Julian E. Bailes

Emerging histomorphologic phenotypes of chronic traumatic encephalopathy in American athletes

BACKGROUND:We define chronic traumatic encephalopathy (CTE) as a progressive neurodegenerative syndrome caused by single, episodic, or repetitive blunt force impacts to the head and transfer of acceleration-deceleration forces to the brain. OBJECTIVE:We present emerging histomorphologic phenotypes of CTE that we identified in our cohort of CTE cases with apolipoprotein E genotyping and causes and manners of death. METHODS:Autopsy brain tissue of 14 professional athletes and 3 high school football players was examined after unexpected deaths. Histochemical and immunohistochemical tissue staining was performed with apolipoprotein E genotyping. RESULTS:Ten of 14 professional athletes (71%) were positive for CTE: 7 of 8 football players, 2 of 4 wrestlers, and 1 boxer. One of 3 high school players manifested incipient CTE. The age range of those with CTE was 18 to 52 years; they were all male athletes. In all cases of CTE, Alzheimer-type cerebral cortical atrophy was absent; negligible to mild neocortical neuronal dropout was present. The fundamental neuropathologic feature of CTE was the topographic distribution of sparse, moderate, and frequent band-shaped, flame-shaped, small and large globose neurofibrillary tangles and neuritic threads in the cerebral cortex, subcortical nuclei/basal ganglia, hippocampus, and brainstem nuclei. Sparse to frequent diffuse amyloid plaques may accompany tauopathy and was seen in only 2 CTE cases. No α-synucleinopathy was present. All 7 CTE-positive professional athletes with known apolipoprotein E genotypes had at least 1 E3 allele comprising 5 E3/E3 (71%) and 2 E3/E4 (29%). Alcohol- and drug-related deaths, suicides, and accidental deaths were overrepresented in our CTE cohort. CONCLUSION:The emerging histomorphologic features of our CTE cohort may specify histologic criteria for CTE diagnosis, may identify emerging histologic variants of CTE and may facilitate more objective surveillance and accurate identification of sentinel CTE cases.

Consensus statement on concussion in sport-the 5th international conference on concussion in sport held in Berlin, October 2016

The 2017 Concussion in Sport Group (CISG) consensus statement is designed to build on the principles outlined in the previous statements1–4 and to develop further conceptual understanding of sport-related concussion (SRC) using an expert consensus-based approach. This document is developed for physicians and healthcare providers who are involved in athlete care, whether at a recreational, elite or professional level. While agreement exists on the principal messages conveyed by this document, the authors acknowledge that the science of SRC is evolving and therefore individual management and return-to-play decisions remain in the realm of clinical judgement. This consensus document reflects the current state of knowledge and will need to be modified as new knowledge develops. It provides an overview of issues that may be of importance to healthcare providers involved in the management of SRC. This paper should be read in conjunction with the systematic reviews and methodology paper that accompany it. First and foremost, this document is intended to guide clinical practice; however, the authors feel that it can also help form the agenda for future research relevant to SRC by identifying knowledge gaps. A series of specific clinical questions were developed as part of the consensus process for the Berlin 2016 meeting. Each consensus question was the subject of a specific formal systematic review, which is published concurrently with this summary statement. Readers are directed to these background papers in conjunction with this summary statement as they provide the context for the issues and include the scope of published research, search strategy and citations reviewed for each question. This 2017 consensus statement also summarises each topic and recommendations in the context of all five CISG meetings (that is, 2001, 2004, 2008, 2012 as well as 2016). Approximately 60 000 published articles were screened by the expert panels for the Berlin …

Chronic traumatic encephalopathy (CTE) in a National Football League Player: Case report and emerging medicolegal practice questions

&NA; We present a case of chronic traumatic encephalopathy (CTE) in a retired National Football League (NFL) Player with autopsy findings, apolipoprotein E genotype, and brain tissue evidence of chronic brain damage. This 44‐year‐old retired NFL player manifested a premortem history of cognitive and neuropsychiatric impairment, which included in part, chronic depression, suicide attempts, insomnia, paranoia, and impaired memory before he finally committed suicide. A full autopsy was performed with Polymerase Chain Reaction‐based analyses of his blood to determine the apolipoprotein genotype. Histochemical and immunohistochemical analyses were performed on topographical gross sections of the brain. Autopsy confirmed a fatal gunshot wound of the head. The apolipoprotein E genotype was E3/E3 and the brain tissue revealed diffuse cerebral taupathy (Neurofibrillary Tangles and Neuritic Threads). This will be the third case of CTE in a national football player, which has been reported in the medical literature. Omalu et al., reported the first two cases in 2005 and 2006. This case series manifested similar premortem history of neuropsychiatric impairment with autopsy evidence of cerebral taupathy without any neuritic amyloidopathy. For a definitive diagnosis of CTE to be made, and for medicolegal purposes, a full autopsy must be performed with histochemical and immunohistochemical analyses of the brain to identify the presence of Neurofibrillary Tangles (NFTs) and Neuritic Threads (NTs). Implications: Further longitudinal prospective studies are required to confirm the common denominators and epidemiology of CTE in professional American football players, which have been identified by this case series.

Head Injury in Athletes

HEAD INJURIES INCURRED during athletic endeavors have been recorded since games were first held. During the last century, our level of understanding of the types of cerebral insults, their causes, and their treatment has advanced significantly. Because of the extreme popularity of sports in the United States and worldwide, the implications of athletic head injury are enormous. This is especially true considering the current realization that mild traumatic brain injury (MTBI) or concussion represents a major health consideration with more long-ranging effects than previously thought. When considering athletic injuries, people who engage in organized sports, as well as the large number of people who engage in recreational activities, should be considered. There are 200 million international soccer players, a group increasingly recognized to be at risk for MTBI. The participation in contact sports of a large number of the population, especially youth, requires a careful and detailed analysis of injury trends and recommended treatment. There are numerous characteristics of this patient population that make management difficult, especially their implicit request to once again be subjected to potential MTBI by participating in contact sports. Recent research has better defined the epidemiological issues related to sports injuries involving the central nervous system and has also led to classification and management paradigms that help guide decisions regarding athletes’ return to play. We currently have methods at our disposal that greatly assist us in managing this group of patients, including improved recognition of the clinical syndromes of MTBI, new testing such as neuropsychological assessment, radiographic evaluations, and a greater appreciation of the pathophysiology of concussive brain injury. The potential for long-term consequences of repetitive MTBI has been recognized, and we no longer consider the “dinged” states of athletic concussions to have the benign connotations they had in the past. We review the historical developments in the recognition and care of athletes with head injuries, the current theory of the pathophysiology and biomechanics of these insults, and the recommended management strategy, including return-to-play criteria.

Chronic traumatic encephalopathy in an Iraqi war veteran with posttraumatic stress disorder who committed suicide.

Following his discovery of chronic traumatic encephalopathy (CTE) in football players in 2002, Dr. Bennet Omalu hypothesized that posttraumatic stress disorder (PTSD) in military veterans may belong to the CTE spectrum of diseases. The CTE surveillance at the Brain Injury Research Institute was therefore expanded to include deceased military veterans diagnosed with PTSD. The authors report the case of a 27-year-old United States Marine Corps (USMC) Iraqi war veteran, an amphibious assault vehicle crewman, who committed suicide by hanging after two deployments to Fallujah and Ramadi. He experienced combat and was exposed to mortar blasts and improvised explosive device blasts less than 50 m away. Following his second deployment he developed a progressive history of cognitive impairment, impaired memory, behavioral and mood disorders, and alcohol abuse. Neuropsychiatric assessment revealed a diagnosis of PTSD with hyperarousal (irritability and insomnia) and numbing. He committed suicide approximately 8 months after his honorable discharge from the USMC. His brain at autopsy appeared grossly unremarkable except for congestive brain swelling. There was no atrophy or remote focal traumatic brain injury such as contusional necrosis or hemorrhage. Histochemical and immunohistochemical brain tissue analysis revealed CTE changes comprising multifocal, neocortical, and subcortical neurofibrillary tangles and neuritic threads (ranging from none, to sparse, to frequent) with the skip phenomenon, accentuated in the depths of sulci and in the frontal cortex. The subcortical white matter showed mild rarefaction, sparse perivascular and neuropil infiltration by histiocytes, and mild fibrillary astrogliosis. Apolipoprotein E genotype was 3/4. The authors report this case as a sentinel case of CTE in an Iraqi war veteran diagnosed with PTSD to possibly stimulate new lines of thought and research in the possible pathoetiology and pathogenesis of PTSD in military veterans as part of the CTE spectrum of diseases, and as chronic sequelae and outcomes of repetitive traumatic brain injuries.

PET Scanning of Brain Tau in Retired National Football League Players: Preliminary Findings

OBJECTIVE Mild traumatic brain injury due to contact sports may cause chronic behavioral, mood, and cognitive disturbances associated with pathological deposition of tau protein found at brain autopsy. To explore whether brain tau deposits can be detected in living retired players, we used positron emission tomography (PET) scans after intravenous injections of 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP). METHODS Five retired National Football League players (age range: 45 to 73 years) with histories of mood and cognitive symptoms received neuropsychiatric evaluations and FDDNP-PET. PET signals in subcortical (caudate, putamen, thalamus, subthalamus, midbrain, cerebellar white matter) and cortical (amygdala, frontal, parietal, posterior cingulate, medial and lateral temporal) regions were compared with those of five male controls of comparable age, education, and body mass index. RESULTS FDDNP signals were higher in players compared with controls in all subcortical regions and the amygdala, areas that produce tau deposits following trauma. CONCLUSIONS The small sample size and lack of autopsy confirmation warrant larger, more definitive studies, but if future research confirms these initial findings, FDDNP-PET may offer a means for premorbid identification of neurodegeneration in contact-sports athletes.

Chronic Traumatic Encephalopathy, Suicides and Parasuicides in Professional American Athletes: The Role of the Forensic Pathologist

We present 5 cases of professional American contact sport athletes who committed parasuicides and suicides aged 50, 45, 44, 36, and 40 years old. Full forensic autopsies and immunohistochemical analyses of the brains revealed chronic traumatic encephalopathy (CTE). The brains appeared grossly normal at autopsy without gross evidence of remote traumatic injuries or neurodegenerative disease. Brain immunohistochemical analyses revealed widespread cerebral taupathy in the form of neurofibrillary tangles and neuritic threads without neuritic amyloid plaques. CTE refers to chronic cognitive and neuropsychiatric symptoms of chronic neurodegeneration following a single episode of severe traumatic brain injury or repeated episodes of mild traumatic brain injury. CTE can only be definitively diagnosed by direct tissue examination. Without full autopsies and immunohistochemical brain analyses these cases would never have been identified. Forensic pathologists will play a vital and central role in the emerging disease surveillance of CTE in professional American athletes, in the identification of CTE cases, and in the establishment of the epidemiology of CTE, with the goal of eventually developing preventive and interventional therapeutic protocols for CTE outcomes.

Chronic traumatic encephalopathy in a professional American wrestler

&NA; We present in this case report the tissue substrates and forensic evidence for chronic traumatic encephalopathy (CTE) in a professional American wrestler with Apolipoprotein E (apoE) genotyping. Professional wrestling is a contact‐sport, with an integral risk for players to sustain repeated concussions over their careers. This case provides the first autopsy evidence of neuropathological abnormalities that accompany CTE in professional American wrestlers. A complete autopsy was performed on a 40‐year‐old Caucasian male, after he died unexpectedly by suicidal hanging after he had killed his wife and son. The brain showed no atrophy and no recent or remote contusions or necrosis. There was a mild to moderate neocortical neuronal dropout without any amyloid plaques. There were diffuse, sparse to frequent tau‐immunoreactive Neurofibrillary Tangles and Neuropil Threads in the neocortex, subcortical ganglia, and brainstem nuclei including the substantia nigra consistent with CTE. The apoE genotype was determined to be E3/E3. Other autopsy findings included cardiomegaly, left ventricular hypertrophy, and bilateral atrioventricular dilatation; toxicologic analyses showed alprazolam and hydrocodone in the blood, and evidence of exogenous testosterone in the urine. Longitudinal studies of professional contact‐sport athletes are needed to identify the differentiating characteristics of athletes who develop CTE and devise strategies for intervention.

Docosahexaenoic Acid Reduces Traumatic Axonal Injury in a Rodent Head Injury Model

Traumatic brain injury (TBI) remains the most common cause of death in persons under age 45 in the Western world. Recent evidence from animal studies suggests that supplementation with omega-3 fatty acids (O3FA) improves functional outcomes following focal neural injury. The purpose of this study is to determine the benefits of DHA supplementation following diffuse axonal injury in rats. Four groups of 10 adult male Sprague-Dawley rats were subjected to an impact acceleration injury and then received 30 days of supplementation with either 10 mg/kg/d or 40 mg/kg/d of docosahexaenoic acid (DHA). Serum fatty acid levels were determined from the isolated plasma phospholipids prior to injury and at the end of the 30 days of DHA supplementation. Following sacrifice, brainstem white matter tracts underwent fluorescent immunohistochemical processing for labeling of β-amyloid precursor protein (APP), a marker of axonal injury. Dietary supplementation with either 10 mg/kg/d or 40 mg/kg/d of DHA for 30 days results in significantly (p < 0.05) increased DHA serum levels of 123% and 175% over baseline, respectively. Immunohistochemical analysis reveals significantly (p < 0.05) decreased numbers of APP-positive axons in animals receiving dietary supplementation with DHA, 26.1 (SD 5.3) for 10 mg/kg/d, and 19.6 (SD 4.7) for 40 mg/kg/d axons per mm(2), versus 147.7 (SD 7.1) axons in unsupplemented animals. Sham-injured animals had 6.4 (SD 13.9) APP positive axons per mm(2). Dietary supplementation with DHA increases serum levels in a dose-dependent manner. DHA supplementation significantly reduces the number of APP-positive axons at 30 days post-injury, to levels similar to seen those in uninjured animals. DHA is safe, affordable, and readily available worldwide to potentially reduce the burden of TBI.

In vivo characterization of chronic traumatic encephalopathy using (F-18)FDDNP PET brain imaging

Significance Mild traumatic brain injuries are frequent events in the general population and are associated with a severe neurodegenerative disease, chronic traumatic encephalopathy (CTE). This disease is characterized by abnormal accumulation of protein aggregates, primarily tau proteins, which accumulate in brain areas responsible for mood, fear, stress, and cognition. There is no definitive clinical diagnosis of CTE at the present time, and this new work shows how a tau-sensitive brain imaging agent, [F-18]FDDNP, may be able to detect the disease in living people with varying degrees of symptoms. Early detection would facilitate the most effective management strategies and provide a baseline to measure the effectiveness of treatments. Chronic traumatic encephalopathy (CTE) is an acquired primary tauopathy with a variety of cognitive, behavioral, and motor symptoms linked to cumulative brain damage sustained from single, episodic, or repetitive traumatic brain injury (TBI). No definitive clinical diagnosis for this condition exists. In this work, we used [F-18]FDDNP PET to detect brain patterns of neuropathology distribution in retired professional American football players with suspected CTE (n = 14) and compared results with those of cognitively intact controls (n = 28) and patients with Alzheimer’s dementia (AD) (n = 24), a disease that has been cognitively associated with CTE. [F-18]FDDNP PET imaging results in the retired players suggested the presence of neuropathological patterns consistent with models of concussion wherein brainstem white matter tracts undergo early axonal damage and cumulative axonal injuries along subcortical, limbic, and cortical brain circuitries supporting mood, emotions, and behavior. This deposition pattern is distinctively different from the progressive pattern of neuropathology [paired helical filament (PHF)-tau and amyloid-β] in AD, which typically begins in the medial temporal lobe progressing along the cortical default mode network, with no or minimal involvement of subcortical structures. This particular [F-18]FDDNP PET imaging pattern in cases of suspected CTE also is primarily consistent with PHF-tau distribution observed at autopsy in subjects with a history of mild TBI and autopsy-confirmed diagnosis of CTE.