2017 Bulletin

Bulletin vol. 31 no. 2 | 25 Thirty-six contact sport male athletes who were neuropathologically diagnosed with only CTE (i.e., there was no other neuropathological evidence of disease, such as AD) were included in the study. Of the 36 subjects, 22 exhibited initial declines in behavior and mood, at a mean age of 35, primarily characterized by explosivity, impulsivity, physical and verbal violence, in addition to depression and related symptoms (e.g., hopelessness, suicidality). Although this behavioral/mood subgroup eventually progressed to develop cognitive symptoms, there was a second distinct subgroup of 11 subjects who had cognitive difficulties as the initial symptom at a mean age of 60, especially in episodic memory and executive function. This cognitive subgroup tended to develop dementia, and had more advanced CTE neuropathology. There were three subjects that were asymptomatic: one was only 17 years old and had early stage CTE neuropathology (stage I) and the other two had advanced graduate degrees and high occupational achievement. Cognitive reserve has been supported as a potential modifier of cognitive and behavioral/mood decline in CTE. 9 Stern et al.'s description of the clinical presentation of CTE was corroborated by the clinical features reported in the recent autopsy case series of 177 American football players who had CTE. 2 Clinical Research Diagnostic Criteria At this time, CTE cannot be detected or diagnosed during life. Provisional research diagnostic criteria for the clinical syndrome associated with CTE and/or exposure to RHI have been proposed by previous authors. Our group has published criteria for what we refer to as, "Traumatic Encephalopathy Syndrome" (TES). 13 The objective of the TES criteria are to facilitate clinical research investigations on CTE and not to be used for clinical diagnostic or medico-legal purposes. TES is based on a comprehensive literature review of the clinical features of neuropathologically- confirmed cases of CTE. A TES diagnosis requires a history of multiple impacts to the head (e.g., from contact sport participation, military service, domestic violence), including concussions and subconcussive injuries, and/or moderate to severe traumatic brain injury (TBI). At least one of three core clinical features must be present, and are based on signs and symptoms found in a majority of neuropathologically-confirmed cases of CTE: 1) Behavioral disturbances (e.g., aggression, impulsivity); 2) Mood dysfunction (e.g., depression and related symptoms); and 3) Cognitive decline, particularly in executive function and episodic memory, that is corroborated by standardized testing. The TES diagnosis also requires the presence of at least two supportive features (impulsivity, anxiety, apathy, paranoia, suicidality, headache, motor signs, documented decline, delayed onset), symptom duration of a minimum of 12 months, and no other neurological disorder that can fully account for the clinical features. The core features form four different TES diagnostic variants: cognitive, behavioral/ mood, mixed, and dementia. TES dementia requires a progressive clinical course and functional impairment. For all variants, motor disturbances and the clinical course (i.e., 'stable,' 'progressive,' or 'unknown/inconsistent') must be indicated. TES describes the clinical syndrome associated with exposure to RHI and is not intended to be specific to underlying CTE neuropathology. TES can be diagnosed in individuals with other neurological conditions and/or neurodegenerative diseases associated with exposure to head trauma. The behavioral, mood, and cognitive features included in the TES diagnosis are not at all specific to CTE. In addition, the specific criteria used for brain trauma exposure are not yet validated. Again, these criteria are meant to be provisional and subject to refinement and modification as new research is conducted. For now, based on the existing model, if an individual meets the TES diagnostic criteria, the next step is to indicate whether the etiology is 'Probable CTE,' 'Possible CTE,' or 'Unlikely CTE.' Similar to diagnostic criteria for Alzheimer's disease (AD) dementia, a 'Probable CTE' diagnosis requires an in vivo biomarker that supports the presence of underlying CTE neuropathology. Without a biomarker to support a 'Probable CTE' diagnosis, only a 'Possible CTE' diagnosis can be made. Proposed In Vivo Biomarkers of CTE Validated in vivo biomarkers of CTE are not yet available, but several have been proposed. Various magnetic resonance imaging (MRI) technologies have been examined in former professional American football players, and provide support for a range of non- specific structural, functional, and molecular biomarkers of CTE. Positron Emission Tomography (PET) tau imaging is anticipated to be the gold standard for the in vivo detection of underlying ptau pathology associated with CTE. The PET ptau ligand [(18) F]-AV1451 (also referred to as T807 or Flortaucipir) is the focus of current research due to its specificity to 3R and 4R paired helical filament tau (i.e., the tau species seen in both AD and CTE). Fluid biomarkers are more pragmatic than PET imaging and may also detect underlying neurodegenerative disease pathology. There is preliminary evidence for plasma exosomal tau 14 and plasma total tau 15 as candidate biomarkers for CTE. Cerebrospinal fluid (CSF) proteins of total tau, ptau, and beta-amyloid are of particular interest as potential fluid markers of CTE and analysis of CSF concentrations in former professional American football players is currently being conducted. Conclusions and Future Directions CTE may be a major public health concern given the millions of contact sport athletes and military personnel exposed to RHI each year, in addition to the many more living individuals with a history of RHI exposure. Despite what may be portrayed by the media, research on this disease is in its initial stages. Provisional clinical research diagnostic criteria for CTE (i.e., TES) have been proposed, but the reliability and validity of TES has yet to be determined. It is currently not possible to detect or diagnose CTE during life, partially because validated in vivo biomarkers for CTE do not yet exist, and the clinical presentation of CTE remains ill-defined. The ability to detect CTE during life using validated in vivo biomarkers is the essential next step in order to facilitate clinical research investigations on the risk factors and epidemiology of CTE, as well as testing of proposed theories for the pathophysiological mechanisms that underpin the association between RHI exposure and CTE, and, perhaps, most importantly, conducting clinical trials for the treatment and prevention of CTE. These knowledge gaps are being addressed through a NINDS-funded, seven- year multicenter study, referred to as, "Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy (DIAGNOSE CTE) Research Project" (PIs: Robert A. Stern [Contact PI], Jeffrey Cummings from Cleveland Clinic, Eric Reiman from Banner Alzheimer's Institute, and Martha Shenton from Brigham and Women's Hospital and Harvard). DIAGNOSE CTE is a longitudinal examination (baseline and three-year follow-up) of 45-74 year old symptomatic and asymptomatic former NFL players, symptomatic and asymptomatic former college football players, and an asymptomatic control group without a history of head trauma or contact sport participation. The DIAGNOSE CTE Research Project involves approximately 50 co-investigators from nine different institutions. Participants are evaluated at one of four centers (in Boston, Las Vegas, Scottsdale/Phoenix, and New York City) and undergo clinical exams (neurological, motor, neuropsychological, neuropsychiatric, and daily functioning), neuroimaging (PET tau and amyloid, MRI, fMRI, DTI, MRS), lumbar puncture, and blood and saliva collection. The ultimate endpoint for the DIAGNOSE CTE Research Project is to develop methods and criteria to diagnose CTE during life in order to initiate clinical trials, and facilitate epidemiological studies on CTE.

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