Yorghos Tripodis

The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy

Chronic traumatic encephalopathy (CTE) is a neurodegeneration characterized by the abnormal accumulation of hyperphosphorylated tau protein within the brain. Like many other neurodegenerative conditions, at present, CTE can only be definitively diagnosed by post-mortem examination of brain tissue. As the first part of a series of consensus panels funded by the NINDS/NIBIB to define the neuropathological criteria for CTE, preliminary neuropathological criteria were used by 7 neuropathologists to blindly evaluate 25 cases of various tauopathies, including CTE, Alzheimer’s disease, progressive supranuclear palsy, argyrophilic grain disease, corticobasal degeneration, primary age-related tauopathy, and parkinsonism dementia complex of Guam. The results demonstrated that there was good agreement among the neuropathologists who reviewed the cases (Cohen’s kappa, 0.67) and even better agreement between reviewers and the diagnosis of CTE (Cohen’s kappa, 0.78). Based on these results, the panel defined the pathognomonic lesion of CTE as an accumulation of abnormal hyperphosphorylated tau (p-tau) in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci and in an irregular pattern. The group also defined supportive but non-specific p-tau-immunoreactive features of CTE as: pretangles and NFTs affecting superficial layers (layers II–III) of cerebral cortex; pretangles, NFTs or extracellular tangles in CA2 and pretangles and proximal dendritic swellings in CA4 of the hippocampus; neuronal and astrocytic aggregates in subcortical nuclei; thorn-shaped astrocytes at the glial limitans of the subpial and periventricular regions; and large grain-like and dot-like structures. Supportive non-p-tau pathologies include TDP-43 immunoreactive neuronal cytoplasmic inclusions and dot-like structures in the hippocampus, anteromedial temporal cortex and amygdala. The panel also recommended a minimum blocking and staining scheme for pathological evaluation and made recommendations for future study. This study provides the first step towards the development of validated neuropathological criteria for CTE and will pave the way towards future clinical and mechanistic studies.

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.

Addressing Social Determinants of Health at Well Child Care Visits: A Cluster RCT

OBJECTIVE: To evaluate the effect of a clinic-based screening and referral system (Well Child Care, Evaluation, Community Resources, Advocacy, Referral, Education [WE CARE]) on families’ receipt of community-based resources for unmet basic needs. METHODS: We conducted a cluster randomized controlled trial at 8 urban community health centers, recruiting mothers of healthy infants. In the 4 WE CARE clinics, mothers completed a self-report screening instrument that assessed needs for child care, education, employment, food security, household heat, and housing. Providers made referrals for families; staff provided requisite applications and telephoned referred mothers within 1 month. Families at the 4 control community health centers received the usual care. We analyzed the results with generalized mixed-effect models. RESULTS: Three hundred thirty-six mothers were enrolled in the study (168 per arm). The majority of families had household incomes <

Age of first exposure to football and later-life cognitive impairment in former NFL players

20 000 (57%), and 68% had ≥2 unmet basic needs. More WE CARE mothers received ≥1 referral at the index visit (70% vs 8%; adjusted odds ratio [aOR] = 29.6; 95% confidence interval [CI], 14.7–59.6). At the 12-month visit, more WE CARE mothers had enrolled in a new community resource (39% vs 24%; aOR = 2.1; 95% CI, 1.2–3.7). WE CARE mothers had greater odds of being employed (aOR = 44.4; 95% CI, 9.8–201.4). WE CARE children had greater odds of being in child care (aOR = 6.3; 95% CI, 1.5–26.0). WE CARE families had greater odds of receiving fuel assistance (aOR = 11.9; 95% CI, 1.7–82.9) and lower odds of being in a homeless shelter (aOR = 0.2; 95% CI, 0.1–0.9). CONCLUSIONS: Systematically screening and referring for social determinants during well child care can lead to the receipt of more community resources for families.

Genome-wide association study of the rate of cognitive decline in Alzheimer's disease

Objective: To determine the relationship between exposure to repeated head impacts through tackle football prior to age 12, during a key period of brain development, and later-life executive function, memory, and estimated verbal IQ. Methods: Forty-two former National Football League (NFL) players ages 40–69 from the Diagnosing and Evaluating Traumatic Encephalopathy using Clinical Tests (DETECT) study were matched by age and divided into 2 groups based on their age of first exposure (AFE) to tackle football: AFE <12 and AFE ≥12. Participants completed the Wisconsin Card Sort Test (WCST), Neuropsychological Assessment Battery List Learning test (NAB-LL), and Wide Range Achievement Test, 4th edition (WRAT-4) Reading subtest as part of a larger neuropsychological testing battery. Results: Former NFL players in the AFE <12 group performed significantly worse than the AFE ≥12 group on all measures of the WCST, NAB-LL, and WRAT-4 Reading tests after controlling for total number of years of football played and age at the time of evaluation, indicating executive dysfunction, memory impairment, and lower estimated verbal IQ. Conclusions: There is an association between participation in tackle football prior to age 12 and greater later-life cognitive impairment measured using objective neuropsychological tests. These findings suggest that incurring repeated head impacts during a critical neurodevelopmental period may increase the risk of later-life cognitive impairment. If replicated with larger samples and longitudinal designs, these findings may have implications for safety recommendations for youth sports.

The source of cognitive complaints predicts diagnostic conversion differentially among nondemented older adults.

Substantial interindividual variability exists in the disease trajectories of Alzheimers disease (AD) patients. Some decline rapidly whereas others decline slowly, and there are no known explanations for this variability. We describe the first genome‐wide association study to examine rate of cognitive decline in a sample of AD patients with longitudinal measures of cognition.

Profile of self-reported problems with executive functioning in college and professional football players.

The objective of this study was to compare whether different sources of cognitive complaint (i.e., subjective and informant) predict diagnostic conversion in nondemented older adults.

Preliminary Study of Plasma Exosomal Tau as a Potential Biomarker for Chronic Traumatic Encephalopathy

Repetitive mild traumatic brain injury (mTBI), such as that experienced by contact-sport athletes, has been associated with the development of chronic traumatic encephalopathy (CTE). Executive dysfunction is believed to be among the earliest symptoms of CTE, with these symptoms presenting in the fourth or fifth decade of life. The present study used a well-validated self-report measure to study executive functioning in football players, compared to healthy adults. Sixty-four college and professional football players were administered the Behavior Rating Inventory of Executive Function, adult version (BRIEF-A) to evaluate nine areas of executive functioning. Scores on the BRIEF-A were compared to published age-corrected normative scores for healthy adults Relative to healthy adults, the football players indicated significantly more problems overall and on seven of the nine clinical scales, including Inhibit, Shift, Emotional Control, Initiate, Working Memory, Plan/Organize, and Task Monitor. These symptoms were greater in athletes 40 and older, relative to younger players. In sum, football players reported more-frequent problems with executive functioning and these symptoms may develop or worsen in the fifth decade of life. The findings are in accord with a growing body of evidence that participation in football is associated with the development of cognitive changes and dementia as observed in CTE.

Validity of International Classification of Disease Codes to Identify Ischemic Stroke and Intracranial Hemorrhage Among Individuals With Associated Diagnosis of Atrial Fibrillation

Background: Chronic traumatic encephalopathy (CTE) is a tauopathy associated with prior exposure to repetitive head impacts, such as those incurred through American football and other collision sports. Diagnosis is made through neuropathological examination. Many of the clinical features of CTE are common in the general population, with and without a history of head impact exposure, making clinical diagnosis difficult. As is now common in the diagnosis of other neurodegenerative disorders, such as Alzheimer’s disease, there is a need for methods to diagnose CTE during life through objective biomarkers. Objective: The aim of this study was to examine tau-positive exosomes in plasma as a potential CTE biomarker. Methods: Subjects were 78 former National Football League (NFL) players and 16 controls. Extracellular vesicles were isolated from plasma. Fluorescent nanoparticle tracking analysis was used to determine the number of vesicles staining positive for tau. Results: The NFL group had higher exosomal tau than the control group (p <  0.0001). Exosomal tau discriminated between the groups, with 82% sensitivity, 100% specificity, 100% positive predictive value, and 53% negative predictive value. Within the NFL group, higher exosomal tau was associated with worse performance on tests of memory (p = 0.0126) and psychomotor speed (p = 0.0093). Conclusion: These preliminary findings suggest that exosomal tau in plasma may be an accurate, noninvasive CTE biomarker.

Microglial neuroinflammation contributes to tau accumulation in chronic traumatic encephalopathy

Background— Because of its association with death and disability, stroke is a focus of outcomes in atrial fibrillation (AF) research. International Classification of Disease-Ninth Revision (ICD-9) edition codes are commonly used to identify stroke in research, particularly in large administrative data. We sought to assess the validity of ICD-9 codes in stroke case ascertainment and for AF across 3 institutions. Methods and Results— Participating centers included Boston Medical Center (safety net hospital), Geisinger Health System (rural Pennsylvania), and the University of Alabama (academic center in the southeastern stroke belt). ICD-9 codes for ischemic stroke (433–434, 436) and intracranial hemorrhage (430–432) identified 1812 stroke cases with an associated code for AF (427.31) from 2006 to 2010. Cases were vetted through chart review with final adjudication by a stroke neurologist. Review considered 94.2% of ICD-9 identified stroke cases valid with decreased accuracy for concurrent AF diagnosis (82.28%) and stroke attributable to AF (72.8%). Among events with “without infarction” modifiers, 7.2% were valid strokes. ICD-9 stroke code accuracy did not differ by stroke type or site. Stroke code 434 displayed higher accuracy than 433 (94.4% versus 85.2%; P<0.01), and primary stroke codes were more accurate than nonprimary codes (97.2% versus 83.7%; P<0.0001). Conclusions— Using ICD-9 stroke and AF codes to identify patients with stroke plus AF resulted in inaccuracies. Given the expanded financial and policy implications of patient-oriented research, conclusions derived solely from administrative data without validation of outcome events should be interpreted with caution.