Risk For Chronic Traumatic Encephalopathy Research Articles

Examination of parkinsonism in former elite American football players

BackgroundFormer American football players are at risk for chronic traumatic encephalopathy (CTE) which may have parkinsonism as a clinical feature. ObjectiveFormer football players were prospectively assessed for parkinsonism. Methods120 former professional football players, 58 former college football players, and 60 same-age asymptomatic men without repetitive head impacts, 45–74 years, were studied using the MDS-UPDRS to assess for parkinsonism, and the Timed Up and Go (TUG). Traumatic encephalopathy syndrome (TES), the clinical syndrome of CTE, was adjudicated and includes parkinsonism diagnosis. Fisher's Exact Test compared groups on parkinsonism due to small cell sizes; analysis of covariance or linear regressions controlling for age and body mass index were used otherwise. ResultsTwenty-two (12.4%) football players (13.3% professional, 10.3% college) met parkinsonism criteria compared with two (3.3%) in the unexposed group. Parkinsonism was higher in professional (p = 0.037) but not college players (p = 0.16). There were no differences on the MDS-UPDRS Part III total scores. Scores on the individual MDS-UPDRS items were low. TUG times were longer in former professional but not college players compared with unexposed men (13.09 versus 11.35 s, p < 0.01). There were no associations between years of football, age of first exposure, position or level of play on motor outcomes. TES status was not associated with motor outcomes. ConclusionsParkinsonism rates in this sample of football players was low and highest in the professional football players. The association between football and parkinsonism is inconclusive and depends on factors related to sample selection, comparison groups, and exposure characteristics.

Risk of chronic traumatic encephalopathy in rugby union is associated with length of playing career.

Risk of chronic traumatic encephalopathy in rugby union is associated with length of playing career.

Akkermansia muciniphila-Nlrp3 is involved in the neuroprotection of phosphoglycerate mutase 5 deficiency in traumatic brain injury mice.

Gut-microbiota-brain axis is a potential treatment to decrease the risk of chronic traumatic encephalopathy following traumatic brain injury (TBI). Phosphoglycerate mutase 5 (PGAM5), a mitochondrial serine/threonine protein phosphatase, resides in mitochondrial membrane and regulates mitochondrial homeostasis and metabolism. Mitochondria mediates intestinal barrier and gut microbiome. This study investigated the association between PGAM5 and gut microbiota in mice with TBI. The controlled cortical impact injury was established in mice with genetically-ablated Pgam5 (Pgam5-/-) or wild type, and WT male mice were treated with fecal microbiota transplantation (FMT) from male Pgam5-/- mice or Akkermansia muciniphila (A. muciniphila). Then the gut microbiota abundance, blood metabolites, neurological function, and nerve injury were detected. Treated with antibiotics for suppressing gut microbiota in Pgam5-/- mice partially relieved the role of Pgam5 deficiency in the improvement of initial inflammatory factors and motor dysfunction post-TBI. Pgam5 knockout exhibited an increased abundance of A. muciniphila in mice. FMT from male Pgam5-/- mice enabled better maintenance of amino acid metabolism and peripherial environment than that in TBI-vehicle mice, which suppressed neuroinflammation and improved neurological deficits, and A. muciniphila was negatively associated with intestinal mucosal injury and neuroinflammation post-TBI. Moreover, A. muciniphila treatment ameliorated neuroinflammation and nerve injury by regulating Nlrp3 inflammasome activation in cerebral cortex with TBI. Thus, the present study provides evidence that Pgam5 is involved in gut microbiota-mediated neuroinflammation and nerve injury, with A. muciniphila-Nlrp3 contributing to peripheral effects.

Symptomatic Concussions, Depression, and Impulsivity in Fighters with a Family History of Dementia

AbstractBackgroundProfessional boxers and Mixed Martial Arts (MMA) fighters regularly sustain blunt force trauma to the head leading to Traumatic Brain Injury (TBI) and concussion; therefore, fighters are at high risk for chronic traumatic encephalopathy and neurodegenerative disease. Family history of dementia (fhD) may significantly modulate fighter response to TBI. Genetic polymorphisms associated with dementia have been reported to modulate an individual’s response to brain injury and to influence emotionality, risk‐taking, and cognition. A recent study in male college athletes found that fhD predisposed athletes to poorer recovery after concussion and to decrements in impulse control following injury. Furthermore, in a population‐based cohort study from the Netherlands, researchers found that parental history of dementia led to increased rates of depression in mid‐life. The present study aims to investigate how fhD in fighters may relate to history of symptomatic concussions, depression, and impulsivity.MethodsUsing data from the Professional Fighters Brain Health Study (longitudinal cohort study of fighters), we included active, professional boxers and MMA fighters (n = 198) for cross‐sectional analyses. The latest study visits with available data were utilized to generate multivariate regression analyses examining the number of self‐reported symptomatic concussions in a fighter’s career, Patient Health Questionnaire (PHQ)‐9 scores, and Barratt Impulsiveness Scale Version 11 (BIS‐11) scores, adjusting for age, sex, education, and number of professional fights.ResultsFhD was significantly associated with more symptomatic concussions during one’s career (p&lt;0.05), higher PHQ‐9 scores (p&lt;0.01), and higher BIS‐11 scores (p&lt;0.01).ConclusionsOur findings suggest that professional boxers and MMA fighters with fhD may be more likely to experience symptomatic concussions, depression, and impulsivity during their active fighting career. We postulate that fhD may predispose fighters to experience a higher burden of neuropsychiatric symptoms after sustaining a TBI, potentially due to differences in the brain’s response to injury. These findings may be used to advise those with fhD to minimize possible exposures to TBI and to educate fighters with fhD regarding risks of chronic neurotrauma exposure. Future research should evaluate potential genetic and/or molecular mechanisms behind these trends and behavioral outcomes associated with the sequelae of TBI in those with fhD.

Rationale and design of the “NEurodegeneration: Traumatic brain injury as Origin of the Neuropathology (NEwTON)” study: a prospective cohort study of individuals at risk for chronic traumatic encephalopathy

BackgroundRepetitive head injury in contact sports is associated with cognitive, neurobehavioral, and motor impairments and linked to a unique neurodegenerative disorder: chronic traumatic encephalopathy (CTE). As the clinical presentation is variable, risk factors are heterogeneous, and diagnostic biomarkers are not yet established, the diagnostic process of CTE remains a challenge. The general objective of the NEwTON study is to establish a prospective cohort of individuals with high risk for CTE, to phenotype the study population, to identify potential fluid and neuroimaging biomarkers, and to measure clinical progression of the disease. The present paper explains the protocol and design of this case-finding study.MethodsNEwTON is a prospective study that aims to recruit participants at risk for CTE, with features of the traumatic encephalopathy syndrome (exposed participants), and healthy unexposed control individuals. Subjects are invited to participate after diagnostic screening at our memory clinic or recruited by advertisement. Exposed participants receive a comprehensive baseline screening, including neurological examination, neuropsychological tests, questionnaires and brain MRI for anatomical imaging, diffusion tensor imaging (DTI), resting-state functional MRI (rsfMRI), and quantitative susceptibility mapping (QSM). Questionnaires include topics on life-time head injury, subjective cognitive change, and neuropsychiatric symptoms. Optionally, blood and cerebrospinal fluid are obtained for storage in the NEwTON biobank. Patients are informed about our brain donation program in collaboration with the Netherlands Brain Brank. Follow-up takes place annually and includes neuropsychological assessment, questionnaires, and optional blood draw. Testing of control subjects is limited to baseline neuropsychological tests, MRI scan, and also noncompulsory blood draw.ResultsTo date, 27 exposed participants have finished their baseline assessments. First baseline results are expected in 2023.ConclusionsThe NEwTON study will assemble a unique cohort with prospective observational data of male and female individuals with high risk for CTE. This study is expected to be a primary explorative base and designed to share data with international CTE-related cohorts. Sub-studies may be added in the future with this cohort as backbone.

Genetic Variant for Alzheimer's Disease May Increase Risk of Chronic Traumatic Encephalopathy After Repetitive Head Impact

Genetic Variant for Alzheimer's Disease May Increase Risk of Chronic Traumatic Encephalopathy After Repetitive Head Impact

Association of APOE Genotypes and Chronic Traumatic Encephalopathy

Repetitive head impact (RHI) exposure is the chief risk factor for chronic traumatic encephalopathy (CTE). However, the occurrence and severity of CTE varies widely among those with similar RHI exposure. Limited evidence suggests that the APOEε4 allele may confer risk for CTE, but previous studies were small with limited scope. To test the association between APOE genotype and CTE neuropathology and related endophenotypes. This cross-sectional genetic association study analyzed brain donors from February 2008 to August 2019 from the Veterans Affairs-Boston University-Concussion Legacy Foundation Brain Bank. All donors had exposure to RHI from contact sports or military service. All eligible donors were included. Analysis took place between June 2020 and April 2022. One or more APOEε4 or APOEε2 alleles. CTE neuropathological status, CTE stage (0-IV), semiquantitative phosphorylated tau (p-tau) burden in 11 brain regions (0-3), quantitative p-tau burden in the dorsolateral frontal lobe (log-transformed AT8+ pixel count per mm2), and dementia. Of 364 consecutive brain donors (100% male; 53 [14.6%] self-identified as Black and 311 [85.4%] as White; median [IQR] age, 65 [47-77] years) 20 years or older, there were 294 individuals with CTE and 70 controls. Among donors older than 65 years, APOEε4 status was significantly associated with CTE stage (odds ratio [OR], 2.34 [95% CI, 1.30-4.20]; false discovery rate [FDR]-corrected P = .01) and quantitative p-tau burden in the dorsolateral frontal lobe (β, 1.39 [95% CI, 0.83-1.94]; FDR-corrected P = 2.37 × 10-5). There was a nonsignificant association between APOEε4 status and dementia (OR, 2.64 [95% CI, 1.06-6.61]; FDR-corrected P = .08). Across 11 brain regions, significant associations were observed for semiquantitative p-tau burden in the frontal and parietal cortices, amygdala, and entorhinal cortex (OR range, 2.45-3.26). Among football players, the APOEε4 association size for CTE stage was similar to playing more than 7 years of football. Associations were significantly larger in the older half of the sample. There was no significant association for CTE status. Association sizes were similar when donors with an Alzheimer disease neuropathological diagnosis were excluded and were reduced but remained significant after adjusting for neuritic and diffuse amyloid plaques. No associations were observed for APOEε2 status. Models were adjusted for age at death and race. APOEε4 may confer increased risk for CTE-related neuropathological and clinical outcomes among older individuals with RHI exposure. Further work is required to validate these findings in an independent sample.

The relationship between first-degree family history of dementia, tau pathology and functional impairment among brain donors at risk for chronic traumatic encephalopathy.

Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impact (RHI) exposure. The clinical presentation of CTE can be progressive, leading to cognitive and functional impairment. CTE presence and severity varies among those with similar RHI exposure, suggesting a role for other factors, genetics among them. Family history (FH) of dementia is a proxy of genetic risk of neurodegenerative disease, but its relationship with CTE is unknown. This study aimed to analyze the relationships between FH of dementia, quantitative tau pathology and functional impairment in brain donors at risk for CTE. 558 brain donors from the Veterans Affairs-Boston University-Concussion Legacy Foundation Brain Bank with known RHI exposure through contact sports or military service were examined for CTE pathology. We performed digital quantification of AT8 immunostaining for tau pathology in the CA4 hippocampal subfield, a region disproportionately affected in CTE. First-degree FH of dementia and the Functional Assessment Questionnaire (FAQ; 30 point scale), a validated measure of instrumental activities of daily living, were collected through telephone interviews with brain donors' next-of-kin. Using a regression framework, we examined the direct and indirect relationships between FH of dementia, CA4 quantitative tau burden and FAQ score, adjusting for age and race. The mean (SD) age at death was 59.9 (20.4) and 362 (65%) had CTE pathology. In separate models, first-degree FH of dementia was significantly associated with increased CA4 tau burden (β=0.27, p=0.01) and with increased FAQ score (β=2.11, p=0.02). Additionally, CA4 tau burden was associated with increased FAQ score (β=2.58, p=0.001). After adjusting for CA4 tau burden, the effect of first-degree FH of dementia was reduced and no longer significant (β=.598, p=.663). Among brain donors with RHI exposure, hippocampal CA4 tau burden may mediate the relationship between first-degree FH of dementia and functional impairment. The findings suggest that the risk of CTE may be heritable and share etiologic mechanisms with other dementing illnesses.

Rationale and design of the NEwTON study: A prospective cohort study of patients at risk of chronic traumatic encephalopathy

AbstractBackgroundTraumatic brain injury increases the risk of neurodegenerative diseases later in life. Repetitive head injury, more specific in contact sports, is associated with cognitive, neurobehavioral and motor impairments in the light of a unique neurodegenerative disorder: chronic traumatic encephalopathy (CTE). Yet, the clinical presentation, risk factors and diagnostic biomarkers of CTE have remained unclear. The general objective of the NEwTON study is to establish a prospective cohort of patients with high risk of CTE, to further study the link between repetitive head injury and neurodegeneration. We aim to phenotype the study population, identify potential biomarkers and measure clinical progression.MethodNEwTON is a prospective cohort study which aims to recruit approximately 80 patients at risk of CTE (features of the traumatic encephalopathy syndrome, Montenigro 2014) and healthy control subjects. Inclusion criteria are: history of repetitive head injury (contact sports, military service, other exposure), progressive cognitive and/or neurobehavioral symptoms, age 45‐75 years and symptom duration of ≥12 months. The control group will consist of age‐matched healthy participants without history of significant traumatic brain injury or participation in contact sports/professional military service. Subjects are invited to participate after diagnostic screening at our memory clinic or recruited by advertisement.ResultPatients will undergo comprehensive baseline screening, including neurological examination, neuropsychological tests, questionnaires and brain magnetic resonance imaging (MRI) for anatomical imaging, diffusion tensor imaging (DTI), resting state functional MRI (rsfMRI) and Quantitative Susceptibility Mapping (QSM). Questionnaires include topics on life‐time head injury, subjective cognitive change and neuropsychiatric symptoms. Blood and cerebrospinal fluid will be stored in the NEwTON biobank. Patients will be informed about our brain donation program in collaboration with the Netherlands Brain Brank. Testing for control subjects will be limited to baseline neuropsychological tests, blood draw and MRI. Patient follow‐up will take place annually and includes neuropsychological assessment, questionnaires and blood draw.ConclusionThe NEwTON study will contain the first cohort in the Netherlands with prospective observational data of patients with high risk of CTE. This study design will be an umbrella protocol and it is expected that other sub‐studies will use this cohort in the future.

Chronic traumatic encephalopathy – current state of knowledge

Introduction and purpose. Chronic traumatic encephalopathy (CTE) is a tauopathy caused by repetitive, mild head injuries. It is characterized by perivascular accumulation of hyperphosphorylated tau protein in the neurons and astrocytes. CTE leads to changes in central nervous system, both on microscopic and macroscopic level. The aim of the study was to present the current knowledge on chronic traumatic encephalopathy among athletes, its predisposing factors, symptoms and consequences, as well as diagnostic methods and treatment.Description. CTE occurs among contact sport players, such as American football, ice hockey, soccer, baseball, box and MMA (mixed martial arts), as well as among soldiers and victims of domestic violence. Repetitive head injuries and long career duration increase the risk of CTE. Symptoms of chronic traumatic encephalopathy include a commonly occurring triad: cognitive disturbances, behavioral problems and mood disturbances. Other symptoms include memory loss, parkinsonism, headaches, speech and walking problems. Currently, the only diagnostic method of CTE is a posthumous detection of neuropathological markers. Methods such as detection of exosomal tau protein in plasma and imaging techniques give hope to diagnose CTE in alive patients. Treatment methods of CTE, such as LIPUS (low intensity pulsed ultrasound) therapy are currently being developed.Conclusions. Chronic traumatic encephalopathy among athletes is a serious problem that affects multiple people due to the popularity of contact sports. Thus, an emphasis should be put on prevention, raising awareness and appropriate protection of athletes through changes in regulations and improvement of protective equipment.

Editors' Note: Association of Position Played and Career Duration and Chronic Traumatic Encephalopathy at Autopsy in Elite Football and Hockey Players

In their retrospective autopsy series of 35 former football and hockey players, Schwab and colleagues found that half (49%) had histopathologic evidence of chronic traumatic encephalopathy (CTE) based on 2015 NINDS consensus criteria. Among their findings, the investigators reported no significant association between CTE risk and surrogate markers for lifetime exposure to sport and aggressive role/style of play, although the study was limited by its small sample size. The investigators conclude that factors other than cumulative physical contact and injury insufficiently explain the risk of CTE. Dr. Mez and colleagues compared these results from their recently published autopsy series of 266 former football players, in which the odds of CTE increased by 30% for every year of football played. In their work, Mez et al. also report no effect of player position (similar to the results of Schwab et al.); however, Mez et al. indicate that the findings reported here were too underpowered to detect any significant relationship between CTE and position or exposure duration. Furthermore, comments by Mez as well as Dr. Dams-O’Connor highlight important limitations in selection of the independent variables, particularly that the surrogate marker for duration of exposure (age at retirement) inadequately captures preprofessional duration of play. Preprofessional exposure and head injury have been shown in some studies to pose considerable risk as injuries accumulate in the developing brains of children and adolescents. The investigators acknowledge the limitation in statistical power, but reiterate a major conclusion that even subjects with relatively brief exposure to contact sports remain at risk of this histopathologic diagnosis, whereas others with protracted exposure may not develop this brain pathology. In their retrospective autopsy series of 35 former football and hockey players, Schwab and colleagues found that half (49%) had histopathologic evidence of chronic traumatic encephalopathy (CTE) based on 2015 NINDS consensus criteria. Among their findings, the investigators reported no significant association between CTE risk and surrogate markers for lifetime exposure to sport and aggressive role/style of play, although the study was limited by its small sample size. The investigators conclude that factors other than cumulative physical contact and injury insufficiently explain the risk of CTE. Dr. Mez and colleagues compared these results from their recently published autopsy series of 266 former football players, in which the odds of CTE increased by 30% for every year of football played. In their work, Mez et al. also report no effect of player position (similar to the results of Schwab et al.); however, Mez et al. indicate that the findings reported here were too underpowered to detect any significant relationship between CTE and position or exposure duration. Furthermore, comments by Mez as well as Dr. Dams-O’Connor highlight important limitations in selection of the independent variables, particularly that the surrogate marker for duration of exposure (age at retirement) inadequately captures preprofessional duration of play. Preprofessional exposure and head injury have been shown in some studies to pose considerable risk as injuries accumulate in the developing brains of children and adolescents. The investigators acknowledge the limitation in statistical power, but reiterate a major conclusion that even subjects with relatively brief exposure to contact sports remain at risk of this histopathologic diagnosis, whereas others with protracted exposure may not develop this brain pathology.

Neuroimaging Biomarkers of Chronic Traumatic Encephalopathy: Targets for the Academic Memory Disorders Clinic.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts, such as those from contact sports. The pathognomonic lesion for CTE is the perivascular accumulation of hyper-phosphorylated tau in neurons and other cell process at the depths of sulci. CTE cannot be diagnosed during life at this time, limiting research on risk factors, mechanisms, epidemiology, and treatment. There is an urgent need for in vivo biomarkers that can accurately detect CTE and differentiate it from other neurological disorders. Neuroimaging is an integral component of the clinical evaluation of neurodegenerative diseases and will likely aid in diagnosing CTE during life. In this qualitative review, we present the current evidence on neuroimaging biomarkers for CTE with a focus on molecular, structural, and functional modalities routinely used as part of a dementia evaluation. Supporting imaging-pathological correlation studies are also presented. We targeted neuroimaging studies of living participants at high risk for CTE (e.g., aging former elite American football players, fighters). We conclude that an optimal tau PET radiotracer with high affinity for the 3R/4R neurofibrillary tangles in CTE has not yet been identified. Amyloid PET scans have tended to be negative. Converging structural and functional imaging evidence together with neuropathological evidence show frontotemporal and medial temporal lobe neurodegeneration, and increased likelihood for a cavum septum pellucidum. The literature offers promising neuroimaging biomarker targets of CTE, but it is limited by cross-sectional studies of small samples where the presence of underlying CTE is unknown. Imaging-pathological correlation studies will be important forthe development and validation of neuroimaging biomarkers of CTE.

Player position in American football influences the magnitude of mechanical strains produced in the location of chronic traumatic encephalopathy pathology: A computational modelling study

American football players are frequently exposed to head impacts, which can cause concussions and may lead to neurodegenerative diseases such as chronic traumatic encephalopathy (CTE). Player position appears to influence the risk of concussion but there is limited work on its effect on the risk of CTE. Computational modelling has shown that large brain deformations during head impacts co-localise with CTE pathology in sulci. Here we test whether player position has an effect on brain deformation within the sulci, a possible biomechanical trigger for CTE. We physically reconstructed 148 head impact events from video footage of American Football games. Players were separated into 3 different position profiles based on the magnitude and frequency of impacts. A detailed finite element model of TBI was then used to predict Green-Lagrange strain and strain rate across the brain and in sulci. Using a one-way ANOVA, we found that in positions where players were exposed to large magnitude and low frequency impacts (e.g. defensive back and wide receiver), strain and strain rate across the brain and in sulci were highest. We also found that rotational head motion is a key determinant in producing large strains and strain rates in the sulci. Our results suggest that player position has a significant effect on impact kinematics, influencing the magnitude of deformations within sulci, which spatially corresponds to where CTE pathology is observed. This work can inform future studies investigating different player-position risks for concussion and CTE and guide design of prevention systems.

Proteomic Profiling of Extracellular Vesicles Separated from Plasma of Former National Football League Players at Risk for Chronic Traumatic Encephalopathy.

Chronic Traumatic Encephalopathy (CTE) is a tauopathy that affects individuals with a history of exposure to repetitive head impacts, including National Football League (NFL) players. Extracellular vesicles (EVs) are known to carry tau in Alzheimer’s disease and other tauopathies. We examined protein profiles of EVs separated from the plasma of former NFL players at risk for CTE. EVs were separated from the plasma from former NFL players and age-matched controls using size-exclusion chromatography. Label-free quantitative proteomic analysis identified 675 proteins in plasma EVs, and 17 proteins were significantly differentially expressed between former NFL players and controls. Total tau (t-tau) and tau phosphorylated at threonie181 (p-tau181) in plasma-derived EVs were measured by ultrasensitive immunoassay. Level of t-tau and p-tau181 in EVs were significantly different, and the area under the receiver operating characteristic curve (AUC) of t-tau and p-tau181 showed 0.736 and 0.715, respectively. Machine learning analysis indicated that a combination of collagen type VI alpha 3 and 1 chain (COL6A3 and COL6A1) and reelin (RELN) can distinguish former NFL players from controls with 85% accuracy (AUC = 0.85). Based on the plasma EV proteomics, these data provide protein profiling of plasma EVs for CTE, and indicate combination of COL6A3, RELN and COL6A1 in plasma EVs may serve as the potential diagnostic biomarkers for CTE.

Evaluation of extracellular vesicles isolated from the cerebrospinal fluid and plasma from former National Football League players at risk for chronic traumatic encephalopathy

AbstractBackgroundChronic Traumatic Encephalopathy (CTE) is a tauopathy that affects individuals with a history of mild repetitive brain injury frequently seen in contact sports. Initial neuropathologic change of CTE consists of perivascular deposition of phosphorylated tau (p‐tau) in cortical neurons. Tau pathology progresses to form neurofibrillary tangles in neurons throughout the brain in later stages when patients show more clinical symptoms. Extracellular vesicles (EV) are known to carry neuropathogenic molecules in neurodegenerative disease and able to cross the blood brain barrier. We therefore examined the protein composition of EV separated from cerebrospinal fluid (CSF) and plasma in former NFL players with cognitive dysfunction, and an age‐matched controls.MethodEVs were separated from CSF and plasma from former NFL players (n=4, 14) and controls (n=5, 12) by affinity separation or size exclusion chromatography, respectively. The EV protein profiling was characterized by SIMOA for tau and p‐tau and mass spectrometry. The protein data was analyzed for EV enrichment, differentially expressed proteins, pathway analysis and correlation with cognitive function, head impact and tau/p‐tau levels by biostatistics and bioinformatics.ResultThe level of t‐tau and p‐tau in plasma EVs from former NFL players was significantly elevated although there was no significant change in CSF EV compared to the control. The 95 proteins were commonly identified between the paired plasma‐CSF from the same patients, but there was no significant correlation with the disease status. Collagen alpha‐3(VI) chain (COL6A3), ‐1(VI) chain (COL6A1) and Reelin (RELN) were differentially expressed in former NFL players’ plasma EVs. A combination of these 3 proteins in plasma EV was able to distinguish former NFL players from controls with 85% accuracy by machine learning.ConclusionThese data suggest that COL6A3, RELN and COL6A1 in plasma EV can be potential biomarker for monitoring the CTE development. We need further evaluation of CSF EV by increasing the sample number size in future studies.

The Role of Acid Sphingomyelinase Inhibition in Repetitive Mild Traumatic Brain Injury

BackgroundChronic traumatic encephalopathy is a consequence of repetitive mild traumatic brain injury (rmTBI). These injuries can result in psychiatric disorders that are treated with amitriptyline. Amitriptyline improves neuronal regeneration in major depression via inhibition of acid sphingomyelinase. We hypothesized that acid sphingomyelinase inhibition would preserve neuronal regeneration and decrease depressive symptoms following rmTBI in a murine model. MethodsA murine model of rmTBI was established using a weight-drop method. Mice were subjected to mTBI every other day for 7 d. Mice received amitriptyline injection 2 h prior to each mTBI. After the final mTBI, mice underwent behavioral studies or biochemical analysis. Hippocampi were analyzed for markers of neurogenesis and phosphorylated tau aggregation. ResultsMice that underwent rmTBI showed increased hippocampal phosphorylated tau aggregation 1 mo following rmTBI as well as decreased neuronal regeneration by bromodeoxyuridine uptake and doublecortin immunohistochemistry. Mice with either genetic deficiency or pharmacologic inhibition of acid sphingomyelinase demonstrated improved neuronal regeneration and decreased phosphorylated tau aggregation compared to untreated rmTBI mice. Behavioral testing showed rmTBI mice spent significantly more time in the dark and waiting to initiate feeding compared to sham mice. These behaviors were partially prevented by the inhibition of acid sphingomyelinase. ConclusionsWe established a murine model of rmTBI that leads to tauopathy, depression, and impaired hippocampal neurogenesis. Inhibition of acid sphingomyelinase prevented the harmful neurologic and behavioral effects of rmTBI. These findings highlight an important opportunity to improve recovery or prevent neuropsychiatric decline in patients at risk for chronic traumatic encephalopathy.

Proteomic Profiling of Extracellular Vesicles Isolated From Cerebrospinal Fluid of Former National Football League Players at Risk for Chronic Traumatic Encephalopathy.

Chronic Traumatic Encephalopathy (CTE) is a tauopathy that affects individuals with a history of repetitive mild traumatic brain injury, such as American football players. Initial neuropathologic changes in CTE include perivascular deposition of phosphorylated microtubule-associated protein tau (p-tau) neurofibrillary tangles and other aggregates in neurons, astrocytes and cell processes in an irregular pattern often at the depths of the cortical sulci. In later stages, the p-tau depositions become widespread and is associated with neurodegeneration. Extracellular vesicles (EVs) are known to carry neuropathogenic molecules, most notably p-tau. We therefore examined the protein composition of EVs isolated from the cerebrospinal fluid (CSF) of former National Football League (NFL) players with cognitive and neuropsychiatric dysfunction, and an age-matched control group (CTRL) with no history of contact sports or traumatic brain injury. EVs were isolated from the CSF samples using an affinity purification kit. Total tau (t-tau) and tau phosphorylated on threonine181 (p-tau181) in CSF-derived EVs from former NFL players and CTRL participants were measured by ultrasensitive immunoassay. The t-tau and p-tau181 levels of CSF-derived EV were positively correlated with the t-tau and p-tau181 levels of total CSF in former NFL players, respectively, but not in the CTRL group. 429 unique proteins were identified from CSF-derived EVs and quantified by TMT-10 plex method. The identified protein molecules were significantly enriched for the extracellular exosome molecules, Alzheimer’s disease pathway and Age/Telomere Length ontology as determined by DAVID Gene Ontology analysis. Ingenuity pathway analysis of the differentially expressed EV proteins revealed enrichment of canonical liver/retinoid X receptor activation pathway. Upstream effect analysis predicted MAPT (tau) as an upstream regulator in former NFL players. These data will be useful for understanding the EV-mediated disease spread and development of novel EV biomarkers for CTE and related disorders.

No Evidence of Increased Chronic Traumatic Encephalopathy Pathology or Neurodegenerative Proteinopathy in Former Military Service Members: A Preliminary Study.

It is presently unknown whether military service members are at risk for chronic traumatic encephalopathy (CTE) or Alzheimer's disease (AD) pathology, due to traumatic brain injury (TBI). Studies with respect to AD have had mixed results with respect to mild TBI, although an increased risk of clinical AD with moderate and severe TBI is more consistently demonstrated. No studies to date have demonstrated a longitudinal progression from TBI to autopsy. We therefore initiated a cross-sectional survey of former military service members. 18 brain specimens have been examined to date, with a mean age of 68.9±16 years (range 32-94). Twelve had a history of psychiatric problems; 10 had a history of PTSD specifically. Five had neurological problems including stroke and seizures. One subject had early-onset AD. Two subjects had a history of TBI and two had a history of blast exposure. Age-related proteinopathy, ranging from AD neuropathologic change A0B1C0 to A3B3C3 by NIA-AA guidelines, was identified. None of the cases showed changes specific for CTE pathology. There was no relationship between p-tau in the amygdala and psychiatric signs. There was no significant difference in phosphorylated tau (p-tau) or amyloid-β burden compared to age-matched controls. These preliminary data suggest that military service per se is not a risk factor for CTE pathology or neurodegenerative proteinopathy. More research is needed to study the relationship, if any, between TBI and neurodegenerative proteinopathy.

Tau PET and multimodal brain imaging in patients at risk for chronic traumatic encephalopathy.

To characterize individual and group-level neuroimaging findings in patients at risk for Chronic Traumatic Encephalopathy (CTE). Eleven male patients meeting criteria for Traumatic Encephalopathy Syndrome (TES, median age: 64) underwent neurologic evaluation, 3-Tesla MRI, and PET with [18F]-Flortaucipir (FTP, tau-PET) and [11C]-Pittsburgh compound B (PIB, amyloid-PET). Six patients underwent [18F]-Fluorodeoxyglucose-PET (FDG, glucose metabolism). We assessed imaging findings at the individual patient level, and in group-level comparisons with modality-specific groups of cognitively normal older adults (CN). Tau-PET findings in patients with TES were also compared to a matched group of patients with mild cognitive impairment or dementia due to Alzheimer's disease (AD). All patients with TES sustained repetitive head injury participating in impact sports, ten in American football. Three patients met criteria for dementia and eight had mild cognitive impairment. Two patients were amyloid-PET positive and harbored the most severe MRI atrophy, FDG hypometabolism, and FTP-tau PET binding. Among the nine amyloid-negative patients, tau-PET showed either mildly elevated frontotemporal binding, a "dot-like" pattern, or no elevated binding. Medial temporal FTP was mildly elevated in a subset of amyloid-negative patients, but values were considerably lower than in AD. Voxelwise analyses revealed a convergence of imaging abnormalities (higher FTP binding, lower FDG, lower gray matter volumes) in frontotemporal areas in TES compared to controls. Mildly elevated tau-PET binding was observed in a subset of amyloid-negative patients at risk for CTE, in a distribution consistent with CTE pathology stages III-IV. FTP-PET may be useful as a biomarker of tau pathology in CTE but is unlikely to be sensitive to early disease stages.

Chronic Traumatic Encephalopathy and Neurodegeneration in Contact Sports and American Football.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by the presence of abnormally phosphorylated tau protein in the depths of one or more cortical sulci. Controversy over the risk of CTE and neurologic disorders later in life among contact sport athletes has taken hold in the public spotlight, most notably in American football. Players, parents, coaches, and legislators have taken action based on the commonly held notion that contact sports invariably lead to neurodegenerative disorders. However, to fully understand the science behind this assumed association, a critical appraisal of the evidence is warranted. With regards to CTE in sports, the objectives of the current report are to: 1) describe the history of CTE, 2) review current CTE definitions, 3) critically evaluate the empiric data, divided into all contact sports and exclusively American football, and 4) summarize notable themes for future research.