Longitudinal relationships between BMI and hs-CRP among people with schizophrenia.

In people with schizophrenia (PwS), inflammation and metabolic issues significantly increase morbidity and mortality. However, our ability to understand inflammatory-metabolic mechanisms in this population has been limited to cross-sectional studies. This study involved 169 PwS and 156 non-psychiatric comparisons (NCs), aged 25-65, observed between 2012 and 2022 with 0 to 5 follow-ups post-baseline. High-sensitivity C-reactive protein (hs-CRP), a marker of inflammation, was measured via a particle-enhanced immuno-turbidimetric assay. Body mass index (BMI) was used as a proxy for metabolic function. The measurement intervals for hs-CRP and BMI ranged between 6 and 48 months. Linear mixed models (LMM) results revealed that at all time points, PwS has a higher hs-CRP (t (316) = 4.73, p < .001) and BMI (t (315) = 4.13, p < .001) than NCs; however, for BMI, this difference decreased over time (t (524) = -5.15, p < .001). To study interrelationships between hs-CRP and BMI, continuous time structural equational modeling (CTSEM) was used, accounting for uneven measurement intervals. CTSEM results showed that both hs-CRP predicted future BMI (Est. = 12.91, 95 % CI [7.70; 17.88]) and BMI predicted future hs-CRP (Est. = 1.54, 95 % CI [1.00; 2.04]), indicating a bidirectional relationship between inflammation and metabolic function. Notably, the influence of hs-CRP on future BMI was more robust than the other lagged relationship (p = .015), especially in PwS (Est. = 2.43, 95 % CI [0.39; 0.97]). Our study highlights the important role of inflammation in metabolic function and offers insights into potential interventions targeting inflammation in PwS.

A New Paradigm for High-dimensional Data: Distance-Based Semiparametric Feature Aggregation Framework via Between-Subject Attributes.

This article proposes a distance-based framework incentivized by the paradigm shift towards feature aggregation for high-dimensional data, which does not rely on the sparse-feature assumption or the permutation-based inference. Focusing on distance-based outcomes that preserve information without truncating any features, a class of semiparametric regression has been developed, which encapsulates multiple sources of high-dimensional variables using pairwise outcomes of between-subject attributes. Further, we propose a strategy to address the interlocking correlations among pairs via the U-statistics-based estimating equations (UGEE), which correspond to their unique efficient influence function (EIF). Hence, the resulting semiparametric estimators are robust to distributional misspecification while enjoying root-n consistency and asymptotic optimality to facilitate inference. In essence, the proposed approach not only circumvents information loss due to feature selection but also improves the model's interpretability and computational feasibility. Simulation studies and applications to the human microbiome and wearables data are provided, where the feature dimensions are tens of thousands.

Intersections of Modifiable Risks: Loneliness is Associated with Poor Subjective Sleep Quality in Older Women at Risk for Alzheimer's Disease.

We examined the relationship between subjective and objective sleep outcomes and loneliness in older women at risk for Alzheimer's disease (AD). Our sample consisted of 39 participants (aged 65+) with mild cognitive deficits who completed the UCLA Loneliness Scale, the Pittsburgh Sleep Quality Index (PSQI), and an at home sleep test, to determine presence of obstructive sleep apnea. Based on sleep quality scores, individuals categorized as "poor sleepers" had significantly higher loneliness scores than "good sleepers." However, total loneliness scores did not significantly differ between groups with or without sleep apnea. We found that higher loneliness was significantly associated to lower habitual sleep efficiency and sleep duration and was also influenced by use of sleep medication. Our findings suggest that increased loneliness relates to worse subjective sleep quality, but not to sleep apnea. These findings suggest that combined interventions targeting loneliness and sleep quality may be important for older women.

Age-Related Changes in Sleep and Its Implications for Cognitive Decline in Aging Persons With Schizophrenia: A Critical Review.

BACKGROUND AND HYPOTHESIS: Cognitive impairment is a core feature of schizophrenia that worsens with aging and interferes with quality of life. Recent work identifies sleep as an actionable target to alleviate cognitive deficits. Cardinal non-rapid eye movement (NREM) sleep oscillations such as sleep spindles and slow oscillations are critical for cognition. People living with schizophrenia (PLWS) and their first-degree relatives have a specific reduction in sleep spindles and an abnormality in their temporal coordination with slow oscillations that predict impaired memory consolidation. While NREM oscillatory activity is reduced in typical aging, it is not known how further disruption in these oscillations contributes to cognitive decline in older PLWS. Another understudied risk factor for cognitive deficits among older PLWS is obstructive sleep apnea (OSA) which may contribute to cognitive decline. STUDY DESIGN: We conducted a narrative review to examine the published literature on aging, OSA, and NREM sleep oscillations in PLWS. STUDY RESULTS: Spindles are propagated via thalamocortical feedback loops, and this circuitry shows abnormal hyperconnectivity in schizophrenia as revealed by structural and functional MRI studies. While the risk and severity of OSA increase with age, older PLWS are particularly vulnerable to OSA-related cognitive deficits because OSA is often underdiagnosed and undertreated, and OSA adds further damage to the circuitry that generates NREM sleep oscillations. CONCLUSIONS: We highlight the critical need to study NREM sleep in older PWLS and propose that identifying and treating OSA in older PLWS will provide an avenue to potentially mitigate and prevent cognitive decline.

Cognition and Functional Capacity: An Initial Comparison of Veteran and Non-Veteran Older Adults.

INTRODUCTION: The U.S. Military Veterans aged 65 and older comprise an estimated 43% of the 22 million living Veterans in the United States. Veterans have high rates of physical, psychiatric, and social challenges, but it is not known whether Veteran status confers additional risk for cognitive or functional impairments in later life. Thus, this investigation specifically compared older Veterans with their non-Veteran peers in cognitive functioning and performance-based functional capacity. MATERIALS AND METHODS: Participants (N = 110; 29 Veterans and 81 non-Veterans) were part of a larger longitudinal study on biopsychosocial functioning in independently living older adult residents of a Continuing Care Senior Housing Community. The University of California San Diego Institutional Review Board approved the study and all participants provided written informed consent. Participants provided demographic and mental health information and were administered a comprehensive neuropsychological battery. Functional capacity was assessed using the UCSD Performance-Based Skills Assessment-Brief (UPSA-B), which uses financial and communication role-plays to assess everyday functioning skills. Neuropsychological scores were appropriately normed prior to analysis. Multivariate Analyses of Variances with post hoc t-tests and an Analysis of Covariance were used to examine neuropsychological and functional capacity differences, respectively, between Veterans and non-Veterans. RESULTS: Veterans did not differ from non-Veterans in educational attainment (16.4 years versus 15.5 years, P = 0.110), but they were significantly older (mean age 86.9 years ± 5.7, versus 81.74 years ± 6.53; P < 0.001) and were more likely to be male (X2 [1, N = 110] = 62.39, P < 0.001). Thus, though neuropsychological norms already accounted for demographic differences in our participants, age and sex were controlled in the Analysis of Covariance predicting UPSA-B score from Veteran status. Results suggested that, compared to non-Veterans, Veterans had significantly worse performance in the list learning portion of a test of verbal memory (Hopkins Verbal Learning Test-Revised, Total Recall; t = 2.56, P = 0.012, d = 0.56). Veterans and non-Veterans did not significantly differ in performance on the delayed recall portion of the verbal learning test and did not differ on a cognitive screening test (Montreal Cognitive Assessment) or on measures of premorbid intellectual functioning (Wide Range Achievement Test-4 Reading), language (Boston Naming Test, Verbal Fluency), visual memory (Brief Visuospatial Memory Test-Revised), attention/working memory (WAIS-IV Digit Span), processing speed (WAIS-IV Digit Symbol Coding), executive function (Delis-Kaplan Executive Function System Trails and Color-Word Test), or functional capacity (UPSA-B). Because our examination of multiple outcomes might have inflated Type I error, we performed a post hoc adjustment of P values using Benjamini-Hochberg procedures and the group difference in verbal learning remained significant. CONCLUSIONS: Despite largely similar function in most domains, Veterans performed significantly more poorly in verbal list learning than their non-Veteran peers. Additional attention should be given to the understanding, assessment, and possible treatment of learning and memory differences in older Veterans, as this may be an area in which Veteran status confers additional risk or vulnerability to decline. This is the first study to compare objective neuropsychological and functional performance between older (age 65+) US Veterans and non-Veterans.

Differences in metabolic biomarkers in people with schizophrenia who are of Mexican descent compared to non-Hispanic whites.

Metabolic dysfunction is highly prevalent and contributes to premature mortality among people with schizophrenia (PwS), especially in Hispanic/Latino/a/x/e PwS, compared to non-Hispanic White (NHW) PwS. This study evaluated the relative contributions of Mexican descent and schizophrenia diagnosis to metabolic biomarker levels. This cross-sectional study included 115 PwS and 102 non-psychiatric comparison (NC) participants - English-speakers aged 26-66 years, 27% Mexican descent, and 52% women across both groups. Assessments included evaluations of BMI, psychopathology, and fasting metabolic biomarkers. We used ANOVA analyses to compare metabolic outcomes between diagnostic and ethnic subgroups, linear regression models to examine associations between Mexican descent and metabolic outcomes, and Spearman's correlations to examine relationships between metabolic outcomes and illness-related variables in PwS. Mexican PwS had higher hemoglobin A1c levels, insulin resistance, and body mass index than NHW PwS. Mexican descent was associated with higher hemoglobin A1c levels, insulin resistance, body mass index, and leptin levels, controlling for age, sex, depression, education, and smoking. Among Mexican PwS, worse negative symptoms were associated with greater insulin resistance. These findings support the possibility of ethnicity-based differences in metabolic dysregulation, though further investigation is warranted to create targeted health interventions for Hispanic PwS.

Developing a novel mobile application for cognitive behavioral therapy for insomnia for people with schizophrenia: integration of wearable and environmental sleep sensors.

BACKGROUND: People with serious mental illnesses (SMIs) have three-fold higher rates of comorbid insomnia than the general population, which has downstream effects on cognitive, mental, and physical health. Cognitive Behavioral Therapy for Insomnia (CBT-i) is a safe and effective first-line treatment for insomnia, though the therapy's effectiveness relies on completing nightly sleep diaries which can be challenging for some people with SMI and comorbid cognitive deficits. Supportive technologies such as mobile applications and sleep sensors may aid with completing sleep diaries. However, commercially available CBT-i apps are not designed for individuals with cognitive deficits. To aid with this challenge, we have developed an integrated mobile application, named "Sleep Catcher," that will automatically incorporate data from a wearable fitness tracker and a bed sensor to track nightly sleep duration, overnight awakenings, bed-times, and wake-times to generate nightly sleep diaries for CBT-i. METHODS: The application development process will be described-writing algorithms to generating useful data, creating a clinician web portal to oversee patients and the mobile application, and integrating sleep data from device platforms and user input. RESULTS: The mobile and web applications were developed using Flutter, IBM Code Engine, and IBM Cloudant database. The mobile application was developed with a user-centered approach and incremental changes informed by a series of beta tests. Special user-interface features were considered to address the challenges of developing a simple and effective mobile application targeting people with SMI. CONCLUSION: There is strong potential for synergy between engineering and mental health expertise to develop technologies for specific clinical populations. Digital health technologies allow for the development of multi-disciplinary solutions to existing health disparities in vulnerable populations, particularly in people with SMI.

Executive functioning trajectories and their prospective association with inflammatory biomarkers in schizophrenia and non-psychiatric comparison participants.

BACKGROUND AND HYPOTHESIS: Cognitive change in people with schizophrenia (PwS) is challenging to assess, but important to understand. Previous studies with limited age ranges and follow-up were subject to practice effects. Controlling for practice effects in a well-established cohort, we examined executive functioning trajectories and their association with inflammatory biomarkers, hypothesizing that PwS will have worsening executive functioning over time compared to non-psychiatric comparison participants (NCs), predicted by higher baseline inflammation with a stronger relationship in PwS than NCs. STUDY DESIGN: Executive functioning was assessed in 350 participants (n = 186 PwS, 164 NCs) at 12-16-month intervals (0 to 7 follow-up visits). Inflammatory biomarkers at baseline included high sensitivity C-Reactive Protein (hs-CRP), Interferon-gamma, Tumor Necrosis Factor (TNF)-alpha, and Interleukin(IL)-6, -8, and - 10. Executive functioning trajectories across diagnostic groups were estimated using a linear mixed-effects model controlling for age, sex, race/ethnicity, and education level, with additional models to assess prediction by baseline inflammation. STUDY RESULTS: Over 4.4 years average follow-up, improvements in executive functioning were attenuated in PwS and older participants. Controlling for practice effects negated improvements, revealing declines among highly educated participants regardless of diagnosis. Higher baseline hs-CRP predicted worse executive functioning only among NCs, while TNF-alpha was predictive of change in all participants only after controlling for practice effects. Only the main effect of hs-CRP on executive function was significant after adjusting for multiple comparisons. None of the other inflammatory biomarkers predicted executive functioning or trajectories of performance among study participants. CONCLUSIONS: Systemic inflammation as reflected by baseline inflammatory biomarker levels did not predict longitudinal declines in executive functioning. Additional studies examining the temporal dynamics of inflammation and cognition in PwS will help further clarify their relationship and associated mechanisms.

An NIMH Workshop on Non-Affective Psychosis in Midlife and Beyond: Research Agenda on Phenomenology, Clinical Trajectories, Underlying Mechanisms, and Intervention Targets.

We present a review of the state of the research in the phenomenology, clinical trajectories, biological mechanisms, aging biomarkers, and treatments for middle-aged and older people with schizophrenia (PwS) discussed at the NIMH sponsored workshop "Non-affective Psychosis in Midlife and Beyond." The growing population of PwS has specific clinical needs that require tailored and mechanistically derived interventions. Differentiating between the effects of aging and disease progression is a key challenge of studying older PwS. This review of the workshop highlights the recent findings in this understudied clinical population and the critical gaps in knowledge and consensus for research priorities. This review showcases the major challenges and opportunities for research to advance clinical care for this growing and understudied population.

Self-compassion, but not compassion toward others, is associated with better physical health: A cross-sectional study.

Compassion is a modifiable construct that is associated with better physical health outcomes but, to our knowledge, has seldom been studied in people with schizophrenia (PwS) despite its applicability to counteract widespread depression in this community that might prevent positive health behaviors. We hypothesized that, compared to non-psychiatric comparison subjects (NCs), PwS would have lower compassion toward self (CTS), lower compassion toward others (CTO), and a positive association between compassion and health outcomes, such as physical wellbeing, comorbidities, and plasma hs-CRP. This cross-sectional study examined differences in physical health, CTS, and CTO in 189 PwS and 166 NCs. We used general linear models to analyze the relationship between compassion and health. As hypothesized, PwS had lower levels of CTS and CTO, worse physical well-being, more comorbidities, and higher levels of plasma hs-CRP than NCs. In the combined sample, higher CTS was significantly associated with better physical well-being and fewer comorbidities, while higher CTO was significantly associated with more comorbidities. In PwS alone, higher CTS was significantly associated with better physical well-being and lower levels of hs-CRP. CTS seemed to have a larger positive association with physical health than CTO, with depression acting as a potential mediator for CTS. Exploring effects of CTS interventions on physical health and health behaviors could be a promising next step.

Dementia among older people with schizophrenia: an update on recent studies.

PURPOSE OF REVIEW: This narrative review examines recently published research that examines the prevalence, underlying causes, and treatments for dementia among people with schizophrenia. RECENT FINDINGS: People with schizophrenia have high rates of dementia, compared with the general population, and cognitive decline has been observed 14 years prior to onset of psychosis with accelerated decline in middle age. Underlying mechanisms of cognitive decline in schizophrenia include low cognitive reserve, accelerated cognitive aging, cerebrovascular disease and medication exposure. Although pharmacologic, psychosocial and lifestyle interventions show early promise for preventing and mitigating cognitive decline, few studies have been conducted in older people with schizophrenia. SUMMARY: Recent evidence supports accelerated cognitive decline and brain changes in middle-aged and older people with schizophrenia, relative to the general population. More research in older people with schizophrenia is needed to tailor existing cognitive interventions and develop novel approaches for this vulnerable and high-risk group.

Latent subgroups with distinct patterns of factors associated with self-rated successful aging among 1,510 community-dwelling Americans: potential role of wisdom as an implicit promoter.

OBJECTIVES: To investigate whether latent subgroups with distinct patterns of factors associated with self-rated successful aging can be identified in community-dwelling adults, and how such patterns obtained from analysis of quantitative data are associated with lay perspectives on successful aging obtained from qualitative responses. METHODS: Cross-sectional data were collected from 1,510 community-dwelling Americans aged 21-99 years. Latent class regression was used to identify subgroups that explained the associations of self-rated successful aging with measures of physical, cognitive, and mental health as well as psychological measures related to resilience and wisdom. Natural language processing was used to extract important themes from qualitative responses to open-ended questions, including the participants' definitions of successful aging. RESULTS: Two latent subgroups were identified, and their main difference was that the wisdom scale was positively associated with self-rated successful aging in only one subgroup. This subgroup had significantly lower self-rated successful aging and worse scores for all health and psychological measures. In the subgroup's qualitative responses, the theme of wisdom was only mentioned by 10.6%; this proportion was not statistically different from the other subgroup, for which the wisdom scale was not statistically associated with the self-rated successful aging. CONCLUSION: Our results showed heterogeneous patterns in the factors underpinning successful aging even in community-dwelling adults. We found the existence of a latent subgroup with lower self-rated successful aging as well as worse health and psychological scores, and we suggest a potential role of wisdom in promoting successful aging for this subgroup, even though individuals may not explicitly recognize wisdom as important for successful aging.

Remotely Administered Resilience- and Wisdom-Focused Intervention to Reduce Perceived Stress and Loneliness: Pilot Controlled Clinical Trial in Older Adults.

OBJECTIVE: Older adults are vulnerable to perceived stress and loneliness, exacerbated by the COVID-19 pandemic. We previously reported inverse relationships between loneliness/perceived stress and wisdom/resilience. There are few evidence-based tele-health interventions for older adults. We tested a new remotely-administered manualized resilience- and wisdom-focused behavioral intervention to reduce perceived stress and loneliness in older adults. METHODS: This pilot controlled clinical trial used a multiple-phase-change single-case experimental design, with three successive 6-week phases: control, intervention, and follow-up periods. The intervention included six once-a-week one-hour sessions. Participants were 20 adults >65 years, without dementia. RESULTS: All 20 participants completed every session. The study indicated feasibility and acceptability of the intervention. While the sample was too small for demonstrating efficacy, there was a reduction (small-to-medium effect size) in perceived stress and loneliness, and increase in resilience, happiness, and components of wisdom and positive perceptions of aging. CONCLUSION: These preliminary data support feasibility, acceptability, and possible efficacy of a remotely-administered resilience- and wisdom-focused intervention in older adults to reduce stress and loneliness.

Effects of intranasal (S)-ketamine on Veterans with co-morbid treatment-resistant depression and PTSD: A retrospective case series.

Background: (S)-ketamine is a glutamatergic drug with potent and rapid acting effects for the treatment of depression. Little is known about the effectiveness of intranasal (S)-ketamine for treating patients with comorbid depression and post-traumatic stress disorder (PTSD). Methods: We performed a retrospective case series analysis of clinical outcomes in 35 Veterans with co-morbid depression and PTSD who were treated with intranasal (S)-ketamine treatments at the VA San Diego Neuromodulation Clinic between Jan 2020 and March 2021. Veterans were not randomized or blinded to treatment. The primary outcome measured was a change in patient health questionnaire-9 (PHQ-9) and PTSD Checklist for DSM-5 (PCL-5) scores across the first 8 treatments (induction period) using a repeated measures analysis of variance (ANOVA). In a smaller sub-group (n = 19) of Veterans who received at least 8 additional treatments, we analyzed whether intranasal (S)-ketamine continued to show treatment effects. Finally, we performed a sub-group and correlation analyses to understand how changes in PHQ-9 and PCL-5 scores were related across treatments. Findings: During the induction phase of treatment there was an absolute reduction of 5.1 (SEM 0.7) on the patient health questionnaire-9 (PHQ-9) rating scale for depression, from 19.8 (SEM 0.7) at treatment 1 to 14.7 (SEM 0.8) at treatment 8 (week 4) (F(7238) = 8.3, p = 1e-6, partial η2 = 0.2). Five Veterans (14%) showed a clinically meaningful response (50% reduction in PHQ-9 score) at treatment 8. There was an absolute reduction of 15.5 +/- 2.4 on the patient checklist 5 (PCL-5) rating scale for PTSD, from 54.8 (SEM 2) at treatment 1 down to 39.3 (SEM 2.5) at treatment 8 (F(7238) = 15.5, p = 2e-7, partial η2 = 0.31). Sixteen Veterans (46%) showed a clinically meaningful response (reduction in PCL-5 of > 30%) in PTSD. Change in PHQ-9 correlated with change in PCL-5 at treatment 8 (r = 0.47, p = 0.005), but a decrease in PTSD symptoms were observable in some individuals with minimal anti-depressant response. Interpretations: While this is an open-label retrospective analysis, our results indicate that both depression and PTSD symptoms in Veterans with dual-diagnoses may improve with repeated intranasal (S)-ketamine treatment. The effects of (S)-ketamine on PTSD symptoms were temporally and individually distinct from those on depression, suggesting potentially different modes of action on the two disorders. This work may warrant formal randomized controlled studies on the effects of intranasal (S)-ketamine for individuals with co-morbid MDD and PTSD. Funding: VA Center of Excellence in Stress and Mental Health, VA ORD (Career Development Award to DSR), Burroughs-Wellcome Fund Award (DSR), NIMH (EL).

Subjective age and its relationships with physical, mental, and cognitive functioning: A cross-sectional study of 1,004 community-dwelling adults across the lifespan.

Perceived younger age is associated with positive health outcomes in existing literature. Few studies have examined these associations using a wide range of variables in large sample of adults of all ages. The objective of present study was to characterize the discrepancy between chronological age (CA) and subjective age (SA) in a large sample of community-dwelling adults across the lifespan, investigate associations with mental, physical, and cognitive health, and examine how it is related to a broad array of psychosocial variables relevant to well-being. Cross-sectional data from 1,004 individuals aged 21-100+ years from the Successful AGing Evaluation (SAGE) study were used for this analysis. Data included self-report measures of physical health (SF-36 - Physical Component), mental health composite score (created using CES-D Happiness scale, Satisfaction with Life Scale, SF-36 Mental Component, Brief Symptom Inventory Anxiety Scale, Patient Health Questionnaire-9, and Perceived Stress Scale), Telephone Interview for Cognitive Status - modified (TICS-m), and validated measures of various positive psychological variables such as meaning in life and optimism. On average, SA was 11.5 years younger than CA (SD 11.3). The discrepancy increased with CA. A younger SA compared to CA was associated with better mental and physical health in all age groups and was positively associated with measures of presence of meaning in life, successful aging, optimism, personal mastery, resilience, curiosity, hope, and social support. The association between age discrepancy and cognitive functioning was not statistically significant. These findings indicate that SA is potentially valuable for the purposes of clinical assessment and intervention, and this possibility should be investigated in future research.

Automated Analysis of Drawing Process to Estimate Global Cognition in Older Adults: Preliminary International Validation on the US and Japan Data Sets.

BACKGROUND: With the aging of populations worldwide, early detection of cognitive impairments has become a research and clinical priority, particularly to enable preventive intervention for dementia. Automated analysis of the drawing process has been studied as a promising means for lightweight, self-administered cognitive assessment. However, this approach has not been sufficiently tested for its applicability across populations. OBJECTIVE: The aim of this study was to evaluate the applicability of automated analysis of the drawing process for estimating global cognition in community-dwelling older adults across populations in different nations. METHODS: We collected drawing data with a digital tablet, along with Montreal Cognitive Assessment (MoCA) scores for assessment of global cognition, from 92 community-dwelling older adults in the United States and Japan. We automatically extracted 6 drawing features that characterize the drawing process in terms of the drawing speed, pauses between drawings, pen pressure, and pen inclinations. We then investigated the association between the drawing features and MoCA scores through correlation and machine learning-based regression analyses. RESULTS: We found that, with low MoCA scores, there tended to be higher variability in the drawing speed, a higher pause:drawing duration ratio, and lower variability in the pen's horizontal inclination in both the US and Japan data sets. A machine learning model that used drawing features to estimate MoCA scores demonstrated its capability to generalize from the US dataset to the Japan dataset (R2=0.35; permutation test, P<.001). CONCLUSIONS: This study presents initial empirical evidence of the capability of automated analysis of the drawing process as an estimator of global cognition that is applicable across populations. Our results suggest that such automated analysis may enable the development of a practical tool for international use in self-administered, automated cognitive assessment.