gene expression via changes in DNA methylation and microRNA (miRNA) expression. Such epigenetic modifications are yet to be investigated in professional Mixed Martial Arts (MMA) fighters subject to highly stressful training involving repetitive head impacts. This study examined differences in DNA methylation and miRNA expression in elite MMA fighters compared to active controls. Global methylation differences between groups were assessed via a LINE-1 assay. At the same time, PCR arrays were used to estimate differential expression in samples of 21 fighters and 15 controls for 192 different miRNAs associated with inflammatory diseases. An Independent-Samples t-Test found no significant difference in LINE-1 methylation between groups. However, an Independent-Samples Mann-Whitney U Test revealed a significant upregulation in the expression of miR-155 in MMA fighter plasma. Since miR-155 has been recognized as an important regulator of neuroinflammation, this dysregulation suggests a possible epigenetic mechanism responsible for chronic inflammation associated with professional-level MMA training. Consistent with other published works, this study highlights the potential of miR-155 not only as a biomarker for monitoring long-term health risks linked to head trauma but also as a target to remediate the impact of chronic neuroinflammation.
... tendon, bone, cartilage, ligament, menisci, fat and brain), which have recently been shown to demonstrate similar and 3-4 fold higher synthetic rates than skeletal muscle tissue (Smeets et al., 2018;Smeets et al., 2019), respectively. Considering that repetitive subconcussive head trauma associated with collisions results in higher blood borne markers of brain trauma in American football players (Jonathan et al., 2018), it is possible that the energy cost of brain tissue turnover contributes in some part to the increased expenditure observed following collisions and young professional RL match-play. ...
The primary aim of this thesis was to evaluate the dietary intake, energy expenditure and energy balance of young professional male rugby league players across the season.
... Current evidence has shown that all three NFLs levels increase in response to different types of neuronal damage in mTBI. Used as a biomarker, NFL-L levels in blood serum showed an increase in patients with mTBI in comparison to the control group [82][83][84]. Another study found that NFL-M levels were significantly higher in patients with mTBI in both CSF and blood serum [35]. ...
Mild traumatic brain injury (mTBI) is the most prevalent type of TBI (80–90%). It is characterized by a loss consciousness for less than 30 minutes, post-traumatic amnesia for less than 24 hours, and Glasgow Coma Score of 13–15. Accurately diagnosing mTBIs can be a challenge because the majority of these injuries do not show noticeable or visible changes on neuroimaging studies. Appropriate determination of mTBI is tremendously important because it might lead in some cases to post-concussion syndrome, cognitive impairments including attention, memory, and speed of information processing problems. The scientists have studied different methods to improve mTBI diagnosis and enhanced approaches that would accurately determine the severity of the trauma. The present review focuses on discussing the role of biomarkers as potential key factors in diagnosing mTBI. The present review focuses on 1) protein based peripheral and CNS markers, 2) genetic biomarkers, 3) imaging biomarkers, 4) neurophysiological biomarkers, and 5) the studies and clinical trials in mTBI. Each section provides information and characteristics on different biomarkers for mTBI.
... Recent technological advancements make possible the detection of blood biomarkers sensitive to low levels of brain injury. Moreover, numerous studies have demonstrated changes in fluid biomarkers at timepoints after RHI exposure in athletes, 23,24 law enforcement, and military personnel. 25,26 While the long-term significance of these acute or sub-acute changes in biomarkers has not been established (i.e., their predictive power for long term neurodegenerative disease), in some instances, these changes in biomarkers have been associated with functional impairment 26 further suggesting that they may serve as a good proxy for brain health. ...
Recently, there has been increased concern over the effect of repetitive head impacts (RHIs, both concussive and subconcussive impacts) on long-term brain health. This concern has led researchers and policy makers to consider establishing RHI thresholds in order to mitigate the potential long-term effects of RHI exposure. However, the concept of thresholding relies on twin streams of information: 1) biomedical research relevant to the short and long-term risks of exposure to RHIs, and 2) societal standards for "acceptable risk." In the case of RHI, these streams of information have not been cogently combined to inform sensible policy making. In the current editorial, we discuss how the history of radiation safety provides an instructive example of an approach to ford these two streams to derive actionable clinically relevant policies surrounding RHI exposures.
... Specifically, NfL concentrations in blood have been found to be increased in American football players after a practice session [84] and after a competitive season [85,86] compared to baseline measures. In boxers, NfL has been found to increase in corticospinal fluid and in blood after a series of boxing bouts [82,87,88]. ...
Sports are yielding a wealth of benefits for cardiovascular fitness, for psychological resilience, and for cognition. The amount of practice, and the type of practiced sports, are of importance to obtain these benefits and avoid any side effects. This is especially important in the context of contact sports. Contact sports are not only known to be a major source of injuries of the musculoskeletal apparatus, they are also significantly related to concussion and sub-concussion. Sub-concussive head impacts accumulate throughout the active sports career, and thus can cause measurable deficits and changes to brain health. Emerging research in the area of cumulative sub-concussions in contact sports has revealed several associated markers of brain injury. For example, recent studies discovered that repeated headers in soccer not only cause measurable signs of cognitive impairment but are also related to a prolonged cortical silent period in transcranial magnetic stimulation measurements. Other cognitive and neuroimaging biomarkers are also pointing to adverse effects of heading. A range of fluid biomarkers completes the picture of cumulating effects of sub-concussive impacts. Those accumulating effects can cause significant cognitive impairment later in life of active contact sportswomen and men. The aim of this review is to highlight the current scientific evidence on the effects of repeated sub-concussive head impacts on contact sports athletes’ brains, identify the areas in need of further investigation, highlight the potential of advanced neuroscientific methods, and comment on the steps governing bodies have made to address this issue. We conclude that there are indeed neural and biofluid markers that can help better understand the effects of repeated sub-concussive head impacts and that some aspects of contact sports should be redefined, especially in situations where sub-concussive impacts and concussions can be minimized.
... 21 Pre-season elevations in biomarkers have been observed in other studies in collegiate football players. 15,22 Considering the players in our cohort had an average of 11 years playing experience and 41% had previously reported concussions, pre-season biomarker elevations could suggest residual circulating biomarkers from prior concussive and subconcussive impacts over their playing career. Subacute (weeks) and chronic (months to years) elevations in GFAP and NF-L concentrations have been found in patients following mild to moderate TBI compared with uninjured control patients with more variability in the pattern of elevations with Tau and UCH-L1. ...
This prospective cohort study examined the relationship between a panel of four serum proteomic biomarkers (GFAP, UCH-L1, total Tau and NF-L) in 52 players from two different cohorts of male collegiate student football athletes from two different competitive seasons of Division I NCAA Football. This study evaluated changes in biomarker concentrations (as indicators of brain injury) over the course of the playing season and also assessed biomarker concentrations by player position using two different published classification systems. Player positions were divided into: 1) speed (quarterbacks, running backs, halfbacks, fullbacks, wide receivers, tight ends, defensive backs, safety, and linebackers) versus non-speed (offensive and defensive linemen), and 2) 'profile 1' (low frequency/high strain magnitudes positions including quarterbacks, wide receivers, and defensive backs), 'profile 2' (mid-range impact frequency and strain positions including linebackers, running backs and tight ends), and 'profile 3' (high frequency/low strains positions including defensive and offensive linemen). There were significant increases in GFAP 39.3 to 45.6 pg/mL and NF-L 3.5 to 5.4 pg/mL over the course of the season (p<0.001) despite only five players being diagnosed with concussion. UCH-L1 decreased significantly, and Tau was not significantly different. In both the pre- and post-season blood samples Tau and NF-L concentrations were significantly higher in speed versus non-speed positions. GFAP increased (by profile 3, 2, 1) from 42.4, to 49.6, to 78.2 respectively (p=0.051). Tau increased from 0.37, to 0.61, to 0.67 respectively (p=0.024). NF-L increased from 3.5, to 4.9, to 8.2 respectively (p<0.001). In the pre-season samples GFAP and Tau showed similar patterns by profile but were not significant. Only NF-L showed significant differences between profiles 2.7, to 3.1, to 4.2 in the pre-season (p=0.042). Blood-based biomarkers (GFAP, Tau, NF-L) provide an additional layer of injury quantification that could contribute to a better understanding of the risks of playing different positions.
... In addition to central inflammation, concussions are associated with an increase in systemic inflammatory molecules (Oliver et al., 2018). As such, a promising approach for brain recovery is to understand better the mechanisms through which the inflammation generated in the periphery after head injury leads to the development of short-and long-term cognitive deficits. ...
Concussions, both single and repetitive, cause brain and body alterations in athletes during contact sports. The role of the brain-gut connection and changes in the microbiota have not been well established after sports-related concussions or repetitive subconcussive impacts. We recruited 33 Division I Collegiate football players and collected blood, stool, and saliva samples at three time points throughout the athletic season: mid-season, following the last competitive game (post-season), and after a resting period in the off-season. Additional samples were collected from four athletes that suffered from a concussion. 16S rRNA sequencing of the gut microbiome revealed a decrease in abundance for two bacterial species, Eubacterium rectale, and Anaerostipes hadrus, after a diagnosed concussion. No significant differences were found regarding the salivary microbiome. Serum biomarker analysis shows an increase in GFAP blood levels in athletes during the competitive season. Additionally, S100β and SAA blood levels were positively correlated with the abundance of Eubacterium rectale species among the group of athletes that did not suffer a diagnosed concussion during the sports season. These findings provide initial evidence that detecting changes in the gut microbiome may help to improve concussion diagnosis following head injury.
... In addition to central inflammation, concussions are associated with an increase in systemic inflammatory molecules (Oliver et al., 2018). As such, a promising approach for brain recovery is to understand better the mechanisms through which the inflammation generated in the periphery after head injury leads to the development of short-and long-term cognitive deficits. ...
Concussions, both single and repetitive, during contact sports cause brain and body alterations in athletes. The role of the brain-gut connection and changes in the microbiota have not been well established after a head injury or concussion-related health consequences. We recruited 33 Division I Collegiate football players and collected blood, stool, and saliva samples throughout the athletic season. Analysis of the gut microbiome reveals a decrease in abundance for two bacterial species, Eubacterium rectale , and Anaerostipes hadrus , after a diagnosed concussion. No significant differences were found regarding the salivary microbiome. Serum biomarker analysis shows an increase in GFAP blood levels in athletes during athletic activity. Additionally, S100β and SAA blood levels were positively correlated with the abundance of Eubacterium rectale species among athletes exposed to subconcussive impacts. These novel findings provide evidence that detecting changes in the gut microbiome may pave the way for improved concussion diagnosis following head injury.
... Many inflammatory biomarkers are substantially altered after concussion when compared with non-injured athletes 16 . Concussions are associated with an increase in systemic inflammatory molecules 17 . As such, a promising approach for brain recovery is to understand better the mechanisms through which the inflammation generated in the periphery after head injury leads to the development of short-and long-term cognitive deficits. ...
Concussions, both single and repetitive, during contact sports cause brain and body alterations in athletes. The role of the brain-gut connection and changes in the microbiota have not been well established after a head injury or concussion-related health consequences. We recruited 33 Division I Collegiate football players and collected blood, stool, and saliva samples throughout the athletic season. Analysis of the gut microbiome reveals a decrease in abundance for two bacterial species, Eubacterium rectale and Anaerostipes hadrus, after a diagnosed concussion. No significant differences were found regarding the salivary microbiome. Serum biomarker analysis shows an increase in GFAP blood levels in athletes during athletic activity. Additionally, S100β and SAA blood levels were positively correlated with the abundance of Eubacterium rectale species among athletes exposed to subconcussive impacts. These novel findings provide evidence that detecting changes in the gut microbiome may pave the way for improved concussion diagnosis following head injury.
... Many in ammatory biomarkers are substantially altered after concussion when compared with non-injured athletes 16 . Concussions are associated with an increase in systemic in ammatory molecules 17 . As such, a promising approach for brain recovery is to understand better the mechanisms through which the in ammation generated in the periphery after head injury leads to the development of short-and long-term cognitive de cits. ...
Concussions, both single and repetitive, during contact sports cause brain and body alterations in athletes. The role of the brain-gut connection and changes in the microbiota have not been well established after a head injury or concussion-related health consequences. We recruited 33 Division I Collegiate football players and collected blood, stool, and saliva samples throughout the athletic season. Analysis of the gut microbiome reveals a decrease in abundance for two bacterial species, Eubacterium rectale and Anaerostipes hadrus , after a diagnosed concussion. No significant differences were found regarding the salivary microbiome. Serum biomarker analysis shows an increase in GFAP blood levels in athletes during athletic activity. Additionally, S100β and SAA blood levels were positively correlated with the abundance of Eubacterium rectale species among athletes exposed to subconcussive impacts. These novel findings provide evidence that detecting changes in the gut microbiome may pave the way for improved concussion diagnosis following head injury.
... Concern for sports-related concussion and traumatic brain injury (TBI) has fueled research toward mechanisms (Gennarelli, 1993;Meaney & Smith, 2011), prevention (Schneider et al., 2017), and rehabilitation (Broglio, Collins, Williams, Mucha, & Kontos, 2015) from symptomatic concussion/ TBI incidents. However, there is accumulating evidence that "subconcussive" hits (i.e., head impacts in the absence of overt symptomology or a clinical diagnosis of "concussion") can also have cumulative, deleterious effects on a variety of neurophysiological, neuromotor, and neuropsychological outcomes (Abbas et al., 2015;Breedlove et al., 2012;Kawata et al., 2016;Oliver et al., 2018;Talavage et al., 2014). Given that evidence indicates a potential relationship between head impact exposure history and brain histopathology (e.g., chronic traumatic encephalopathy; McKee et al., 2009;Omalu et al., 2005Omalu et al., , 2006Omalu, Hamilton, Kamboh, DeKosky, & Bailes, 2010), techniques capable of quantifying in vivo brain structure alterations are critical for understanding the neurologic effects of repeated head impact exposure in asymptomatic athletes. ...
The purpose of this clinical trial was to examine whether internal jugular vein compression (JVC)-using an externally worn neck collar-modulated the relationships between differential head impact exposure levels and pre- to postseason changes in diffusion tensor imaging (DTI)-derived diffusivity and anisotropy metrics of white matter following a season of American tackle football. Male high-school athletes (n = 284) were prospectively assigned to a non-collar group or a collar group. Magnetic resonance imaging data were collected from participants pre- and postseason and head impact exposure was monitored by accelerometers during every practice and game throughout the competitive season. Athletes' accumulated head impact exposure was systematically thresholded based on the frequency of impacts of progressively higher magnitudes (10 g intervals between 20 to 150 g) and modeled with pre- to postseason changes in DTI measures of white matter as a function of JVC neck collar wear. The findings revealed that the JVC neck collar modulated the relationships between greater high-magnitude head impact exposure (110 to 140 g) and longitudinal changes to white matter, with each group showing associations that varied in directionality. Results also revealed that the JVC neck collar group partially preserved longitudinal changes in DTI metrics. Collectively, these data indicate that a JVC neck collar can provide a mechanistic response to the diffusion and anisotropic properties of brain white matter following the highly diverse exposure to repetitive head impacts in American tackle football. Clinicaltrials.gov: NCT# 04068883.
... Nf-L has been identified in peripheral blood collected weeks or months after TBI (23). Tau and Nf-L are currently the most widely used biomarkers applied to acute-subacute mTBI or concussion with variable results (24)(25)(26)(27). Amyloid precursor protein (APP), an integral membrane protein predominantly expressed in the synapses of neurons, is the precursor of amyloid beta (Aβ) peptides, which have been shown to be elevated in blood of both patients and animal models after TBI (28). ...
Background: Overpressure (OP) is an increase in air pressure above normal atmospheric levels. Military personnel are repeatedly exposed to low levels of OP caused by various weapon systems. Repeated OP may increase risk of neurological disease or psychological disorder diagnoses. A means to detect early phase effects that may be relevant to brain trauma remain elusive. Therefore, development of quantitative and objective OP-mediated effects during acute timeframes would vastly augment point-of-care or field-based decisions. This pilot study evaluated the amplitude of traumatic brain injury (TBI)–associated biomarkers in serum as a consequence of repeated OP exposure from .50-caliber rifle use over training multiple days.
Objective: To determine the acute temporal profile of TBI-associated serum biomarkers and their relationship with neurocognitive decrements or self-reported symptoms among participants exposed to low-level, repeated OP from weapons used in a training environment.
Methods: Study participants were enrolled in .50-caliber sniper rifle training and exposed to mild OP (peak pressure 3.8–4.5 psi, impulse 19.27–42.22 psi-ms per day) for three consecutive days (D1–D3). Defense automated neurobehavioral assessment (DANA) neurocognitive testing, symptom reporting, and blood collection were conducted 2–3 h before (pre-) and again 0.45–3 h after (post-) OP exposure. The TBI-associated serum biomarkers, glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), neurofilament light (Nf-L), tau, and amyloid beta peptides (Aβ-40 and Aβ-42) were measured using digital ELISAs.
Results: Serum GFAP decreased on D1 and D3 but not D2 after OP exposure. Nf-L was suppressed on D3 alone. Aβ-40 was elevated on D2 alone while Aβ-42 was elevated each day after OP exposure. Suppression of GFAP and elevation of Aβ-42 correlated to OP-mediated impulse levels measured on D3.
Conclusions: Acute measurement of Aβ-peptides may have utility as biomarkers of subconcussive OP caused by rifle fire. Fluctuation of GFAP, Nf-L, and particularly Aβ peptide levels may have utility as acute, systemic responders of subconcussive OP exposure caused by rifle fire even in the absence of extreme operational deficits or clinically defined concussion.
... 31 Both T-Tau and NF-L require continued research to assess their diagnostic utility in acute SRC and to build on recent efforts to measure effects of repetitive subclinical head impact exposure in collision sport athletes. 18,[33][34][35][36] Added value of serum biomarkers to routine clinical tests in SRC identification Discrepancies between clinical and physiological effects of SRC are expected and increasingly documented. 3 The few SRC biomarker studies that incorporate clinical assessments have demonstrated weak relationships between biomarker changes and test measurements or acute symptom severity. ...
We prospectively evaluated serum concentrations of glial fibrillary acidic protein (GFAP), ubiquitin c-terminal hydrolase L1 (UCH-L1), total tau (T-Tau), and neurofilament light (NF-L) from collegiate athletes at baseline and acutely after sport-related concussion (SRC) using the Quanterix Neurology 4Plex "B" (N4PB) multiplex assay. Uninjured controls were matched on age, sex, race, sport, and concussion history. Clinical outcomes included acute symptom severity, balance, rapid automated naming, computerized cognitive testing, and recovery duration. Baseline (n=110; median [IQR] age =19 [18-20] years, 54% male, 61% white/Caucasian) and post-SRC (n=36; median [IQR] age = 19 [18-20] years, 50% male, 61% white/Caucasian) blood samples were analyzed. We observed post-SRC elevations from baseline for GFAP (p=.001, d=1.7), T-Tau (p=.004, d=1.3), and NF-L (p=.010, d=1.1). GFAP (AUC=.958, 95%CI .927-.989, p<.001) and NF-L (AUC=.904, 95%CI .851-.957, p<.001) accurately discriminated SRC from control cases. There were no associations between biomarker concentrations and clinical measurements post-SRC or recovery duration. These findings suggest that, using the multiplex assay, GFAP, T-Tau, and NF-L elevate from baseline acutely after SRC, and both GFAP and NF-L excellently distinguished concussed from control cases. Serum biomarker changes do not necessarily correspond with clinical measurements or recovery duration. Key Words: Concussion, TBI, biomarkers, multiplex, brain injury.
... Regardless of the type of contact sport, there seems to be a relationship between NF-L levels and the frequency and magnitude of the head impact [58,61-64, 151,152]. It is not yet clear, however, whether NF-L may serve as a biomarker for prediction of when it is safe to return to contact sports without the risk of permanent disability and chronic traumatic encephalopathy [153]. ...
Neurofilaments (NFs) are quickly becoming the biomarkers of choice in the field of neurology, suggesting their use as an unspecific screening marker, much like the use of elevated plasma C-reactive protein (CRP) in other fields. With sensitive techniques being readily available, evidence is growing about the diagnostic and prognostic value of NFs in many neurological disorders. Here, we review the latest literature on the structure and function of NFs and report the strengths and pitfalls of NFs as markers of neurodegeneration in the context of neurological diseases of the central and peripheral nervous systems.
... Pioneering studies directed at finding reliable biomarkers for TBI and/or CTE in the circulating blood, blood components, or cerebrospinal fluid, have been reported by Mondello et al. [11], Pasinetti et al. [12], and Oliver et al. [13]. ...
Traumatic brain injury (TBI) is a leading cause of death and disability, contributing to ~30% of all injury-related deaths in the US. TBI occurs when a force transmitted to the head causes neuropathologic damage and impairment of brain function. TBI doubles risk of suicide and is the major determinant of acquired seizure disorders. TBI arising from closed head trauma (CHT) significantly increases the risk of developing Alzheimer's disease (AD), Parkinson's disease (PD) and chronic traumatic encephalopathy (CTE). Evidence for a possible role of TBI as a risk factor for sporadic amyotrophic lateral sclerosis (sALS) has been provided by studies of professional players of European football. Depending on age, genetic make-up (in particular, being a carrier of one or two ApoE4 alleles), the number of TBIs sustained, their severity, the time periods involved, and many other factors that affect vulnerability, decades may pass after occurrence of one or more TBIs before sequelae such as AD, PD, sALS or CTE become clinically evident. Among college and professional football players who experience repeated concussions and sub-concussive blows to the head, the risk of developing CTE increases with the number of years actively devoted to the sport, and the degree of exposure to physical impacts inherent in the position played. Following a moderate or severe concussion, or a series of mild blows to the head, the brain may undergo subtle pathophysiological changes that are unlikely to be detected with confidence using available diagnostic methods. Biomarkers are being sought that can help the attending physician infer the likely presence of an ongoing occult neurodegenerative process. One example of the adverse effect of collision on the brain is "heading" the soccer ball-a feat that, repeated over years of competition, has been found to produce severe brain damage in veteran players. CTE has attracted increasing national attention because of its devastating effects in a high proportion of retired professional players of American football. In a study of brains from deceased former football players, contributed mostly by family members, CTE was neuropathologically diagnosed in 110 of 111 of National Football League (NFL) veterans. In the CTE-positive subjects, the authors observed extensive brain atrophy, astrogliosis, myelinated axonopathy, microvascular injury, perivascular neuroinflammation, and phosphorylated tau protein pathology. CTE's neuropathology has been formally defined as a tauopathy characterized by a distinct perivascular accumulation of hyperphosphorylated tau in neurons and astrocytes within cerebral sulci. Although the mechanism that underlies the unforeseen emergence of CTE long after the occurrence of one or more closed head traumas is unknown, an explanation proposed by Albayram and associates is persuasive. They discovered TBI-induced neuronal production of the toxic compound cis P-tau, an abnormal and destructive isomer of the normal and benign trans P-tau, in mouse models of CTE. Cis P-tau produced a CTE-like syndrome via a process they termed cistauosis. Cistauosis can be blocked in laboratory animals by cis P-tau monoclonal antibody, which prevents later development of tau tangles, brain atrophy and virtual CTE. In a subsequent study, the same group found in human samples obtained post-TBI from a variety of causes, that cis P-tau is induced in cortical axons and cerebrospinal fluid and positively correlates with axonal injury and clinical outcome. Thus, cis P-tau appears to contribute to short-term and long-term sequelae after TBI, but may be subject to neutralization by cis-antibody treatment.
... Recent research has further assessed the clinical importance and deleterious effects of these ''silent'' impacts, including impairments in oculomotor and neuropsychological function, alterations in serum levels of markers for neuroanatomical injury, and increasing susceptibility for sports-related mTBI. [1][2][3][4][5][6][7] Given that these athletes are asymptomatic and are thus not referred for clinical evaluation, researchers have utilized neuroimaging to explore potential effects of repetitive, subconcussive impacts on brain structure. ...
Competitive sport participation, in contact and collision sports, exposes athletes to repetitive head impacts. Although these impacts do not always result in overt symptomology or a diagnosed "concussion," evidence indicates that cumulative repetitive impacts affect brain pathophysiology. The purpose of this study was to perform a systematic review of prospective, longitudinal trials evaluating repetitive head impact exposure on white matter (WM) microstructure in collision and contact sport athletes to inform clinical care and treatment strategies. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed to determine studies that met predetermined inclusion and exclusion criteria. Initially, 2498 abstracts were identified, and 20 studies were critically evaluated herein. The majority of studies demonstrated significant longitudinal changes in anisotropy and/or diffusivity metrics that were associated with the quantity and/or the magnitude of head impact exposure, highlighting the utility of diffusion tensor imaging (DTI) for measuring changes in WM microstructure. Our review also comments on study methodology and describes how age, sex, sport, and time between sport cessation and DTI measures contribute to divergent findings within the literature. Suggestions for future research are also provided to overcome previous study limitations and maximize our understanding of the role of repetitive head impact exposure on WM integrity and long-term neurological sequela.
... Football athletes are also at an increased risk of head trauma, 7 which, even in the absence of a clinically discernible injury, results in quantifiable pathophysiological changes. 22 Indeed, a lifetime of head trauma associated with participation in sport may lead to long-term neurologic consequences. 23 A unique pathologic consequence of traumatic brain injury (TBI) in animal models is a reduction in neuronal DHA after injury, 24 and deficient brain DHA content in animal models, as induced by dietary restriction, heightens the pathophysiological response to injury. ...
Context:
The essential omega-3 fatty acids (ω-3 FAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) exhibit vital biological roles and are critical for cardiovascular and neurologic health. Compared with the general population, football athletes may be at an increased risk of cardiovascular disease. Further, those same athletes are also exposed to repetitive head impacts, which may lead to long-term neurologic deficits. Both diets high in ω-3 FAs and supplementation with ω-3 FAs have been reported to reduce the risk of cardiovascular disease, and early evidence suggests a potential neuroprotective effect of supplementation.
Objective:
To determine the (1) erythrocyte content of DHA and EPA, as measured by the Omega-3 Index, expressed as a percentage of total fatty acids, in National Collegiate Athletic Association Division I football athletes and (2) distribution across the Omega-3 Index risk zones established for cardiovascular disease: high risk, <4%; intermediate risk, 4% to 8%; and low risk, >8%.
Design:
Cross-sectional descriptive study.
Setting:
Multicenter trial.
Patients or other participants:
Deidentified data including complete erythrocyte fatty acid profile from the 2017-2018 season, age at time of testing, height, weight, and ethnicity were collected from 404 athletes.
Main outcome measure(s):
Omega-3 Index.
Results:
About 34% of athletes (n = 138) had an Omega-3 Index considered high risk (<4%), and 66% (n = 266) had a risk considered intermediate (4%-8%). None had a low-risk Omega-3 Index.
Conclusions:
The Omega-3 Index is a simple, minimally invasive test of ω-3 FA status. Our data indicate that football athletes may be deficient in the ω-3 FAs DHA and EPA. The fact that no athlete had an Omega-3 Index associated with low risk suggests football athletes may be at increased risk for cardiovascular disease in later life.
Background
Amidst growing concern about the safety of sport-related repetitive subconcussive head impacts (RSHI), biofluid markers may provide sensitive, informative, and practical assessment of the effects of RSHI exposure.
Objective
This scoping review aimed to systematically examine the extent, nature, and quality of available evidence from studies investigating the effects of RSHI on biofluid markers, to identify gaps and to formulate guidelines to inform future research.
Methods
PRISMA extension for Scoping Reviews guidelines were adhered to. The protocol was pre-registered through publication. MEDLINE, Scopus, SPORTDiscus, CINAHL, PsycINFO, Cochrane Library, OpenGrey, and two clinical trial registries were searched (until March 30, 2022) using descriptors for subconcussive head impacts, biomarkers, and contact sports. Included studies were assessed for risk of bias and quality.
Results
Seventy-nine research publications were included in the review. Forty-nine studies assessed the acute effects, 23 semi-acute and 26 long-term effects of RSHI exposure. The most studied sports were American football, boxing, and soccer, and the most investigated markers were (in descending order): S100 calcium-binding protein beta (S100B), tau, neurofilament light (NfL), glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), brain-derived neurotrophic factor (BDNF), phosphorylated tau (p-tau), ubiquitin C-terminal hydrolase L1 (UCH-L1), and hormones. High or moderate bias was found in most studies, and marker-specific conclusions were subject to heterogeneous and limited evidence. Although the evidence is weak, some biofluid markers—such as NfL—appeared to show promise. More markedly, S100B was found to be problematic when evaluating the effects of RSHI in sport.
Conclusion
Considering the limitations of the evidence base revealed by this first review dedicated to systematically scoping the evidence of biofluid marker levels following RSHI exposure, the field is evidently still in its infancy. As a result, any recommendation and application is premature. Although some markers show promise for the assessment of brain health following RSHI exposure, future large standardized and better-controlled studies are needed to determine biofluid markers’ utility.
Objective:
Repetitive head impacts in professional fighting commonly lead to head injuries. Increased exposure to repetitive head trauma, measured by the number of professional fights and years of fighting, has been associated with slower processing speed and smaller brain volumes. The impact of win-loss outcomes has been investigated in other sports, with several studies suggesting that individuals on losing teams experience more head injuries. Here, the authors hypothesized that fighters with a worse fight record would exhibit poorer brain health outcomes.
Methods:
The Professional Fighters Brain Health Study examined changes in neuropsychiatric symptoms, regional brain volume, and cognition among professional boxers and mixed martial arts fighters. These data were used to evaluate the relationship between win-loss ratios and brain health outcomes among professional fighters (N=212) by using validated neuropsychiatric symptom and cognitive measures and MRI data.
Results:
Retired fighters with a better record demonstrated more impulsiveness (B=0.21, df=48) and slower processing speed (B=-0.42, df=31). More successful fighters did not perform better than fighters with worse records on any neuropsychiatric or cognitive test. Retired fighters with better fight records had smaller brain volumes in the subcortical gray matter, anterior corpus callosum, left and right hippocampi, left and right amygdala, and left thalamus. More successful active fighters had a smaller left amygdala volume.
Conclusions:
These findings suggest that among retired fighters, a better fight record was associated with greater impulsiveness, slower processing speed, and smaller brain volume in certain regions. This study shows that even successful fighters experience adverse effects on brain health.
Background: Amidst growing concern about the safety of sport-related repetitive subconcussive head impacts (RSHI), biofluid markers may provide sensitive, informative, and practical assessment of the effects of RSHI exposure.
Objective: This scoping review aimed to systematically examine the extent, nature, and quality of available evidence from studies investigating the effects of RSHI on biofluid markers, to identify gaps and to formulate guidelines to inform future research.
Methods: PRISMA extension for Scoping Reviews guidelines were adhered to. The protocol was pre-registered through publication. MEDLINE, Scopus, SPORTDiscus, CINAHL, PsycINFO, Cochrane Library, OpenGrey and two clinical trial registries were searched (until 30th March 2022) using descriptors for subconcussive head impacts, biomarkers, and contact sports. Included studies were assessed for risk of bias and quality.
Results: Seventy-nine research publications were included in the review. Forty-nine studies assessed the acute effects, 23 semi-acute and 26 long-term effects of RSHI exposure. The most studied sports were American football, boxing and soccer, and the most investigated markers were (in ascending order): S100 calcium-binding protein beta (S100B), tau, neurofilament light (NfL), glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), brain-derived neurotrophic factor (BDNF), phosphorylated tau (p-tau), ubiquitin C-terminal hydrolase L1 (UCH-L1), and hormones. High or moderate bias was found in most studies, and marker-specific conclusions were subject to heterogeneous and limited evidence. Although the evidence is weak, some biofluid markers – such as NfL – appeared to show promise. More markedly, S100B was found to be problematic when evaluating the effects of RSHI in sport.
Conclusion: Considering the limitations of the evidence-base revealed by this first review dedicated to systematically scoping the evidence of biofluid marker levels following RSHI exposure, the field is evidently still in its infancy. As a result, any recommendation and application is premature. Although some markers show promise for the assessment of brain health following RSHI exposure, future large standardized and better-controlled studies are needed to determine biofluid markers’ utility.
Background
Artificial turf fields and environmental conditions may influence sports concussion risk, but existing research is limited by uncontrolled confounding factors, limited sample size, and the assumption that risk factors are independent of one another. The purpose of this study was to examine how playing surface, time of season, and game temperature relate to diagnosed concussion risk in the National Football League (NFL).
Methods
This retrospective cohort study examined data from the 2012-2019 NFL regular season. We fit Bayesian negative binomial regression models to relate how playing surface, game temperature, and week of the season independently related to diagnosed concussion risk and any interactions among these factors.
Results
We identified 1096 diagnosed concussions in 1830 games. There was a >99% probability that concussion risk was reduced on grass surface (median incidence rate ratio (IRR) = 0.78 [95% credible interval: 0.68, 0.89], >99% probability that concussion risk was lower at higher temperatures (IRR=0.85 [0.76,0.95] for each 7.9 ° C), and >91% probability that concussion risk increased with each week of the season (IRR=1.02 [1.00,1.04]). There was an >84% probability for a surface × temperature interaction (IRR=1.01 [0.96, 1.28]) and >75% probability for a surface × week interaction (IRR=1.02 [0.99, 1.05]).
Conclusions
Diagnosed concussion risk is increased on artificial turf compared to natural grass, and this is exacerbated in cold weather and, independently, later in the season. The complex interplay between these factors necessitates accounting for multiple factors and their interactions when investigating sports injury risk factors and devising mitigation methods.
Background
Neurocognitive impairment linked to head impact exposure in otherwise healthy, non-concussed athletes may be associated with adverse long-term outcomes. The primary purpose of this study was to evaluate whether a dietary supplement, Synaquell TM , supports brain function and structure in male Junior A ice hockey players over the course of a season.
Methods
Players underwent pre-season testing, were randomized into a placebo or dietary supplement group, then were retested after the season. Objective tests included: NeuroCatch ® portable evoked potential platform, King-Devick Test of rapid number naming, and blood biomarker assay for neurofilament light chain (NfL).
Results
Multivariate analysis revealed significant differences in neurocognitive changes between groups from pre to postseason after controlling for covariates related to head impact exposure. Post-hoc tests showed significant within-subject differences between groups from pre- to post-season in both N100 latency (p = 0.005) and King-Devick score (p = 0.043). Univariate tests of the NeuroCatch results replicated prior findings of a N400 amplitude decrease (p = 0.017) and N100 latency increase (p = 0.049) in the placebo group, but not in the dietary supplement group.
Conclusions
This prospective, randomized trial showed that, compared to the placebo group, a multi-ingredient dietary supplement significantly affected objective measures of brain function and structure in Junior A ice hockey players from pre- to post-season. Further investigation into the effects of dietary supplementation on the contact athlete’s brain is warranted.
Developing objective means to clinically diagnose sport-related concussion (SRC) is a top priority in sport medicine, particularly in the pediatric context given the vulnerability of the developing brain. While advances in SRC blood biomarkers are being made in adult populations, little work is being done in youth. Clinical validation of these biomarkers post-SRC will first require investigation into their presentation in a healthy uninjured state. Furthermore, rapid pubertal changes in this age group may implicate possible interactions with circulating sex hormones, and specifically the menstrual cycle for female athletes. This cross-sectional study aimed to characterize pre-injury plasma levels of glial fibrillary acidic protein (GFAP), neurofilament light (NF-L), ubiquitin C-terminal hydrolase-L1 (UCH-L1), total tau (T-tau), and phosphorylated tau-181 (P-tau-181) considering the influence of previous concussion, age, and sex in healthy youth sport participants. Possible associations with menstrual cycle phase and circulating sex hormone levels (progesterone, estradiol, and testosterone) were also explored. Pre-injury blood samples were obtained from 149 healthy youth (48% female, ages 11-18) participating in the larger SHRed Concussions multi-site longitudinal cohort study. Main outcomes were natural log (ln) transformed plasma GFAP, NF-L, UCH-L1, T-tau, and P-tau-181 concentrations (quantified on the Quanterix Simoa HD-X platform). Mixed-effects multivariable linear regression was used to assess the associations between biomarkers and self-reported history of previous concussion (yes/no), age (years), sex (male/female), objectively determined menstrual cycle phase (follicular/luteal), plasma progesterone, estradiol, and testosterone. Males had 19.8% lower UCH-L1 (β=-0.221, 95% CI [-0.396, -0.046]), 18.9% lower GFAP (β=-0.210, 95% CI [-0.352, -0.068]), and 21.8% higher P-tau-181 (β=0.197, 95% CI [0.048, 0.346]) compared to females, adjusting for age and previous concussion. GFAP decreased 9.5% with each 1-year increase in age, adjusting for previous concussion and sex (β=-0.100, 95% CI [-0.152, -0.049]). No biomarkers were associated with a history of previous concussion. Exploratory investigations found no associations between biomarkers and menstrual cycle phase. However, females displayed an age-adjusted negative association between T-tau and progesterone (β=-0.010, 95%CI [-0.018, -0.002]), whereas males had a negative age-adjusted association between UCH-L1 and testosterone (β=-0.020, 95%CI [-0.037, -0.002]). These results indicate age and sex-specific reference intervals may be warranted for pediatric athlete populations prior to clinical validation of blood biomarkers for SRC. Additionally, hormonal associations highlight the need to consider puberty and development in adolescent studies. Overall, findings suggest these biomarkers are resilient to a history of previous concussion and menstrual cycle phase, supporting their continued research in youth SRC.
This prospective longitudinal trial aimed to 1) determine the role of head impact exposure on behavioral/cognitive outcomes, and 2) assess the protective effect(s) of a jugular vein compression (JVC) collar on behavioral/cognitive outcomes following one season of high-school football. Participants included 284 male high-school football players aged 13-18 years enrolled from seven midwestern high-schools. Schools were allocated to the JVC collar intervention(four teams, 140 players) or non-collar/no intervention control (three teams, 144 players) condition. Head impact exposure was measured throughout the season using CSx accelerometers. Outcome measures included post season parent and adolescent report on Strengths and Weaknesses of ADHD Symptoms and Normal Behavior Scale (SWAN) and Post-Concussion Symptom Inventory (PCSI), as well as adolescent performance on Attention Network Task (ANT), digital Trail Making Task (dTMT), and Cued Switching task. No significant effect of head impact exposure or JVC collar use on post-season SWAN or PCSI scores or performance on dTMT and Cued Switching task were noted. There was no effect of head impact exposure on ANT performance; however, the JVC collar group had greater post-season Alerting network scores than the non-collar group (p=.026, d=.22). Findings provide preliminary evidence that the JVC collar may provide some protection to the alerting attention system. These findings should be interpreted cautiously as a greater understanding of the long-term sequalae of head impact exposure and the role of cumulative head impact exposure behavioral/cognitive outcomes is required.
A lack of convenient and reliable biomarkers for diagnosis and prognosis is a common challenge for neurodegenerative diseases such as Alzheimer’s disease (AD). Recent advancement in ultrasensitive protein assays has allowed the quantification of tau and phosphorylated tau proteins in peripheral plasma. Here we identified 66 eligible studies reporting quantification of plasma tau and phosphorylated tau 181 (ptau181) using four ultrasensitive methods. Meta-analysis of these studies confirmed that the AD patients had significantly higher plasma tau and ptau181 levels compared with controls, and that the plasma tau and ptau181 could predict AD with high-accuracy area under curve of the Receiver Operating Characteristic. Therefore, plasma tau and plasma ptau181 can be considered as biomarkers for AD diagnosis.
Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease linked to repeated traumatic brain injury (TBI). This disorder is mainly observed in subjects at risk for brain traumatisms including boxers, American football and European football (soccer) players as well as war veterans. Neuropathological findings are marked by abnormally phosphorylated tau accumulations at the depth of cerebral sulci as well as TDP43, Aβ and α-synuclein positive staining. It has been described 3 clinical variants: the behavioral/mood variant, the cognitive variant and the mixed behavioral/cognitive variant. Cerebral MRI revealed signs of diffuse atrophy with abnormal axonal findings using the diffusion tensor imaging methods. Cerebral PET tau revealed increased standardized uptake value ratio (SUVR) levels in various brain regions of CTE patients compared to controls. The place of CTE among other neurodegenerative diseases is still debated. The focus of CTE management must be on prevention. The best way to prevent CTE in athletes is to put in place strict and appropriate measures by physicians. An individual with concussion should not be allowed to play again immediately (and sometimes never) in cases of abnormal neurological symptoms or imaging abnormalities.
While neuroimaging and blood biomarker have been two of the most active areas of research in the neurotrauma community, these fields rarely intersect to delineate subconcussive brain injury. The aim of the study was to examine the association between diffusion MRI techniques [diffusion tensor imaging (DTI) and neurite orientation/dispersion density imaging (NODDI)] and brain-injury blood biomarker levels [tau, neurofilament-light (NfL), glial-fibrillary-acidic-protein (GFAP)] in high-school football players at their baseline, aiming to detect cumulative neuronal damage from prior seasons. Twenty-five football players were enrolled in the study. MRI measures and blood samples were obtained during preseason data collection. The whole-brain, tract-based spatial statistics was conducted for six diffusion metrics: fractional anisotropy (FA), mean diffusivity (MD), axial/radial diffusivity (AD, RD), neurite density index (NDI), and orientation dispersion index (ODI). Five players were ineligible for MRIs, and three serum samples were excluded due to hemolysis, resulting in 17 completed set of diffusion metrics and blood biomarker levels for association analysis. Our permutation-based regression model revealed that serum tau levels were significantly associated with MD and NDI in various axonal tracts; specifically, elevated serum tau levels correlated to elevated MD (p = 0.0044) and reduced NDI (p = 0.016) in the corpus callosum and surrounding white matter tracts (e.g., longitudinal fasciculus). Additionally, there was a negative association between NfL and ODI in the focal area of the longitudinal fasciculus. Our data suggest that high school football players may develop axonal microstructural abnormality in the corpus callosum and surrounding white matter tracts, such as longitudinal fasciculus. A future study is warranted to determine the longitudinal multimodal relationship in response to repetitive exposure to sports-related head impacts.
American football athletes are routinely exposed to sub-concussive impacts over the course of the season. This study sought to examine the effect of a season of American football on plasma tau, a potential marker of axonal damage. Nineteen (n =19) National Collegiate Association (NCAA) American football athletes underwent serial blood sampling over the course of the 2014-2015 season at those times in which the number and magnitude of head impacts likely changed. Non-contact, sport-control, NCAA men's swim athletes (n=19) provided a single plasma sample for comparison. No significant differences were observed between control swim athletes and American football athletes following a period of non-contact (p = 0.569) or a period of contact (p = 0.076). Those American football athletes categorized as starters (n=11) had higher tau concentrations than non-starters (n=8) following a period of non-contact (p = 0.039) and contact (p = 0.036), but not higher than swimmers (p = 1.000 and p = 1.000, respectively). No difference was noted over the course of the season in American football athletes irrespective of starter status. Despite routine head impacts, common to the sport of American football, no changes were observed over the course of the season in American football athletes, irrespective of starter status. Further, no difference was observed between American football athletes and non-contact control swim athletes following a period of non-contact or contact. These data suggest that plasma tau is not sensitive enough to detect damage associated with repetitive sub-concussive impacts sustained by collegiate level American football athletes.
Objective:
To evaluate whether the axonal protein neurofilament light (NFL) in serum is a sensitive biomarker to detect subtle brain injury or concussion in contact sports athletes.
Methods:
Two prospective cohort studies involving (1) 14 Swedish amateur boxers who underwent fluid biomarker assessments at 7-10 days after bout and after 3 months of rest from boxing and (2) 35 Swedish professional hockey players who underwent blood biomarker assessment at 1, 12, 36, and 144 hours after concussion and when the players returned to play were performed. Fourteen healthy nonathletic controls and 12 athletic controls were also enrolled. Serum NFL was measured using ultrasensitive single molecule array technology.
Results:
Serum NFL concentrations were increased in boxers 7-10 days after bout as compared to the levels after 3 months rest as well as compared with controls (p = 0.0007 and p < 0.0001, respectively). NFL decreased following 3 months of rest, but was still higher than in controls (p < 0.0001). Boxers who received many (>15) hits to the head or were groggy after bout had higher concentrations of serum NFL as compared to those who received fewer hits to the head (p = 0.0023). Serum NFL increased over time in hockey players, and the levels returned to normal at return to play. Importantly, serum NFL could separate players with rapidly resolving postconcussion symptoms (PCS) from those with prolonged PCS.
Conclusions:
The results from these 2 independent cohort studies suggest that serum NFL is a highly sensitive biomarker for concussion.
The cumulative effect of repetitive subconcussive collisions on the structural and functional integrity of the brain remains largely unknown. Athletes in collision sports, like football, experience a large number of impacts across a single season of play. The majority of these impacts, however, are generally overlooked, and their long-term consequences remain poorly understood. This study sought to examine the effects of repetitive collisions across a single competitive season in NCAA Football Bowl Subdivision athletes using advanced neuroimaging approaches. Players were evaluated before and after the season using multiple MRI sequences, including T1-weighted imaging, diffusion tensor imaging (DTI), arterial spin labeling (ASL), resting-state functional MRI (rs-fMRI), and susceptibility weighted imaging (SWI). While no significant differences were found between pre- and post-season for DTI metrics or cortical volumes, seed-based analysis of rs-fMRI revealed significant (p < 0.05) changes in functional connections to right isthmus of the cingulate cortex (ICC), left ICC, and left hippocampus. ASL data revealed significant (p < 0.05) increases in global cerebral blood flow (CBF), with a specific regional increase in right postcentral gyrus. SWI data revealed that 44% of the players exhibited outlier rates (p < 0.05) of regional decreases in SWI signal. Of key interest, athletes in whom changes in rs-fMRI, CBF and SWI were observed were more likely to have experienced high G impacts on a daily basis. These findings are indicative of potential pathophysiological changes in brain integrity arising from only a single season of participation in the NCAA Football Bowl Subdivision, even in the absence of clinical symptoms or a diagnosis of concussion. Whether these changes reflect compensatory adaptation to cumulative head impacts or more lasting alteration of brain integrity remains to be further explored.
The aim of this study was to evaluate longitudinal changes in the diffusion characteristics of brain white matter (WM) in collegiate athletes at three time points: prior to the start of the football season (T1), after one season of football (T2), followed by six months of no-contact rest (T3). Fifteen male collegiate football players and 5 male non-athlete student controls underwent diffusion MR imaging and computerized cognitive testing at all three timepoints. Whole-brain tract-based spatial statistics (TBSS) were used to compare fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AD), and trace between all timepoints. Average diffusion values were obtained from statistically significant clusters for each individual. No athlete suffered a concussion during the study period. After one season of play (T1 to T2), we observed a significant increase in trace in a cluster located in the brainstem and left temporal lobe, and a significant increase in FA in the left parietal lobe. After six months of no-contact rest (T2 to T3), there was a significant decrease in trace and FA in clusters that were partially overlapping or in close proximity with the initial clusters (T1 to T2), with no significant changes from T1 to T3. Repetitive head impacts (RHI) sustained during a single football season may result in alterations of the brain’s WM in collegiate football players. These changes appear to return to baseline after 6 months of no-contact rest, suggesting remission of WM alterations. Our preliminary results suggest that collegiate football players might benefit from periods without exposure to RHI.
Objective:
To determine whether tau changes after sport-related concussion (SRC) relate to return to play (RTP).
Methods:
Collegiate athletes underwent preseason plasma sampling and cognitive testing and were followed. After a SRC (n = 46), athletes and controls (n = 37) had sampling at 6 hours, and at 24 hours, 72 hours, and 7 days after SRC. A sample of 21 nonathlete controls were compared at baseline. SRC athletes were grouped by long (>10 days, n = 23) and short (≤10 days, n = 18) RTP. Total tau was measured using an ultrasensitive immunoassay.
Results:
Both SRC and athlete controls had significantly higher mean tau at baseline compared to nonathlete healthy controls (F101,3 = 19.644, p < 0.01). Compared to SRC athletes with short RTP, those with long RTP had higher tau concentrations overall, after controlling for sex (F39,1 = 3.59, p = 0.022), compared to long RTP athletes, at 6 (p < 0.01), 24 (p < 0.01), and 72 hours (p = 0.02). Receiver operator characteristic analyses showed that higher plasma tau 6 hours post-SRC was a significant predictor of RTP >10 days (area under the curve 0.81; 95% confidence interval 0.62-0.97, p = 0.01).
Conclusions:
Elevated plasma tau concentration within 6 hours following a SRC was related to having a prolonged RTP, suggesting that tau levels may help inform RTP.
Axonal white matter injury is believed to be a major determinant of adverse outcomes following traumatic brain injury (TBI). We hypothesized that measurement of neurofilament light protein (NF-L), a protein found in long white-matter axons, in blood samples, may serve as a suitable biomarker for neuronal damage in TBI patients. To test our hypotheses, we designed a study in two parts: i) we developed an immunoassay based on Single molecule array technology for quantification of NF-L in blood, and ii) in a proof-of-concept study, we tested our newly developed method on serial serum samples from severe TBI (sTBI) patients (n = 72) and controls (n = 35). We also compared the diagnostic and prognostic utility of NF-L with the established blood biomarker S100B. NF-L levels were markedly increased in sTBI patients compared with controls. NF-L at admission yielded an AUC of 0.99 to detect TBI versus controls (AUC 0.96 for S100B), and increased to 1.00 at day 12 (0.65 for S100B). Importantly, initial NF-L levels predicted poor 12-month clinical outcome. In contrast, S100B was not related to outcome. Taken together, our data suggests that measurement of serum NF-L may be useful to assess the severity of neuronal injury following sTBI.
Glial fibrillary acidic protein (GFAP), tau, and amyloid β peptide (Aβ42) have been proposed as diagnostic and prognostic biomarkers in traumatic brain injury (TBI). Single Molecule Array (Simoa) is a novel technology which employs highly sensitive immunoassays. Our objective was to trace the trajectory of tau, GFAP, and Aβ42 levels in plasma from the acute through subacute stages after TBI, compared with controls.
Samples from 34 TBI subjects were studied. Injury severity was assessed by Glasgow Coma Scale (GCS) and admission CT. Glasgow Outcome Scale Extended (GOSE) was assessed 6 month after injury. Plasma was collected within 24 hours (Day 0), 30 and 90 days after the TBI.
At every time point, increases were noted in plasma GFAP (p<0.0001 for all comparisons), tau (p<0.0001, p<0.0001, and p=0.0044, at Days 0, 30 and 90, respectively) and Aβ42 (p<0.001, p<0.0001, and p=0.0203, respectively) in TBI cases compared to controls. The levels were maximal at Day 0 for GFAP and tau and at Day 30 for Aβ42. Area under curve (AUC) for Day 0 GFAP and tau were excellent for discrimination of cmTBI from controls (0.936 and 0.901, correspondingly). Discriminant component analysis (DCA) for three biomarkers at Days 0 and 30 differentiated controls from cmTBI (91.1% and 89.7% correctly classified, at each time point). Duration of posttraumatic amnesia (PTA) correlated weakly with tau at 30 days (Spearman’s r = 0.40 (95% CI 0.0003-0.60, p=0.044). The Marshall CT Grade correlated with day 30 tau (Spearman’s r 0.41 (95% CI 0.04-0.68, p = 0.027). Day 30 Aβ42 correlated with GOSE.
GFAP, tau and Aβ42 are increased up to 90 days after TBI compared to controls. Total tau levels correlated with clinical and radiological variables of TBI severity. Aβ42 correlated with clinical outcome. Combination of biomarkers at Days 0 and 30 differentiates cmTBI populations and may be useful in acute and subacute phases.
Despite being underreported, American football boasts the highest incidence of concussion among all team sports likely due to exposure to head impacts that vary in number and magnitude over the season. This study compared a biological marker of head trauma in American football athletes with non-contact sport athletes and examined changes over the course of a season. Baseline serum neurofilament light polypeptide (NFL) was measured after 9 weeks of no contact and compared to a non-contact sport. Serum NFL was then measured over the course of the entire season at 8 time points coincident with expected changes in likelihood of increased head impacts. Data were compared between starters (n=11) and non-starters (n=9). Compared to non-starters (mean ± SD) (7.30±3.57 pg•mL-1) and controls (6.75±1.68 pg•mL-1), serum NFL in starters (8.45±5.90 pg•mL-1) was higher at baseline (mean difference; ±90CI) (1.69; ±1.96 pg•mL-1 and 1.15; ±1.4 pg•mL-1, respectively). Over the course of the season, an increase (Effect size (ES) = 1.8; p < 0.001) was observed Post-Camp relative to baseline (1.52; ±1.18 pg•mL-1) which remained elevated until conference play, when a second increase was observed (ES = 2.6; p = 0.008) over baseline (4.82; ±2.64 pg•mL-1). A lack of change in non-starters resulted in substantial differences between starters and non-starters over the course of the season. These data suggest that a season of collegiate American football is associated with elevations in serum NFL, which is indicative of axonal injury, as a result of head impacts.
Traumatic brain injury (TBI) is common in boxing and other contact sports. The long term irreversible and progressive aftermath of TBI in boxers depicted as punch drunk syndrome was described almost a century ago and is now widely referred as chronic traumatic encephalopathy (CTE). The short term sequelae of acute brain injury including subdural haematoma and catastrophic brain injury may lead to death, whereas mild TBI, or concussion, causes functional disturbance and axonal injury rather than gross structural brain damage. Following concussion, symptoms such as dizziness, nausea, reduced attention, amnesia and headache tend to develop acutely but usually resolve within a week or two. Severe concussion can also lead to loss of consciousness. Despite the transient nature of the clinical symptoms, functional neuroimaging, electrophysiological, neuropsychological and neurochemical assessments indicate that the disturbance of concussion takes over a month to return to baseline and neuropathological evaluation shows that concussion-induced axonopathy may persist for years. The developing brains in children and adolescents are more susceptible to concussion than adult brain. The mechanism by which acute TBI may lead to the neurodegenerative process of CTE associated with tau hyperphosphorylation and the development of neurofibrillary tangles (NFTs) remains speculative. Focal tau-positive NFTs and neurites in close proximity to focal axonal injury and foci of microhaemorrhage and the predilection of CTE-tau pathology for perivascular and subcortical regions suggest that acute TBI-related axonal injury, loss of microvascular integrity, breach of the blood brain barrier, resulting inflammatory cascade and microglia and astrocyte activation are likely to be the basis of the mechanistic link of TBI and CTE. This article provides an overview of the acute and long-term neurological consequences of TBI in sports. Clinical, neuropathological and the possible pathophysiological mechanisms are discussed. This article is part of a Special Issue entitled 'Traumatic Brain Injury'.
Copyright © 2015. Published by Elsevier Inc.
Traumatic brain injury (TBI) from penetrating or closed forces to the cranium can result in a range of forms of neural damage, which culminate in mortality or impart mild to significant neurological disability. In this regard, diffuse axonal injury (DAI) is a major neuronal pathophenotype of TBI and is associated with a complex set of cytoskeletal changes. The neurofilament triplet proteins are key structural cytoskeletal elements, which may also be important contributors to the tensile strength of axons. This has significant implications with respect to how axons may respond to TBI. It is not known, however, whether neurofilament compaction and the cytoskeletal changes that evolve following axonal injury represent a component of a protective mechanism following damage, or whether they serve to augment degeneration and progression to secondary axotomy. Here we review the structure and role of neurofilament proteins in normal neuronal function. We also discuss the processes that characterize DAI and the resultant alterations in neurofilaments, highlighting potential clues to a possible protective or degenerative influence of specific neurofilament alterations within injured neurons. The potential utility of neurofilament assays as biomarkers for axonal injury is also discussed. Insights into the complex alterations in neurofilaments will contribute to future efforts in developing therapeutic strategies to prevent, ameliorate or reverse neuronal degeneration in the central nervous system (CNS) following traumatic injury.
It is difficult to obtain insight into the mechanisms occurring within live cells during mechanical loading, because this complex environment is dynamic and evolving. This is a particular challenge from a subcellular mechanics perspective, where temporal and spatial information on the evolving cytoskeletal structures is required under loading. Using fluorescently labeled proteins, we visualize 3-dimensional live subcellular cytoskeletal populations under mechanical loading using a high-resolution confocal microscope. The mechanical forces are determined using a computational (finite element) model that is validated by integrating instrumentation into the testing platform. Transfected microtubules and neurofilaments of E17 rat neuronal axons are imaged before, during, and after loading. Comparisons between unloaded and loaded live cells demonstrate both spatial and temporal changes for cytoskeletal populations within the imaged volume. NF signal decreases by 24%, yet the microtubule signal exhibits no significant change 20-35 s after loading. Transmission electron microscopy assesses cytoskeletal structure spatial distribution for undeformed and deformed axons. While cytoskeletal degeneration occurs at prolonged time intervals following loads, our data provides insights into real time cytoskeletal evolution occurring in situ. Our findings suggest that, for axons undergoing traumatic injury in response to applied mechanical loads, changes at the substructural level of neurofilaments may precede microtubule rupture and degeneration.-Fournier, A. J., Rajbhandari, L., Shrestha, S., Venkatesan, A., Ramesh, K. T. In vitro and in situ visualization of cytoskeletal deformation under load: traumatic axonal injury.
Long-term neurological damage as a result of head trauma while playing sports is a major concern for football athletes today. Repetitive concussions have been linked to many neurological disorders. Recently, it has been reported that repetitive sub-concussive events can be a significant source of accrued damage. Since football athletes can experience hundreds of sub-concussive hits during a single season, it is of utmost importance to understand their effect on brain health in the short- and long-term. In this study, resting state functional magnetic resonance imaging (rs-fMRI) was used to study changes in the Default Mode Network (DMN) after repetitive sub-concussive mTBI. Twenty-two high school American football athletes, clinically asymptomatic, were scanned using rs-fMRI for a single season. Baseline scans were acquired before the start of the season, and follow-up scans were obtained during and after the season to track the potential changes in the DMN as a result of experienced trauma. Ten non-collision-sport athletes were scanned over two sessions as controls. Overall, football athletes had significantly different functional connectivity measures than controls for most of the year. The presence of this deviation of football athletes from their healthy peers even before the start of the season suggests a neurological change that has accumulated over the years of playing the sport. Football athletes also demonstrate short-term changes relative to their own baseline at start of the season. Football athletes exhibited hyper-connectivity in the DMN compared to controls for most of the sessions, which indicates that, despite the absence of symptoms typically associated with concussion, the repetitive trauma accrued produced long-term brain changes compared to their healthy peers.
Repetitive head impacts (RHI) sustained in contact sports are thought to be necessary for the long-term development of chronic traumatic encephalopathy (CTE). Our objectives were to: 1) characterize the magnitude and persistence of RHI-induced white matter (WM) changes; 2) determine their relationship to kinematic measures of RHI; and 3) explore their clinical relevance.
Prospective, observational study of 10 Division III college football players and 5 non-athlete controls during the 2011-12 season. All subjects underwent diffusion tensor imaging (DTI), physiologic, cognitive, and balance testing at pre-season (Time 1), post-season (Time 2), and after 6-months of no-contact rest (Time 3). Head impact measures were recorded using helmet-mounted accelerometers. The percentage of whole-brain WM voxels with significant changes in fractional anisotropy (FA) and mean diffusivity (MD) from Time 1 to 2, and Time 1 to 3 was determined for each subject and correlated to head impacts and clinical measures.
Total head impacts for the season ranged from 431-1,850. No athlete suffered a clinically evident concussion. Compared to controls, athletes experienced greater changes in FA and MD from Time 1 to 2 as well as Time 1 to 3; most differences at Time 2 persisted to Time 3. Among athletes, the percentage of voxels with decreased FA from Time 1 to 2 was positively correlated with several helmet impact measures. The persistence of WM changes from Time 1 to 3 was also associated with changes in serum ApoA1 and S100B autoantibodies. WM changes were not consistently associated with cognition or balance.
A single football season of RHIs without clinically-evident concussion resulted in WM changes that correlated with multiple helmet impact measures and persisted following 6 months of no-contact rest. This lack of WM recovery could potentially contribute to cumulative WM changes with subsequent RHI exposures.
Importance
Lack of objective biomarkers for brain damage hampers acute diagnosis and clinical decision making about return to play after sports-related concussion.Objectives
To determine whether sports-related concussion is associated with elevated levels of blood biochemical markers of injury to the central nervous system and to assess whether plasma levels of these biomarkers predict return to play in professional ice hockey players with sports-related concussion.Design, Setting, and Participants
Multicenter prospective cohort study involving all 12 teams of the top professional ice hockey league in Sweden, the Swedish Hockey League. Two hundred eighty-eight professional ice hockey players from 12 teams contesting during the 2012-2013 season consented to participate. All players underwent clinical preseason baseline testing regarding concussion assessment measures. Forty-seven players from 2 of the 12 ice hockey teams underwent blood sampling prior to the start of the season. Thirty-five players had a concussion from September 13, 2012, to January 31, 2013; of these players, 28 underwent repeated blood sampling at 1, 12, 36, and 144 hours and when the players returned to play.Main Outcomes and Measures
Total tau, S-100 calcium-binding protein B, and neuron-specific enolase concentrations in plasma and serum were measured.Results
Concussed players had increased levels of the axonal injury biomarker total tau (median, 10.0 pg/mL; range, 2.0-102 pg/mL) compared with preseason values (median, 4.5 pg/mL; range, 0.06-22.7 pg/mL) (P < .001). The levels of the astroglial injury biomarker S-100 calcium-binding protein B were also increased in players with sports-related concussion (median, 0.075 μg/L; range, 0.037-0.24 μg/L) compared with preseason values (median, 0.045 μg/L; range, 0.005-0.45 μg/L) (P < .001). The highest biomarker concentrations of total tau and S-100 calcium-binding protein B were measured immediately after a concussion, and they decreased during rehabilitation. No significant changes were detected in the levels of neuron-specific enolase from preseason values (median, 6.5 μg/L; range, 3.45-18.0 μg/L) to postconcussion values (median, 6.1 μg/L; range, 3.6-12.8 μg/L) (P = .10).Conclusions and Relevance
Sports-related concussion in professional ice hockey players is associated with acute axonal and astroglial injury. This can be monitored using blood biomarkers, which may be developed into clinical tools to guide sport physicians in the medical counseling of athletes in return-to-play decisions.
The benefits of regular exercise, physical fitness and sports participation on cardiovascular and brain health are undeniable. Physical activity reduces the risk for cardiovascular disease, type 2 diabetes, hypertension, obesity, and stroke, and produces beneficial effects on cholesterol levels, antioxidant systems, inflammation, and vascular function. Exercise also enhances psychological health, reduces age-related loss of brain volume, improves cognition, reduces the risk of developing dementia, and impedes neurodegeneration. Nonetheless, the play of sports is associated with risks, including a risk for mild TBI (mTBI) and, rarely, catastrophic traumatic injury and death. There is also growing awareness that repetitive mTBIs, such as concussion and subconcussion, can occasionally produce persistent cognitive, behavioral, and psychiatric problems as well as lead to the development of a neurodegeneration, chronic traumatic encephalopathy (CTE). In this review, we summarize the beneficial aspects of sports participation on psychological, emotional, physical and cognitive health, and specifically analyze some of the less common adverse neuropathological outcomes, including concussion, second-impact syndrome, juvenile head trauma syndrome, catastrophic sudden death, and CTE. CTE is a latent neurodegeneration clinically associated with behavioral changes, executive dysfunction and cognitive impairments, and pathologically characterized by frontal and temporal lobe atrophy, neuronal and axonal loss, and abnormal deposits of paired helical filament (PHF)-tau and 43 kDa TAR deoxyribonucleic acid (DNA)-binding protein (TDP-43). CTE often occurs as a sole diagnosis, but may be associated with other neurodegenerative disorders, including motor neuron disease (CTE-MND). Although the incidence and prevalence of CTE are not known, CTE has been reported most frequently in American football players and boxers. Other sports associated with CTE include ice hockey, professional wrestling, soccer, rugby, and baseball.
Chronic traumatic encephalopathy is a progressive tauopathy that occurs as a consequence of repetitive mild traumatic brain injury. We analysed post-mortem brains obtained from a cohort of 85 subjects with histories of repetitive mild traumatic brain injury and found evidence of chronic traumatic encephalopathy in 68 subjects: all males, ranging in age from 17 to 98 years (mean 59.5 years), including 64 athletes, 21 military veterans (86% of whom were also athletes) and one individual who engaged in self-injurious head banging behaviour. Eighteen age- and gender-matched individuals without a history of repetitive mild traumatic brain injury served as control subjects. In chronic traumatic encephalopathy, the spectrum of hyperphosphorylated tau pathology ranged in severity from focal perivascular epicentres of neurofibrillary tangles in the frontal neocortex to severe tauopathy affecting widespread brain regions, including the medial temporal lobe, thereby allowing a progressive staging of pathology from stages I-IV. Multifocal axonal varicosities and axonal loss were found in deep cortex and subcortical white matter at all stages of chronic traumatic encephalopathy. TAR DNA-binding protein 43 immunoreactive inclusions and neurites were also found in 85% of cases, ranging from focal pathology in stages I-III to widespread inclusions and neurites in stage IV. Symptoms in stage I chronic traumatic encephalopathy included headache and loss of attention and concentration. Additional symptoms in stage II included depression, explosivity and short-term memory loss. In stage III, executive dysfunction and cognitive impairment were found, and in stage IV, dementia, word-finding difficulty and aggression were characteristic. Data on athletic exposure were available for 34 American football players; the stage of chronic traumatic encephalopathy correlated with increased duration of football play, survival after football and age at death. Chronic traumatic encephalopathy was the sole diagnosis in 43 cases (63%); eight were also diagnosed with motor neuron disease (12%), seven with Alzheimer's disease (11%), 11 with Lewy body disease (16%) and four with frontotemporal lobar degeneration (6%). There is an ordered and predictable progression of hyperphosphorylated tau abnormalities through the nervous system in chronic traumatic encephalopathy that occurs in conjunction with widespread axonal disruption and loss. The frequent association of chronic traumatic encephalopathy with other neurodegenerative disorders suggests that repetitive brain trauma and hyperphosphorylated tau protein deposition promote the accumulation of other abnormally aggregated proteins including TAR DNA-binding protein 43, amyloid beta protein and alpha-synuclein.
Sports-related head trauma is common but still there is no established laboratory test used in the diagnostics of minimal or mild traumatic brain injuries. Further the effects of recurrent head trauma on brain injury markers are unknown. The purpose of this study was to investigate the relationship between Olympic (amateur) boxing and cerebrospinal fluid (CSF) brain injury biomarkers.
The study was designed as a prospective cohort study. Thirty Olympic boxers with a minimum of 45 bouts and 25 non-boxing matched controls were included in the study. CSF samples were collected by lumbar puncture 1-6 days after a bout and after a rest period for at least 14 days. The controls were tested once. Biomarkers for acute and chronic brain injury were analysed.
NFL (mean ± SD, 532±553 vs 135±51 ng/L p = 0.001), GFAP (496±238 vs 247±147 ng/L p<0.001), T-tau (58±26 vs 49±21 ng/L p<0.025) and S-100B (0.76±0.29 vs 0.60±0.23 ng/L p = 0.03) concentrations were significantly increased after boxing compared to controls. NFL (402±434 ng/L p = 0.004) and GFAP (369±113 ng/L p = 0.001) concentrations remained elevated after the rest period.
Increased CSF levels of T-tau, NFL, GFAP, and S-100B in >80% of the boxers demonstrate that both the acute and the cumulative effect of head trauma in Olympic boxing may induce CSF biomarker changes that suggest minor central nervous injuries. The lack of normalization of NFL and GFAP after the rest period in a subgroup of boxers may indicate ongoing degeneration. The recurrent head trauma in boxing may be associated with increased risk of chronic traumatic brain injury.
Current approaches to diffusion tensor imaging (DTI) analysis do not permit identification of individual-level changes in DTI indices. We investigated the ability of wild bootstrapping analysis to detect subject-specific changes in brain white matter (WM) before and after sports-related concussion.
A prospective cohort study was performed in nine high school athletes engaged in hockey or football and six controls. Subjects underwent DTI pre- and postseason within a 3-month interval. One athlete was diagnosed with concussion (scanned within 72 h), and eight suffered between 26 and 399 subconcussive head blows. Fractional anisotropy (FA) and mean diffusivity (MD) were measured in each WM voxel. Bootstrap samples were generated, and a permuted t test was used to compare voxel-wise FA/MD changes in each subject pre- vs. postseason.
The percentage of WM voxels with significant (p<.05) pre-post FA changes was highest for the concussion subject (3.2%), intermediary for those with subconcussive head blows (mean 1.05%±.15%) and lowest for controls (mean 0.28%±.01%). Similarly, the percentage of WM voxels with significant MD changes was highest for the concussion subject (3.44%), intermediary for those with subconcussive head blows (mean 1.48%±.17%) and lowest for controls (mean 0.48%±.05%). Significantly changed FA and MD voxels colocalized in the concussion subject to the right corona radiata and right inferior longitudinal fasciculus.
Wild bootstrap analysis detected significantly changed WM in a single concussed athlete. Athletes with multiple subconcussive head blows had significant changes in a percentage of their WM that was over three times higher than controls. Efforts to understand the significance of these WM changes and their relationship to head impact forces appear warranted.
Impacts to the head are common in collision sports such as football. Emerging research has begun to elucidate concussion tolerance levels, but sub-concussive impacts that do not result in clinical signs or symptoms of concussion are much more common, and are speculated to lead to alterations in cerebral structure and function later in life. We investigated the cumulative number of head impacts and their associated acceleration burden in 95 high school football players across four seasons of play using the Head Impact Telemetry System (HITS). The 4-year investigation resulted in 101,994 impacts collected across 190 practice sessions and 50 games. The number of impacts per 14-week season varied by playing position and starting status, with the average player sustaining 652 impacts. Linemen sustained the highest number of impacts per season (868); followed by tight ends, running backs, and linebackers (619); then quarterbacks (467); and receivers, cornerbacks, and safeties (372). Post-impact accelerations of the head also varied by playing position and starting status, with a seasonal linear acceleration burden of 16,746.1g, while the rotational acceleration and HIT severity profile burdens were 1,090,697.7 rad/sec(2) and 10,021, respectively. The adolescent athletes in this study clearly sustained a large number of impacts to the head, with an impressive associated acceleration burden as a direct result of football participation. These findings raise concern about the relationship between sub-concussive head impacts incurred during football participation and late-life cerebral pathogenesis, and justify consideration of ways to best minimize impacts and mitigate cognitive declines.
Measuring head impact exposure is a critical step toward understanding the mechanism and prevention of sport-related mild traumatic brain (concussion) injury, as well as the possible effects of repeated subconcussive impacts.
To quantify the frequency and location of head impacts that individual players received in 1 season among 3 collegiate teams, between practice and game sessions, and among player positions.
Cohort study.
Collegiate football field.
One hundred eighty-eight players from 3 National Collegiate Athletic Association football teams.
Participants wore football helmets instrumented with an accelerometer-based system during the 2007 fall season.
The number of head impacts greater than 10 g and location of the impacts on the player's helmet were recorded and analyzed for trends and interactions among teams (A, B, or C), session types, and player positions using Kaplan-Meier survival curves.
The total number of impacts players received was nonnormally distributed and varied by team, session type, and player position. The maximum number of head impacts for a single player on each team was 1022 (team A), 1412 (team B), and 1444 (team C). The median number of head impacts on each team was 4.8 (team A), 7.5 (team B), and 6.6 (team C) impacts per practice and 12.1 (team A), 14.6 (team B), and 16.3 (team C) impacts per game. Linemen and linebackers had the largest number of impacts per practice and per game. Offensive linemen had a higher percentage of impacts to the front than to the back of the helmet, whereas quarterbacks had a higher percentage to the back than to the front of the helmet.
The frequency of head impacts and the location on the helmet where the impacts occur are functions of player position and session type. These data provide a basis for quantifying specific head impact exposure for studies related to understanding the biomechanics and clinical aspects of concussion injury, as well as the possible effects of repeated subconcussive impacts in football.
Head trauma and concussion in football players has recently received considerable attention. Post-mortem evidence suggests that accrual of damage to the brain may occur with repeated blows to the head, even when individual blows fail to produce clinical symptoms. There is an urgent need for improved detection and characterization of head trauma to reduce future injury risk and promote development of new therapies. This study examined neurologic performance and health in the presence of head collision events in high school football players, using longitudinal measures of collision events (HIT system), neurocognitive testing (ImPACT), and functional MRI (fMRI). Longitudinal assessment (including baseline) was conducted in 11 males (ages 15-19) participating on the varsity and junior varsity football teams at a single high school. We expected and observed subjects in two previously described categories: (1) no clinically-diagnosed concussion and no changes in neurological behavior and (2) clinically-diagnosed concussion with changes in neurological behavior. Additionally, we observed players in a previously undiscovered third category who exhibited no clinically-observed symptoms associated with concussion, but who demonstrated measurable neurocognitive (primarily visual working memory) and neurophysiologic (altered activation in dorsolateral prefrontal cortex, DLPFC) impairments. This new category was associated with significantly higher numbers of head collision events to the top-front of the head, directly above DLPFC. Observation of this category suggests that more players are suffering neurologic injury than are presently detected via traditional concussion-assessment mechanisms. These individuals are unlikely to undergo clinical evaluation and thus continue to participate in football-related activities even when changes in brain physiology (and potential brain health) are present, likely increasing risk of future neurologic injury.
Mild traumatic brain injury (TBI) accounts for up to 80% of clinical TBI and can result in cognitive impairment and white matter damage that may develop and persist over several years. Clinically relevant models of mild TBI for investigation of neurobiological changes and the development of therapeutic strategies are poorly developed. In this study we investigated the temporal profile of axonal and somal injury that may contribute to cognitive impairments in a mouse model of mild TBI. Neuronal perikaryal damage (hematoxylin and eosin and Fluoro-Jade C), myelin integrity (myelin basic protein and myelin-associated glycoprotein), and axonal damage (amyloid precursor protein), were evaluated by immunohistochemistry at 4 h, 24 h, 72 h, 4 weeks, and 6 weeks after mild lateral fluid percussion brain injury (0.9 atm; righting time 167 +/- 15 sec). At 3 weeks post-injury spatial reference learning and memory were tested in the Morris water maze (MWM). Levels of damage to neuronal cell bodies were comparable in the brain-injured and sham groups. Myelin integrity was minimally altered following injury. Clear alterations in axonal damage were observed at various time points after injury. Axonal damage was localized to the cingulum at 4 h post-injury. At 4 and 6 weeks post-injury, axonal damage was evident in the external capsule, and was seen at 6 weeks in the dorsal thalamic nuclei. At 3 weeks post-injury, injured mice showed an impaired ability to learn the water maze task, suggesting injury-induced alterations in search strategy learning. The evolving localization of axonal damage points to ongoing degeneration after injury that is concomitant with a deficit in learning.
Sport concussion represents the majority of brain injuries occurring in the United States with 1.6–3.8 million cases annually. Understanding the biomechanical properties of this injury will support the development of better diagnostics and preventative techniques.
We monitored all football related head impacts in 78 high school athletes (mean age = 16.7 yr) from 2005 to 2008 to better understand the biomechanical characteristics of concussive impacts.
Using the Head Impact Telemetry System, a total of 54,247 impacts were recorded, and 13 concussive episodes were captured for analysis. A classification and regression tree analysis of impacts indicated that rotational acceleration (95582.3 rad·s−²), linear acceleration (996.1g), and impact location (front, top, and back) yielded the highest predictive value of concussion.
These threshold values are nearly identical with those reported at the collegiate and professional level. If the Head Impact Telemetry System were implemented for medical use, sideline personnel can expect to diagnose one of every five athletes with a concussion when the impact exceeds these tolerance levels. Why all athletes did not sustain a concussion when the impacts generated variables in excess of our threshold criteria is not entirely clear, although individual differences between participants may play a role. A similar threshold to concussion in adolescent athletes compared with their collegiate and professional counterparts suggests an equal concussion risk at all levels of play.
The ability of a eukaryotic cell to resist deformation, to transport intracellular cargo and to change shape during movement depends on the cytoskeleton, an interconnected network of filamentous polymers and regulatory proteins. Recent work has demonstrated that both internal and external physical forces can act through the cytoskeleton to affect local mechanical properties and cellular behaviour. Attention is now focused on how cytoskeletal networks generate, transmit and respond to mechanical signals over both short and long timescales. An important insight emerging from this work is that long-lived cytoskeletal structures may act as epigenetic determinants of cell shape, function and fate.
This study addresses impact biomechanics from boxing punches causing translational and rotational head acceleration. Olympic boxers threw four different punches at an instrumented Hybrid III dummy and responses were compared with laboratory-reconstructed NFL concussions.
Eleven Olympic boxers weighing 51 to 130 kg (112-285 lb) delivered 78 blows to the head of the Hybrid III dummy, including hooks, uppercuts and straight punches to the forehead and jaw. Instrumentation included translational and rotational head acceleration and neck loads in the dummy. Biaxial acceleration was measured in the boxer's hand to determine punch force. High-speed video recorded each blow. Hybrid III head responses and finite element (FE) brain modeling were compared to similarly determined responses from reconstructed NFL concussions.
The hook produced the highest change in hand velocity (11.0 +/- 3.4 m/s) and greatest punch force (4405 +/- 2318 N) with average neck load of 855 +/- 537 N. It caused head translational and rotational accelerations of 71.2 +/- 32.2 g and 9306 +/- 4485 r/s. These levels are consistent with those causing concussion in NFL impacts. However, the head injury criterion (HIC) for boxing punches was lower than for NFL concussions because of shorter duration acceleration. Boxers deliver punches with proportionately more rotational than translational acceleration than in football concussion. Boxing punches have a 65 mm effective radius from the head cg, which is almost double the 34 mm in football. A smaller radius in football prevents the helmets from sliding off each other in a tackle.
Olympic boxers deliver punches with high impact velocity but lower HIC and translational acceleration than in football impacts because of a lower effective punch mass. They cause proportionately more rotational acceleration than in football. Modeling shows that the greatest strain is in the midbrain late in the exposure, after the primary impact acceleration in boxing and football.
We generated mice with doxycycline control of a human neurofilament light (NF-L) transgene in the context of the absence (tTA;hNF-L;NF-L(-/-)) or presence (tTA;hNF-L;NF-L(+/-)) of endogenous mouse NF-L proteins. Doxycycline treatment caused the rapid disappearance of human NF-L (hNF-L) mRNA in tTA;hNF-L mice, but the hNF-L proteins remained with a half-life of 3 weeks in the brain. In the sciatic nerve, the disappearance of hNF-L proteins after doxycycline treatment occurred in synchrony along the sciatic nerve, suggesting a proteolysis of NF proteins along the entire axon. The presence of permanent NF network in tTA;hNF-L;NF-L(+/-) mice further stabilized and extended longevity of hNF-L proteins by several months. Surprisingly, after cessation of doxycycline treatment, there was no evidence of leading front of newly synthesized hNF-L proteins migrating into sciatic nerve axons devoid of NF structures. The hNF-L proteins detected at weekly intervals reappeared and accumulated in synchrony at similar rate along nerve segments, a phenomenon consistent with a fast hNF-L transport into axons. We estimated the hNF-L transport rate to be of approximately 10 mm/d in axons devoid of NF structures based on the use of an adenovirus encoding tet-responsive transcriptional activator to transactivate the hNF-L transgene in hypoglossal motor neurons. These results provide in vivo evidence that the stationary NF network in axons is a key determinant of half-life and transport rate of NF proteins.
Diffuse axonal injury (DAI) is an important cause of morbidity in patients with traumatic brain injury (TBI). There is a lack of a simple and reliable technique to early identify patients with DAI and to prognosticate long-term outcome in this patient group. In the present study we examined acute serum concentrations of NFL (neurofilament light) in nine patients with severe TBI and DAI using a novel ultrasensitive Single molecule array (Simoa) assay. The relationships between the NFL concentrations and MRI in the acute stage as well as clinical outcome and MR-DTI parameters at 12 months were analysed. We found that the mean NFL concentrations among the patients displayed a 30-fold increase compared to the controls and that the NFL completely discriminated between the patients and the controls. We also found a relation between serum NFL and MR-DTI parameters, with higher NFL concentrations in patients with higher trace (R<sup>2</sup>=0.79) and lower FA (R<sup>2</sup>=0.83). These results suggest that serum NFL may be a valuable blood biomarker for TBI reflecting the severity of DAI.
Purpose:
American football athletes are exposed to sub-concussive impacts over the course of the season resulting in elevations in serum neurofilament light (NFL), a biomarker of axonal injury. Docosahexaenoic acid (DHA) has been reported to reduce axonal trauma associated with traumatic brain injury in rodent models. However, the optimal dose in American football athletes is unknown. This study examined the effect of differing doses of DHA on serum NFL over the course of a season of American football.
Methods:
In a randomized, double-blind, placebo-controlled, parallel design eighty-one (n = 81) National Collegiate Athletic Association (NCAA) Division I American football athletes were assigned to ingest either 2 g•d, 4 g•d, 6 g•d of DHA, or placebo. Blood was sampled at specific times over the course 189 days coincident with changes in intensity, hours of contact, and likely changes in head impacts. Standardized magnitude-based inference was used to define outcomes.
Results:
DHA supplementation increased plasma DHA in dose-dependent manner (mean difference from baseline; ± 90% CL; 2 g•d: 1.3; ±0.6; 4 g•d: 1.6; ±0.7%; 6 g•d: 2.8; ±1.2%). Serum NFL increased to a greater extent in starters (AUC, 1995 ± 1383 pg•mL•day) versus non-starters (1398 ± 581 pg•mL•day; p = 0.024). Irrespective of dose, supplemental DHA likely attenuated serum NFL coincident with increases in serum NFL by likely small and moderate magnitude (ES = 0.4 to 0.7).
Conclusion:
Findings from this study, the first large scale study examining potential prophylactic use of DHA in American football athletes, include identification of optimal dose of DHA suggest a neuroprotective effect of DHA supplementation.
Given questions about "lower thresholds" for concussion, as well as possible effects of repetitive concussion and chronic traumatic encephalopathy (CTE), and associated controversy, there is increasing interest in "subconcussive" blows and their potential significance.
A formative review with critical examination of the developing literature on subconcussive blows in athletes with an emphasis on clinical outcomes.
Studies of biomechanical, performance and/or symptom-based, and neuroimaging data were identified via PubMed search and critically reviewed. Five studies of symptom reporting/performance and 4 studies of neuroimaging were included.
The relation between biomechanical parameters and diagnosed concussion is not straightforward (ie, it is not the case that greater and more force leads to more severe injury or cognitive/behavioral sequelae). Neuropsychological studies of subconcussive blows within a single athletic season have failed to demonstrate any strong and consistent relations between number and severity of subconcussive events and cognitive change. Recent studies using neuroimaging have demonstrated a potential cumulative effect of subconcussive blows, at least in a subset of individuals.
Human studies of the neurological/neuropsychological impact of subconcussive blows are currently quite limited. Subconcussive blows, in the short-term, have not been shown to cause significant clinical effects. To date, findings suggest that any effect of subconcussive blows is likely to be small or nonexistent, perhaps evident in a subset of individuals on select measures, and maybe even beneficial in some cases. Longer-term prospective studies are needed to determine if there is a cumulative dose effect.
Cited By (since 1996):2, Export Date: 18 October 2014
The purpose of this study is to determine if the cumulative effects of head impacts from a season of high school football produce magnetic resonance imaging (MRI) measureable changes in the brain in the absence of clinically diagnosed concussion. Players from a local high school football team were instrumented with the Head Impact Telemetry System (HITs) during all practices and games. All players received pre- and post-season MRI, including diffusion tensor imaging (DTI). Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) was also conducted. Total impacts and Risk Weighted cumulative Exposure (RWE), including linear (RWELinear), rotational (RWERotational), and combined components (RWECP) were computed from the sensor data. Fractional, linear, planar and spherical anisotropies (FA, CL, CP, CS, respectively), as well as mean diffusivity (MD), were used to determine total number of abnormal white matter voxels defined as 2 standard deviations above or below the group mean. Delta (post-pre season) ImPACT scores for each individual were computed and compared to the DTI measures using the Spearman's rank correlation coefficient. None of the players analyzed experienced clinical concussion (N = 24). Regression analysis revealed a statistically significant linear relationship between RWECP and FA. Secondary analyses demonstrated additional statistically significant linear associations between RWE (RWECP and RWELinear) and all DTI measures. There was also a strong correlation between DTI measures and change in Verbal Memory subscore of the ImPACT. We demonstrate that a single season of football can produce brain MRI changes in the absence of clinical concussion. Similar brain MRI changes have been previously associated with mild traumatic brain injury.
To determine whether exposure to repetitive head impacts over a single season affects white matter diffusion measures in collegiate contact sport athletes.
A prospective cohort study at a Division I NCAA athletic program of 80 nonconcussed varsity football and ice hockey players who wore instrumented helmets that recorded the acceleration-time history of the head following impact, and 79 non-contact sport athletes. Assessment occurred preseason and shortly after the season with diffusion tensor imaging and neurocognitive measures.
There was a significant (p = 0.011) athlete-group difference for mean diffusivity (MD) in the corpus callosum. Postseason fractional anisotropy (FA) differed (p = 0.001) in the amygdala (0.238 vs 0.233). Measures of head impact exposure correlated with white matter diffusivity measures in several brain regions, including the corpus callosum, amygdala, cerebellar white matter, hippocampus, and thalamus. The magnitude of change in corpus callosum MD postseason was associated with poorer performance on a measure of verbal learning and memory.
This study suggests a relationship between head impact exposure, white matter diffusion measures, and cognition over the course of a single season, even in the absence of diagnosed concussion, in a cohort of college athletes. Further work is needed to assess whether such effects are short term or persistent.
Objectives:
The aim of this study was to investigate if olympic (amateur) boxing is associated with elevation of brain injury biomarkers in peripheral blood compared to controls.
Materials and methods:
Thirty olympic boxers competing in at least 47 bouts were compared to 25 controls. Blood was collected from the controls at one occasion and from the boxers within 1-6 days after a bout and after a rest period of at least 14 days. Tau concentration in plasma was determined using a novel single molecule ELISA assay and S-100B, glial fibrillary acidic protein, brain-derived neurotrophic factor and amyloid β 1-42 were determined using standard immunoassays.
Results:
None of the boxers had been knocked-out during the bout. Plasma-tau was significantly increased in the boxers after a bout compared to controls (mean ± SD, 2.46 ± 5.10 vs. 0.79 ± 0.961 ng L(-1), p = 0.038). The other brain injury markers did not differ between the groups. Plasma-tau decreased significantly in the boxers after a resting period compared to after a bout (p = 0.030).
Conclusions:
Olympic boxing is associated with elevation of tau in plasma. The repetitive minimal head injury in boxing may lead to axonal injuries that can be diagnosed with a blood test.
Mild traumatic brain injury (TBI), which is defined as a head trauma resulting in a brief loss of consciousness and/or alteration of mental state, is usually benign, but occasionally causes persistent and sometimes progressive symptoms. Whether a threshold for the amount of brain injury and/or individual vulnerability might contribute to the development of these long-term consequences is unknown. Furthermore, reliable diagnostic methods that can establish whether a blow to the head has affected the brain (and in what way) are lacking. In this Review, we discuss potential biomarkers of injury to different structures and cell types in the CNS that can be detected in body fluids. We present arguments in support of the need for further development and validation of such biomarkers, and for their use in assessing patients with head trauma in whom the brain might have been affected. Specifically, we focus on the need for such biomarkers in the management of sports-related concussion, the most common cause of mild TBI in young individuals, to prevent long-term neurological sequelae due to concussive or subconcussive blows to the head.
Neurofilaments (NF) are the most abundant cytoskeletal component of large myelinated axons from adult central and peripheral nervous system. Here, we provide an overview of the complementary approaches, including biochemistry, cell biology and transgenic technology that were used to investigate the assembly, axonal transport and functions of NF in normal and pathological situations. Following their synthesis and assembly in the cell body, NFs are transported along the axon. This process is finely regulated via phosphorylation of the carboxy-terminal part of the two high-molecular-weight subunits of NF. The correct formation of an axonal network of NF is crucial for the establishment and maintenance of axonal calibre and consequently for the optimisation of conduction velocity. The frequent disorganisation of NF network observed in several neuropathologies support their contribution. However, despite the presence of NF mutations found in some patients, the exact relations between these mutations, the abnormal NF organisation and the pathological process remain a challenging field of investigation.
Previous concussion biomechanics research has relied heavily on the animal model or laboratory reconstruction of concussive injuries captured on video footage. Real-time data collection involves a novel approach to better understanding the medical issues related to sport concussion. Recent studies suggest that a concussive injury threshold is elusive and may, in fact, be irrelevant when predicting the clinical outcome.
Since the 1920s, it has been known that the repetitive brain trauma associated with boxing may produce a progressive neurological deterioration, originally termed dementia pugilistica, and more recently, chronic traumatic encephalopathy (CTE). We review 48 cases of neuropathologically verified CTE recorded in the literature and document the detailed findings of CTE in 3 profession althletes, 1 football player and 2 boxers. Clinically, CTE is associated with memory disturbances, behavioral and personality changes, parkinsonism, and speech and gait abnormalities. Neuropathologically, CTE is characterized by atrophy of the cerebral hemispheres, medial temporal lobe, thalamus, mammillary bodies, and brainstem, with ventricular dilatation and a fenestrated cavum septum pellucidum. Microscopically, there are extensive tau-immunoreactive neurofibrillary tangles, astrocytic tangles, and spindle-shaped and threadlike neurites throughout the brain. The neurofibrillary degeneration of CTE is distinguished from other tauopathies by preferential involvement of the superficial cortical layers, irregular patchy distribution in the frontal and temporal cortices, propensity for sulcal depths, prominent perivascular, periventricular, and subpial distribution, and marked accumulation of tau-immunoreactive astrocytes. Deposition of beta-amyloid, most commonly as diffuse plaques, occurs in fewer than half the cases. Chronic traumatic encephalopathy is a neuropathologically distinct slowly progressive tauopathy with a clear environmental etiology.
Tau, a microtubule-associated protein which copurifies with tubulin through successive cycles of polymerization and depolymerization, has been isolated from tubulin by phosphocellulose chromatography and purified to near homogeneity. The purified protein is seen to migrate during electrophoresis on acrylamide gels as four closely spaced bands of apparent molecular weights between 55,000 and 62,000. Specific activity for induction of microtubule formation from purified tubulin has been assayed by quantitative electron microscopy and is seen to be enhanced three- to fourfold in the purified tau when compared with the unfractionated microtubule-associated proteins. Nearly 90% of available tubulin at 1 mg/ml is found to be polymerizable into microtubules with elevated levels of tau. Moreover, the critical concentration for polymerization of the reconstituted tau + tubulin system is seen to be a function of tau concentration and may be lowered to as little as 30 μg of tubulin per ml. Under depolymerizing conditions, 50% of the tubulin at only 1 mg/ml may be driven into ring structures. A separate purification procedure for isolation of tau directly from cell extracts has been developed and data from this purification suggest that tau is present in the extract in roughly the same proportion to tubulin as is found in microtubules purified by cycles of assembly and disassembly. Tau is sufficient for both nucleation and elongation of microtubules from purified tubulin and hence the reconstituted tau + tubulin system defines a complete microtubule assembly system under standard buffer conditions. In an accompanying paper (Cleveland et al., 1977) the physical and chemical properties of tau are discussed and a model by which tau may function in microtubule assembly is presented.
The most common definition of cerebral concussion is that of a transient loss of neurological function without macroscopic or microscopic abnormality in the brain. However, some patients have persistent symptoms and subtle neuropsychological deficits, particularly affecting memory. We have studied five patients aged 59-89 years who sustained mild concussive head injury and died of other causes (2-99 days post-injury). Immunostaining with an antibody to amyloid precursor protein, a marker of fast axonal transport, showed multifocal axonal injury in all five. All had axonal damage in the fornices, which are important in memory function.
To compare accelerational forces to the head in high school-level football, hockey, and soccer athletes.
Acceleration of impact was measured within the helmet of high school hockey and football players during actual game play. A triaxial accelerometer was placed at the vertex of the helmet immediately adjacent to the players head. Peak acceleration (in g's) was measured and the Gadd Severity Index and Head Injury Criterion score calculated during actual play periods in several games over four seasons. We also recorded acceleration of head impacts in high school-level soccer players who headed a soccer ball while equipped with a football helmet instrumented identically to the helmet used to record during football games.
Peak accelerations inside the helmet for football averaged 29.2 g compared with 35 g for hockey (p = .004). There were no incidents of concussion or other traumatic brain injury during the recorded periods. In contrast, the peak accelerations associated with heading a soccer ball was 54.7 g (p = 2 x 10(-5) vs. hockey).
Peak accelerations as measured at the surface of the head were 160 to 180% greater from heading a soccer ball than from routine (noninjurious) impacts during hockey or football, respectively. The effect of cumulative impacts at this level may lead to neurologic sequelae.
Biomechanics of sport concussion: quest for the elusive injury threshold
- K M Guskiewicz
- J P Mihalik
- Guskiewicz KM
Guskiewicz KM, Mihalik JP: Biomechanics of sport concussion: quest for the elusive injury threshold. Exerc Sport Sci
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Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury
- A C Mckee
- R C Cantu
- C J Nowinski
- E T Hedley-Whyte
- B E Gavett
- A E Budson
- McKee AC
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in athletes: progressive tauopathy after repetitive head injury.
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The spectrum of disease in chronic traumatic encephalopathy
- A C Mckee
- R A Stern
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- T D Stein
- V E Alvarez
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- McKee AC
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- T M Talavage
- E A Nauman
- E L Breedlove
- U Yoruk
- A E Dye
- K E Morigaki
- Talavage TM
Alteration of default mode network in high school football athletes due to repetitive subconcussive mild traumatic brain injury: a resting-state functional magnetic resonance imaging study
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- M T Jones
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- E J Pellman
- C A Bir
- L Zhang
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- Viano DC
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- T Bogoslovsky
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