A Phenome-Wide Association Study (PheWAS) of Late Onset Alzheimer Disease Genetic Risk in Children of European Ancestry at Middle Childhood: Results from the ABCD Study.

Genetic risk for Late Onset Alzheimer Disease (AD) has been associated with lower cognition and smaller hippocampal volume in healthy young adults. However, whether these and other associations are present during childhood remains unclear. Using data from 5556 genomically-confirmed European ancestry youth who completed the baseline session of the ongoing the Adolescent Brain Cognitive DevelopmentSM Study (ABCD Study®), our phenome-wide association study estimating associations between four indices of genetic risk for late-onset AD (i.e., AD polygenic risk scores (PRS), APOE rs429358 genotype, AD PRS with the APOE region removed (ADPRS-APOE), and an interaction between ADPRS-APOE and APOE genotype) and 1687 psychosocial, behavioral, and neural phenotypes revealed no significant associations after correction for multiple testing (all ps > 0.0002; all pfdr > 0.07). These data suggest that AD genetic risk may not phenotypically manifest during middle-childhood or that effects are smaller than this sample is powered to detect.

Regional Vulnerability Indices in Youth With Persistent and Distressing Psychoticlike Experiences.

Importance: Distressing and persistent psychoticlike experiences (PLEs) in youth are associated with greater odds of developing psychiatric conditions in adulthood. Despite this risk, it is unclear whether early PLEs show similar brain patterns compared with adults with psychiatric and neurologic conditions. Objective: To examine the degree to which persistent and distressing PLEs exhibit neural metrics that show similarity to adults with chronic psychiatric and neurologic conditions. Design, Setting, and Participants: This cohort study used Adolescent Brain Cognitive Development (ABCD) Study examining the persistence and distress associated with PLEs across the first 3 waves of data with baseline structural magnetic resonance imaging data. Analyzed data were collected between September 1, 2016, and September 27, 2021. Children were recruited from 21 research sites across the US. Exposures: Psychoticlike experiences were assessed using the Prodromal Questionnaire-Brief Child Version, and participants were categorized into groups based on the persistence and distress associated with PLEs. Main Outcomes and Measures: Cortical and subcortical regional vulnerability indices (RVIs) were created by quantifying the similarity of participants' baseline neuroimaging measures to the expected patterns found in adult neuropsychiatric samples. The PLE groups were compared on the following RVI cortical and subcortical metrics: schizophrenia spectrum disorders, bipolar disorder, major depressive disorder, Parkinson disease, Alzheimer disease, and metabolic diseases. Results: Analyses examined PLE groups created from 8242 children in the ABCD sample (52.5% male; mean [SD] age, 9.93 [0.63] years; and 56.3% White), including persistent distressing PLEs (n = 329), transient distressing PLEs (n = 396), persistent nondistressing PLEs (n = 234), transient nondistressing PLEs (n = 390), and low distressing PLEs (n = 6893) groups. Participants with persistent or transient distressing PLEs broadly showed increased subcortical RVI scores across most RVI metrics, with persistent distressing PLEs additionally showing increased scores for cortical RVI metrics. The greatest effect sizes were found for persistent distressing PLEs with cortical RVI-schizophrenia spectrum disorders (ß estimate, 1.055; 95% CI, 0.326-1.786) and RVI-Alzheimer disease (ß estimate, 2.473; 95% CI, 0.930-4.018). Conclusions and Relevance: In this cohort study of ABCD participants, the findings suggest that especially the persistent distressing PLEs in children were associated with neural metrics resembling those observed in adults with severe psychiatric and neurologic conditions. These findings support the potential use of brain-based risk scores for early identification and precision medicine approaches in the assessment of PLEs.

Associations Between Polygenic Scores for Cognitive and Non-cognitive Factors of Educational Attainment and Measures of Behavior, Psychopathology, and Neuroimaging in the Adolescent Brain Cognitive Development Study.

Background: Both cognitive and non-cognitive (e.g., traits like curiosity) factors are critical for social and emotional functioning and independently predict educational attainment. These factors are heritable and genetically correlated with a range of health-relevant traits and behaviors in adulthood (e.g., risk-taking, psychopathology). However, whether these associations are present during adolescence, and to what extent these relationships diverge, could have implications for adolescent health and well-being. Methods: Using data from 5,517 youth of European ancestry from the ongoing Adolescent Brain Cognitive DevelopmentSM Study, we examined associations between polygenic scores (PGS) for cognitive and non-cognitive factors and outcomes related to cognition, socioeconomic status, risk tolerance and decision-making, substance initiation, psychopathology, and brain structure. Results: Cognitive and non-cognitive PGSs were both positively associated with cognitive performance and family income, and negatively associated with ADHD and severity of psychotic-like experiences. The cognitive PGS was also associated with greater risk-taking, delayed discounting, and anorexia, as well as lower likelihood of nicotine initiation. The cognitive PGS was further associated with cognition scores and anorexia in within-sibling analyses, suggesting these results do not solely reflect the effects of assortative mating or passive gene-environment correlations. The cognitive PGS showed significantly stronger associations with cortical volumes than the non-cognitive PGS and was associated with right hemisphere caudal anterior cingulate and pars-orbitalis in within-sibling analyses, while the non-cognitive PGS showed stronger associations with white matter fractional anisotropy and a significant within-sibling association for right superior corticostriate-frontal cortex. Conclusions: Our findings suggest that PGSs for cognitive and non-cognitive factors show similar associations with cognition and socioeconomic status as well as other psychosocial outcomes, but distinct associations with regional neural phenotypes in this adolescent sample.

Chromatin accessibility profiling by ATAC-seq.

The assay for transposase-accessible chromatin using sequencing (ATAC-seq) provides a simple and scalable way to detect the unique chromatin landscape associated with a cell type and how it may be altered by perturbation or disease. ATAC-seq requires a relatively small number of input cells and does not require a priori knowledge of the epigenetic marks or transcription factors governing the dynamics of the system. Here we describe an updated and optimized protocol for ATAC-seq, called Omni-ATAC, that is applicable across a broad range of cell and tissue types. The ATAC-seq workflow has five main steps: sample preparation, transposition, library preparation, sequencing and data analysis. This protocol details the steps to generate and sequence ATAC-seq libraries, with recommendations for sample preparation and downstream bioinformatic analysis. ATAC-seq libraries for roughly 12 samples can be generated in 10 h by someone familiar with basic molecular biology, and downstream sequencing analysis can be implemented using benchmarked pipelines by someone with basic bioinformatics skills and with access to a high-performance computing environment.

Optimized design of a hyperflexible sieve electrode to enhance neurovascular regeneration for a peripheral neural interface.

One in 190 Americans is currently living with the loss of a limb resulted from injury, amputation, or neurodegenerative disease. Advanced neuroprosthetic devices combine peripheral neural interfaces with sophisticated prosthetics and hold great potential for the rehabilitation of impaired motor and sensory functions. While robotic prosthetics have advanced very rapidly, peripheral neural interfaces have long been limited by the capability of interfacing with the peripheral nervous system. In this work, we developed a hyperflexible regenerative sieve electrode to serve as a peripheral neural interface. We examined tissue neurovascular integration through this novel device. We demonstrated that we could enhance the neurovascular invasion through the device with directional growth factor delivery. Furthermore, we demonstrated that we could reduce the tissue reaction to the device often seen in peripheral neural interfaces. Finally, we show that we can create a stable tissue device interface in a long-term implantation that does not impede the normal regenerative processes of the nerve. Our study developed an optimal platform for the continued development of hyperflexible sieve electrode peripheral neural interfaces.