Accelerated epigenetic age is associated with whole-brain functional connectivity and impaired cognitive performance in older adults.

While chronological age is a strong predictor for health-related risk factors, it is an incomplete metric that fails to fully characterize the unique aging process of individuals with different genetic makeup, neurodevelopment, and environmental experiences. Recent advances in epigenomic array technologies have made it possible to generate DNA methylation-based biomarkers of biological aging, which may be useful in predicting a myriad of cognitive abilities and functional brain network organization across older individuals. It is currently unclear which cognitive domains are negatively correlated with epigenetic age above and beyond chronological age, and it is unknown if functional brain organization is an important mechanism for explaining these associations. In this study, individuals with accelerated epigenetic age (i.e. AgeAccelGrim) performed worse on tasks that spanned a wide variety of cognitive faculties including both fluid and crystallized intelligence (N = 103, average age = 68.98 years, 73 females, 30 males). Additionally, fMRI connectome-based predictive models suggested a mediating mechanism of functional connectivity on epigenetic age acceleration-cognition associations primarily in medial temporal lobe and limbic structures. This research highlights the important role of epigenetic aging processes on the development and maintenance of healthy cognitive capacities and function of the aging brain.

A Genetically Informed Study of the Association Between Perceived Stress and Loneliness.

Although research shows a strong positive association between perceived stress and loneliness, the genetic and environmental etiology underlying their association remains unknown. People with a genetic predisposition to perceived stress, for example, may be more prone to feeling lonely and vice versa. Conversely, unique factors in people's lives may explain differences in perceived stress levels that, in turn, affect feelings of loneliness. We tested whether genetic factors, environmental factors, or both account for the association between perceived stress and loneliness. Participants were 3,066 individual twins (nFemale = 2,154, 70.3%) from the Washington State Twin Registry who completed a survey during April-May, 2020. Structural equation modeling was used to analyze the item-level perceived stress and loneliness measures. The correlation between latent perceived stress and latent loneliness was .68. Genetic and nonshared environmental variance components underlying perceived stress accounted for 3.71% and 23.26% of the total variance in loneliness, respectively. The genetic correlation between loneliness and perceived stress was .45 and did not differ significantly between men and women. The nonshared environmental correlation was .54 and also did not differ between men and women. Findings suggest that holding constant the strong genetic association between perceived stress and loneliness, unique life experiences underlying people's perceived stress account for individual differences in loneliness.

DNA methylation of the oxytocin receptor interacts with age to impact neural response to social stimuli.

Introduction: Social isolation is one of the strongest predictors of increased risk of mortality in older adulthood. The ability to form and maintain the social relationships that mitigate this risk is partially regulated by the oxytocinergic system and one's ability to attend to and process social information. We have previously shown that an epigenetic change to the DNA of the oxytocin receptor gene (OXTR methylation) affects the salience of social information in young adults. Little is known about how the oxytocinergic system ages and what effect this aging system has on social cognitive abilities throughout the lifespan. Methods: Here we explored age-related differences in the association between neural response during selective social attention and OXTR DNA methylation in young (age 18-31) and older (age 58-81) adults. Participants underwent fMRI during a selective social attention task and provided a DNA sample for the assessment of OXTR methylation. Results and Discussion: We found that older adults activated diffuse areas of visual cortex and dorsolateral prefrontal cortex during selective social attention, consistent with the dedifferentiation and compensatory neural activation commonly reported in aging. We found a significant age-by-OXTR methylation interaction on neural response when attending to social stimuli in a complex display; young adults displayed a positive association between OXTR methylation and neural activation, replicating our prior finding that young adults with presumed diminished endogenous access to oxytocin recruit regions of the attentional cortex to a greater extent. This association did not hold for older adults. Instead, perceived social support interacted with OXTR methylation to influence neural response during selective social attention. These data suggest that environmental factors like social support moderate biological processes in aging and highlight the importance of a lifespan perspective for understanding associations between individual differences in the oxytocinergic system, neural function, and social behavior.

Associations Between Longitudinal Loneliness, DNA Methylation Age Acceleration, and Cognitive Functioning.

OBJECTIVES: Loneliness may influence aging biomarkers related to cognitive functioning, for example, through accelerated DNA methylation (DNAm) aging. METHODS: In the present study, we tested whether six common DNAm age acceleration measures mediated the effects of baseline loneliness and five different longitudinal loneliness trajectories on general cognitive ability, immediate memory recall, delayed memory recall, and processing speed in 1,814 older adults in the Health and Retirement Study. RESULTS: We found that baseline loneliness and individuals who belong to the highest loneliness trajectories had poorer general cognitive ability and memory scores. Only DNAm age acceleration measures that index physiological comorbidities, unhealthy lifestyle factors (e.g., smoking), and mortality risk-mediated effects of baseline loneliness on general cognitive ability and memory functioning but not processing speed. These same DNAm measures mediated effects of the moderate-but-declining loneliness trajectory on cognitive functioning. Additionally, immediate and delayed memory scores were mediated by GrimAge Accel in the lowest and two highest loneliness trajectory groups. Total and mediated effects of loneliness on cognitive functioning outcomes were mainly accounted for by demographic, social, psychological, and physiological covariates, most notably self-rated health, depressive symptomatology, objective social isolation, and body mass index. DISCUSSION: Current findings suggest that DNAm biomarkers of aging, particularly GrimAge Accel, have promise for explaining the prospective association between loneliness and cognitive functioning outcomes.

Epigenetic and neural correlates of selective social attention across adulthood.

Social isolation is one of the strongest predictors of increased risk of mortality in older adulthood. The ability to form and maintain the social relationships that mitigate this risk is partially regulated by the oxytocinergic system and one's ability to attend to and process social information. We have previously shown that an epigenetic change to the DNA of the oxytocin receptor gene ( OXTR methylation) affects the salience of social information in young adults. Little is known about how the oxytocinergic system ages and what effect this aging system has on social cognitive abilities throughout the lifespan. Here we explore age-related differences in the association between neural response during selective social attention and OXTR DNA methylation in young and older adults. We find that older adults activate diffuse areas of visual cortex and dorsolateral prefrontal cortex during selective social attention, consistent with the dedifferentiation and compensatory neural activation commonly reported in aging. We find a significant age-by- OXTR methylation interaction on neural response when attending to social stimuli in a complex display; young adults display a positive association between OXTR methylation and neural activation, replicating our prior finding that young adults with presumed diminished endogenous access to oxytocin recruit regions of the attentional cortex to a greater extent. This association does not hold for older adults. Instead, perceived social support interacts with OXTR methylation to influence neural response during selective social attention. These data suggest that environmental factors like social support moderate biological processes in aging and highlight the importance of a lifespan perspective for understanding associations between individual differences in the oxytocinergic system, neural function, and social behavior.

Remember This: Age Moderation of Genetic and Environmental Contributions to Verbal Episodic Memory from Midlife through Late Adulthood.

It is well documented that memory is heritable and that older adults tend to have poorer memory performance than younger adults. However, whether the magnitudes of genetic and environmental contributions to late-life verbal episodic memory ability differ from those at earlier ages remains unresolved. Twins from 12 studies participating in the Interplay of Genes and Environment in Multiple Studies (IGEMS) consortium constituted the analytic sample. Verbal episodic memory was assessed with immediate word list recall (N = 35,204 individuals; 21,792 twin pairs) and prose recall (N = 3,805 individuals; 2,028 twin pairs), with scores harmonized across studies. Average test performance was lower in successively older age groups for both measures. Twin models found significant age moderation for both measures, with total inter-individual variance increasing significantly with age, although it was not possible definitively to attribute the increase specifically to either genetic or environmental sources. Pooled results across all 12 studies were compared to results where we successively dropped each study (leave-one-out) to assure results were not due to an outlier. We conclude the models indicated an overall increase in variance for verbal episodic memory that was driven by a combination of increases in the genetic and nonshared environmental parameters that were not independently statistically significant. In contrast to reported results for other cognitive domains, differences in environmental exposures are comparatively important for verbal episodic memory, especially word list learning.

Measuring vagal activity in postictal bradycardia.

Alterations to cardiac electrical conduction are some of the most frequently observed systemic complications of seizures, with autonomic dysregulation cited as the principal driver for these alterations. In this prospective study, we use 6-lead continuous ECG monitoring in hospitalized patients with epilepsy to trend heart rate patterns in the postictal period. A total of 117 seizures in 45 patients met the criteria for analysis. There was a postictal heart rate increase of 61% (n = 72 seizures), and a decline in heart rate (deceleration) following 38.5% (n = 45). Using 6-lead ECGs for waveform analysis revealed that there was PR prolongation accompanying those seizures that were associated with postictal bradycardia.

A Genetically Informed Longitudinal Study of Loneliness and Dementia Risk in Older Adults.

Although several studies have shown small longitudinal associations between baseline loneliness and subsequent dementia risk, studies rarely test whether change in loneliness predicts dementia risk. Furthermore, as both increase with advancing age, genetic and environmental selection processes may confound the putative causal association between loneliness and dementia risk. We used a sample of 2,476 individual twins from three longitudinal twin studies of aging in the Swedish Twin Registry to test the hypothesis that greater positive change in loneliness predicts greater dementia risk. We then used a sample of 1,632 pairs of twins to evaluate the hypothesis that effects of change in loneliness on dementia risk would remain after adjusting for effects of genetic and environmental variance. Phenotypic model results suggest that mild levels of baseline loneliness predict greater dementia risk. Contrary to our hypothesis, change in loneliness did not correlate with dementia risk, regardless of whether genetic and environmental selection confounds were taken into account. Worsening loneliness with age may not confer greater dementia risk.

Synergistic effect of sleep depth and seizures correlates with postictal heart rate.

Our objective was to determine the effect of sleep on heart rate following a recorded seizure. We prospectively acquired heart rate data in hospitalized epilepsy monitoring unit patients. We analyzed heart rate trends for multiple seizures (n = 101) in patients (n = 42) with electroencephalographically confirmed events. The patient's sleep state was scored for the 5 min preceding each seizure and correlated with the postictal nadir heart rate (PINHR). The depth of sleep during the 5 min before a seizure correlated (correlation coefficient [CC] = -.229, p < .05) with PINHR. This result was more significant and strengthened (CC = -.272, 95% confidence interval = -.392 to -.152, p < .001) when adjusted for covariates of age, generalized tonic-clonic seizures, and baseline heart rate. Sleep depth is an independent predictor of the change in heart rate following a seizure. Diminished heart rate following a seizure in the setting of sleep is likely secondary to non-rapid eye movement sleep's synergistic effect on parasympathetic tone.

Impact of Coping and Communication Skills Program on Physician Burnout, Quality of Life, and Emotional Flooding.

BACKGROUND: Physician behaviors that undermine a culture of safety have gained increasing attention as health-care organizations strive to create a culture of safety and reduce medical errors. We developed, implemented, and assessed a course to teach physicians skills regarding effective coping and interpersonal communication skills and present our results regarding outcomes. METHODS: We examined a professional development program specifically designed to address unprofessional or distressed behaviors of physicians, and we evaluated the impact on burnout, quality of life, and emotional flooding scores of the physicians. Assessments of burnout, quality of life, and emotional flooding were assessed preintervention and postintervention. RESULTS: Results demonstrated statistically significant reductions over time in physicians' emotional flooding and emotional exhaustion (EE). Specifically, using a Wilcoxon Signed-Rank test, results revealed that flooding scores at follow-up were statistically significantly lower than at baseline, V = 590, p < 0.05, and EE and personal accomplishment distributions were found to significantly deviate from normal as indicated by Shapiro-Wilks tests (p < 0.05). A Wilcoxon signed-rank test indicated that EE scores were significantly higher at baseline compared to follow-up 1, V = 285, p < 0.05. CONCLUSION: We conclude that the physician participants who enrolled in the educational skills training program improved scores on emotional flooding and EE and that this may be indicative of improved skills related to their experiences and learning in the program. These improved skills in physicians may have a positive impact on the overall culture of safety in the health system setting.