Imaging Brain Injury in Former National Football League Players.

Importance: Pilot studies that involved early imaging of the 18 kDa translocator protein (TSPO) using positron emission tomography (PET) indicated high levels of TSPO in the brains of active or former National Football League (NFL) players. If validated further in larger studies, those findings may have implications for athletes involved in collision sport. Objective: To test for higher TSPO that marks brain injury and repair in a relatively large, unique cohort of former NFL players compared with former elite, noncollision sport athletes. Design, Setting, and Participants: This cross-sectional study used carbon 11-labeled N,N-diethyl-2-(4-methoxyphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-acetamide positron emission tomography ([11C]DPA-713 PET) data from former NFL players within 12 years of last participation in the NFL and elite noncollision sport athletes from across the US. Participants were enrolled between April 2018 and February 2023. Main outcomes and measures: Regional [11C]DPA-713 total distribution volume from [11C]DPA-713 PET that is a measure of regional brain TSPO; regional brain volumes on magnetic resonance imaging; neuropsychological performance, including attention, executive function, and memory domains. Results: This study included 27 former NFL players and 27 former elite, noncollision sport athletes. Regional TSPO levels were higher in former NFL players compared with former elite, noncollision sport athletes (unstandardized ß coefficient, 1.08; SE, 0.22; 95% CI, 0.65 to 1.52; P < .001). The magnitude of the group difference depended on region, with largest group differences in TSPO in cingulate and frontal cortices as well as hippocampus. Compared with noncollision sport athletes, former NFL players performed worse in learning (mean difference [MD], -0.70; 95% CI, -1.14 to -0.25; P = .003) and memory (MD, -0.77; 95% CI, -1.24 to -0.30; P = .002), with no correlation between total gray matter TSPO and these cognitive domains. Conclusions and relevance: In this cross-sectional study using [11C]DPA-713 PET, higher brain TSPO was found in former NFL players compared with noncollision sport athletes. This finding is consistent with neuroimmune activation even after cessation of NFL play. Future longitudinal [11C]DPA-713 PET and neuropsychological testing promises to inform whether neuroimmune-modulating therapy may be warranted.

Serotonin Degeneration and Amyloid-ß Deposition in Mild Cognitive Impairment: Relationship to Cognitive Deficits.

BACKGROUND: Neuropathological and neuroimaging studies have demonstrated degeneration of the serotonin system in Alzheimer's disease (AD). Neuroimaging studies have extended these observations to the preclinical stages of AD, mild cognitive impairment (MCI). Serotonin degeneration has been observed also in transgenic amyloid mouse models, prior to widespread cortical distribution of amyloid-ß (Aß). OBJECTIVE: The present study evaluated the regional distribution of the serotonin transporter (5-HTT) and of Aß in individuals with MCI and healthy older controls, as well as the contribution of 5-HTT and Aß to cognitive deficits. METHODS: Forty-nine MCI participants and 45 healthy older controls underwent positron emission tomography (PET) imaging of 5-HTT and Aß, structural magnetic resonance imaging and neuropsychological assessments. RESULTS: Lower cortical, striatal, and limbic 5-HTT and higher cortical Aß was observed in MCIs relative to healthy controls. Lower 5-HTT, mainly in limbic regions, was correlated with greater deficits in auditory-verbal and visual-spatial memory and semantic, not phonemic fluency. Higher cortical A ß was associated with greater deficits in auditory-verbal and visual-spatial memory and in semantic, not phonemic fluency. When modeling the association between cognition, gray matter volumes and Aß, inclusion of 5-HTT in limbic and in select cortical regions significantly improved model fit for auditory-verbal and visual-spatial memory and semantic, but not phonemic fluency. CONCLUSIONS: These results support the role of serotonin degeneration in the memory and semantic fluency deficits observed in MCI.

Harm reduction behaviors are associated with carrying naloxone among patients on methadone treatment.

BACKGROUND: Despite the widespread availability of naloxone, US opioid overdose rates continue to rise. The "Cascade of Care" (CoC) is a public health approach that identifies steps in achieving specific outcomes and has been used to identify gaps in naloxone carriage among individuals with opioid use disorder (OUD). We sought to apply this framework to a treatment-seeking population with OUD that may be more inclined to engage in harm reduction behaviors. METHODS: Patients were recruited from an urban methadone program to complete a survey. We assessed naloxone familiarity, availability, obtainability, training, and possession, as well as naloxone carriage rates, demographics, and harm reduction behaviors. A multivariable logistic regression examined associations between naloxone carriage and individual-level factors. RESULTS: Participants (n = 97) were majority male (59%), with a mean age of 48 (SD = 12), 27% had college education or higher, 64% indicated injection drug use, and 84% reported past naloxone training. All participants endorsed familiarity with naloxone, but only 42% regularly carried naloxone. The following variables were associated with carrying naloxone: White race (aOR = 2.94, 95% CI 1.02-8.52), college education (aOR = 8.11, 95% CI 1.76-37.47), and total number of self-reported harm reduction behaviors (aOR = 1.45, 95% CI 1.00-2.11). CONCLUSION: We found low rates of naloxone carriage among methadone-treated patients. Methadone programs provide opportunities for naloxone interventions and should target racial/ethnic minorities and individuals with lower education. The spectrum of harm reduction behaviors should be encouraged among these populations to enhance naloxone carriage.

Striatal bases of temporal discounting in early adolescents.

Steeper rates of temporal discounting-the degree to which smaller-sooner (SS) rewards are preferred over larger-later (LL) ones-have been associated with impulsive and ill-advised behaviors in adolescence. Yet, the underlying neural systems remain poorly understood. Here we used a well-established temporal discounting paradigm and functional MRI (fMRI) to examine engagement of the striatum-including the caudate, putamen, and ventral striatum (VS)-in early adolescence (13-15 years; N = 27). Analyses provided evidence of enhanced activity in the caudate and VS during impulsive choice. Exploratory analyses revealed that trait impulsivity was associated with heightened putamen activity during impulsive choices. A more nuanced pattern was evident in the cortex, with the dorsolateral prefrontal cortex mirroring the putamen and posterior parietal cortex showing the reverse association. Taken together, these observations provide an important first glimpse at the distributed neural systems underlying economic choice and trait-like individual differences in impulsivity in the early years of adolescence, setting the stage for prospective-longitudinal and intervention research.

Trait impulsivity during early adolescence predicts steepness of alcohol use escalation across adolescence.

BACKGROUND AND AIMS: Alcohol use during adolescence is a significant public health concern with serious implications. Both early initiation and rate of escalation of alcohol use during adolescence forecast long-term alcohol-related difficulties and alcohol use disorders (AUDs), underscoring the need to understand psychological factors that contribute to these risk behaviors. One factor that contributes to alcohol use during adolescence is trait impulsivity. The purpose of the present prospective study was to examine associations between trait impulsivity and changes in alcohol use from early adolescence through late adolescence. METHODS: Two hundred forty-six participants (45% female; M age = 13.06; 52.5% Caucasian ethnicity) were drawn from a larger study. Levels of impulsivity and alcohol use were measured at every assessment using self-report questionnaires. Data were analyzed using a latent growth modeling approach (LGM) and fit was examined across four indices. RESULTS: Consistent with previous studies, our findings indicate that trait impulsivity decreased and alcohol use increased during adolescence, and initial levels of impulsivity were associated with concurrent levels of alcohol use. Further, level of trait impulsivity during early adolescence predicted the rate of escalation of alcohol use during adolescence. CONCLUSIONS: In the present research, trait impulsivity assessed during early adolescence predicted the steepness of alcohol use escalation during adolescence, a variable with significant prognostic value for long-term AUDs and behavioral problems. This research underscores the importance of understanding trait impulsivity during early adolescence, and suggests that early trait impulsivity may have predictive value with respect to later alcohol abuse and behavioral problems.

mutation3D: Cancer Gene Prediction Through Atomic Clustering of Coding Variants in the Structural Proteome.

A new algorithm and Web server, mutation3D (http://mutation3d.org), proposes driver genes in cancer by identifying clusters of amino acid substitutions within tertiary protein structures. We demonstrate the feasibility of using a 3D clustering approach to implicate proteins in cancer based on explorations of single proteins using the mutation3D Web interface. On a large scale, we show that clustering with mutation3D is able to separate functional from nonfunctional mutations by analyzing a combination of 8,869 known inherited disease mutations and 2,004 SNPs overlaid together upon the same sets of crystal structures and homology models. Further, we present a systematic analysis of whole-genome and whole-exome cancer datasets to demonstrate that mutation3D identifies many known cancer genes as well as previously underexplored target genes. The mutation3D Web interface allows users to analyze their own mutation data in a variety of popular formats and provides seamless access to explore mutation clusters derived from over 975,000 somatic mutations reported by 6,811 cancer sequencing studies. The mutation3D Web interface is freely available with all major browsers supported.