A twin analysis to estimate genetic and environmental factors contributing to variation in weighted gene co-expression network module eigengenes.

Multivariate network-based analytic methods such as weighted gene co-expression network analysis are frequently applied to human and animal gene-expression data to estimate the first principal component of a module, or module eigengene (ME). MEs are interpreted as multivariate summaries of correlated gene-expression patterns and network connectivity across genes within a module. As such, they have the potential to elucidate the mechanisms by which molecular genomic variation contributes to individual differences in complex traits. Although increasingly used to test for associations between modules and complex traits, the genetic and environmental etiology of MEs has not been empirically established. It is unclear if, and to what degree, individual differences in blood-derived MEs reflect random variation versus familial aggregation arising from heritable or shared environmental influences. We used biometrical genetic analyses to estimate the contribution of genetic and environmental influences on MEs derived from blood lymphocytes collected on a sample of N = 661 older male twins from the Vietnam Era Twin Study of Aging (VETSA) whose mean age at assessment was 67.7 years (SD = 2.6 years, range = 62-74 years). Of the 26 detected MEs, 14 (56%) had statistically significant additive genetic variation with an average heritability of 44% (SD = 0.08, range = 35%-64%). Despite the relatively small sample size, this demonstration of significant family aggregation including estimates of heritability in 14 of the 26 MEs suggests that blood-based MEs are reliable and merit further exploration in terms of their associations with complex traits and diseases.

Parental dementia and subjective memory impairment in the health and retirement study.

OBJECTIVES: To examine relationships between subjective memory impairment (SMI) and parental dementia among in older adults while considering the interactive influence of depressive symptoms, ethnicity, and race. METHOD: The sample was drawn from the Health and Retirement Study, a nationally representative longitudinal study of aging (n = 3,809; Mage = 66.09; SD = 1.88; 84.20% White; 12.23% Black; 7.88% Hispanic). Biennial assessments included two measures of SMI (current memory problems and perceived memory decline), depressive symptoms, and parental dementia, over periods of up to sixteen years. Multilevel modeling analyses examined longitudinal relationships between parental dementia and SMI and whether depressive symptoms, ethnicity, and race interactively influenced this association. RESULTS: Results showed that when older adults reported parental dementia, they were more likely to report a decline in memory in the past two years. They also reported poorer current memory problems, especially when they experienced increased depressive symptoms. Associations of parental dementia were consistent across ethnicity and race. CONCLUSIONS: Results demonstrate the importance of considering parental dementia as a factor that may contribute to SMI in older adults.

Probable chronic pain, brain structure, and Alzheimer's plasma biomarkers in older men.

Chronic pain leads to tau accumulation and hippocampal atrophy in mice. In this study, we provide one of the first assessments in humans, examining the associations of probable chronic pain with hippocampal volume, integrity of the locus coeruleus (LC)-an upstream site of tau deposition-and Alzheimer's Disease-related plasma biomarkers. Participants were mostly cognitively unimpaired men. Probable chronic pain was defined as moderate-to-severe pain in 2+ study waves at average ages 56, 62, and 68. At age 68, 424 participants underwent structural magnestic resonance imaging (MRI) of hippocampal volume and LC-sensitive MRI providing an index of LC integrity (LC contrast-to-noise ratio). Analyses adjusted for confounders including major health conditions, depressive symptoms, and opioid use. Models showed that men with probable chronic pain had smaller hippocampal volume and lower rostral-middle-but not caudal-LC contrast-to-noise ratio compared to men without probable chronic pain. Men with probable chronic pain also had higher levels of plasma total tau, beta-amyloid-42, and beta-amyloid-40 compared to men without probable chronic pain. These findings suggest that probable chronic pain is associated with tau accumulation and reduced structural brain integrity in regions affected early in the development of Alzheimer's Disease. PERSPECTIVE: Probable chronic pain was associated with plasma biomarkers and brain regions that are affected early in Alzheimer's disease (AD). Reducing pain in midlife and elucidating biological mechanisms may help to reduce the risk of AD in older adults.

Elevated C-Reactive Protein in Older Men with Chronic Pain: Association with Plasma Amyloid Levels and Hippocampal Volume.

BACKGROUND: Chronic pain leads to tau accumulation and hippocampal atrophy, which may be moderated through inflammation. In older men, we examined associations of chronic pain with AD-related plasma biomarkers and hippocampal volume as moderated by systemic inflammation. METHODS: Participants were men without dementia. Chronic pain was defined as moderate-to-severe pain in 2+ study waves at average ages 56, 62, and 68. At age 68, we measured plasma amyloid-beta (Aß42, n=871), Aß40 (n=887), total tau (t-tau, n=841), and neurofilament light chain (NfL, n=915), and serum high-sensitivity C-reactive protein (hs-CRP, n=968), a marker of systemic inflammation. A subgroup underwent structural MRI to measure hippocampal volume (n=385). Analyses adjusted for medical morbidities, depressive symptoms, and opioid use. RESULTS: Chronic pain related to higher Aß40 (ß=.25, p=.009), but hs-CRP was unrelated to AD-related biomarkers (ps>05). There was a significant interaction such that older men with both chronic pain and higher levels of hs-CRP had higher levels of Aß42 (ß=.36, p=.001) and Aß40 (ß=.29, p=.003). Chronic pain and hs-CRP did not interact to predict levels of Aß42/Aß40, t-tau, or NfL. Furthermore, there were significant interactions such that Aß42 and Aß40 were associated with lower hippocampal volume, particularly when levels of hs-CRP were elevated (hs-CRP*Aß42: ß=-.19, p=.002; hs-CRP*Aß40: ß=-.21, p=.001), regardless of chronic pain status. CONCLUSIONS: Chronic pain was associated with higher plasma Aß, especially when hs-CRP was also elevated. Higher hs-CRP and Aß levels were both related to smaller hippocampal volumes. Chronic pain, when accompanied by systemic inflammation, may elevate risk of neurodegeneration in AD-vulnerable regions.

Increasing Pain Interference Is Associated With Cognitive Decline Over Four Years Among Older Puerto Rican Adults.

BACKGROUND: Pain is associated with cognitive decline among older adults, but few studies have investigated bidirectional associations between pain and cognitive decline, especially in older Hispanic populations. Our objective was to assess the bidirectional association between pain interference and cognitive performance in a sample of older Puerto Rican adults. METHODS: Data came from baseline and 4-year follow-up of the Puerto Rican Elderly: Health Conditions Study, a longitudinal representative study of Puerto Rican older adults aged 60 and older. Pain and cognitive performance were assessed at each wave. A pain interference variable was created using the sum of pain status (yes/no) and pain interference (yes/no; range 0-2). Global cognitive performance was assessed with the Mini-Mental Cabán. We tested bidirectional associations using a path model with concurrent and cross-lagged paths between pain and cognitive performance, adjusting for sociodemographic and health factors (n = 2 349). RESULTS: Baseline pain interference was not associated with baseline cognitive performance (p = .636) or with cognitive performance at follow-up (p = .594). However, increased pain interference at follow-up was associated with greater cognitive decline at follow-up (ß = -0.07, standard error [SE] = 0.02, p = .003). Greater baseline cognitive performance was associated with lower pain interference at follow-up (ß = -0.07, SE = 0.02, p = .007). CONCLUSIONS: These findings highlight the importance of worsening pain interference as a potentially modifiable risk factor for cognitive decline, as pain treatment options exist. Additionally, better baseline cognitive performance may be a protective factor for pain, providing further evidence of the dynamic relationship between pain and cognitive performance.

Erectile Function, Sexual Satisfaction, and Cognitive Decline in Men From Midlife to Older Adulthood.

BACKGROUND AND OBJECTIVES: Vascular theories of cognitive aging have focused on macrovascular changes and cognitive decline. However, according to the artery-size hypothesis, microvascular changes, such as those that underlie changes in erectile function, may also play an important role in contributing to cognitive decline. Thus, we examined associations between erectile function, sexual satisfaction, and cognition starting in middle age because this represents a transition period where declines in these areas emerge. RESEARCH DESIGN AND METHODS: We examined 818 men from the Vietnam Era Twin Study of Aging across three waves at mean ages 56, 61, and 68. Erectile function and sexual satisfaction were measured using the International Index of Erectile Function. Cognitive performance was measured using factor scores for episodic memory, executive function, and processing speed. We tested multilevel models hierarchically, adjusting for demographics, frequency of sexual activity, and physical and mental health confounders to examine how changes in erectile function and sexual satisfaction related to changes in cognitive performance. RESULTS: Lower erectile function at baseline was related to poorer performance in all cognitive domains at baseline and faster declines in processing speed over time. However, baseline sexual satisfaction was unrelated to cognitive performance. Decreases in erectile function and sexual satisfaction were both associated with memory decline. DISCUSSION AND IMPLICATIONS: Decreasing sexual health may signal an increased risk for cognitive decline. We discuss potential mechanisms, including microvascular changes and psychological distress. Discussing and tracking sexual health in middle-aged men may help to identify those likely to face memory decline.

A Traitlike Dimension of Subjective Memory Concern Over 30 Years Among Adult Male Twins.

Importance: Subjective memory concern has long been considered a state-related indicator of impending cognitive decline or dementia. The possibility that subjective memory concern may itself be a heritable trait is largely ignored, yet such an association would substantially confound its use in clinical or research settings. Objective: To assess the heritability and traitlike dimensions of subjective memory concern and its clinical correlates. Design, Setting, and Participants: This longitudinal twin cohort study was conducted from 1967 to 2019 among male adults with a mean (SD) age of 37.75 (2.52) years to follow-up at mean ages of 56.15 (2.72), 61.50 (2.43), and 67.35 (2.57) years (hereafter, 38, 56, 62, and 67 years, respectively) in the Vietnam Era Twin Study of Aging. The study included a national community-dwelling sample with health, education, and lifestyle characteristics comparable to a general sample of US men in this age cohort. Participants were monozygotic and dizygotic twins randomly recruited from the Vietnam Era Twin Registry. Data were analyzed from May 2021 to December 2022. Main Outcomes and Measures: Measures included subjective memory concern at 4 time points; objective memory, depressive symptoms, and anxiety at the last 3 time points; negative emotionality (trait neuroticism) at age 56 years; polygenic risk scores (PRSs) for neuroticism, depression, and Alzheimer disease; APOE genotype; and parental history of dementia. Primary outcomes were heritability and correlations between subjective memory concern and other measures. Results: The sample included 1555 male adults examined at age 38 years, 520 at age 56 years (due to late introduction of subjective memory concern questions), 1199 at age 62 years, and 1192 at age 67 years. Phenotypically, subjective memory concerns were relatively stable over time. At age 56 years, subjective memory concern had larger correlations with depressive symptoms (r, 0.32; 95% CI, 0.21 to 0.42), anxiety (r, 0.36; 95% CI, 0.18 to 0.51), and neuroticism (r, 0.34; 95% CI, 0.26 to 0.41) than with objective memory (r, -0.24; 95% CI, -0.33 to -0.13). Phenotypic results were similar at ages 62 and 67 years. A best-fitting autoregressive twin model indicated that genetic influences on subjective memory concern accumulated and persisted over time (h2 = 0.26-0.34 from age 38-67 years). At age 56 years, genetic influences for subjective memory concern were moderately correlated with genetic influences for anxiety (r, 0.36; 95% CI, 0.18 to 0.51), negative emotionality (r, 0.51; 95% CI, 0.44-0.57), and depressive symptoms (r, 0.20; 95% CI, 0.10 to 0.29) as well as objective memory (r, -0.22; 95% CI, -0.30 to -0.14). Similar genetic correlations were seen at ages 62 and 67 years. The neuroticism PRS was associated with subjective memory concern at age 38 years (r, 0.10; 95% CI, 0.03. to 0.18) and age 67 years (r, 0.09; 95% CI, 0.01 to 0.16). Subjective memory concern was not associated with any Alzheimer disease risk measures. Conclusions and Relevance: This cohort study found stable genetic influences underlying subjective memory concern dating back to age 38 years. Subjective memory concern had larger correlations with affect-related measures than with memory-related measures. Improving the utility of subjective memory concern as an indicator of impending cognitive decline and dementia may depend on isolating its statelike component from its traitlike component.

Social and Neighborhood Context Moderates the Associations Between Processing Speed and Driving Mobility: A 10-year Analysis of the ACTIVE Study.

Objectives: Processing speed is essential to functional independence in later life, such as driving a vehicle. Few studies have examined processing speed and driving mobility in the context of racial differences and social determinants of health (SDoH). This study characterized the longitudinal association between processing speed and driving mobility, and how it varied by race and SDoH. Methods: Using data from the control arm of the Advanced Cognitive Training in Vital Elderly study (n = 581, 24.5% Black), multilevel models examined longitudinal associations between processing speed and driving mobility outcomes (driving space, exposure, and difficulty). Race and SDoH moderations were explored. Results: Decline in processing speed measures was associated with increased self-reported driving difficulty, but only for older adults with below-average to average scores for neighborhood and built environments and social community context SDoH domains. Discussion: Findings emphasize the influence of physical and social environmental characteristics on processing speed and driving mobility.

Genetic and Environmental Influences on Structural and Diffusion-Based Alzheimer's Disease Neuroimaging Signatures Across Midlife and Early Old Age.

BACKGROUND: Composite scores of magnetic resonance imaging-derived metrics in brain regions associated with Alzheimer's disease (AD), commonly termed AD signatures, have been developed to distinguish early AD-related atrophy from normal age-associated changes. Diffusion-based gray matter signatures may be more sensitive to early AD-related changes compared with thickness/volume-based signatures, demonstrating their potential clinical utility. The timing of early (i.e., midlife) changes in AD signatures from different modalities and whether diffusion- and thickness/volume-based signatures each capture unique AD-related phenotypic or genetic information remains unknown. METHODS: Our validated thickness/volume signature, our novel mean diffusivity (MD) signature, and a magnetic resonance imaging-derived measure of brain age were used in biometrical analyses to examine genetic and environmental influences on the measures as well as phenotypic and genetic relationships between measures over 12 years. Participants were 736 men from 3 waves of the Vietnam Era Twin Study of Aging (VETSA) (baseline/wave 1: mean age [years] = 56.1, SD = 2.6, range = 51.1-60.2). Subsequent waves occurred at approximately 5.7-year intervals. RESULTS: MD and thickness/volume signatures were highly heritable (56%-72%). Baseline MD signatures predicted thickness/volume signatures over a decade later, but baseline thickness/volume signatures showed a significantly weaker relationship with future MD signatures. AD signatures and brain age were correlated, but each measure captured unique phenotypic and genetic variance. CONCLUSIONS: Cortical MD and thickness/volume AD signatures are heritable, and each signature captures unique variance that is also not explained by brain age. Moreover, results are in line with changes in MD emerging before changes in cortical thickness, underscoring the utility of MD as a very early predictor of AD risk.

Higher cortical thickness/volume in Alzheimer's-related regions: protective factor or risk factor?

Some evidence suggests a biphasic pattern of changes in cortical thickness wherein higher, rather than lower, thickness is associated with very early Alzheimer's disease (AD) pathology. We examined whether integrating information from AD brain signatures based on mean diffusivity (MD) can aid in the interpretation of cortical thickness/volume as a risk factor for future AD-related changes. Participants were 572 men in the Vietnam Era Twin Study of Aging who were cognitively unimpaired at baseline (mean age = 56 years; range = 51-60). Individuals with both high thickness/volume signatures and high MD signatures at baseline had lower cortical thickness/volume in AD signature regions and lower episodic memory performance 12 years later compared to those with high thickness/volume and low MD signatures at baseline. Groups did not differ in level of young adult cognitive reserve. Our findings are in line with a biphasic model in which increased cortical thickness may precede future decline and establish the value of examining cortical MD alongside cortical thickness to identify subgroups with differential risk for poorer brain and cognitive outcomes.

A Longitudinal Investigation of Falls and Motor Vehicle Crashes in Older Drivers.

Objective: To assess the longitudinal association between fall history reported at a driver's license screening visit and the likelihood of subsequent vehicle crashes. Method: A total of 1,127 older adults were recruited from Maryland State Motor Vehicle Administration sites and interviewed annually over 15 years. Results: Individuals who reported a previous fall were more likely to be female, perform worse on physical functioning and divided attention tasks, and report more situational driving avoidance compared with non-fallers at baseline. Females who reported a fall at baseline had a 2.6× greater likelihood of subsequently reporting a crash over the 15 years than males. Among those who reported a fall at baseline, greater weekly driving exposure over the 15 years was associated with a 23% higher likelihood of a subsequent crash. Discussion: These findings support the utility of investigating nontraditional driver screening methods to identify drivers who may be at increased risk of future driving difficulties.

Assessment of Caregiver-Targeted Interventions for Use of Motor Vehicle Passenger Safety Systems for Children: A Systematic Review and Meta-analysis.

Importance: Caregiver-targeted interventions to improve the use of child restraint systems (CRS) in motor vehicles are common and heterogeneous in their implementation. The effectiveness of these interventions is unknown. Objectives: To quantify the effects of caregiver-targeted interventions using meta-analytic methods, assess the quality of published studies, and assess for publication bias. Data Sources: PubMed and PsychINFO (January 1, 2004, to April 1, 2019) were searched for English-language studies using a list of search terms. The search and screening process was completed between May 25, 2018, and April 1, 2019. Study Selection: Studies met inclusion criteria if they included a caregiver-targeted intervention that focused on increasing CRS use for children (age, ≤9 years) and report the use of CRS before and after the intervention. Data Extraction and Syntheses: Cochrane and PRISMA guidelines were used for the meta-analysis and risk-of-bias review. Information was extracted on intervention type, setting, implementation, and attributes of the study independently between 2 coders. Data were pooled from independent samples, with 1 outcome measure from each intervention implementation or study. Main Outcomes and Measures: This study was an exploratory random-effects meta-analysis. Unadjusted odds ratios were calculated using the sample size and the observed number of children in incorrect or correct restraints in motor vehicles before and after the intervention to determine the odds of incorrect CRS use after completing an intervention. Setting, measurement method, randomization, use of vouchers, and types of restraint were tested as moderators. A funnel plot was used to assess for publication bias. Results: Of 1240 potential articles, 51 were deemed eligible for screening and 10 (8238 participants total) were included in the meta-analysis. Caregiver-targeted interventions were associated with a reduction in the number of children not riding in a CRS (odds ratio, 0.51; 95% CI, 0.36-0.71; P < .001). Variance in the averaged effect size was driven by self-report methods (when removed from analyses, I2 = 61.8%; R2 change = 26.3; P = .02) and hospital settings (when removed from analyses, I2 = 70.7%; R2 change = 17.4; P = .002). Risk of bias was high in most studies; however, there was low evidence for publication bias. Conclusions and Relevance: In this meta-analysis, caregiver-targeted interventions were associated with a reduction in the number of children not riding in a CRS in motor vehicles; however, the methodological rigor of intervention studies should be enhanced.

Prevalence and Safety of Left-Footed Driving Following Right Foot Surgery Patients Including a Driving Simulation.

BACKGROUND: For many patients, returning to driving after right foot and ankle surgery is a concern, and it is not uncommon for patients to ask if driving may be performed with their left foot. A paucity of literature exists to guide physician recommendations for return to driving. The purpose of this study was to describe the driving habits of patients after right-sided foot surgery and assess the safety of left-footed driving using a driving simulator. METHODS: Patients who underwent right foot or ankle operations between January 2015 and December 2015 were retrospectively identified. A survey assessing driving habits prior to surgery and during the recovery period was administered via a REDCap database through email or telephone. Additionally, simulated driving scenarios were conducted using a driving simulator in 20 volunteer subjects to compare characteristics of left- versus right-footed driving. RESULTS: Thirty-six of 96 (37%) patients who responded to the survey reported driving with the left foot postoperatively. No trends were found associating left-footed driving prevalence and socioeconomic status. In driving simulations, patients exceeded the speed limit significantly more (P < .001) and hit other vehicles more (P < .026) when driving with the right foot than the left. The time to fully brake and fully release the throttle in response to vehicular hazards was significantly prolonged in left-footed driving compared with right (P = .019 and P = .034, respectively). CONCLUSION: A significant proportion of right foot ankle surgery patients engaged in left-footed driving during postoperative recovery. Driving with both the right and left foot presents a risk of compromised safety. This study provides novel objective data regarding the potential risks of unipedal left-footed driving using a standard right-footed console, which indicates that driving with the left foot may prolong brake and throttle release times. Further studies are warranted for physicians to be able to appropriately advise patients about driving after foot and ankle surgery. LEVEL OF EVIDENCE: Level IV, case series.

A Description and Critical Analysis of the Therapeutic Uses of Transcranial Direct Current Stimulation: Implications for Clinical Practice and Research.

For centuries, since the advent of harnessing magnetic and electrical energies, humans have been applying such energies to various body parts, including the brain, with the goal of improving health. Advancements over the past two decades in the production and affordability of such devices that precisely deliver such energies have resulted in novel therapeutic uses. One technique in particular, transcranial Direct Current Stimulation (tDCS), uses electrodes placed on the scalp to deliver a low electrical current to various areas on the surface of the neocortex. Such electrical currents stimulate neurons, which depending on the area of the neocortex it is applied and certain stimulation parameters, can either excite or inhibit certain functions within the brain that may result in alterations in mood, cognition, and behavior. This article provides an overview of this approach, explains how it is used, describes the hypothesized neurobiomechanisms involved, and explores its therapeutic potential. From this overview, implications for nursing practice and innovative uses for nursing research are posited.