Baseline delayed verbal recall predicts response to high definition transcranial direct current stimulation targeting the superior medial frontal cortex.

Anodal high definition transcranial direct current stimulation (HD-tDCS) targeting the pre-supplementary motor area/dorsal anterior cingulate cortex (pre-SMA/dACC) has recently been shown to improve verbal retrieval deficits in veterans with chronic traumatic brain injury (TBI) (Motes et al., 2020), but predictors of treatment response are unclear. We hypothesized that baseline delayed verbal recall, a sensitive measure for post-TBI chronic cognitive decline, would predict therapeutic effects of HD-tDCS targeting the pre-SMA/dACC for verbal retrieval deficits. Standardized verbal retrieval measures were administered at baseline, immediately after and 8 weeks after treatment completion. We applied mixed generalized linear modeling as a post-hoc subgroup analysis to the verbal retrieval scores that showed significant improvement in Motes at el. (2020) to examine effects of active stimulation across the groups with baseline-intact delayed recall (N = 10) and baseline-impaired delayed recall (N = 8), compared to sham (N = 7). Individuals with impaired baseline delayed recall showed significant improvement (compared to baseline) in both category fluency and color-word inhibition/switch, while individuals with intact delayed recall showed significant improvement only in color-word inhibition/switch. Baseline delayed verbal recall may therefore be considered as a predictor for future electromodulation studies targeting frontal structures to treat TBI-related verbal deficits.

Age at First Exposure to Tackle Football is Associated with Cortical Thickness in Former Professional American Football Players.

Younger age at first exposure (AFE) to repetitive head impacts while playing American football increases the risk for later-life neuropsychological symptoms and brain alterations. However, it is not known whether AFE is associated with cortical thickness in American football players. Sixty-three former professional National Football League players (55.5 ± 7.7 years) with cognitive, behavioral, and mood symptoms underwent neuroimaging and neuropsychological testing. First, the association between cortical thickness and AFE was tested. Second, the relationship between clusters of decreased cortical thickness and verbal and visual memory, and composite measures of mood/behavior and attention/psychomotor speed was assessed. AFE was positively correlated with cortical thickness in the right superior frontal cortex (cluster-wise P value [CWP] = 0.0006), the left parietal cortex (CWP = 0.0003), and the occipital cortices (right: CWP = 0.0023; left: CWP = 0.0008). A positive correlation was found between cortical thickness of the right superior frontal cortex and verbal memory (R = 0.333, P = 0.019), and the right occipital cortex and visual memory (R = 0.360, P = 0.012). In conclusion, our results suggest an association between younger AFE and decreased cortical thickness, which in turn is associated with worse neuropsychological performance. Furthermore, an association between younger AFE and signs of neurodegeneration later in life in symptomatic former American football players seems likely.

Clinical Presentation of Chronic Traumatic Encephalopathy.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive head impacts (RHI), such as those received in contact/collision sports, blast injury in military veterans, and domestic violence. Currently, CTE can only be diagnosed following death. Although the clinical features of former boxers have been described for almost a century, and there is increasing evidence of long-term cognitive and neuropsychiatric impairments in living former American football players, the specific clinical presentation associated with underlying CTE neuropathology remains unclear. These features include diverse and nonspecific changes in cognition, mood, behavior, and motor functioning. Currently, there are no validated and widely accepted clinical diagnostic criteria. Proposed criteria are primarily based on retrospective telephonic interviews with the next of kin of individuals who were diagnosed with CTE postmortem. Prospective studies involving individuals presumably at high risk for CTE are underway; these will hopefully clarify the clinical features and course of CTE, allow the diagnostic criteria to be refined, and lead to the development and validation of in vivo biomarkers. This article reviews what is currently known about the clinical presentation of CTE and describes the evolution of this knowledge from early case reports of "punch drunk" boxers through larger case series of neuropathologically confirmed CTE. This article concludes with a discussion of gaps in research and future directions to address these areas.

Chronic traumatic encephalopathy: understanding the facts and debate.

PURPOSE OF REVIEW: Chronic traumatic encephalopathy (CTE) is hypothesized to be a progressive neurodegenerative disease leading to dementia after repetitive head impacts. This review summarizes the recent evidence on CTE to highlight the facts currently known and the areas that remain poorly understood. RECENT FINDINGS: Increasing evidence suggests that many of the prior assertions about CTE in relation to repetitive head trauma are premature. First, CTE lesions have been observed in individuals with no history of head trauma/impacts. In addition, attempts to characterize possible clinical markers of CTE have had several shortcomings, notably an absence of detailed clinical assessments during life, vague/nonspecific symptom reports, and crude methodology. Moreover, recent studies demonstrate that current CTE pathological criteria have limitations and are in need of refinement/validation. SUMMARY: CTE is still in the early stages of research as a neuropathological condition and no specific clinical criteria exist. Claims about CTE being a progressive disease entity and caused exclusively by head trauma/impacts are not well supported at present. Such assertions may have impeded our understanding of the frequency and significance of this disorder. Refining diagnostic criteria to reduce ambiguity in classifying cases will be essential before risk factors and/or possible clinical markers may be identified.

Long-term cognitive impairment without diffuse axonal injury following repetitive mild traumatic brain injury in rats.

Repetitive mild traumatic brain injuries (TBI) impair cognitive abilities and increase risk of neurodegenerative disorders in humans. We developed two repetitive mild TBI models in rats with different time intervals between successive weight-drop injuries. Rats were subjected to repetitive Sham (no injury), single mild (mTBI), repetitive mild (rmTBI - 5 hits, 24 h apart), rapid repetitive mild (rapTBI - 5 hits, 5 min apart) or a single severe (sTBI) TBI. Cognitive performance was assessed 2 and 8 weeks after TBI in the novel object recognition test (NOR), and 6-7 weeks after TBI in the water maze (MWM). Acute immunohistochemical markers were evaluated 24 h after TBI, and blood biomarkers were measured with ELISA 8 weeks after TBI. In the NOR, both rmTBI and rapTBI showed poor performance at 2 weeks post-injury. At 8 weeks post-injury, the rmTBI group still performed worse than the Sham and mTBI groups, while the rapTBI group recovered. In the MWM, the rapTBI group performed worse than the Sham and mTBI groups. Acute APP and RMO-14 immunohistochemistry showed axonal injury at the pontomedullary junction in the sTBI, but not in other groups. ELISA showed increased serum GFAP levels 8 weeks after sTBI, while no differences were found between the injury groups in the levels of phosphorylated-tau and S100ß. Results suggest that the rmTBI protocol is the most suitable model for testing cognitive impairment after mild repetitive head injuries and that the prolonged cognitive impairment after repetitive mild TBI originates from different structural and molecular mechanisms compared to similar impairments after single sTBI.

Risk of Misdiagnosing Chronic Traumatic Encephalopathy in Men With Depression.

OBJECTIVE: In recent years, it has been proposed that depression represents one clinical subtype of chronic traumatic encephalopathy (CTE). This is the first study to examine the specificity of the research criteria for the clinical diagnosis of CTE in men with depression from the general population. METHODS: Data from the National Comorbidity Survey Replication, an in-person survey that examined the prevalence and correlates of mental disorders in the United States, were used for this study. Men diagnosed as having a major depressive episode in the past 30 days were included (N=101; mean age=39.4 years, SD=12.9, range=18-71). They were deemed to meet research criteriafor CTE if they presented with the purported supportive clinical features of CTE (e.g., impulsivity and substance abuse, anxiety, apathy, suicidality, and headache). RESULTS: Approximately half of the sample (52.5%) met the proposed research criteria for CTE (i.e., traumatic encephalopathy syndrome). If one accepts the delayed-onset criterion as being present, meaning that the men in the sample were presenting with depression years after retirement from sports or the military, then 83.2% of this sample would meet the research criteria for diagnosis. CONCLUSIONS: The clinical problems attributed to CTE, such as depression, suicidality, anxiety, anger control problems, and headaches, co-occurred in this sample of men with depression from the general population-illustrating that these problems are not specific or unique to CTE. More research is needed to determine whether depression is, in fact, a clinical subtype of CTE.

The Administration of the New Pyrimidine Derivative-4-{2-[2-(3,4-Dimethoxyphenyl)-Vinyl]-6-Ethyl-4-Oxo-5-Phenyl-4H-Pyrimidine-1-Il}Benzsulfamide Restores the Activity of Brain Cells in Experimental Chronic Traumatic Encephalopathy by Maintaining Mitochondrial Function.

Background and objectives: To evaluate the effect of a new pyrimidine derivative on the change of mitochondrial function in experimental chronic traumatic encephalopathy. Materials and methods: The study was performed on male mice of the BALB/c line (acute toxicity was assessed) and male rats of the Wistar line, which were modeled chronic traumatic encephalopathy by the method of free fall of the load (weight 150 g from a 50 cm height). The injury to rats was reproduced once a day for 7 days. Further, cognitive functions, changes in sensorimotor deficiency, cerebral blood flow, neuron-specific enolase(NSE), S100ß, glial fibrillary acidic protein (GFAP) (in blood serum) and ß-amyloid, adenosine triphosphate (ATP) (in brain tissue supernatant) were evaluated. Mitochondrial respiration was also measured. Choline alfoscerate (100 mg/kg) was used as a reference drug. Results: The study found that the use of a new pyrimidine derivative contributed to the preservation of the mitochondrial respirometric function and cognitive functions in rats. In addition, against the administration of test-object marked increase in the concentration of ATP, the velocity of cerebral blood flow was 4.2 times (p < 0.05) and 35.6% (p < 0.05), respectively, as well as reduced concentration and GFAP,NSE, S100ß, ß-amyloid and sensorimotor deficit at 2.7 (p < 0.05) times; 2 times (p < 0.05); 2.4 times (p < 0.05); of 30.4% (p < 0.05 and 46.5% (p < 0.05), respectively. The LD50 (per os) for the test-object was 4973.56 ± 573.72 mg/kg. Conclusion: Based on the obtained data, high therapeutic efficacy and low systemic toxicity of the application are assumed 4-{2-[2-(3,4-dimethoxyphenyl)-vinyl]-6-ethyl-4-oxo-5-phenyl-4H-pyrimidine-1-Il}benzsulfamide in chronic traumatic encephalopathy.

Sports-Related Concussion: Neurometabolic Aspects.

Concussion is a transitory brain injury resulting from a blow to the head. Concussion is considered a mild traumatic brain injury (mTBI), which is self-limited. Repetitive mTBI has been associated with chronic, progressive neurological damage. Extreme biochemical changes occur in neuron cells as a result of mTBI. These metabolic disturbances may reflect the symptoms observed in patients who had suffered concussions. However, it has been difficult to correlate clinical signs and symptoms. Currently, there are no laboratory tests to diagnose concussion, though several biomarkers are being investigated. Further studies are needed to elucidate the biochemical details of the metabolic cascade and the associated time frame, which will help determine when an athlete can safely return to the game.

Dangers of Mixed Martial Arts in the Development of Chronic Traumatic Encephalopathy.

Chronic traumatic encephalopathy (CTE) was first discovered in professional boxers after they exhibited memory impairments, mood and behavioral changes after years of boxing. However, there is now a growing acceptance that CTE can develop in athletes of other sports due to the repetitive head trauma they receive. We present a case of a middle-aged male who presented with worsening memory, poor concentration, and behavioral changes for a year. On further cognitive testing, it was revealed that he had difficulties with short-term memory and processing speed as well as difficulties in organizing and multitasking. He had been practicing mixed martial arts (MMA) for 10 years, and later was an instructor of the sport. Through a detailed examination of his history, it was discovered that he sustained recurrent minor head concussions due to his line of work. To date, there has been limited large-scale research on head trauma in MMA. There is thus an urgent need for more studies in this area as CTE can be a chronic and debilitating illness with incapacitating neuropsychiatric sequelae. This case highlights the importance of public awareness of the risks of MMA and the dangers it poses to the brain, especially with more young people being attracted to this sport.

Limbic system structure volumes and associated neurocognitive functioning in former NFL players.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts. CTE has been linked to disruptions in cognition, mood, and behavior. Unfortunately, the diagnosis of CTE can only be made post-mortem. Neuropathological evidence suggests limbic structures may provide an opportunity to characterize CTE in the living. Using 3 T magnetic resonance imaging, we compared select limbic brain regional volumes - the amygdala, hippocampus, and cingulate gyrus - between symptomatic former National Football League (NFL) players (n = 86) and controls (n = 22). Moreover, within the group of former NFL players, we examined the relationship between those limbic structures and neurobehavioral functioning (n = 75). The former NFL group comprised eighty-six men (mean age = 55.2 ± 8.0 years) with at least 12 years of organized football experience, at least 2 years of active participation in the NFL, and self-reported declines in cognition, mood, and behavior within the last 6 months. The control group consisted of men (mean age = 57.0 ± 6.6 years) with no history of contact-sport involvement or traumatic brain injury. All control participants provided neurobehavioral data. Compared to controls, former NFL players exhibited reduced volumes of the amygdala, hippocampus, and cingulate gyrus. Within the NFL group, reduced bilateral cingulate gyrus volume was associated with worse attention and psychomotor speed (r = 0.4 (right), r = 0.42 (left); both p < 0.001), while decreased right hippocampal volume was associated with worse visual memory (r = 0.25, p = 0.027). Reduced volumes of limbic system structures in former NFL players are associated with neurocognitive features of CTE. Volume reductions in the amygdala, hippocampus, and cingulate gyrus may be potential biomarkers of neurodegeneration in those at risk for CTE.

A novel repetitive mild traumatic brain injury mouse model for chronic traumatic encephalopathy research.

BACKGROUND: Athletes, military personnel and mobility-declined elderly people are prone to repetitive mild traumatic brain injury (rmTBI). The injury does not cause acute pathological changes, but leads to chronic neurodegeneration, long-term cognitive dysfunction and even chronic traumatic encephalopathy (CTE). Many existing rmTBI animal models reported uncontrollable adverse effects and long experiment period. Therefore, an improved model needs to be designed. NEW METHOD: Our rmTBI mouse model is a modification of the closed head injury method using electronic controlled cortical impact system. Discontinuous 4 impacts with 48-h interval were performed. A key facet of the model is the use of our designed molded acrylic cast and concave metal disc (as a helmet). They could scatter and transmit hitting power to the whole brain, thus produced a mild diffused injury. The procedure does not require scalp incision or craniotomy, which allows the impacting to be completed in 2 min. RESULTS: Our model did not induce acute macroscopic brain damage and brain edema. It could lead to sustained neuroinflammation and chronic neurodegeneration in injured brain, and resulted in cognitive dysfunction within 5 weeks post-injury. COMPARISON WITH EXISTING METHODS: Previously reported adverse effects including skull fractures, hemorrhage and brain tissue loss were not observed in our model. An experiment period of 5 weeks was allowed for observing chronic neurodegeneration and cognitive dysfunction. CONCLUSIONS: Our model is beneficial to use for simplicity, reproducibility and time saver. It could serve as a platform for research on the pathogenesis, diagnosis and potential therapeutics for rmTBI and CTE.

Lewy Body Pathology and Chronic Traumatic Encephalopathy Associated With Contact Sports.

Traumatic brain injury has been associated with increased risk of Parkinson disease and parkinsonism, and parkinsonism and Lewy body disease (LBD) can occur with chronic traumatic encephalopathy (CTE). To test whether contact sports and CTE are associated with LBD, we compared deceased contact sports athletes (n = 269) to cohorts from the community (n = 164) and the Boston University Alzheimer disease (AD) Center (n = 261). Participants with CTE and LBD were more likely to have ß-amyloid deposition, dementia, and parkinsonism than CTE alone (p < 0.05). Traditional and hierarchical clustering showed a similar pattern of LBD distribution in CTE compared to LBD alone that was most frequently neocortical, limbic, or brainstem. In the community-based cohort, years of contact sports play were associated with neocortical LBD (OR = 1.30 per year, p = 0.012), and in a pooled analysis a threshold of >8 years of play best predicted neocortical LBD (ROC analysis, OR = 6.24, 95% CI = 1.5-25, p = 0.011), adjusting for age, sex, and APOE ɛ4 allele status. Clinically, dementia was significantly associated with neocortical LBD, CTE stage, and AD; parkinsonism was associated with LBD pathology but not CTE stage. Contact sports participation may increase risk of developing neocortical LBD, and increased LBD frequency may partially explain extrapyramidal motor symptoms sometimes observed in CTE.

Age of first exposure to tackle football and chronic traumatic encephalopathy.

OBJECTIVE: To examine the effect of age of first exposure to tackle football on chronic traumatic encephalopathy (CTE) pathological severity and age of neurobehavioral symptom onset in tackle football players with neuropathologically confirmed CTE. METHODS: The sample included 246 tackle football players who donated their brains for neuropathological examination. Two hundred eleven were diagnosed with CTE (126 of 211 were without comorbid neurodegenerative diseases), and 35 were without CTE. Informant interviews ascertained age of first exposure and age of cognitive and behavioral/mood symptom onset. RESULTS: Analyses accounted for decade and duration of play. Age of exposure was not associated with CTE pathological severity, or Alzheimer's disease or Lewy body pathology. In the 211 participants with CTE, every 1 year younger participants began to play tackle football predicted earlier reported cognitive symptom onset by 2.44 years (p < 0.0001) and behavioral/mood symptoms by 2.50 years (p < 0.0001). Age of exposure before 12 predicted earlier cognitive (p < 0.0001) and behavioral/mood (p < 0.0001) symptom onset by 13.39 and 13.28 years, respectively. In participants with dementia, younger age of exposure corresponded to earlier functional impairment onset. Similar effects were observed in the 126 CTE-only participants. Effect sizes were comparable in participants without CTE. INTERPRETATION: In this sample of deceased tackle football players, younger age of exposure to tackle football was not associated with CTE pathological severity, but predicted earlier neurobehavioral symptom onset. Youth exposure to tackle football may reduce resiliency to late-life neuropathology. These findings may not generalize to the broader tackle football population, and informant-report may have affected the accuracy of the estimated effects. Ann Neurol 2018;83:886-901.

Glymphatic system disruption as a mediator of brain trauma and chronic traumatic encephalopathy.

Traumatic brain injury (TBI) is an increasingly important issue among veterans, athletes and the general public. Difficulties with sleep onset and maintenance are among the most commonly reported symptoms following injury, and sleep debt is associated with increased accumulation of beta amyloid (Aß) and phosphorylated tau (p-tau) in the interstitial space. Recent research into the glymphatic system, a lymphatic-like metabolic clearance mechanism in the central nervous system (CNS) which relies on cerebrospinal fluid (CSF), interstitial fluid (ISF), and astrocytic processes, shows that clearance is potentiated during sleep. This system is damaged in the acute phase following mTBI, in part due to re-localization of aquaporin-4 channels away from astrocytic end feet, resulting in reduced potential for waste removal. Long-term consequences of chronic dysfunction within this system in the context of repetitive brain trauma and insomnia have not been established, but potentially provide one link in the explanatory chain connecting repetitive TBI with later neurodegeneration. Current research has shown p-tau deposition in perivascular spaces and along interstitial pathways in chronic traumatic encephalopathy (CTE), pathways related to glymphatic flow; these are the main channels by which metabolic waste is cleared. This review addresses possible links between mTBI-related damage to glymphatic functioning and physiological changes found in CTE, and proposes a model for the mediating role of sleep disruption in increasing the risk for developing CTE-related pathology and subsequent clinical symptoms following repetitive brain trauma.

Head and neck size and neck strength predict linear and rotational acceleration during purposeful soccer heading.

There is increasing societal concern about the long-term effects of repeated impacts from soccer heading, but there is little information about ways to reduce head impact severity. The purpose of this study was to identify factors that contribute to head acceleration during soccer heading. One-hundred soccer players completed 12 controlled soccer headers. Peak linear (PLA) and rotational (PRA) accelerations were measured using a triaxial accelerometer and gyroscope. Head acceleration contributing factors were grouped into 3 categories: size (head mass, neck girth), strength (sternocleidomastoid, upper trapezius) and technique [kinematics (trunk, head-to-trunk range-of-motion), sternocleidomastoid and upper trapezius activity]. Multiple regression analyses indicated size variables explained 22.1% of the variance in PLA and 23.3% of the variance in PRA; strength variables explained 13.3% of the variance in PLA and 17.2% of the variance in PRA; technique variables did not significantly predict PLA or PRA. These findings suggest that head and neck size and neck strength predict PLA and PRA. Anthropometric and neck strength measurements should be considered when determining an athlete's readiness to begin soccer heading.

Chronic traumatic encephalopathy-integration of canonical traumatic brain injury secondary injury mechanisms with tau pathology.

In recent years, a new neurodegenerative tauopathy labeled Chronic Traumatic Encephalopathy (CTE), has been identified that is believed to be primarily a sequela of repeated mild traumatic brain injury (TBI), often referred to as concussion, that occurs in athletes participating in contact sports (e.g. boxing, American football, Australian football, rugby, soccer, ice hockey) or in military combatants, especially after blast-induced injuries. Since the identification of CTE, and its neuropathological finding of deposits of hyperphosphorylated tau protein, mechanistic attention has been on lumping the disorder together with various other non-traumatic neurodegenerative tauopathies. Indeed, brains from suspected CTE cases that have come to autopsy have been confirmed to have deposits of hyperphosphorylated tau in locations that make its anatomical distribution distinct for other tauopathies. The fact that these individuals experienced repetitive TBI episodes during their athletic or military careers suggests that the secondary injury mechanisms that have been extensively characterized in acute TBI preclinical models, and in TBI patients, including glutamate excitotoxicity, intracellular calcium overload, mitochondrial dysfunction, free radical-induced oxidative damage and neuroinflammation, may contribute to the brain damage associated with CTE. Thus, the current review begins with an in depth analysis of what is known about the tau protein and its functions and dysfunctions followed by a discussion of the major TBI secondary injury mechanisms, and how the latter have been shown to contribute to tau pathology. The value of this review is that it might lead to improved neuroprotective strategies for either prophylactically attenuating the development of CTE or slowing its progression.

Traumatic Brain Injury as a Trigger of Neurodegeneration.

Although millions of individuals suffer a traumatic brain injury (TBI) worldwide each year, it is only recently that TBI has been recognized as a major public health problem. Beyond the acute clinical manifestations, there is growing recognition that a single severe TBI (sTBI) or repeated mild TBIs (rTBI) can also induce insidious neurodegenerative processes, which may be associated with early dementia, in particular chronic traumatic encephalopathy (CTE). Identified at autopsy examination in individuals with histories of exposure to sTBI or rTBI, CTE is recognized as a complex pathology featuring both macroscopic and microscopic abnormalities. These include cavum septum pellucidum, brain atrophy and ventricular dilation, together with pathologies in tau, TDP-43, and amyloid-ß. However, the establishment and characterization of CTE as a distinct disease entity is in its infancy. Moreover, the relative "dose" of TBI, such as the frequency and severity of injury, associated with risk of CTE remains unknown. As such, there is a clear and pressing need to improve the recognition and diagnosis of CTE and to identify mechanistic links between TBI and chronic neurodegeneration.