BACKGROUND: Sports-related head trauma has become a major public health concern with significant consequences including persistent post-concussion syndrome (pPCS) and chronic traumatic encephalopathy (CTE). pPCS is a condition where symptoms of single concussion persist years beyond the initial injury. CTE has been characterized as a condition with insidious onset following a latent period after substantial exposure to repetitive head impacts (RHI). Timing of symptom onset usually distinguishes these conditions, however in certain clinical situations a definitive diagnosis is not always clear. For these situations, a measurable distinguishing variable is necessary. LITERATURE REVIEW: Concussions are the most common form of traumatic brain injury (TBI) and are associated with a variety of neurological symptoms that usually resolve within weeks. Post-concussion syndrome (PCS) refers to cases where symptoms continue months beyond this window, and pPCS is defined as symptoms continuing over years. These conditions are temporally related single concussive events. CTE is the hallmark condition related to RHI and remains difficult to fully characterize as it currently can only be diagnosed post-mortem. Clinical features of CTE are similar to those of pPCS with notable behavioral/mood symptoms in its earliest stages, and progression to severe cognitive decline over time. Current research has shown executive dysfunction to be a common impairment among these conditions. The difference in level of dysfunction between them, if one exists, is yet to be measured. PROPOSED PROJECT: A cross-sectional analysis of executive function in four groups. A control without history of mTBI or football exposure (Non-Football – pPCS), a second control of asymptomatic subjects with football exposure (Football – pPCS), a group of pPCS patients with non-athletic mTBI history (Non-Football + pPCS), and a group of pPCS patients with football exposure (Football + pPCS). Executive functioning will be evaluated using the BRIEF-A assessment. Results will be compared to determine if significant differences in executive functioning exist between the groups. CONCLUSIONS: With previous studies showing a correlation between CTE pathological stage, worsening executive function, and increased RHI exposure, further investigation into using executive function as a distinguishing variable between early stage CTE and pPCS is warranted. SIGNIFICANCE: Results of this study, if significant, could be applied clinically to assess risk of early stage CTE in athletes with prolonged post-concussion symptoms. If results are not significant, they may still be utilized for a better understanding of the effects of isolated mTBIs and RHI on executive functioning, and provide valuable information for ongoing longitudinal studies.

京都大学 / 0048 / 新制・課程博士 / 博士(農学) / 甲第19770号 / 農博第2166号 / 新制||農||1040(附属図書館) / 学位論文||H28||N4986(農学部図書室) / 32806 / 京都大学大学院農学研究科食品生物科学専攻 / (主査)教授 河田 照雄, 教授 保川 清, 教授 橋本 渉 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DGAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21680号 / 医博第4486号 / 新制||医||1036(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 伊佐 正, 教授 村井 俊哉, 教授 松原 和夫 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Neonatal asphyxia is the third largest cause of neonatal mortality in Vietnam, and many of the surviving patients suffer from permanent brain damage. A cooling mattress used for treatment of infants suffering from asphyxia has been shown to have problems with providing a stable body temperature for the patients. The main purpose of this project is to assess potential problems with routines and the use of the most central technical equipment used to treat newborns suffering from asphyxia, as well as constructing a phantom to simulate a newborn infant in the process of cooling. The purpose of the simulation is to investigate new methods of using the cooling mattress to achieve a more stable body temperature when cooling the patient. The project was done at Phu San Hostpial and Vietnam National Children's Hospital in Hanoi, Vietnam. The technical evaluation was conducted with observations, interviews and a question form. The results showed that there were issues with the sensors connected to the ventilators, noise level from alarms and routines concerning sanitation. The phantom was based on a water bottle, an interest heater and a pump to mix the water. It proved not possible to construct a phantom that met the necessary criteria. / Asfyxi hos nyfödda är den tredje största orsaken till neonatal dödlighet i Vietnam, och många av de överlevande får permanenta hjärnskador. En nedkylningsmadrass som används till behandling av nyfödda med asfyxi har visat sig ha problem med att hålla patientens kroppstemperatur stabil. Arbetets huvudsakliga syfte är att undersöka potentiella problem med rutiner och användningen av den viktigaste tekniken vid behandling av nyfödda som lider av asfyxi, samt även konstruera en fantom som ska kunna simulera en nyfödd vid nedkylning. Simuleringen har som syfte att undersöka nya användningsmetoder av nedkylningsmadrassen för att uppnå en mer stabil kroppstemperatur hos patienten. Arbetet gjordes vid Phu San Hospital, och National Children’s Hospital i Hanoi, Vietnam. Utvärderingen av teknikens användning gjordes via observationer, intervjuer och ett frågeformulär. Resultaten sammanställdes för att hitta potentiella förbättringar till teknikens användning. Det framkom problem med sensorerna kopplat till ventilatorerna, ljudnivån från alarmer och rutiner kring sanitering. Fantomet baserades på en vattenflaska, en doppvärmare och en pump som blandade vattnet. Det visade sig inte vara möjligt att konstruera en fantom som uppfyllde alla kriterier med de resurser som var tillgängliga.

Ceftriaxone is the most used third-generation cephalosporin anti-microbial agent in treating infections caused by gram-positive and gram-negative organisms. Chorea is a movement disorder characterized by involuntary and hyperkinetic movements of the affected body parts due to rapid and unpredictable contractions. We report an uncommon case of ceftriaxone-induced acute reversible chorea. 84-year-old male with a medical history of diabetes mellitus, hypertension, previous myocardial infarction, and gouty arthritis was admitted to the hospital with complaints of altered mental status (AMS) and right 1st metacarpal-phalangeal joint (MTP) swelling, erythema and ruptured wound draining pus-like fluid. The patient was febrile with a temperature of 101.3 F. The rest of the vitals were normal. The patient had an initial workup and was empirically started on ceftriaxone and vancomycin for skin and soft tissue infection. His wound cultures and blood cultures grew pan-sensitive streptococcus agalactiae. His antibiotics were de-escalated to ceftriaxone. X-ray showed severe soft tissue swelling and erosive changes at the base of the proximal phalanx of the first digit secondary to gout or osteomyelitis. MRI of the right foot was attempted, but the patient could not tolerate it. TTE was negative for Endocarditis. The patient had initial improvement in his AMS, but 72 hours later, he became increasingly confused with choreiform movements. Ceftriaxone was discontinued, and Ertapenem was started. Patient’s confusion and choreiform movements improved after the discontinuation of ceftriaxone. Patient was discharged to a rehabilitation facility with four weeks of IV Ertapenem. Ceftriaxone is a third-generation cephalosporin that inhibits mucopeptide synthesis in the bacterial cell wall. Ceftriaxone is a well-tolerated anti-microbial agent with a low toxicity profile. Common adverse effects include gastrointestinal disturbances, skin rashes, and hematological disorders. Neurological symptoms like encephalopathy is an uncommon adverse effect. Chorea is a movement disorder due to hereditary or acquired causes. Drug-induced chorea is one of the rare causes of acquired chorea. History and physical examination are essential in diagnosing acquired causes of chorea. Further workup with laboratory tests and neuroimaging are required to evaluate secondary causes. Chorea due to ceftriaxone is described in a patient with end-stage renal disease on hemodialysis in a case report previously, but our patient did not have any chronic kidney disease [1]. It is postulated that beta-lactam antibiotics increase neurological hyperexcitability by increased glutamate release in the striatum and cerebral cortex, causing movement disorders [2]. It is noted that pre-existing neurological conditions and excessive dosage are shown to be significant risk factors for cephalosporin neurotoxicity. Our patient, however, did not have any neurological condition but was treated with 2 grams of ceftriaxone daily before he had choreiform movements. Upon removal, the patient improved significantly within 36-48 hours. Ceftriaxone is a widely used anti-microbial with broad coverage. Although uncommon, recognizing that neurotoxicity due to third generation cephalosporins is essential. Prompt diagnosis and withdrawal of the offending agent is critical in improving the patient’s symptoms. Age, prior neurological conditions, kidney disease, and dosage must be carefully evaluated before administration.

Youth football players ages 8-12 may incur hundreds of repeated head impacts (RHI) each season. Evidence suggests concussive brain injury during childhood may disrupt normal developmental processes resulting in long-term impairments. However, little research has investigated the long-term effects of incurring RHI during critical periods of neurodevelopment. Rapid myelination and cerebral blood flow rates, peaks in regional cortical thickness and volumes of specific structures, refinement of regional connectivity, and other neurodevelopmental changes occurring in the brain from ages 10-12 could create a window of vulnerability to RHI. The objective of this research was to determine the relationship between exposure to RHI prior to age 12, during a critical period of neurodevelopment, and later-life brain structure and function. Former National Football League (NFL) players ages 40-65 were divided into two groups based on their age of first exposure (AFE) to RHI through tackle football: AFE <12 and AFE ≥12. In the first study, we observed significantly lower scores on objective tests of executive functioning, memory, and estimated verbal IQ in those who began playing football prior to age 12 compared to those who began playing at age 12 or older. Next, we used diffusion tensor imaging (DTI) to examine the structural integrity of the corpus callosum (CC) and observed that the AFE <12 group had significantly lower fractional anisotropy (FA) as well as a greater decline in FA with age in anterior CC regions than the AFE ≥12 group. Lastly, we used advanced DTI tractography techniques to examine seven CC regions. Significant differences between AFE groups in associations between CC diffusion measures and cognition, mood, and behavior were found. The results of this research suggest that incurring RHI through tackle football during a critical neurodevelopmental period prior to age 12 may result in later-life structural and functional consequences, including cognitive, mood, and behavioral impairments; alterations in white matter structure; and greater vulnerability of white matter to the normal aging process. If replicated with longitudinal designs, larger samples, and athletes whose highest level of play was youth, high school, or college, these findings may have implications for safety recommendations for youth sports.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by a pathognomonic distribution of hyperphosphorylated tau accumulations in neurons, astrocytes, and cell processes, situated around vessels at the depths of cortical sulci. Case reports of CTE pathology exhibit a common exposure to repetitive head impacts (RHI), suggesting that RHI are a necessary factor in the disease’s etiology. Currently, it is only possible to definitively diagnose CTE after death using histopathological techniques and consensus-based neuropathological diagnostic criteria recently established by the National Institute of Health and National Institute of Neurological Disorders and Stroke. Though considerable progress has been made in characterizing the neuropathology of CTE, less is known about the clinical aspects of the disease. Specifically, additional research is needed to identify disease-specific clinical manifestations, clinicopathological correlations, and a means of diagnosis during life, all of which are critical to developing future epidemiological studies, preventative measures, and treatment trials. Moreover, it is not yet known which specific aspects of RHI exposure (type, frequency, duration) are causally linked to developing clinically meaningful neurological impairments or CTE neuropathology, nor have studies identified risk-modifying factors, such as genotype (e.g. APOE). The objective of this dissertation’s published works was to systematically address these gaps in knowledge. First, to define a common clinical presentation of CTE, we conducted a retrospective analysis of medical records and semi-structured next-of-kin reports of 36 former athletes with autopsy-confirmed CTE without comorbid neurodegenerative disease. We then published clinical diagnostic criteria for CTE based on a systematic review of clinical features exhibited in 202 former athlete cases and a pooled analysis of 83 neuropathologically confirmed CTE cases. In subsequent analyses, we operationalized clinical criteria to investigate specific clinicopathological associations between tau, amyloid beta, age, APOE genotype, and clinical outcomes and utilized the clinical criteria to explore potential risk-factors related to RHI from boxing and football. Lastly, we developed a metric to quantify cumulative RHI exposure in retired, living, football players. Using this metric, our study was the first to indicate a causal relationship between cumulative RHI exposure and risk of later life cognitive, mood, and behavioral impairment. These studies are preliminary, and our results require replication and validation in larger, longitudinal prospective studies.

Clinical Researchers recently identified NFL players and US military veterans as high-risk populations for sustaining repetitive Traumatic Brain Injury (TBI) and developing the neurodegenerative disease Chronic Traumatic Encephalopathy (CTE). American culture celebrates military veterans as national heroes, and NFL players as popular athletes and social icons. Both subcultures are constructed around hyper-masculine ideals embedded in tenants of violence and aggression, suffer repeated TBIs due to this nature, and are ultimately at high-risk for developing CTE. The TBI/CTE phenomenon also affects family members who assume care-taking responsibilities for these first two populations as their loved one’s symptoms persist. The purpose of this research is to understand the TBI/CTE experiences of NFL players, military veterans, and their caretakers, and how all three populations intersect with mediatization and the social and medical legitimation of TBI/CTE in America. Using narratives from all three populations, I explore how power dynamics within the NFL and US military have intersected with modern media outlets and functioned to socio-medically legitimize a sick role for those who suffer from persistent symptoms of TBI and CTE.

CTE is a progressive neurodegenerative disease defined by p-tau lesions in characteristic locations of the brain, leading to cognitive impairment as well as mood and behavioral dysfunction. Exposure to repetitive head impacts is a major risk factor for developing CTE; however, additional risk factors and secondary modulating factors, which may expand available treatment and prevention options, are still being elucidated. Studies into the glymphatic system, a system of waste clearance in the brain thought to be activated during sleep, have implicated glymphatic dysfunction in the clearance of toxic proteins like amyloid-beta and hyperphosphorylated tau, as well as in cognitive decline in neurodegenerative disorders like Alzheimer’s Disease, bringing into question whether sleep, through impacting glymphatic clearance, may act as a modulating factor in the development of CTE. In the present study, we began to characterize the presence of sleep disorders and their co-morbid conditions in a cohort of former college football players to gain better insight into their prevalence and the health outcomes of those with sleep conditions. Our results found higher rates of sleep apnea in the study sample, as well as an association between diagnosis with sleep apnea and diagnosis with dementia, AD, MCI, CTE, and similar disorders. Sleep apnea was significantly associated with depression, anxiety, high cholesterol, and diabetes. Further research into whether sleep disorders exacerbate CTE pathology or clinical symptoms, and whether treatment of sleep symptoms leads to better outcomes for patients with CTE, is necessary to further elucidate a potential connection.