RASopathies influences on neuroanatomical variation in children.

BACKGROUND: RASopathies are a group of disorders characterized by pathogenic mutations in the Ras-mitogen-activated protein kinase (Ras/MAPK) signaling pathway. Distinct pathogenic variants in genes encoding proteins in the Ras/MAPK pathway cause Noonan syndrome (NS) and neurofibromatosis type 1 (NF1), which are associated with increased risk for autism spectrum disorder (ASD) and attention deficit and hyperactivity disorder (ADHD). METHODS: This study examines the effect RASopathies (NS and NF1) has on human neuroanatomy, specifically on surface area (SA), cortical thickness (CT), and subcortical volumes. We compared structural T1-weighted images, using vertex-based analysis for cortical measures and Desikan ROI parcellation for subcortical volumes on children with RASopathies (n=91, mean age = 8.81, SD = 2.12) to sex- and age-matched TD (n=74, mean age=9.07, SD = 1.77). RESULTS: Compared to TD, RASopathies had convergent effects on SA and CT, exhibiting increased SA in the precentral gyrus, decreased SA in occipital regions, and thinner CT in the precentral gyrus. RASopathies exhibit divergent effects on subcortical volumes, with syndrome-specific influences from NS and NF1. Overall children with NS display decreased volumes in striatal and thalamic structures and children with NF1 display increased volumes in the hippocampus, amygdala, and thalamus. CONCLUSIONS: Our study reveals the converging and diverging neuroanatomical effects of RASopathies on human neurodevelopment. The convergence of cortical effects on SA and CT indicates a shared influence of Ras/MAPK hyperactivation on the human brain. Therefore, considering these measures as objective outcome indicators for targeted treatments is imperative.

Do We Become More Lonely With Age? A Coordinated Data Analysis of Nine Longitudinal Studies.

Loneliness is a pervasive experience with adverse impacts on health and well-being. Despite its significance, notable gaps impede a full understanding of how loneliness changes across the adult life span and what factors influence these changes. To address this, we conducted a coordinated data analysis of nine longitudinal studies encompassing 128,118 participants ages 13 to 103 from over 20 countries. Using harmonized variables and models, we examined loneliness trajectories and predictors. Analyses revealed that loneliness follows a U-shaped curve, decreasing from young adulthood to midlife and increasing in older adulthood. These patterns were consistent across studies. Several baseline factors (i.e., sex, marital status, physical function, education) were linked to loneliness levels, but few moderated the loneliness trajectories. These findings highlight the dynamic nature of loneliness and underscore the need for targeted interventions to reduce social disparities throughout adulthood.

Longitudinal Associations Between Multimorbidities and Patient-Reported Quality of Life.

OBJECTIVES: The global prevalence of multimorbidity is increasing as the population ages. As individuals get older, they are likely to develop multiple chronic conditions, and nearly two-thirds of older adults in the United States are estimated to experience 2 or more chronic conditions. The present preregistered study examined whether multimorbidity was associated with longitudinal changes in health-related quality of life (i.e., anxiety, depression, and physical function) and whether these associations were moderated by sociodemographic factors (i.e., sex, race, marital status, income, insurance, and education). METHODS: Data come from the Health Literacy and Cognitive Function Among Older Adults Longitudinal Study (LitCog), a prospective cohort study of English-speaking older adults (N = 900). At each measurement occasion, participants reported anxiety, depression, and physical function using the Patient Reported Outcomes Information System, chronic conditions, and sociodemographic characteristics. We employed multilevel growth models to estimate changes in health-related quality of life, with multimorbidities as a predictor and sociodemographics as covariates. RESULTS: Results indicated that individuals with multiple chronic conditions reported persistently high levels of anxiety and depression, and worse physical function. We found evidence for racial health disparities, such that individuals who identified as non-White experienced worse health-related quality of life as multimorbidities increased, relative to White participants. DISCUSSION: These results contribute to the current conversation about the long-term impacts of structural and systemic barriers experienced by minoritized groups. We further discuss the public health implications of multimorbidity in older adulthood.

Well-Being as a Protective Factor Against Cognitive Decline and Dementia: A Review of the Literature and Directions for Future Research.

OBJECTIVES: Treatments that target the biological causes of dementia remain limited, making prevention critically important. Well-being-defined broadly as living in accordance with one's potential and experiencing one's life as enjoyable and satisfying-is a promising avenue for prevention. It can be targeted by large-scale, noninvasive interventions and has been linked with better cognitive health and lower dementia risk. In the current review, we begin by summarizing empirical evidence linking well-being to cognitive functioning, cognitive decline, dementia diagnosis, and dementia-related neuropathology. Then, we highlight 3 key areas for future research. METHODS: We searched the literature on wellbeing, cognitive decline, and dementia, focusing on prospective and longitidinal evidence. RESULTS: The research reviewed here provides consistent evidence for associations of well-being with cognitive decline, dementia risk, and cognitive resilience to neuropathology. However, several open questions remain regarding (1) causality and mechanism(s), (2) specificity versus generalizability of associations, and (3) timing. DISCUSSION: To inform potential intervention efforts, the field must address complex open questions about whether, how, when, and for whom well-being influences dementia risk. The majority of existing research on well-being and cognitive health is correlational, and few studies have tested potential mechanisms that may explain those associations. Further, relatively little is known about the generalizability of associations across different aspects of well-being and for different sociocultural groups. Finally, we do not yet understand when in the life span and on what timescale well-being might influence cognitive health. We discuss challenges and opportunities for addressing each of these open questions, including concrete recommendations for research designs and use of open science practices.