Sex-specific associations of a ferroalloy metal mixture with motor function in Italian adolescents.

BACKGROUND: Motor function is critical for childrens health, yet remains an understudied neurodevelopmental domain. Exposure to metals has been linked with motor function, but no study has examined the joint effects of metal mixtures. METHODS: We evaluated cross-sectional associations between a metal mixture and motor function among 569 adolescents (10-14 years old) living near the ferroalloy industry. Concentrations of blood lead, hair manganese, hair copper, and hair chromium were quantified using inductively coupled plasma mass spectrometry. Neuropsychologists administered multiple fine motor function assessments: pursuit aiming, finger tapping, visual reaction time (VRT), and subtests from the Luria Nebraska battery. We estimated associations between motor function and the metal mixture using quantile-based g-computation and multivariable linear regression, adjusting for child age, sex, and socioeconomic status. We explored sex-specific associations in stratified models. RESULTS: Associations between the metal mixture and motor function were mostly null but were modified by sex. We observed a beneficial association among females: a quartile increase in all metals in the mixture was associated with a 2.6% faster average response time on the VRT (95% confidence interval [CI] = -4.7%, -0.5%), driven by Cu and Cr. In contrast, this association was adverse among males (ß = 1.5% slower response time [95% CI = -0.7%, 3.9%]), driven by Cu and Mn. CONCLUSIONS: Results suggest that males may be more susceptible to the adverse effects of metal exposure on motor function during adolescence than females. Future studies, particularly prospective study designs, are warranted to further understand the associations of metal mixtures with motor function

Estimating State-Specific Contributions to PM2.5- and O3-Related Health Burden from Residential Combustion and Electricity Generating Unit Emissions in the United States

BACKGROUND: Residential combustion (RC) and electricity generating unit (EGU) emissions adversely impact air quality and human health by increasing ambient concentrations of fine particulate matter (PM2.5) and ozone (O3). Studies to date have not isolated contributing emissions by state of origin (source-state), which is necessary for policy makers to determine efficient strategies to decrease health impacts. OBJECTIVES: In this study, we aimed to estimate health impacts (premature mortalities) attributable to PM2.5 and O3 from RC and EGU emissions by precursor species, source sector, and source-state in the continental United States for 2005. METHODS: We used the Community Multiscale Air Quality model employing the decoupled direct method to quantify changes in air quality and epidemiological evidence to determine concentration-response functions to calculate associated health impacts. RESULTS: We estimated 21,000 premature mortalities per year from EGU emissions, driven by sulfur dioxide emissions forming PM2.5. More than half of EGU health impacts are attributable to emissions from eight states with significant coal combustion and large downwind populations. We estimate 10,000 premature mortalities per year from RC emissions, driven by primary PM2.5 emissions. States with large populations and significant residential wood combustion dominate RC health impacts. Annual mortality risk per thousand tons of precursor emissions (health damage functions) varied significantly across source-states for both source sectors and all precursor pollutants. CONCLUSIONS: Our findings reinforce the importance of pollutant-specific, location-specific, and source-specific models of health impacts in design of health-risk minimizing emissions control policies. Citation: Penn SL, Arunachalam S, Woody M, Heiger-Bernays W, Tripodis Y, Levy JI. 2017. Estimating state-specific contributions to PM2.5- and O3-related health burden from residential combustion and electricity generating unit emissions in the United States. Environ Health Perspect 125:324-332; http://dx.doi.org/10.1289/EHP550

REPIMPACT - a prospective longitudinal multisite study on the effects of repetitive head impacts in youth soccer

Repetitive head impacts (RHI) are common in youth athletes participating in contact sports. RHI differ from concussions; they are considered hits to the head that usually do not result in acute symptoms and are therefore also referred to as \textquotedblsubconcussive\textquotedbl head impacts. RHI occur e.g., when heading the ball or during contact with another player. Evidence suggests that exposure to RHI may have cumulative effects on brain structure and function. However, little is known about brain alterations associated with RHI, or about the risk factors that may lead to clinical or behavioral sequelae. REPIMPACT is a prospective longitudinal study of competitive youth soccer players and non-contact sport controls aged 14 to 16~years. The study aims to characterize consequences of exposure to RHI with regard to behavior (i.e., cognition, and motor function), clinical sequelae (i.e., psychiatric and neurological symptoms), brain structure, function, diffusion and biochemistry, as well as blood- and saliva-derived measures of molecular processes associated with exposure to RHI (e.g., circulating microRNAs, neuroproteins and cytokines). Here we present the structure of the REPIMPACT Consortium which consists of six teams of clinicians and scientists in six countries. We further provide detailed information on the specific aims and the design of the REPIMPACT study. The manuscript also describes the progress made in the study thus far. Finally, we discuss important challenges and approaches taken to overcome these challenges

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.This study received support from NINDS (grants U01 NS086659, R01 NS078337, R56 NS078337, U01 NS093334, and F32 NS096803), the National Institute on Aging (grants K23 AG046377, P30AG13846 and supplement 0572063345-5, R01 AG1649), the US Department of Defense (grant W81XWH-13-2-0064), the US Department of Veterans Affairs (I01 CX001038), the Veterans Affairs Biorepository (CSP 501), the Veterans Affairs Rehabilitation Research and Development Traumatic Brain Injury Center of Excellence (grant B6796-C), the Department of Defense Peer Reviewed Alzheimer’s Research Program (grant 13267017), the National Operating Committee on Standards for Athletic Equipment, the Alzheimer’s Association (grants NIRG-15-362697 and NIRG-305779), the Concussion Legacy Foundation, the Andlinger Family Foundation, the WWE, and the NFL

Association of war zone–related stress with alterations in limbic gray matter microstructure

IMPORTANCE: Military service members returning from theaters of war are at increased risk for mental illness, but despite high prevalence and substantial individual and societal burden, the underlying pathomechanisms remain largely unknown. Exposure to high levels of emotional stress in theaters of war and mild traumatic brain injury (mTBI) are presumed factors associated with risk for the development of mental disorders. OBJECTIVE: To investigate (1) whether war zone–related stress is associated with microstructural alterations in limbic gray matter (GM) independent of mental disorders common in this population, (2) whether associations between war zone–related stress and limbic GM microstructure are modulated by a history of mTBI, and (3) whether alterations in limbic GM microstructure are associated with neuropsychological functioning. DESIGN, SETTING, AND PARTICIPANTS: This cohort study was part of the TRACTS (Translational Research Center for TBI and Stress Disorders) study, which took place in 2010 to 2014 at the Veterans Affair Rehabilitation Research and Development TBI National Network Research Center. Participants included male veterans (aged 18-65 years) with available diffusion tensor imaging data enrolled in the TRACTS study. Data analysis was performed between December 2017 to September 2021. EXPOSURES: The Deployment Risk and Resilience Inventory (DRRI) was used to measure exposure to war zone–related stress. The Boston Assessment of TBI-Lifetime was used to assess history of mTBI. Stroop Inhibition (Stroop-IN) and Inhibition/Switching (Stroop-IS) Total Error Scaled Scores were used to assess executive or attentional control functions. MAIN OUTCOMES AND MEASURES: Diffusion characteristics (fractional anisotropy of tissue [FA(T)]) of 16 limbic and paralimbic GM regions and measures of functional outcome. RESULTS: Among 384 male veterans recruited, 168 (mean [SD] age, 31.4 [7.4] years) were analyzed. Greater war zone–related stress was associated with lower FA(T) in the cingulate (DRRI-combat left: P = .002, partial r = −0.289; DRRI-combat right: P = .02, partial r = −0.216; DRRI-aftermath left: P = .004, partial r = −0.281; DRRI-aftermath right: P = .02, partial r = −0.219), orbitofrontal (DRRI-combat left medial orbitofrontal cortex: P = .02, partial r = −0.222; DRRI-combat right medial orbitofrontal cortex: P = .005, partial r = −0.256; DRRI-aftermath left medial orbitofrontal cortex: P = .02, partial r = −0.214; DRRI-aftermath right medial orbitofrontal cortex: P = .005, partial r = −0.260; DRRI-aftermath right lateral orbitofrontal cortex: P = .03, partial r = −0.196), and parahippocampal (DRRI-aftermath right: P = .03, partial r = −0.191) gyrus, as well as with higher FA(T) in the amygdala-hippocampus complex (DRRI-combat: P = .005, partial r = 0.254; DRRI-aftermath: P = .02, partial r = 0.223). Lower FA(T) in the cingulate-orbitofrontal gyri was associated with impaired response inhibition (Stroop-IS left cingulate: P < .001, partial r = −0.440; Stroop-IS right cingulate: P < .001, partial r = −0.372; Stroop-IS left medial orbitofrontal cortex: P < .001, partial r = −0.304; Stroop-IS right medial orbitofrontal cortex: P < .001, partial r = −0.340; Stroop-IN left cingulate: P < .001, partial r = −0.421; Stroop-IN right cingulate: P < .001, partial r = −0.300; Stroop-IN left medial orbitofrontal cortex: P = .01, partial r = −0.223; Stroop-IN right medial orbitofrontal cortex: P < .001, partial r = −0.343), whereas higher FA(T) in the mesial temporal regions was associated with improved short-term memory and processing speed (left amygdala-hippocampus complex: P < .001, partial r = −0.574; right amygdala-hippocampus complex: P < .001, partial r = 0.645; short-term memory left amygdala-hippocampus complex: P < .001, partial r = 0.570; short-term memory right amygdala-hippocampus complex: P < .001, partial r = 0.633). A history of mTBI did not modulate the association between war zone–related stress and GM diffusion. CONCLUSIONS AND RELEVANCE: This study revealed an association between war zone–related stress and alteration of limbic GM microstructure, which was associated with cognitive functioning. These results suggest that altered limbic GM microstructure may underlie the deleterious outcomes of war zone–related stress on brain health. Military service members may benefit from early therapeutic interventions after deployment to a war zone

Interactive Effects of Racial Identity and Repetitive Head Impacts on Cognitive Function, Structural MRI-Derived Volumetric Measures, and Cerebrospinal Fluid Tau and A beta

Background: Factors of increased prevalence among individuals with Black racial identity (e.g., cardiovascular disease, CVD) may influence the association between exposure to repetitive head impacts (RHI) from American football and later-life neurological outcomes. Here, we tested the interaction between racial identity and RHI on neurobehavioral outcomes, brain volumetric measures, and cerebrospinal fluid (CSF) total tau (t-tau), phosphorylated tau (p-tau181), and Aβ1–42 in symptomatic former National Football League (NFL) players. Methods: 68 symptomatic male former NFL players (ages 40–69; n = 27 Black, n = 41 White) underwent neuropsychological testing, structural MRI, and lumbar puncture. FreeSurfer derived estimated intracranial volume (eICV), gray matter volume (GMV), white matter volume (WMV), subcortical GMV, hippocampal volume, and white matter (WM) hypointensities. Multivariate generalized linear models examined the main effects of racial identity and its interaction with a cumulative head impact index (CHII) on all outcomes. Age, years of education, Wide Range Achievement Test, Fourth Edition (WRAT-4) scores, CVD risk factors, and APOEε4 were included as covariates; eICV was included for MRI models. P-values were false discovery rate adjusted. Results: Compared to White former NFL players, Black participants were 4 years younger (p = 0.04), had lower WRAT-4 scores (mean difference = 8.03, p = 0.002), and a higher BMI (mean difference = 3.09, p = 0.01) and systolic blood pressure (mean difference = 8.15, p = 0.03). With regards to group differences on the basis of racial identity, compared to White former NFL players, Black participants had lower GMV (mean adjusted difference = 45649.00, p = 0.001), lower right hippocampal volume (mean adjusted difference = 271.96, p = 0.02), and higher p-tau181/t-tau ratio (mean adjusted difference = −0.25, p = 0.01). There was not a statistically significant association between the CHII with GMV, right hippocampal volume, or p-tau181/t-tau ratio. However, there was a statistically significant Race x CHII interaction for GMV (b = 2206.29, p = 0.001), right hippocampal volume (b = 12.07, p = 0.04), and p-tau181/t-tau ratio concentrations (b = −0.01, p = 0.004). Conclusion: Continued research on racial neurological disparities could provide insight into risk factors for long-term neurological disorders associated with American football play

Exposure to repetitive head impacts is associated with corpus callosum microstructure and plasma total tau in former professional American football players

BACKGROUND: Exposure to repetitive head impacts (RHI) is associated with an increased risk of later-life neurobehavioral dysregulation and neurodegenerative disease. The underlying pathomechanisms are largely unknown. PURPOSE: To investigate whether RHI exposure is associated with later-life corpus callosum (CC) microstructure and whether CC microstructure is associated with plasma total tau and neuropsychological/neuropsychiatric functioning. STUDY TYPE: Retrospective cohort study. POPULATION: Seventy-five former professional American football players (age 55.2 ± 8.0 years) with cognitive, behavioral, and mood symptoms. FIELD STRENGTH/SEQUENCE: Diffusion-weighted echo-planar MRI at 3 T. ASSESSMENT: Subjects underwent diffusion MRI, venous puncture, neuropsychological testing, and completed self-report measures of neurobehavioral dysregulation. RHI exposure was assessed using the Cumulative Head Impact Index (CHII). Diffusion MRI measures of CC microstructure (i.e., free-water corrected fractional anisotropy (FA), trace, radial diffusivity (RD), and axial diffusivity (AD)) were extracted from seven segments of the CC (CC1-7), using a tractography clustering algorithm. Neuropsychological tests were selected: Trail Making Test Part A (TMT-A) and Part B (TMT-B), Controlled Oral Word Association Test (COWAT), Stroop Interference Test, and the Behavioral Regulation Index (BRI) from the Behavior Rating Inventory of Executive Function, Adult version (BRIEF-A). STATISTICAL TESTS: Diffusion MRI metrics were tested for associations with RHI exposure, plasma total tau, neuropsychological performance, and neurobehavioral dysregulation using generalized linear models for repeated measures. RESULTS: RHI exposure was associated with increased AD of CC1 (correlation coefficient (r) = 0.32, P < 0.05) and with increased plasma total tau (r = 0.34, P < 0.05). AD of the anterior CC1 was associated with increased plasma total tau (CC1: r = 0.30, P < 0.05; CC2: r = 0.29, P < 0.05). Higher trace, AD, and RD of CC1 were associated with better performance (P < 0.05) in TMT-A (trace, r = 0.33; AD, r = 0.31; and RD, r = 0.28) and TMT-B (trace, r = 0.31; RD, r = 0.34). Higher FA and AD of CC2 were associated with better performance (P < 0.05) in TMT-A (FA, r = 0.36; AD, r = 0.28), TMT-B (FA, r = 0.36; AD, r = 0.27), COWAT (FA, r = 0.36; AD, r = 0.32), and BRI (AD, r = 0.29). DATA CONCLUSION: These results suggest an association among RHI exposure, CC microstructure, plasma total tau, and clinical functioning in former professional American football players. LEVEL OF EVIDENCE: 3 Technical Efficacy Stage: 1

Impaired Cognitive Performance in Youth Athletes Exposed to Repetitive Head Impacts

Worldwide, more than 22 million children and adolescents are exposed to repetitive head impacts (RHI) in soccer. Evidence indicates cumulative effects on brain structure, but it is not known whether exposure to RHI affects cognitive improvement in adolescents. The aim of the study was to determine whether exposure to RHI while heading the ball in soccer affects improvement in cognitive performance in adolescents over time. The study group consisted of a convenience sample of 16 male soccer players (mean age 15.7 ± 0.7 years). A comparison cohort of 14 male non-contact sports athletes (mean age 14.9 ± 1.1 years) was recruited from competitive athletic clubs and group-matched in age. Using the ProPoint and AntiPoint tasks, sensorimotor and cognitive functions were measured over both immediate (pre- vs. post-training) as well as across multiple time points within a play season. The number and type of head impacts that occurred during the training were counted. The main outcome measure was the change in response time (RT) in the ProPoint and AntiPoint tasks. The immediate (pre- vs. post-training) and longer-term (across a play season) change in RT was analyzed, and the effect of the number and type of head impacts was tested. Thirty athletes with and without exposure to RHI demonstrated a decrease in RT in both tasks immediately after training. Over the play season, both groups showed improvement in sensorimotor function. While the control group also improved in cognitive performance, the soccer players did not, however. Further, the more long headers performed, the slower the improvement in RT over the season. Youth athletes experience an immediate cognitive improvement after training most likely because of physical exercise. Results of this study also suggest an association between exposure to specific RHI (long headers) and lack of improvement in cognitive performance in youth athletes over time