Impact of blood glucose on cognitive function in insulin resistance: novel insights from ambulatory assessment.

BACKGROUND/OBJECTIVES: Insulin resistance (IR)-related disorders and cognitive impairment lead to reduced quality of life and cause a significant strain on individuals and the public health system. Thus, we investigated the effects of insulin resistance (IR), and blood glucose fluctuations on cognitive function under laboratory and free-living conditions, using ecological momentary assessment (EMA). SUBJECTS/METHODS: Baseline assessments included neuropsychological tests and blood analysis. Individuals were classified as either insulin-sensitive (<2) or insulin-resistant (≥2), based on their Homeostatic Model Assessment (HOMA-IR) values. Continuous glucose monitoring (CGM) using a percutaneous sensor was performed for 1 week. Using multiple linear regression, we examined the effects of HOMA-IR and CGM metrics on cognitive domains. Working memory (WM) performance, which was assessed using EMA, 4 times a day for 3 consecutive days, was matched to short-term pre-task CGM metrics. Multilevel analysis was used to map the within-day associations of HOMA-IR, short-term CGM metrics, and WM. RESULTS: Analyses included 110 individuals (mean age 48.7 ± 14.3 years, 59% female, n = 53 insulin-resistant). IR was associated with lower global cognitive function (b = -0.267, P = 0.027), and WM (b = -0.316; P = 0.029), but not with executive function (b = -0.216; P = 0.154) during baseline. EMA showed that higher HOMA-IR was associated with lower within-day WM performance (ß = -0.20, 95% CI -0.40 to -0.00). CGM metrics were not associated with cognitive performance. CONCLUSIONS: The results confirm the association between IR and decrements in global cognitive functioning and WM, while no effects of CGM metrics were observed, making IR a crucial time point for intervention. Targeting underlying mechanisms (e.g., inflammation) in addition to glycemia could be promising to minimize adverse cognitive effects. Registered under https://drks.de/register/de identifier no. DRKS00022774.

Assessing the Accuracy of Smartwatch-Based Estimation of Maximum Oxygen Uptake Using the Apple Watch Series 7: Validation Study.

BACKGROUND: Determining maximum oxygen uptake (VO2max) is essential for evaluating cardiorespiratory fitness. While laboratory-based testing is considered the gold standard, sports watches or fitness trackers offer a convenient alternative. However, despite the high number of wrist-worn devices, there is a lack of scientific validation for VO2max estimation outside the laboratory setting. OBJECTIVE: This study aims to compare the Apple Watch Series 7's performance against the gold standard in VO2max estimation and Apple's validation findings. METHODS: A total of 19 participants (7 female and 12 male), aged 18 to 63 (mean 28.42, SD 11.43) years were included in the validation study. VO2max for all participants was determined in a controlled laboratory environment using a metabolic gas analyzer. Thereby, they completed a graded exercise test on a cycle ergometer until reaching subjective exhaustion. This value was then compared with the estimated VO2max value from the Apple Watch, which was calculated after wearing the watch for at least 2 consecutive days and measured directly after an outdoor running test. RESULTS: The measured VO2max (mean 45.88, SD 9.42 mL/kg/minute) in the laboratory setting was significantly higher than the predicted VO2max (mean 41.37, SD 6.5 mL/kg/minute) from the Apple Watch (t18=2.51; P=.01) with a medium effect size (Hedges g=0.53). The Bland-Altman analysis revealed a good overall agreement between both measurements. However, the intraclass correlation coefficient ICC(2,1)=0.47 (95% CI 0.06-0.75) indicated poor reliability. The mean absolute percentage error between the predicted and the actual VO2max was 15.79%, while the root mean square error was 8.85 mL/kg/minute. The analysis further revealed higher accuracy when focusing on participants with good fitness levels (mean absolute percentage error=14.59%; root-mean-square error=7.22 ml/kg/minute; ICC(2,1)=0.60 95% CI 0.09-0.87). CONCLUSIONS: Similar to other smartwatches, the Apple Watch also overestimates or underestimates the VO2max in individuals with poor or excellent fitness levels, respectively. Assessing the accuracy and reliability of the Apple Watch's VO2max estimation is crucial for determining its suitability as an alternative to laboratory testing. The findings of this study will apprise researchers, physical training professionals, and end users of wearable technology, thereby enhancing the knowledge base and practical application of such devices in assessing cardiorespiratory fitness parameters.

Exploring weight-related self-monitoring as a potential risk factor for eating disorder symptoms in adults - A systematic review and meta-analysis.

OBJECTIVE: Weight-related self-monitoring (WRSM), which involves the intentional tracking of body weight metrics, has been considered a potential risk factor for eating disorders. Therefore, the aim of this study was to systematically summarize the current state of the literature and to quantify the possible association between WRSM and eating disorder symptoms in adults. METHOD: Preregistration was carried out using PROSPERO (ID CRD42022366133). The PubMed, PsycInfo, and Web of Science databases were searched until December 21, 2023. A study had to be 1) be available in English or German, 2) be peer-reviewed and quantitative, 3) include adult participants (age ≥18 years) from the general population, 4) assess eating disorder symptoms via at least one of the following questionnaires: EDI, EAT, FEV, TFEQ, DEBQ, EDE-Q, Munich ED-Quest or IEG, and 5) include WRSM. Data analyses included descriptive analyses and three-level meta-analysis, corrected for correlations, for the global score and the different subscales of the eating disorder questionnaires. RESULTS: A total of 28 studies (n = 17,370 participants), with an overall fair methodological quality, were included in the systematic review. Out of these studies, nine studies with n = 13,507 participants were ultimately analyzed in the meta-analysis. The three-level meta-analysis did not reveal a significant association between WRSM and the eating disorder global score (r = 0.13, 95% CI [-0.02, 0.28]; p = 0.08), with this pattern also being evident in the subgroup analysis (diet monitoring). DISCUSSION: WRSM alone does not generally translate into an increased risk of disordered eating symptoms in the general population. We assume that individual factors are likely to determine whether the use of WRSM could lead to eating disorder symptoms. These factors should be accounted for in future research.

Efficacy of a synbiotic in the management of adults with Attention-Deficit and Hyperactivity Disorder and/or Borderline Personality Disorder and high levels of irritability: Results from a multicenter, randomized, placebo-controlled, "basket" trial.

Irritability worsens prognosis and increases mortality in individuals with Attention-Deficit and Hyperactivity Disorder (ADHD) and/or Borderline Personality Disorder (BPD). However, treatment options are still insufficient. The aim of this randomized, double blind, placebo-controlled study was to investigate the superiority of a synbiotic over placebo in the management of adults with ADHD and/or BPD and high levels of irritability. The study was conducted between February 2019 and October 2020 at three European clinical centers located in Hungary, Spain and Germany. Included were patients aged 18-65 years old diagnosed with ADHD and/or BPD and high levels of irritability (i.e., an Affectivity Reactivity Index (ARI-S) ≥ 5, plus a Clinical Global Impression-Severity Scale (CGI-S) score ≥ 4). Subjects were randomized 1(synbiotic):1(placebo); the agent was administered each day, for 10 consecutive weeks. The primary outcome measure was end-of-treatment response (i.e., a reduction ≥ 30 % in the ARI-S total score compared to baseline, plus a Clinical Global Impression-Improvement (CGI-I) total score of < 3 (very much, or much improved) at week 10). Between-treatment differences in secondary outcomes, as well as safety were also investigated. Of the 231 included participants, 180 (90:90) were randomized and included in the intention-to-treat-analyses. Of these, 117 (65 %) were females, the mean age was 38 years, ADHD was diagnosed in 113 (63 %), BPD in 44 (24 %), both in 23 (13 %). The synbiotic was well tolerated. At week 10, patients allocated to the synbiotic experienced a significantly higher response rate compared to those allocated to placebo (OR: 0.2, 95 % CI:0.1 to 0.7; P = 0.01). These findings suggest that that (add-on) treatment with a synbiotic may be associated with a clinically meaningful improvement in irritability in, at least, a subgroup of adults with ADHD and/or BPD. A superiority of the synbiotic over placebo in the management of emotional dysregulation (-3.6, 95 % CI:-6.8 to -0.3; P = 0.03), emotional symptoms (-0.6, 95 % CI:-1.2 to -0.05; P = 0.03), inattention (-1.8, 95 % CI: -3.2 to -0.4; P = 0.01), functioning (-2.7, 95 % CI: -5.2 to -0.2; P = 0.03) and perceived stress levels (-0.6, 95 % CI: -1.2 to -0.05; P = 0.03) was also suggested. Higher baseline RANK-L protein levels were associated with a significantly lower response rate, but only in the synbiotic group (OR: 0.1, 95 % CI: -4.3 to - 0.3, P = 0.02). In the placebo group, higher IL-17A levels at baseline were significantly associated with a higher improvement in in particular, emotional dysregulation (P = 0.04), opening a door for new (targeted) drug intervention. However, larger prospective studies are warranted to confirm the findings. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03495375.

Medical comorbidities in bipolar disorder (BIPCOM): clinical validation of risk factors and biomarkers to improve prevention and treatment. Study protocol.

BACKGROUND: BIPCOM aims to (1) identify medical comorbidities in people with bipolar disorder (BD); (2) examine risk factors and clinical profiles of Medical Comorbidities (MC) in this clinical group, with a special focus on Metabolic Syndrome (MetS); (3) develop a Clinical Support Tool (CST) for the personalized management of BD and medical comorbidities. METHODS: The BIPCOM project aims to investigate MC, specifically MetS, in individuals with BD using various approaches. Initially, prevalence rates, characteristics, genetic and non-genetic risk factors, and the natural progression of MetS among individuals with BD will be assessed by analysing Nordic registers, biobanks, and existing patient datasets from 11 European recruiting centres across 5 countries. Subsequently, a clinical study involving 400 participants from these sites will be conducted to examine the clinical profiles and incidence of specific MetS risk factors over 1 year. Baseline assessments, 1-year follow-ups, biomarker analyses, and physical activity measurements with wearable biosensors, and focus groups will be performed. Using this comprehensive data, a CST will be developed to enhance the prevention, early detection, and personalized treatment of MC in BD, by incorporating clinical, biological, sex and genetic information. This protocol will highlight the study's methodology. DISCUSSION: BIPCOM's data collection will pave the way for tailored treatment and prevention approaches for individuals with BD. This approach has the potential to generate significant healthcare savings by preventing complications, hospitalizations, and emergency visits related to comorbidities and cardiovascular risks in BD. BIPCOM's data collection will enhance BD patient care through personalized strategies, resulting in improved quality of life and reduced costly interventions. The findings of the study will contribute to a better understanding of the relationship between medical comorbidities and BD, enabling accurate prediction and effective management of MetS and cardiovascular diseases. TRIAL REGISTRATION: ISRCTN68010602 at https://www.isrctn.com/ISRCTN68010602 . Registration date: 18/04/2023.

Local patterns of genetic sharing challenge the boundaries between neuropsychiatric and insulin resistance-related conditions.

The co-occurrence of insulin resistance (IR)-related metabolic conditions with neuropsychiatric disorders is a complex public health challenge. Evidence of the genetic links between these phenotypes is emerging, but little is currently known about the genomic regions and biological functions that are involved. To address this, we performed Local Analysis of [co]Variant Association (LAVA) using large-scale (N=9,725-933,970) genome-wide association studies (GWASs) results for three IR-related conditions (type 2 diabetes mellitus, obesity, and metabolic syndrome) and nine neuropsychiatric disorders. Subsequently, positional and expression quantitative trait locus (eQTL)-based gene mapping and downstream functional genomic analyses were performed on the significant loci. Patterns of negative and positive local genetic correlations (|rg|=0.21-1, pFDR<0.05) were identified at 109 unique genomic regions across all phenotype pairs. Local correlations emerged even in the absence of global genetic correlations between IR-related conditions and Alzheimer's disease, bipolar disorder, and Tourette's syndrome. Genes mapped to the correlated regions showed enrichment in biological pathways integral to immune-inflammatory function, vesicle trafficking, insulin signalling, oxygen transport, and lipid metabolism. Colocalisation analyses further prioritised 10 genetically correlated regions for likely harbouring shared causal variants, displaying high deleterious or regulatory potential. These variants were found within or in close proximity to genes, such as SLC39A8 and HLA-DRB1, that can be targeted by supplements and already known drugs, including omega-3/6 fatty acids, immunomodulatory, antihypertensive, and cholesterol-lowering drugs. Overall, our findings underscore the complex genetic landscape of IR-neuropsychiatric multimorbidity, advocating for an integrated disease model and offering novel insights for research and treatment strategies in this domain.

Exploring the Link between Lifestyle, Inflammation, and Insulin Resistance through an Improved Healthy Living Index.

Lifestyle factors-such as diet, physical activity (PA), smoking, and alcohol consumption-have a significant impact on mortality as well as healthcare costs. Moreover, they play a crucial role in the development of type 2 diabetes mellitus (DM2). There also seems to be a link between lifestyle behaviours and insulin resistance, which is often a precursor of DM2. This study uses an enhanced Healthy Living Index (HLI) integrating accelerometric data and an Ecological Momentary Assessment (EMA) to explore differences in lifestyle between insulin-sensitive (IS) and insulin-resistant (IR) individuals. Moreover, it explores the association between lifestyle behaviours and inflammation. Analysing data from 99 participants of the mPRIME study (57 women and 42 men; mean age 49.8 years), we calculated HLI scores-ranging from 0 to 4- based on adherence to specific low-risk lifestyle behaviours, including non-smoking, adhering to a healthy diet, maximally moderate alcohol consumption, and meeting World Health Organization (WHO) PA guidelines. Insulin sensitivity was assessed using a Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and C-reactive protein (CRP) levels were used as a proxy for inflammation. Lifestyle behaviours, represented by HLI scores, were significantly different between IS and IR individuals (U = 1529.0; p = 0.023). The difference in the HLI score between IR and IS individuals was mainly driven by lower adherence to PA recommendations in the IR group. Moreover, reduced PA was linked to increased CRP levels in the IR group (r = -0.368, p = 0.014). Our findings suggest that enhancing PA, especially among individuals with impaired insulin resistance, holds significant promise as a preventive strategy.

Inflammatory biotype of ADHD is linked to chronic stress: a data-driven analysis of the inflammatory proteome.

The association between Attention Deficit Hyperactivity Disorder (ADHD) and low-grade inflammation has been explored in children but rarely in adults. Inflammation is characteristic of some, but not all, patients with ADHD and might be influenced by ADHD medication but also lifestyle factors including nutrition, smoking, and stress. It is also still unclear if any specific symptoms are related to inflammation. Therefore, we assessed 96 inflammatory proteins in a deeply phenotyped cohort of 126 adult ADHD participants with a stable medication status using OLINK technology. A data-based, unsupervised hierarchical clustering method could identify two distinct biotypes within the 126 ADHD participants based on their inflammatory profile: a higher inflammatory potential (HIP) and a lower inflammatory protein potential (LIP) group. Biological processes that differed strongest between groups were related to the NF-κB pathway, chemokine signaling, IL-17 signaling, metabolic alterations, and chemokine attraction. A comparison of sample characteristics revealed that the HIP group was more likely to have higher levels of chronic stress (p < 0.001), a higher clinical global impression scale score (p = 0.030), and a higher risk for suicide (p = 0.032). Medication status did not influence protein levels significantly (p ≥ 0.074), but psychotropic co-medication (p ≤ 0.009) did. In conclusion, our data suggest the presence of two distinct biotypes in adults with ADHD. Higher levels of inflammatory proteins in ADHD are linked to higher levels of chronic perceived stress in a linear fashion. Further research on inflammation in adults with ADHD should take stress levels into account.

Age-related changes in energy metabolism in peripheral mononuclear blood cells (PBMCs) and the brains of cognitively healthy seniors.

Mitochondrial dysfunction is a hallmark of cellular senescence and many age-related neurodegenerative diseases. We therefore investigated the relationship between mitochondrial function in peripheral blood cells and cerebral energy metabolites in young and older sex-matched, physically and mentally healthy volunteers. Cross-sectional observational study involving 65 young (26.0 ± 0.49 years) and 65 older (71.7 ± 0.71 years) women and men recruited. Cognitive health was evaluated using established psychometric methods (MMSE, CERAD). Blood samples were collected and analyzed, and fresh peripheral blood mononuclear cells (PBMCs) were isolated. Mitochondrial respiratory complex activity was measured using a Clarke electrode. Adenosine triphosphate (ATP) and citrate synthase activity (CS) were determined by bioluminescence and photometrically. N-aspartyl-aspartate (tNAA), ATP, creatine (Cr), and phosphocreatine (PCr) were quantified in brains using 1H- and 31P-magnetic resonance spectroscopic imaging (MRSI). Levels of insulin-like growth factor 1 (IGF-1) were determined using a radio-immune assay (RIA). Complex IV activity (CIV) (- 15%) and ATP levels (- 11%) were reduced in PBMCs isolated from older participants. Serum levels of IGF-1 were significantly reduced (- 34%) in older participants. Genes involved in mitochondrial activity, antioxidant mechanisms, and autophagy were unaffected by age. tNAA levels were reduced (- 5%), Cr (+ 11%), and PCr (+ 14%) levels were increased, and ATP levels were unchanged in the brains of older participants. Markers of energy metabolism in blood cells did not significantly correlate with energy metabolites in the brain. Age-related bioenergetic changes were detected in peripheral blood cells and the brains of healthy older people. However, mitochondrial function in peripheral blood cells does not reflect energy related metabolites in the brain. While ATP levels in PBMCs may be be a valid marker for age-related mitochondrial dysfunction in humans, cerebral ATP remained constant.

Young people at risk for developing bipolar disorder: Two-year findings from the multicenter prospective, naturalistic Early-BipoLife study.

Early identification and intervention of individuals with an increased risk for bipolar disorder (BD) may improve the course of illness and prevent long­term consequences. Early-BipoLife, a multicenter, prospective, naturalistic study, examined risk factors of BD beyond family history in participants aged 15-35 years. At baseline, positively screened help-seeking participants (screenBD at-risk) were recruited at Early Detection Centers and in- and outpatient depression and attention-deficit/hyperactivity disorder (ADHD) settings, references (Ref) drawn from a representative cohort. Participants reported sociodemographics and medical history and were repeatedly examined regarding psychopathology and the course of risk factors. N = 1,083 screenBD at-risk and n = 172 Ref were eligible for baseline assessment. Within the first two years, n = 31 screenBD at-risk (2.9 %) and none of Ref developed a manifest BD. The cumulative transition risk was 0.0028 at the end of multistep assessment, 0.0169 at 12 and 0.0317 at 24 months (p = 0.021). The transition rate with a BD family history was 6.0 %, 4.7 % in the Early Phase Inventory for bipolar disorders (EPIbipolar), 6.6 % in the Bipolar Prodrome Interview and Symptom Scale-Prospective (BPSS-FP) and 3.2 % with extended Bipolar At-Risk - BARS criteria). In comparison to help-seeking young patients from psychosis detection services, transition rates in screenBD at-risk participants were lower. The findings of Early-BipoLife underscore the importance of considering risk factors beyond family history in order to improved early detection and interventions to prevent/ameliorate related impairment in the course of BD. Large long-term cohort studies are crucial to understand the developmental pathways and long-term course of BD, especially in people at- risk.

Prediction of estimated risk for bipolar disorder using machine learning and structural MRI features.

BACKGROUND: Individuals with bipolar disorder are commonly correctly diagnosed a decade after symptom onset. Machine learning techniques may aid in early recognition and reduce the disease burden. As both individuals at risk and those with a manifest disease display structural brain markers, structural magnetic resonance imaging may provide relevant classification features. METHODS: Following a pre-registered protocol, we trained linear support vector machine (SVM) to classify individuals according to their estimated risk for bipolar disorder using regional cortical thickness of help-seeking individuals from seven study sites (N = 276). We estimated the risk using three state-of-the-art assessment instruments (BPSS-P, BARS, EPIbipolar). RESULTS: For BPSS-P, SVM achieved a fair performance of Cohen's κ of 0.235 (95% CI 0.11-0.361) and a balanced accuracy of 63.1% (95% CI 55.9-70.3) in the 10-fold cross-validation. In the leave-one-site-out cross-validation, the model performed with a Cohen's κ of 0.128 (95% CI -0.069 to 0.325) and a balanced accuracy of 56.2% (95% CI 44.6-67.8). BARS and EPIbipolar could not be predicted. In post hoc analyses, regional surface area, subcortical volumes as well as hyperparameter optimization did not improve the performance. CONCLUSIONS: Individuals at risk for bipolar disorder, as assessed by BPSS-P, display brain structural alterations that can be detected using machine learning. The achieved performance is comparable to previous studies which attempted to classify patients with manifest disease and healthy controls. Unlike previous studies of bipolar risk, our multicenter design permitted a leave-one-site-out cross-validation. Whole-brain cortical thickness seems to be superior to other structural brain features.

Microtemporal Dynamics of Dietary Intake, Physical Activity, and Impulsivity in Adult Attention-Deficit/Hyperactivity Disorder: Ecological Momentary Assessment Study Within Nutritional Psychiatry.

BACKGROUND: Increasing attention is being paid to lifestyle factors, such as nutrition and physical activity (PA), as potential complementary treatment options in attention-deficit/hyperactivity disorder (ADHD). Previous research indicates that sugar and saturated fat intake may be linked to increased impulsivity, a core symptom of ADHD, whereas protein intake and PA may be related to reduced impulsivity. However, most studies rely on cross-sectional data that lack microtemporal resolution and ecological validity, wherefore questions of microtemporal dynamics (eg, is the consumption of foods high in sugar associated with increased impulsivity within minutes or hours?) remain largely unanswered. Ecological momentary assessment (EMA) has the potential to bridge this gap. OBJECTIVE: This study is the first to apply EMA to assess microtemporal associations among macronutrient intake, PA, and state impulsivity in the daily life of adults with and without ADHD. METHODS: Over a 3-day period, participants reported state impulsivity 8 times per day (signal-contingent), recorded food and drink intake (event-contingent), and wore an accelerometer. Multilevel 2-part models were used to study the association among macronutrient intake, PA, and the probability to be impulsive as well as the intensity of impulsivity (ADHD: n=36; control: n=137). RESULTS: No association between macronutrient intake and state impulsivity was found. PA was not related to the intensity of impulsivity but to a higher probability to be impulsive (ADHD: ß=-.09, 95% CI -0.14 to -0.04; control: ß=-.03, 95% CI -0.05 to -0.01). No evidence was found that the combined intake of saturated fat and sugar amplified the increase in state impulsivity and that PA alleviated the positive association between sugar or fat intake and state impulsivity. CONCLUSIONS: Important methodological considerations are discussed that can contribute to the optimization of future EMA protocols. EMA research in the emerging field of nutritional psychiatry is still in its infancy; however, EMA is a highly promising and innovative approach as it offers insights into the microtemporal dynamics of psychiatric symptomology, dietary intake, and PA in daily life.

Machine Learning Prediction of Estimated Risk for Bipolar Disorders Using Hippocampal Subfield and Amygdala Nuclei Volumes.

The pathophysiology of bipolar disorder (BD) remains mostly unclear. Yet, a valid biomarker is necessary to improve upon the early detection of this serious disorder. Patients with manifest BD display reduced volumes of the hippocampal subfields and amygdala nuclei. In this pre-registered analysis, we used structural MRI (n = 271, 7 sites) to compare volumes of hippocampus, amygdala and their subfields/nuclei between help-seeking subjects divided into risk groups for BD as estimated by BPSS-P, BARS and EPIbipolar. We performed between-group comparisons using linear mixed effects models for all three risk assessment tools. Additionally, we aimed to differentiate the risk groups using a linear support vector machine. We found no significant volume differences between the risk groups for all limbic structures during the main analysis. However, the SVM could still classify subjects at risk according to BPSS-P criteria with a balanced accuracy of 66.90% (95% CI 59.2-74.6) for 10-fold cross-validation and 61.9% (95% CI 52.0-71.9) for leave-one-site-out. Structural alterations of the hippocampus and amygdala may not be as pronounced in young people at risk; nonetheless, machine learning can predict the estimated risk for BD above chance. This suggests that neural changes may not merely be a consequence of BD and may have prognostic clinical value.

Impact of insulin and insulin resistance on brain dopamine signalling and reward processing - An underexplored mechanism in the pathophysiology of depression?

Type 2 diabetes and major depressive disorder (MDD) are the leading causes of disability worldwide and have a high comorbidity rate with fatal outcomes. Despite the long-established association between these conditions, the underlying molecular mechanisms remain unknown. Since the discovery of insulin receptors in the brain and the brain's reward system, evidence has accumulated indicating that insulin modulates dopaminergic (DA) signalling and reward behaviour. Here, we review the evidence from rodent and human studies, that insulin resistance directly alters central DA pathways, which may result in motivational deficits and depressive symptoms. Specifically, we first elaborate on the differential effects of insulin on DA signalling in the ventral tegmental area (VTA) - the primary DA source region in the midbrain - and the striatum as well as its effects on behaviour. We then focus on the alterations induced by insulin deficiency and resistance. Finally, we review the impact of insulin resistance in DA pathways in promoting depressive symptoms and anhedonia on a molecular and epidemiological level and discuss its relevance for stratified treatment strategies.

Individual differences in the dietary response to stress in ecological momentary assessment: Does the individual-difference model need expansion?

According to the individual-difference model, individuals differ in the way stress changes their eating behaviour. Research shows that some increase, some decrease, and others show no change in food intake. Despite numerous efforts to identify moderating variables that explain these individual (i.e., between-person) differences, evidence remains inconclusive. The present study aims at deepening the understanding of the stress and eating relationship by applying ecological momentary assessment to study (1) the influence of stress on whether and how much individuals eat and (2) the moderating role of gender, age, BMI, trait stress-eating, and eating styles. The APPetite-mobile-app was used for 3 days to capture actual food intake (event-contingent) and perceived stress (signal-contingent). Data of 154 healthy adults suggest that stress is not associated with whether but how much individuals eat. Only gender moderated the relationship between stress and the amount of food intake. Individual differences were small indicating that an individual's dietary response to stress might not be as stable as yet assumed. Moreover, a study suggests that time-varying factors (e.g., food availability) moderate the stress and eating relationship. Hence, intraindividual (i.e., within-person) variability may be relevant. Therefore, we propose an expansion of the individual-difference model, which accounts for time-varying factors.

Bacon, Brownie, or Broccoli? Beliefs about Stress-Relieving Foods and Their Relationship to Orthorexia Nervosa.

BACKGROUND: Nutritional beliefs play an important role when it comes to food choice. However, little attention has been paid to which foods individuals believe to be comforting when experiencing stress. With increasing health awareness in the general public, this study aims to examine whether the nutritional belief exists that only healthy foods relieve stress. If so, we are interested in its relationship to Orthorexia Nervosa (ON) tendencies. METHODS: 175 participants (mean age 28.5 ± 7.8 years, 124 females) completed questionnaires to assess beliefs about stress-relieving foods and ON tendencies. Principal component analysis was used to reduce foods to food groups. Subsequently, a latent profile analysis was performed to identify groups with distinct nutritional beliefs. RESULTS: Among eight distinct groups, one group (8% of the sample) reported the belief that exclusively healthy foods relieve stress. Multinominal logistic regressions showed that higher ON tendencies were associated with that group. CONCLUSIONS: Our findings suggest that individuals with stronger ON tendencies believe that, in particular, healthy foods relieve stress. This indicates that nutritional beliefs in ON concern not only the somatic consequences of certain foods, but also psychological consequences, which might also drive orthorexic behaviour. This offers a new target for the diagnosis and treatment of ON.

Regulation of CD4+ and CD8+ T Cell Biology by Short-Chain Fatty Acids and Its Relevance for Autoimmune Pathology.

The gut microbiota encodes a broad range of enzymes capable of synthetizing various metabolites, some of which are still uncharacterized. One well-known class of microbiota-derived metabolites are the short-chain fatty acids (SCFAs) such as acetate, propionate, butyrate and valerate. SCFAs have long been considered a mere waste product of bacterial metabolism. Novel results have challenged this long-held dogma, revealing a central role for microbe-derived SCFAs in gut microbiota-host interaction. SCFAs are bacterial signaling molecules that act directly on host T lymphocytes by reprogramming their metabolic activity and epigenetic status. They have an essential biological role in promoting differentiation of (intestinal) regulatory T cells and in production of the anti-inflammatory cytokine interleukin-10 (IL-10). These small molecules can also reach the circulation and modulate immune cell function in remote tissues. In experimental models of autoimmune and inflammatory diseases, such as inflammatory bowel disease, multiple sclerosis or diabetes, a strong therapeutic potential of SCFAs through the modulation of effector T cell function was observed. In this review, we discuss current research activities toward understanding a relevance of microbial SCFA for treating autoimmune and inflammatory pathologies from in vitro to human studies.

Investigating the Association Between Polygenic Risk Scores for Alzheimer's Disease With Cognitive Performance and Intrinsic Functional Connectivity in Healthy Adults.

Background: Alzheimer's disease (AD) pathology is present many years before the onset of clinical symptoms. AD dementia cannot be treated. Timely and early detection of people at risk of developing AD is key for primary and secondary prevention. Moreover, understanding the underlying pathology that is present in the earliest stages of AD, and the genetic predisposition to that might contribute to the development of targeted disease-modifying treatments. Objectives: In this study, we aimed to explore whether genetic disposition to AD in asymptomatic individuals is associated with altered intrinsic functional connectivity as well as cognitive performance on neuropsychological tests. Methods: We examined 136 cognitively healthy adults (old group: mean age = 69.32, SD = 4.23; young group: mean age = 31.34, SD = 13.12). All participants had undergone resting-state functional magnetic resonance imagining (fMRI), DNA genotyping to ascertain polygenic risk scores (PRS), and neuropsychological testing for global cognition, working memory, verbal fluency, and executive functions. Results: Two-step hierarchical regression analysis revealed that higher PRS was significantly associated with lower scores in working memory tasks [Letter Number Span: ΔR 2 = 0.077 (p < 0.05); Spatial Span: ΔR 2 = 0.072 (p < 0.05)] in older adults (>60 years). PRS did not show significant modulations of the intrinsic functional connectivity of the posterior cingulate cortex (PCC) with other regions of interest in the brain that are affected in AD. Conclusion: Allele polymorphisms may modify the effect of other AD risk factors. This potential modulation warrants further investigations, particularly in cognitively healthy adults.

Non-mental diseases associated with ADHD across the lifespan: Fidgety Philipp and Pippi Longstocking at risk of multimorbidity?

Several non-mental diseases seem to be associated with an increased risk of ADHD and ADHD seems to be associated with increased risk for non-mental diseases. The underlying trajectories leading to such brain-body co-occurrences are often unclear - are there direct causal relationships from one disorder to the other, or does the sharing of genetic and/or environmental risk factors lead to their occurring together more frequently or both? Our goal with this narrative review was to provide a conceptual synthesis of the associations between ADHD and non-mental disease across the lifespan. We discuss potential shared pathologic mechanisms, genetic background and treatments in co-occurring diseases. For those co-occurrences for which published studies with sufficient sample sizes exist, meta-analyses have been published by others and we discuss those in detail. We conclude that non-mental diseases are common in ADHD and vice versa and add to the disease burden of the patient across the lifespan. Insufficient attention to such co-occurring conditions may result in missed diagnoses and suboptimal treatment in the affected individuals.