Validity of the 2014 traumatic encephalopathy syndrome criteria for CTE pathology.

INTRODUCTION: Validity of the 2014 traumatic encephalopathy syndrome (TES) criteria, proposed to diagnose chronic traumatic encephalopathy (CTE) in life, has not been assessed. METHODS: A total of 336 consecutive brain donors exposed to repetitive head impacts from contact sports, military service, and/or physical violence were included. Blinded to clinical information, neuropathologists applied National Institute on Neurological Disorders and Stroke/National Institute of Biomedical Imaging and Bioengineering CTE criteria. Blinded to neuropathological information, clinicians interviewed informants and reviewed medical records. An expert panel adjudicated TES diagnoses. RESULTS: A total of 309 donors were diagnosed with TES; 244 donors had CTE pathology. TES criteria demonstrated sensitivity and specificity of 0.97 and 0.21, respectively. Cognitive (odds ratio [OR] = 3.6; 95% confidence interval [CI]: 1.2-5.1), but not mood/behavior or motor symptoms, were significantly associated with CTE pathology. Having Alzheimer's disease (AD) pathology was significantly associated with reduced TES accuracy (OR = 0.27; 95% CI: 0.12-0.59). DISCUSSION: TES criteria provided good evidence to rule out, but limited evidence to rule in, CTE pathology. Requiring cognitive symptoms in revised criteria and using AD biomarkers may improve CTE pathology prediction.

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.

Cognitive Reserve as a Modifier of Clinical Expression in Chronic Traumatic Encephalopathy: A Preliminary Examination.

This study conducted a preliminary examination on cognitive reserve (CR) as a modifier of symptom expression in subjects with autopsy-confirmed chronic traumatic encephalopathy (CTE). The sample included 25 former professional football players neuropathologically diagnosed with CTE stage III or IV. Next of kin interviews ascertained age at cognitive and behavioral/mood symptom onset and demographic/athletic characteristics. Years of education and occupational attainment defined CR. High occupational achievement predicted later age at cognitive (p=0.02) and behavioral/mood (p=0.02) onset. Education was not an individual predictor. These preliminary findings suggest that CR may forestall the clinical manifestation of CTE.

Clinicopathological Evaluation of Chronic Traumatic Encephalopathy in Players of American Football.

Importance: Players of American football may be at increased risk of long-term neurological conditions, particularly chronic traumatic encephalopathy (CTE). Objective: To determine the neuropathological and clinical features of deceased football players with CTE. Design, Setting, and Participants: Case series of 202 football players whose brains were donated for research. Neuropathological evaluations and retrospective telephone clinical assessments (including head trauma history) with informants were performed blinded. Online questionnaires ascertained athletic and military history. Exposures: Participation in American football at any level of play. Main Outcomes and Measures: Neuropathological diagnoses of neurodegenerative diseases, including CTE, based on defined diagnostic criteria; CTE neuropathological severity (stages I to IV or dichotomized into mild [stages I and II] and severe [stages III and IV]); informant-reported athletic history and, for players who died in 2014 or later, clinical presentation, including behavior, mood, and cognitive symptoms and dementia. Results: Among 202 deceased former football players (median age at death, 66 years [interquartile range, 47-76 years]), CTE was neuropathologically diagnosed in 177 players (87%; median age at death, 67 years [interquartile range, 52-77 years]; mean years of football participation, 15.1 [SD, 5.2]), including 0 of 2 pre-high school, 3 of 14 high school (21%), 48 of 53 college (91%), 9 of 14 semiprofessional (64%), 7 of 8 Canadian Football League (88%), and 110 of 111 National Football League (99%) players. Neuropathological severity of CTE was distributed across the highest level of play, with all 3 former high school players having mild pathology and the majority of former college (27 [56%]), semiprofessional (5 [56%]), and professional (101 [86%]) players having severe pathology. Among 27 participants with mild CTE pathology, 26 (96%) had behavioral or mood symptoms or both, 23 (85%) had cognitive symptoms, and 9 (33%) had signs of dementia. Among 84 participants with severe CTE pathology, 75 (89%) had behavioral or mood symptoms or both, 80 (95%) had cognitive symptoms, and 71 (85%) had signs of dementia. Conclusions and Relevance: In a convenience sample of deceased football players who donated their brains for research, a high proportion had neuropathological evidence of CTE, suggesting that CTE may be related to prior participation in football.

A randomized, double-blind, placebo controlled, parallel group, efficacy study of alpha BRAIN® administered orally.

OBJECTIVE: Alpha BRAIN® is a nootropic supplement that purports to enhance cognitive functioning in healthy adults. The goal of this study was to investigate the efficacy of this self-described cognitive enhancing nootropic on cognitive functioning in a group of healthy adults by utilizing a randomized, double blind, placebo-controlled design. METHODS: A total of 63-treatment naïve individuals between 18 and 35 years of age completed the randomized, double-blind, placebo controlled trial. All participants completed a 2-week placebo run in before receiving active product, Alpha BRAIN® or new placebo, for 6 weeks. Participants undertook a battery of neuropsychological tests at randomization and at study completion. Primary outcome measures included a battery of neuropsychological tests and measures of sleep. RESULTS: Compared with placebo, Alpha BRAIN® significantly improved on tasks of delayed verbal recall and executive functioning. Results also indicated significant time-by-group interaction in delayed verbal recall for the Alpha BRAIN® group. CONCLUSIONS: The use of Alpha BRAIN® for 6 weeks significantly improved recent verbal memory when compared with controls, in a group of healthy adults. While the outcome of the study is encouraging, this is the first randomized controlled trial of Alpha BRAIN®, and the results merit further study.

Chronic traumatic encephalopathy: a neurodegenerative consequence of repetitive traumatic brain injury.

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease that develops as a result of repetitive mild traumatic brain injury. Chronic traumatic encephalopathy is characterized by a unique pattern of accumulation of hyperphosphorylated tau in neurons and astrocytes. The tau abnormalities begin focally and perivascularly at the depths of the cerebral sulci, spread to the superficial layers of the adjacent cortex, and eventually become widespread throughout the medial temporal lobes, diencephalon, and brainstem. Abnormalities in 43 kDa TAR DNA-binding protein are also found in most cases of CTE. To date, CTE can only be diagnosed by postmortem neuropathological examination, although there are many ongoing research studies examining imaging techniques and biomarkers that might prove to have diagnostic utility. Currently, the incidence and prevalence of CTE are unknown, although great strides are being made to better understand the clinical symptoms and signs of CTE. Further research is critically needed to better identify the genetic and environmental risk factors for CTE as well as potential rehabilitation and therapeutic strategies.

Measurement model exploring a syndemic in emerging adult gay and bisexual men.

The current study was designed to develop a better understanding of the nature of the relationships between mental health burden, drug use, and unprotected sexual behavior within a sample of emerging adult gay and bisexual men, ages 18-19 (N = 598) and to test a theory of syndemics using structural equation modeling. Participants were actively recruited from community-based settings and the Internet for participation in a seven-wave cohort study. Data for participant characteristics and mental health were collected via computer-assisted survey, while drug use and unprotected sex behaviors for the month prior to assessment were collected via a calendar-based technique. Using the baseline data, we developed and tested structural equation models for mental health burden, drug use, and unprotected sex and also tested a second-order model for a single syndemic. First-order measurement models for each of the three epidemics were successfully identified using observed data. Tests of a second-order model seeking to explain the three epidemics as a single syndemic fit poorly. However, a second-order construct comprised of mental health burden and drug use fit the data well and was highly associated with the first-order construct of unprotected sex. The findings advance a theory of syndemics and suggest that in order to be maximally effective both HIV prevention and HIV care must be delivered holistically such that sexual risk behaviors are addressed in relation to, and in sync with, the drug use and mental health of the individual.

Targeting HIV prevention messaging to a new generation of gay, bisexual, and other young men who have sex with men.

HIV prevention messaging has been shown to reduce or delay high-risk sexual behaviors in young men who have sex with men (YMSM). Since the onset of the HIV/AIDS epidemic, a new generation of YMSM has come of age during an evolution in communication modalities. Because both these communication technologies and this new generation remain understudied, the authors investigated the manner in which YMSM interact with HIV prevention messaging. In particular, the authors examined 6 venues in which YMSM are exposed to, pay attention to, and access HIV prevention information: the Internet, bars/dance clubs, print media, clinics/doctors' offices, community centers/agencies, and educational classes. Data were drawn from a community-based sample of 481 racially and ethnically diverse YMSM from New York City. Significant differences in exposure to HIV prevention messaging venues emerged with respect to age, race/ethnicity, and sexual orientation. Attention paid to HIV prevention messages in various venues differed by age and sexual orientation. Across all venues, multivariate modeling indicated YMSM were more likely to access HIV messaging from the same venues at which they paid attention, with some variability explained by person characteristics (age and perceived family socioeconomic status). This suggests that the one-size-fits-all approach does not hold true, and both the venue and person characteristics must be considered when generating and disseminating HIV prevention messaging.

Evaluating passive physiological data collection during Spravato treatment.

Spravato and other drugs with consciousness-altering effects show significant promise for treating various mental health disorders. However, the effects of these treatments necessitate a substantial degree of patient monitoring which can be burdensome to healthcare providers and may make these treatments less accessible for prospective patients. Continuous passive monitoring via digital devices may be useful in reducing this burden. This proof-of-concept study tested the MindMed Session Monitoring System™ (MSMS™), a continuous passive monitoring system intended for use during treatment sessions involving pharmaceutical products with consciousness-altering effects. Participants completed 129 Spravato sessions with MSMS at an outpatient psychiatry clinic specializing in Spravato treatment. Results indicated high rates of data quality and self-reported usability among participants and health care providers (HCPs). These findings demonstrate the potential for systems such as MSMS to be used in consciousness-altering treatment sessions to assist with patient monitoring.

Alcohol use among young men who have sex with men.

This study reveals associations between alcohol use and demographic variables, as well as the relation between alcohol use and sexual activity, using episodic data. Data were obtained during summer and fall 2008 from a sample of 558 gay, bisexual, and other young men who have sex with men (YMSM), ages of 13-29 years in New York City. Recruitment strategies targeted potential participants at gay-related venues and public spaces often frequented by YMSM. Alcohol use varied by race/ethnicity, with White YMSM consuming significantly more alcohol than other races/ethnicities. Participants over the age of 21 drank significantly more alcohol than participants ages 13-20. Alcohol use was not found to be associated with sexual risk-taking activity. Our findings are enriched by a large, diverse sample of urban YMSM. Study limitations are noted.

Sex parties among young gay, bisexual, and other men who have sex with men in New York City: attendance and behavior.

Very little information exists with regard to sex party behaviors in young men who have sex with men (YMSM), often defined as men ranging in age from 13 to 29 years. The current analysis examines sex party attendance and behavior in a sample of 540 emergent adult gay, bisexual, and other YMSM in New York City, ages 18-29 years. Findings indicate that 8.7% (n = 47) of the sample had attended a sex party 3 months prior to assessment. Sex party attendees reported that parties included both HIV-positive and HIV-negative men; attendees also reported unprotected sex and limited access to condoms and lubricant. As compared with those who did not attend sex parties, those who did indicated significantly more lifetime and recent (last 3 months) casual sex partners, drug use (both number of different drugs used and total lifetime use), psychosocial burden (history of partner violence and number of arrests), and total syndemic burden (a composite of unprotected anal sex, drug use and psychosocial burden). These results indicate that while only a small percentage of the overall sample attended sex parties, the intersection of both individual risk factors coupled with risk factors engendered within the sex party environment itself has the potential to be a catalyst in the proliferation of the HIV/AIDS epidemic in urban settings. Lastly, given that sex parties are different than other sex environments, commercial and public, with regard to how they are accessed, public health strategies may need to become more tailored in order to reach this potentially highly risky group.

Methamphetamine use among gay, bisexual and non-identified men-who-have-sex-with-men: an analysis of daily patterns.

This study sought to understand the patterns, methods of administration and contexts for methamphetamine use (MA) in a sample of racially diverse men who have sex with men (MSM). Inclusion into the study required participants to be classified as clinically dependent on MA, but indicate no other illicit substance use. Use was assessed using Timeline Followback for a period of 30 days. Of the 900 assessed days, MA use was reported on 217. Participants reported an average of seven days of use, with the majority of use occurring on the weekend. The weekend usage pattern suggests an incorporation of drugs into the lives of gay men as a means of socialization and recreation.

Methamphetamine abuse and impairment of social functioning: a review of the underlying neurophysiological causes and behavioral implications.

The highly addictive drug methamphetamine has been associated with impairments in social cognitions as evidenced by changes in users' behaviors. Physiological changes in brain structure and functioning, particularly in the frontal lobe, have also been identified. The authors propose a biopsychosocial approach to understanding the effects of methamphetamine addiction by relating the physiological effects of the drug to the behaviors and social cognitions of its users, through the application of the theory of mind paradigm. Although onset of methamphetamine use has been linked to the desire for socialization, chronic use has been associated with an increase in depression, aggressiveness, and social isolation, behaviors that also implicate involvement of the frontal lobe. The reviewed literature provides strong circumstantial evidence that social-cognitive functioning is significantly impacted by methamphetamine use and that the social isolation, depression, and aggressiveness associated with chronic use is due to more than just the social withdrawal associated with addiction. Treatment considerations for methamphetamine must therefore consider the role of social cognition, and pharmacological responses must address the documented impact of the drug on frontal lobe functioning.

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.

CCL11 is increased in the CNS in chronic traumatic encephalopathy but not in Alzheimer's disease.

CCL11, a protein previously associated with age-associated cognitive decline, is observed to be increased in the brain and cerebrospinal fluid (CSF) in chronic traumatic encephalopathy (CTE) compared to Alzheimer's disease (AD). Using a cohort of 23 deceased American football players with neuropathologically verified CTE, 50 subjects with neuropathologically diagnosed AD, and 18 non-athlete controls, CCL11 was measured with ELISA in the dorsolateral frontal cortex (DLFC) and CSF. CCL11 levels were significantly increased in the DLFC in subjects with CTE (fold change = 1.234, p < 0.050) compared to non-athlete controls and AD subjects with out a history of head trauma. This increase was also seen to correlate with years of exposure to American football (ß = 0.426, p = 0.048) independent of age (ß = -0.046, p = 0.824). Preliminary analyses of a subset of subjects with available post-mortem CSF showed a trend for increased CCL11 among individuals with CTE (p = 0.069) mirroring the increase in the DLFC. Furthermore, an association between CSF CCL11 levels and the number of years exposed to football (ß = 0.685, p = 0.040) was observed independent of age (ß = -0.103, p = 0.716). Finally, a receiver operating characteristic (ROC) curve analysis demonstrated CSF CCL11 accurately distinguished CTE subjects from non-athlete controls and AD subjects (AUC = 0.839, 95% CI 0.62-1.058, p = 0.028). Overall, the current findings provide preliminary evidence that CCL11 may be a novel target for future CTE biomarker studies.

Overdependence on degraded gist memory in Alzheimer's disease.

Alzheimer's disease (AD) reduces associative effects on false recognition in the Deese-Roediger-McDermott task, either due to impaired memory for gist or impaired use of gist in memory decisions. Gist processes were manipulated by blocking or mixing studied words according to their associations and by varying the associative strength between studied and nonstudied words at test. Both associative blocking and associative strength had smaller effects on false recognition in AD patients than in control participants, consistent with gist memory impairments. However, unlike the case with control participants, blocking influenced true and false recognition equally in AD patients, demonstrating an overdependence on gist when making memory decisions. AD also impaired item-specific recollections, relative to control participants, as true recognition of studied words was reduced even when the two groups were equated on gist-based false recognition. We propose that the overdependence on degraded gist memory in AD is caused by even larger impairments in item-specific recollections.

Temporal relations between methamphetamine use and HIV seroconversion in gay, bisexual, and other men who have sex with men.

Data from a cross-sectional study of gay, bisexual, and other men who have sex with men who were active methamphetamine users were analyzed to assess temporal relations between HIV seroconversion and initiation of methamphetamine use. Of the 100 men, 58 reported being HIV-positive. Most HIV-positive participants (65%) initiated methamphetamine use after seroconverting. Among those who initiated use before seroconversion, 8 years elapsed between onset of use and time of infection. Findings suggest the need to develop nuanced and targeted interventions aimed at disentangling the "meth-sex" link in this population. Findings also suggest use of the drug as a coping mechanism for those living with HIV.

Microglial neuroinflammation contributes to tau accumulation in chronic traumatic encephalopathy.

The chronic effects of repetitive head impacts (RHI) on the development of neuroinflammation and its relationship to chronic traumatic encephalopathy (CTE) are unknown. Here we set out to determine the relationship between RHI exposure, neuroinflammation, and the development of hyperphosphorylated tau (ptau) pathology and dementia risk in CTE. We studied a cohort of 66 deceased American football athletes from the Boston University-Veteran's Affairs-Concussion Legacy Foundation Brain Bank as well as 16 non-athlete controls. Subjects with a neurodegenerative disease other than CTE were excluded. Counts of total and activated microglia, astrocytes, and ptau pathology were performed in the dorsolateral frontal cortex (DLF). Binary logistic and simultaneous equation regression models were used to test associations between RHI exposure, microglia, ptau pathology, and dementia. Duration of RHI exposure and the development and severity of CTE were associated with reactive microglial morphology and increased numbers of CD68 immunoreactive microglia in the DLF. A simultaneous equation regression model demonstrated that RHI exposure had a significant direct effect on CD68 cell density (p < 0.0001) and ptau pathology (p < 0.0001) independent of age at death. The effect of RHI on ptau pathology was partially mediated through increased CD68 positive cell density. A binary logistic regression demonstrated that a diagnosis of dementia was significantly predicted by CD68 cell density (OR = 1.010, p = 0.011) independent of age (OR = 1.055, p = 0.007), but this effect disappeared when ptau pathology was included in the model. In conclusion, RHI is associated with chronic activation of microglia, which may partially mediate the effect of RHI on the development of ptau pathology and dementia in CTE. Inflammatory molecules may be important diagnostic or predictive biomarkers as well as promising therapeutic targets in CTE.

Age- and education-matched comparison of aging HIV+ men who have sex with men to general population on common neuropsychological assessments.

Little is known about the impact of HIV and aging on cognitive functioning. This New York City cross-sectional study of aging HIV-positive gay and bisexual men assessed their neuropsychological state. Working memory and verbal abstract reasoning were relatively intact. After 55 years of age, attention abilities were impaired. Executive function impairment was present regardless of age and education. Results suggest the need for HIV-specific norms, and the use of neuropsychological assessments (i.e. baseline and over time) as a cost-effective way to assess HIV-related cognitive decline in developed and under-developed countries.

Assessing clinicopathological correlation in chronic traumatic encephalopathy: rationale and methods for the UNITE study.

INTRODUCTION: Chronic traumatic encephalopathy (CTE) is a progressive neurodegeneration associated with repetitive head impacts. Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) is a U01 project recently funded by the National Institute of Neurological Disorders and Stroke and the National Institute of Biomedical Imaging and Bioengineering. The goal of the UNITE project is to examine the neuropathology and clinical presentation of brain donors designated as "at risk" for the development of CTE based on prior athletic or military exposure. Here, we present the rationale and methodology for UNITE. METHODS: Over the course of 4 years, we will analyze the brains and spinal cords of 300 deceased subjects who had a history of repetitive head impacts sustained during participation in contact sports at the professional or collegiate level or during military service. Clinical data are collected through medical record review and retrospective structured and unstructured family interviews conducted by a behavioral neurologist or neuropsychologist. Blinded to the clinical data, a neuropathologist conducts a comprehensive assessment for neurodegenerative disease, including CTE, using published criteria. At a clinicopathological conference, a panel of physicians and neuropsychologists, blinded to the neuropathological data, reaches a clinical consensus diagnosis using published criteria, including proposed clinical research criteria for CTE. RESULTS: We will investigate the validity of these clinical criteria and sources of error by using recently validated neuropathological criteria as a gold standard for CTE diagnosis. We also will use statistical modeling to identify diagnostic features that best predict CTE pathology. CONCLUSIONS: The UNITE study is a novel and methodologically rigorous means of assessing clinicopathological correlation in CTE. Our findings will be critical for developing future iterations of CTE clinical diagnostic criteria.