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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-tau ), and Aβ in symptomatic former National Football League (NFL) players. 68 symptomatic male former NFL players (ages 40-69; = 27 Black, = 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 ε4 were included as covariates; eICV was included for MRI models. -values were false discovery rate adjusted. Compared to White former NFL players, Black participants were 4 years younger ( = 0.04), had lower WRAT-4 scores (mean difference = 8.03, = 0.002), and a higher BMI (mean difference = 3.09, = 0.01) and systolic blood pressure (mean difference = 8.15, = 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, = 0.001), lower right hippocampal volume (mean adjusted difference = 271.96, = 0.02), and higher p-tau /t-tau ratio (mean adjusted difference = -0.25, = 0.01). There was not a statistically significant association between the CHII with GMV, right hippocampal volume, or p-tau /t-tau ratio. However, there was a statistically significant Race x CHII interaction for GMV ( = 2206.29, = 0.001), right hippocampal volume ( = 12.07, = 0.04), and p-tau /t-tau ratio concentrations ( = -0.01, = 0.004). Continued research on racial neurological disparities could provide insight into risk factors for long-term neurological disorders associated with American football play.

Later-life brain alterations in former tackle football players are poorly understood, particularly regarding their relationship with repetitive head impacts (RHIs) and clinical function. We examined white matter signal abnormalities (WMSAs) and their association with RHIs and clinical function in former National Football League (NFL) players. Eighty-six clinically symptomatic former NFL players and 23 same-age reportedly asymptomatic controls without head trauma exposure underwent magnetic resonance imaging and neuropsychological testing. FreeSurfer calculated WMSAs. A cumulative head impact index quantified RHIs. In former NFL players, increased volume of WMSAs was associated with higher cumulative head impact index scores (P = .043) and worse psychomotor speed and executive function (P = .015). Although former NFL players had greater WMSA volume than controls (P = .046), these findings are inconclusive due to recruitment of controls based on lack of clinical symptoms and head trauma exposure. In former NFL players, WMSAs may reflect long-term microvascular and nonmicrovascular pathologies from RHIs that negatively impact cognition. •Repetitive head impact exposure was positively associated with WMSAs in former NFL players.•In former NFL players, greater WMSAs was associated with worse psychomotor speed and executive function.•The pathologies of WMSAs may contribute to the clinical presentation of chronic traumatic encephalopathy.

Abstract 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 β-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.

Cerebral amyloid angiopathy (CAA) consists of beta-amyloid deposition in the walls of the cerebrovasculature and is commonly associated with Alzheimer’s disease (AD). However, the association of CAA with repetitive head impacts (RHI) and with chronic traumatic encephalopathy (CTE) is unknown. We evaluated the relationship between RHI from contact sport participation, CTE, and CAA within a group of deceased contact sport athletes (n = 357), a community-based cohort (n = 209), and an AD cohort from Boston University AD Center (n = 241). Unsupervised hierarchal cluster analysis demonstrated a unique cluster (n = 11) with increased CAA in the leptomeningeal vessels compared to the intracortical vessels (p < 0.001) comprised of participants with significantly greater frequencies of CTE (7/11) and history of RHI. Overall, participants with CTE (n = 251) had more prevalent (p < 0.001) and severe (p = 0.010) CAA within the frontal leptomeningeal vessels compared to intracortical vessels. Compared to those with AD, participants with CTE had more severe CAA in frontal than parietal lobes (p < 0.001) and more severe CAA in leptomeningeal than intracortical vessels (p = 0.002). The overall frequency of CAA in participants with CTE was low, and there was no significant association between contact sport participation and the presence of CAA. However, in those with CAA, a history of contact sports was associated with increased CAA severity in the frontal leptomeningeal vessels (OR = 4.01, 95% CI 2.52–6.38, p < 0.001) adjusting for AD, APOE ε4 status, and age. Participants with CAA had increased levels of sulcal tau pathology and decreased levels of the synaptic marker PSD-95 (p’s < 0.05), and CAA was a predictor of dementia (OR = 1.75, 95% CI 1.02–2.99, p = 0.043) adjusting for age, sex, and comorbid pathology. Overall, contact sport participation and CTE were associated with more severe frontal and leptomeningeal CAA, and CAA was independently associated with worse pathological and clinical outcomes.

ObjectiveThe association between allergy and multiple sclerosis (MS) is still unclear. In our study, we assessed the association between a self-reported history of allergic conditions with MS clinical and MRI disease activity.MethodsA subset of 1349 patients enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women’s Hospital (CLIMB) study completed a self-administered questionnaire on environmental, food and drug allergies. Patients were distributed among four allergy groups: (1) environmental, (2) food, (3) drug, (4) no known allergies (NKA). Clinical (number of attacks, expanded disability status scale (EDSS), MS severity score (MSSS)) and radiological variables (presence of gadolinium-enhancing lesions and lesion count), and their associations with the different allergy groups or those with NKA, were assessed.ResultsThe food allergy group had a 1.38 times higher rate for cumulative number of attacks compared with the NKA group (P=0.0062); this difference remained significant in the adjusted analysis (relapse rate ratio 1.27, P=0.0305). The food allergy group showed more than twice the likelihood (OR 2.53, P=0.0096) of having gadolinium-enhancing lesions on MRI. The environmental and drug allergy groups did not show significant differences when compared with the NKA group. The EDSS and MSSS were not affected by any type of allergy.ConclusionsMS patients with food allergy had more relapses and a higher likelihood of gadolinium-enhancing lesions compared with patients with no known allergy. Future prospective studies are needed to confirm our findings and investigate underlying biological mechanisms, which may unveil new therapeutic and preventative strategies for MS.

The long-term neurologic consequences of exposure to repetitive head impacts (RHI) are not well understood. This study used magnetic resonance spectroscopy (MRS) to examine later-life neurochemistry and its association with RHI and clinical function in former National Football League (NFL) players. The sample included 77 symptomatic former NFL players and 23 asymptomatic individuals without a head trauma history. Participants completed cognitive, behavior, and mood measures. N-acetyl aspartate, glutamate/glutamine, choline, myo-inositol, creatine, and glutathione were measured in the posterior (PCG) and anterior (ACG) cingulate gyrus, and parietal white matter (PWM). A cumulative head impact index (CHII) estimated RHI. In former NFL players, a higher CHII correlated with lower PWM creatine (r = −0.23, p = 0.02). Multivariate mixed-effect models examined neurochemical differences between the former NFL players and asymptomatic individuals without a history of head trauma. PWM N-acetyl aspartate was lower among the former NFL players (mean diff. = 1.02, p = 0.03). Between-group analyses are preliminary as groups were recruited based on symptomatic status. The ACG was the only region associated with clinical function, including positive correlations between glutamate (r = 0.32, p = 0.004), glutathione (r = 0.29, p = 0.02), and myo-inositol (r = 0.26, p = 0.01) with behavioral/mood symptoms. Other positive correlations between ACG neurochemistry and clinical function emerged (i.e., behavioral/mood symptoms, cognition), but the positive directionality was unexpected. All analyses controlled for age, body mass index, and education (for analyses examining clinical function). In this sample of symptomatic former NFL players, there was a direct effect between RHI and reduced cellular energy metabolism (i.e., lower creatine). MRS neurochemicals associated with neuroinflammation also correlated with behavioral/mood symptoms.

Automated segmentation of brain MRI scans into tissue classes is commonly used for the assessment of multiple sclerosis (MS). However, manual correction of the resulting brain tissue label maps by an expert reader remains necessary in many cases. Since automated segmentation data awaiting manual correction are “missing”, we proposed to use multiple imputation (MI) to fill-in the missing manually-corrected MRI data for measures of normalized whole brain volume (brain parenchymal fraction—BPF) and T2 hyperintense lesion volume (T2LV). Automated and manually corrected MRI measures from 1300 patients enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB) were identified. Simulation studies were conducted to assess the performance of MI with missing data both missing completely at random and missing at random. An imputation model including the concurrent automated data as well as clinical and demographic variables explained a high proportion of the variance in the manually corrected BPF (R2=0.97) and T2LV (R2=0.89), demonstrating the potential to accurately impute the missing data. Further, our results demonstrate that MI allows for the accurate estimation of group differences with little to no bias and with similar precision compared to an analysis with no missing data. We believe that our findings provide important insights for efficient correction of automated MRI measures to obviate the need to perform manual correction on all cases. •Multiple imputation (MI) was used to fill-in missing manually-corrected MRI data.•An imputation model with concurrent automated measures is efficient for MI.•Our imputation model explained a high proportion of variance in the missing MRI data.•MI can be used to fill-in missing data with little impact on bias or variance.

Longitudinal assessments are crucial in evaluating the disease state and trajectory in patients of neurodegenerative diseases. Neuropsychological outcomes measured over time often have a non-linear trajectory with autocorrelated residuals and skewed distributions. Due to these issues, statistical analysis and interpretation involving longitudinal cognitive outcomes can be a difficult and controversial task, thus hindering most convenient transformations (e.g. logarithmic) to avoid the assumption violations of common statistical modelling techniques. We propose the Adjusted Local Linear Trend (ALLT) model, an extended state space model in lieu of the commonly-used linear mixed-effects model (LMEM) in modeling longitudinal neuropsychological outcomes. Our contributed model has the capability to utilize information from the stochasticity of the data while accounting for subject-specific trajectories with the inclusion of covariates and unequally-spaced time intervals. The first step of model fitting involves a likelihood maximization step to estimate the unknown variances in the model before parsing these values into the Kalman Filter and Kalman Smoother recursive algorithms. Results from simulation studies showed that the ALLT model is able to attain lower bias, lower standard errors and high power, particularly in short longitudinal studies with equally-spaced time intervals, as compared to the LMEM. The ALLT model also outperforms the LMEM when data is missing completely at random (MCAR), missing at random (MAR) and, in certain cases, even in data with missing not at random (MNAR). In terms of model selection, likelihood-based inference is applicable for the ALLT model. Although a Chi-Square distribution with k degrees of freedom, where k is the number of parameter lost during estimation, was not the asymptotic distribution in the case of ALLT, we were able to derive an asymptotic distribution approximation of the likelihood ratio test statistics using the power transformation method for the utility of a Gaussian distribution to facilitate model selections for ALLT. In light of these findings, we believe that our proposed model will shed light into longitudinal data analysis not only in the neuropsychological data realm but also on a broader scale for statistical analysis of longitudinal data.

Ecological momentary assessments (EMAs) are short, repeated surveys designed to collect information on experiences in real-time, real-life contexts. Embedding periodic bursts of EMAs within cohort studies enables the study of experiences on multiple timescales and could greatly enhance the accuracy of self-reported information. However, the burden on participants may be high and should be minimized to optimize EMA response rates. We aimed to evaluate the effects of study design features on EMA response rates. Embedded within an ongoing cohort study (Health@NUS), 3 bursts of EMAs were implemented over a 7-month period (April to October 2021). The response rate (percentage of completed EMA surveys from all sent EMA surveys; 30-42 individual EMA surveys sent/burst) for each burst was examined. Following a low response rate in burst 1, changes were made to the subsequent implementation strategy (SMS text message announcements instead of emails). In addition, 2 consecutive randomized controlled trials were conducted to evaluate the efficacy of 4 different reward structures (with fixed and bonus components) and 2 different schedule lengths (7 or 14 d) on changes to the EMA response rate. Analyses were conducted from 2021 to 2022 using ANOVA and analysis of covariance to examine group differences and mixed models to assess changes across all 3 bursts. Small changes to the implementation strategy (SMS text messages instead of emails) may have contributed to increasing the response rate over time. Changing the available rewards did not lead to a significant difference in the response rate, whereas changing the schedule length did lead to a significant difference in the response rate. Our study provides novel insights on how to implement EMA surveys in ongoing cohort studies. This knowledge is essential for conducting high-quality studies using EMA surveys.