Multi-omics of human plasma reveals molecular features of dysregulated inflammation and accelerated aging in schizophrenia.

Schizophrenia is a devastating psychiatric illness that detrimentally affects a significant portion of the worldwide population. Aging of schizophrenia patients is associated with reduced longevity, but the potential biological factors associated with aging in this population have not yet been investigated in a global manner. To address this gap in knowledge, the present study assesses proteomics and metabolomics profiles in the plasma of subjects afflicted with schizophrenia compared to non-psychiatric control patients over six decades of life. Global, unbiased analyses of circulating blood plasma can provide knowledge of prominently dysregulated molecular pathways and their association with schizophrenia, as well as features of aging and gender in this disease. The resulting data compiled in this study represent a compendium of molecular changes associated with schizophrenia over the human lifetime. Supporting the clinical finding of schizophrenia's association with more rapid aging, both schizophrenia diagnosis and age significantly influenced the plasma proteome in subjects assayed. Schizophrenia was broadly associated with prominent dysregulation of inflammatory and metabolic system components. Proteome changes demonstrated increased abundance of biomarkers for risk of physiologic comorbidities of schizophrenia, especially in younger individuals. These findings advance our understanding of the molecular etiology of schizophrenia and its associated comorbidities throughout the aging process.

Rates of Cognitive and Functional Impairments in Older Adults Residing in a Continuing Care Senior Housing Community.

OBJECTIVE: The current cross-sectional study examined cognition and performance-based functional abilities in a continuing care senior housing community (CCSHC) that is comparable to other CCSHCs in the US with respect to residents' demographic characteristics. METHOD: Participants were 110 older adult residents of the independent living unit. We assessed sociodemographics, mental health, neurocognitive functioning, and functional capacity. RESULTS: Compared to normative samples, participants performed at or above expectations in terms of premorbid functioning, attention span and working memory, processing speed, timed set-shifting, inhibitory control, and confrontation naming. They performed below expectation in verbal fluency and verbal and visual learning and memory, with impairment rates [31.4% (>1 SD below the mean) and 18.49% (>1.5 SD below the mean)] well above the general population (16% and 7%, respectively). Within the cognitive test battery, two tests of delayed memory were most predictive of a global deficit score. Most cognitive test scores correlated with performance-based functional capacity. CONCLUSIONS: Overall, results suggest that a subset of older adults in the independent living sector of CCSHCs are cognitively and functionally impaired and are at risk for future dementia. Results also argue for the inclusion of memory tests in abbreviated screening batteries in this population. We suggest that CCSHCs implement regular cognitive screening procedures to identify and triage those older adults who could benefit from interventions and, potentially, a transition to a higher level of care.

Physical and Mental Health Characteristics of 2,962 Adults With Subjective Cognitive Complaints.

We investigated subjective cognitive complaints (SCCs), as well as physical and mental health factors, in adults and older adults. U.S. residents (N = 2,962) were recruited via the Amazon Mechanical Turk platform and completed a 90-item survey. Overall, 493/1930 (25.5%) of younger adults and 278/1032 (26.9%) of older adults endorsed SCCs. Analyses revealed worse physical and mental health characteristics in the SCC+ compared to the SCC- group, with primarily medium (Cohen's d = 0.50) to large (0.80) effect sizes. Age did not moderate relationships between SCCs and physical/mental health. Results suggest that SCCs are associated with a diverse set of negative health characteristics such as poor sleep and high body mass index, and lower levels of positive factors, including happiness and wisdom. Effect sizes of psychological correlates were at least as large as those of physical correlates, indicating that mental health is critical to consider when evaluating SCCs.

Gut microbiome in Schizophrenia: Altered functional pathways related to immune modulation and atherosclerotic risk.

Emerging evidence has linked the gut microbiome changes to schizophrenia. However, there has been limited research into the functional pathways by which the gut microbiota contributes to the phenotype of persons with chronic schizophrenia. We characterized the composition and functional potential of the gut microbiota in 48 individuals with chronic schizophrenia and 48 matched (sequencing plate, age, sex, BMI, and antibiotic use) non-psychiatric comparison subjects (NCs) using 16S rRNA sequencing. Patients with schizophrenia demonstrated significant beta-diversity differences in microbial composition and predicted genetic functional potential compared to NCs. Alpha-diversity of taxa and functional pathways were not different between groups. Random forests analyses revealed that the microbiome predicts differentiation of patients with schizophrenia from NCs using taxa (75% accuracy) and functional profiles (67% accuracy for KEGG orthologs, 70% for MetaCyc pathways). We utilized a new compositionally-aware method incorporating reference frames to identify differentially abundant microbes and pathways, which revealed that Lachnospiraceae is associated with schizophrenia. Functional pathways related to trimethylamine-N-oxide reductase and Kdo2-lipid A biosynthesis were altered in schizophrenia. These metabolic pathways were associated with inflammatory cytokines and risk for coronary heart disease in schizophrenia. Findings suggest potential mechanisms by which the microbiota may impact the pathophysiology of the disease through modulation of functional pathways related to immune signaling/response and lipid and glucose regulation to be further investigated in future studies.

Study of loneliness and wisdom in 482 middle-aged and oldest-old adults: a comparison between people in Cilento, Italy and San Diego, USA.

OBJECTIVES: There has been growing research interest in loneliness and wisdom in recent decades, but no cross-cultural comparisons of these constructs using standardized rating measures in older adults, especially the oldest-old. This was a cross-sectional study of loneliness and wisdom comparing middle-aged and oldest-old adults in Cilento, Italy and San Diego, United States. METHOD: We examined loneliness and wisdom, using the UCLA Loneliness Scale Version 3 (UCLA-3) and San Diego Wisdom Scale (SD-WISE), respectively, in four subject groups: adults aged 50-65 and those ≥90 years from Cilento, Italy (N = 212 and 47, respectively) and San Diego, California, USA (N = 138 and 85, respectively). RESULTS: After controlling for education, there were no significant group differences in levels of loneliness, while on SD-WISE the Cilento ≥90 group had lower scores compared to the other three groups. There was a strong inverse correlation between loneliness and wisdom in each of the four subject groups. Loneliness was negatively associated while wisdom was positively associated with general health, sleep quality, and happiness in most groups, with varying levels of significance. CONCLUSION: These results largely support cross-cultural validity of the constructs of loneliness and wisdom, and extend previous findings of strong inverse correlations between these two entities. Loneliness has become a growing public health problem, and the results of our study suggest that wisdom could be a protective factor against loneliness, although alternative explanations are also possible. Research on interventions to reduce loneliness by enhancing wisdom in older adults is needed.

Beyond artificial intelligence: exploring artificial wisdom.

BACKGROUND: The ultimate goal of artificial intelligence (AI) is to develop technologies that are best able to serve humanity. This will require advancements that go beyond the basic components of general intelligence. The term "intelligence" does not best represent the technological needs of advancing society, because it is "wisdom", rather than intelligence, that is associated with greater well-being, happiness, health, and perhaps even longevity of the individual and the society. Thus, the future need in technology is for artificial wisdom (AW). METHODS: We examine the constructs of human intelligence and human wisdom in terms of their basic components, neurobiology, and relationship to aging, based on published empirical literature. We review the development of AI as inspired and driven by the model of human intelligence, and consider possible governing principles for AW that would enable humans to develop computers which can operationally utilize wise principles and result in wise acts. We review relevant examples of current efforts to develop such wise technologies. RESULTS: AW systems will be based on developmental models of the neurobiology of human wisdom. These AW systems need to be able to a) learn from experience and self-correct; b) exhibit compassionate, unbiased, and ethical behaviors; and c) discern human emotions and help the human users to regulate their emotions and make wise decisions. CONCLUSIONS: A close collaboration among computer scientists, neuroscientists, mental health experts, and ethicists is necessary for developing AW technologies, which will emulate the qualities of wise humans and thus serve the greatest benefit to humanity. Just as human intelligence and AI have helped further the understanding and usefulness of each other, human wisdom and AW can aid in promoting each other's growth.

Abnormal levels of vascular endothelial biomarkers in schizophrenia.

Schizophrenia is associated with chronic low-grade inflammation, which has been linked to increased vascular risk and rates of cardiovascular disease. Levels of vascular endothelial growth factor (VEGF), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) have been related to aging and neurodegeneration, but their role in schizophrenia remains uncertain. Using a cross-sectional, case-control design, this study included 99 outpatients with schizophrenia and 99 healthy comparison subjects (HCs). Sociodemographic and clinical data were collected, and plasma levels of VEGF, ICAM-1, and VCAM-1 were assayed. A "vascular endothelial index" (VEI) was computed using logistic regression to create a composite measure that maximally differed between groups. General linear models were conducted to examine the possible role of demographic, physical, and lifestyle factors. A linear combination of ICAM-1 and VCAM-1 levels best distinguished the groups, with significantly higher levels of this composite VEI in persons with schizophrenia than HCs. Group differences in the VEI persisted after adjustment for BMI and cigarette smoking. Neither age nor gender was significantly related to the VEI. Schizophrenia patients with higher VEI had earlier age of disease onset, higher systolic and diastolic blood pressure, lower high-density lipoprotein cholesterol, higher insulin resistance, lower levels of mental well-being, and higher Framingham Coronary Heart Disease Risk scores. Schizophrenia is characterized by an elevation of vascular endothelial biomarkers, specifically cell adhesion molecules poised at the intersection between inflammatory response and vascular risk. Interventions aimed at reducing vascular risk may help reduce vascular endothelial abnormalities and prevent cardiovascular morbidity and mortality in schizophrenia.

Steeper Slope of Age-Related Changes in White Matter Microstructure and Processing Speed in Bipolar Disorder.

OBJECTIVES: Bipolar disorder (BD) is associated with compromised white matter (WM) integrity and deficits in processing speed (PS). Few studies, however, have investigated age relationships with WM structure and cognition to understand possible changes in brain health over the lifespan. This investigation explored whether BD and healthy counterpart (HC) participants exhibited differential age-related associations with WM and cognition, which may be suggestive of accelerated brain and cognitive aging. DESIGN: Cross-sectional study. SETTING: University of California San Diego and the Veterans Administration San Diego Healthcare System. PARTICIPANTS: 33 euthymic BD and 38 HC participants. MEASUREMENTS: Diffusion tensor imaging was acquired as a measure of WM integrity, and tract-specific fractional anisotropy (FA) was extracted utilizing the Johns Hopkins University probability atlas. PS was assessed with the Number and Letter Sequencing conditions of the Delis-Kaplan Executive Function System Trail Making Test. RESULTS: BD participants demonstrated slower PS compared with the HC group, but no group differences were found in FA across tracts. Multiple linear regressions revealed a significant group-by-age interaction for the right uncinate fasciculus, the left hippocampal portion of the cingulum, and for PS, such that older age was associated with lower FA values and slower PS in the BD group only. The relationship between age and PS did not significantly change after accounting for uncinate FA, suggesting that the observed age associations occur independently. CONCLUSIONS: Results provide support for future study of the accelerated aging hypothesis by identifying markers of brain health that demonstrate a differential age association in BD.

Dietary Nutrient Intake in School-Aged Children With Heavy Prenatal Alcohol Exposure.

BACKGROUND: Nutrition is an important factor that affects brain development. Nutritional deficiencies can exacerbate alcohol's damaging effects. Conversely, nutritional supplementation can serve a protective role against alcohol damage and may prove to be a worthwhile intervention strategy. This study investigated dietary intake in school-aged children with heavy prenatal alcohol exposure to understand their nutritional status, compared to a national sample of typically developing children and Dietary Reference Intakes. METHODS: Dietary intake data were collected from children with confirmed histories of heavy prenatal alcohol exposure (5 to 10 years, n = 55) using the Automated Self-Administered 24-Hour Dietary Recall (ASA24). Observed nutrient levels were compared to the Dietary Reference Intakes to evaluate adequacy of nutrient intake as well as to national averages for same-aged children (What We Eat in America, NHANES 2007-2008). RESULTS: Alcohol-exposed children exhibited poorer nutritional status compared to the typically developing NHANES sample, consuming lower levels of protein, omega-3 fatty acids, magnesium, potassium, zinc, vitamins C and K, niacin, and choline. Moreover, their diets did not meet Recommended Dietary Allowance or Adequate Intake for dietary fiber, potassium, vitamins E and K, omega-3 fatty acids, and choline. CONCLUSIONS: The present findings are consistent with prior studies investigating nutritional intake in preschoolers with FASD, indicating that these children are vulnerable to nutritional inadequacies. Moreover, data suggest a specific profile of dietary intake in this population. As several nutrients are important for cognitive development, targeted interventions in clinical populations might be effective in boosting outcomes. Thus, further clinical investigation into the role of nutrition in improving cognitive outcomes is warranted.

The Use of Open- and Closed-Loop Control During Goal-Directed Force Responses by Children with Heavy Prenatal Alcohol Exposure.

BACKGROUND: Many daily functional activities involve goal-directed responses based on open-loop and closed-loop motor control, yet little is known about how children with heavy prenatal alcohol exposure organize and regulate these 2 types of control systems when completing a goal-directed force response. METHODS: Children with (n = 19) or without (n = 23) heavy prenatal alcohol exposure were required to match a target force (25 and 50% of maximum voluntary force) in a specified target time (200, 800, and 2,000 ms). Target force and produced force were visually displayed on a computer monitor. The analog force-time record was parsed into 2 segments: the period beginning from force initiation to the first reversal in force was designated the open-loop phase, and the remainder of the response was the closed-loop phase. RESULTS: Compared to controls, alcohol-exposed children produced a significantly shorter duration of open-loop control, a higher open-loop phase rate of force development, a shorter time to reach maximum force during the closed-loop phase, and greater absolute target force error. Increasing target force magnitude did not differentially alter the performance of the clinical group. CONCLUSIONS: The results indicate that alcohol-exposed children experience deficits in completing goal-directed force responses that likely stem from an alcohol-related insult to the central nervous system. Therapeutic exercises should be designed to recalibrate internal timing systems and improve visuomotor integration.

The clinical utility and specificity of parent report of executive function among children with prenatal alcohol exposure.

Prenatal alcohol exposure and attention-deficit/hyperactivity disorder (ADHD) result in behavioral issues related to poor executive function (EF). This overlap may hinder clinical identification of alcohol-exposed children. This study examined the relation between parent and neuropsychological measures of EF and whether parent ratings aid in differential diagnosis. Neuropsychological measures of EF, including the Delis-Kaplan Executive Function System (D-KEFS), were administered to four groups of children (8-16 years): alcohol-exposed with ADHD (AE+, n=80), alcohol-exposed without ADHD (AE-, n=36), non-exposed with ADHD (ADHD, n=93), and controls (CON, n=167). Primary caregivers completed the Behavior Rating Inventory of Executive Function (BRIEF). For parent ratings, multivariate analyses of variance revealed main effects of Exposure and ADHD and an interaction between these factors, with significant differences between all groups on nearly all BRIEF scales. For neuropsychological measures, results indicated main effects of Exposure and ADHD, but no interaction. Discriminant function analysis indicated the BRIEF accurately classifies groups. These findings confirm compounded behavioral, but not neuropsychological, effects in the AE+ group over the other clinical groups. Parent-report was not correlated with neuropsychological performance in the clinical groups and may provide unique information about neurobehavior. Parent-report measures are clinically useful in predicting alcohol exposure regardless of ADHD. Results contribute to a neurobehavioral profile of prenatal alcohol exposure.

Children with heavy prenatal alcohol exposure experience reduced control of isotonic force.

BACKGROUND: Heavy prenatal alcohol exposure can result in diverse and extensive damage to the central nervous system, including the cerebellum, basal ganglia, and cerebral cortex. Given that these brain regions are involved in the generation and maintenance of motor force, we predicted that prenatal alcohol exposure would adversely affect this parameter of motor control. We previously reported that children with gestational alcohol exposure experience significant deficits in regulating isometric (i.e., constant) force. The purpose of this study was to determine whether these children exhibit similar deficits when producing isotonic (i.e., graded) force. METHODS: Children with heavy prenatal alcohol exposure and typically developing children completed a series of isotonic force contractions by exerting force on a load cell to match a criterion target force displayed on a computer monitor. Two levels of target force (5 or 20% of maximum voluntary force) were investigated in combination with varying levels of visual feedback. RESULTS: Compared with control children, children with heavy prenatal alcohol exposure generated isotonic force signals that were less accurate, more variable, and less complex in the time domain. Specifically, interactions were found between group and visual feedback for response accuracy and signal complexity, suggesting that these children have greater difficulty altering their motor output when visual feedback is low. CONCLUSIONS: These data suggest that prenatal alcohol exposure produces deficits in regulating isotonic force, which presumably result from alcohol-related damage to developing brain regions involved in motor control. These children will most likely experience difficulty performing basic motor skills and daily functional skills that require coordination of finely graded force. Therapeutic strategies designed to increase feedback and, consequently, facilitate visual-motor integration could improve isotonic force production in these children.

Deciphering the 'gut-brain axis' through microbiome diversity.

Incentivised by breakthroughs and data generated by the high-throughput sequencing technology, this paper proposes a distance-based framework to fulfil the emerging needs in elucidating insights from the high-dimensional microbiome data in psychiatric studies. By shifting focus from traditional methods that focus on the observations from each subject to the between-subject attributes that aggregate two or more subjects' entire feature vectors, the described approach revolutionises the conventional prescription for high-dimensional observations via microbiome diversity. To this end, we enrich the classical generalised linear models to articulate the multivariable regression relationship between distance-based variables. We also discuss a robust and computationally feasible semiparametric inference technique. Benefitting from the latest advances in the semiparametric efficiency theory for such attributes, the proposed estimators enjoy robustness and good asymptotic properties that guarantee sensitivity in detecting signals between clinical outcomes and microbiome diversity. It offers a readily implementable and easily interpretable solution for deciphering the gut-brain axis in mental health research.

The Microbiome and Mental Health Across the Lifespan.

INTRODUCTION: The combined genetic material of the microorganisms in the human body, known as the microbiome, is being increasingly recognized as a major determinant of human health and disease. Although located predominantly on mucosal surfaces, these microorganisms have profound effects on brain functioning through the gut-brain axis. METHOD: The content of the chapter is based on a study group session at the annual meeting of the American College of Neuropsychopharmacology (ACNP). The objective was to discuss the emerging relationship between the human microbiome and mental health as relevant to ACNP's interests in developing and evaluating novel neuropsychiatric treatment strategies. The focus is on specific brain disorders, such as schizophrenia, substance use, and Alzheimer's disease, as well as on broader clinical issues such as suicidality, loneliness and wisdom in old age, and longevity. RESULTS: Studies of schizophrenia indicate that the microbiome of individuals with this disorder differs from that of non-psychiatric comparison groups in terms of diversity and composition. Differences are also found in microbial metabolic pathways. An early study in substance use disorders found that individuals with this disorder have lower levels of beta diversity in their oral microbiome than a comparison group. This measure, along with others, was used to distinguish individuals with substance use disorders from controls. In terms of suicidality, there is preliminary evidence that persons who have made a suicide attempt differ from psychiatric and non-psychiatric comparison groups in measures of beta diversity. Exploratory studies in Alzheimer's disease indicate that gut microbes may contribute to disease pathogenesis by regulating innate immunity and neuroinflammation and thus influencing brain function. In another study looking at the microbiome in older adults, positive associations were found between wisdom and alpha diversity and negative associations with subjective loneliness. In other studies of older adults, here with a focus on longevity, individuals with healthy aging and unusually long lives had an abundance of specific microorganisms which distinguished them from other individuals. DISCUSSION: Future studies would benefit from standardizing methods of sample collection, processing, and analysis. There is also a need for the standardized collection of relevant demographic and clinical data, including diet, medications, cigarette smoking, and other potentially confounding factors. While still in its infancy, research to date indicates a role for the microbiome in mental health disorders and conditions. Interventions are available which can modulate the microbiome and lead to clinical improvements. These include microbiome-altering medications as well as probiotic microorganisms capable of modulating the inflammation in the brain through the gut-brain axis. This research holds great promise in terms of developing new methods for the prevention and treatment of a range of human brain disorders.

Children with heavy prenatal alcohol exposure exhibit deficits when regulating isometric force.

BACKGROUND: Production of isometric (i.e., constant) force is an essential component of performing everyday functional tasks, yet no studies have investigated how this type of force is regulated in children with confirmed histories of heavy prenatal alcohol exposure. METHODS: Children 7 to 17 years old with heavy prenatal alcohol exposure (n = 25) and without exposure (n = 18) applied force to a load cell to generate an isometric force that matched a criterion target force displayed on a computer monitor. Two levels of target force were investigated in combination with 3 levels of visual feedback frequency that appeared on the computer monitor as a series of yellow dots. Force was maintained for 20 seconds and participants completed 6 trials per test condition. RESULTS: Root-mean-square error, signal-to-noise ratio, and sample entropy indexed response accuracy, response variability, and signal complexity, respectively. The analyses revealed that in comparison with controls, children with gestational ethanol exposure were significantly less accurate and more variable in regulating their force output and generated a response signal with greater regularity and less complexity in the time domain. CONCLUSIONS: Children with prenatal alcohol exposure experience significant deficits in isometric force production that may impede their ability to perform basic motor skills and activities in everyday tasks.

The Microbiota-Gut-Brain Axis in Alzheimer's Disease: A Review of Taxonomic Alterations and Potential Avenues for Interventions.

OBJECTIVE: The gut microbiome is a complex community of microorganisms that inhabit the gastrointestinal tract. The microbiota-gut-brain axis encompasses a bidirectional communication system that allows the gut to influence the brain via neural, endocrine, immune, and metabolic signaling. Differences in the gut microbiome have been associated with psychiatric and neurological disorders, including Alzheimer's Disease (ad). Understanding these ad-associated alterations may offer novel insight into the pathology and treatment of ad. METHOD: We conducted a narrative review of clinical studies investigating the gut microbiome in ad, organizing the results by phyla to understand the biological contributions of the gut microbial community to ad pathology and clinical features. We also reviewed randomized clinical trials of interventions targeting the microbiome to ameliorate ad symptoms and biomarkers. RESULTS: Alpha diversity is reduced in patients with ad. Within Firmicutes, taxa that produce beneficial metabolites are reduced in ad, including Clostridiaceae, Lachnospiraceae, Ruminococcus, and Eubacterium. Within Bacteroidetes, findings were mixed, with studies showing either reduced or increased abundance of Bacteroides in mild cognitive impairment or ad patients. Proteobacteria that produce toxins tend to be increased in ad patients, including Escherichia/Shigella. A Mediterranean-ketogenic dietary intervention significantly increased beneficial short-chain fatty acids and taxa that were inversely correlated with changes in ad pathological markers. Probiotic supplementation with Lactobacillus spp. and Bifidobacterium spp. improved cognitive function and reduced inflammatory and metabolic markers in patients with ad. CONCLUSIONS: The gut microbiome may provide insight into ad pathology and be a novel target for intervention. Potential therapeutics include probiotics and dietary intervention.