Genomic loci influence patterns of structural covariance in the human brain.

Normal and pathologic neurobiological processes influence brain morphology in coordinated ways that give rise to patterns of structural covariance (PSC) across brain regions and individuals during brain aging and diseases. The genetic underpinnings of these patterns remain largely unknown. We apply a stochastic multivariate factorization method to a diverse population of 50,699 individuals (12 studies and 130 sites) and derive data-driven, multi-scale PSCs of regional brain size. PSCs were significantly correlated with 915 genomic loci in the discovery set, 617 of which are newly identified, and 72% were independently replicated. Key pathways influencing PSCs involve reelin signaling, apoptosis, neurogenesis, and appendage development, while pathways of breast cancer indicate potential interplays between brain metastasis and PSCs associated with neurodegeneration and dementia. Using support vector machines, multi-scale PSCs effectively derive imaging signatures of several brain diseases. Our results elucidate genetic and biological underpinnings that influence structural covariance patterns in the human brain.

Altered cortical synaptic lipid signaling leads to intermediate phenotypes of mental disorders.

Excitation/inhibition (E/I) balance plays important roles in mental disorders. Bioactive phospholipids like lysophosphatidic acid (LPA) are synthesized by the enzyme autotaxin (ATX) at cortical synapses and modulate glutamatergic transmission, and eventually alter E/I balance of cortical networks. Here, we analyzed functional consequences of altered E/I balance in 25 human subjects induced by genetic disruption of the synaptic lipid signaling modifier PRG-1, which were compared to 25 age and sex matched control subjects. Furthermore, we tested therapeutic options targeting ATX in a related mouse line. Using EEG combined with TMS in an instructed fear paradigm, neuropsychological analysis and an fMRI based episodic memory task, we found intermediate phenotypes of mental disorders in human carriers of a loss-of-function single nucleotide polymorphism of PRG-1 (PRG-1R345T/WT). Prg-1R346T/WT animals phenocopied human carriers showing increased anxiety, a depressive phenotype and lower stress resilience. Network analysis revealed that coherence and phase-amplitude coupling were altered by PRG-1 deficiency in memory related circuits in humans and mice alike. Brain oscillation phenotypes were restored by inhibtion of ATX in Prg-1 deficient mice indicating an interventional potential for mental disorders.

Left ventricular hypertrophy as a risk factor for accelerated brain aging: Results from the Study of Health in Pomerania.

Previous studies provided evidence for the importance of cardiac structure abnormalities, in particular greater left ventricular (LV) mass, for brain aging, but longitudinal studies are lacking to date. We included 926 individuals (median age 48 years; 53% women) from the TREND cohort of the Study of Health in Pomerania (SHIP) without reduced ejection fraction or a history of myocardial infarction. LV mass index (LVMI) was determined by echocardiography at baseline. Brain morphometric measurements were derived from magnetic resonance images at baseline and 7-year follow-up. Direct effects of baseline LVMI on brain morphometry at follow-up were estimated using linear regression models with adjustment for baseline brain morphometry. At baseline, median LVMI was 40 g/m2.7 and 241 individuals (26%) met the criterion of LV hypertrophy. After correction for multiple testing, baseline LVMI was directly associated with reduced global cortical thickness and increased cortical brain age at follow-up independent from hypertension and blood pressure. Exposure-outcome relations were nonlinear and significantly stronger in the upper half of the exposure distribution. Specifically, an increase in baseline LVMI from the 50% quantile to the 95% quantile was associated additional 2.7 years (95% confidence interval = [1.5 years, 3.8 years]) of cortical brain age at follow-up. Additional regional analyses yielded bilateral effects on multiple frontal cortical regions. Our findings highlight the role of cardiac structure in brain aging. LVMI constitutes an easily measurable marker that might help to identify persons at risk for cognitive impairment and dementia.

Nonalcoholic fatty liver disease, liver fibrosis, and structural brain imaging: The Cross-Cohort Collaboration.

BACKGROUND AND PURPOSE: Prior studies reported conflicting findings regarding the association of nonalcoholic fatty liver disease (NAFLD) and liver fibrosis with measures of brain health. We examined whether NAFLD and liver fibrosis are associated with structural brain imaging measures in middle- and old-age adults. METHODS: In this cross-sectional study among dementia- and stroke-free individuals, data were pooled from the Offspring and Third Generation cohorts of the Framingham Heart Study (FHS), the Rotterdam Study (RS), and the Study of Health in Pomerania. NAFLD was assessed through abdominal imaging. Transient hepatic elastography (FibroScan) was used to assess liver fibrosis in FHS and RS. Linear regression models were used to explore the relation of NAFLD and liver fibrosis with brain volumes, including total brain, gray matter, hippocampus, and white matter hyperintensities, adjusting for potential confounders. Results were combined using fixed effects meta-analysis. RESULTS: In total, 5660 and 3022 individuals were included for NAFLD and liver fibrosis analyses, respectively. NAFLD was associated with smaller volumes of total brain (ß = -3.5, 95% confidence interval [CI] = -5.4 to -1.7), total gray matter (ß = -1.9, 95% CI = -3.4 to -0.3), and total cortical gray matter (ß = -1.9, 95% CI = -3.7 to -0.01). In addition, liver fibrosis (defined as liver stiffness measure ≥8.2 kPa) was related to smaller total brain volumes (ß = -7.3, 95% CI = -11.1 to -3.5). Heterogeneity between studies was low. CONCLUSIONS: NAFLD and liver fibrosis may be directly related to brain aging. Larger and prospective studies are warranted to validate these findings and identify liver-related preventive strategies for neurodegeneration.

Association Between Psychosocial Stress and Brain Aging: Results of the Population-Based Cohort Study of Health in Pomerania (SHIP).

OBJECTIVE: Recent studies suggest that psychosocial factors can have an impact on brain health. Yet, it is unclear whether psychosocial stress affects aging of the brain. The aim of the study was to investigate the association between psychosocial stress and brain aging. METHODS: Data from the German population-based cohort Study of Health in Pomerania (N=991; age range 20-78 years) were used to calculate a total psychosocial stress score by combining subscores from five domains: stress related to the living situation, the occupational situation, the social situation, danger experiences, and emotions. Associations with brain aging, indicated by an MRI-derived score quantifying age-related brain atrophy, were estimated by using regression models adjusted for age, gender, education, diabetes, problematic alcohol consumption, smoking, and hypertension. RESULTS: The relative risk ratio for advanced brain aging was 1.21 (95% CI=1.04-1.41) for stress related to emotions in fully adjusted models. The interactions between stress related to emotions and mental health symptoms were also significantly associated with advanced brain aging. The association between higher total psychosocial stress and brain aging was not statistically significant. CONCLUSIONS: These findings highlight that high stress related to emotions is associated with advanced brain aging. To protect brain health in older age, more research is needed to explore the role of emotional distress.

Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI.

Cerebral white matter hyperintensities on MRI are markers of cerebral small vessel disease, a major risk factor for dementia and stroke. Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation has received little attention. We investigated the association between white matter hyperintensity burden and DNA methylation in blood at ∼450 000 cytosine-phosphate-guanine (CpG) sites in 9732 middle-aged to older adults from 14 community-based studies. Single CpG and region-based association analyses were carried out. Functional annotation and integrative cross-omics analyses were performed to identify novel genes underlying the relationship between DNA methylation and white matter hyperintensities. We identified 12 single CpG and 46 region-based DNA methylation associations with white matter hyperintensity burden. Our top discovery single CpG, cg24202936 (P = 7.6 × 10-8), was associated with F2 expression in blood (P = 6.4 × 10-5) and co-localized with FOLH1 expression in brain (posterior probability = 0.75). Our top differentially methylated regions were in PRMT1 and in CCDC144NL-AS1, which were also represented in single CpG associations (cg17417856 and cg06809326, respectively). Through Mendelian randomization analyses cg06809326 was putatively associated with white matter hyperintensity burden (P = 0.03) and expression of CCDC144NL-AS1 possibly mediated this association. Differentially methylated region analysis, joint epigenetic association analysis and multi-omics co-localization analysis consistently identified a role of DNA methylation near SH3PXD2A, a locus previously identified in genome-wide association studies of white matter hyperintensities. Gene set enrichment analyses revealed functions of the identified DNA methylation loci in the blood-brain barrier and in the immune response. Integrative cross-omics analysis identified 19 key regulatory genes in two networks related to extracellular matrix organization, and lipid and lipoprotein metabolism. A drug-repositioning analysis indicated antihyperlipidaemic agents, more specifically peroxisome proliferator-activated receptor-alpha, as possible target drugs for white matter hyperintensities. Our epigenome-wide association study and integrative cross-omics analyses implicate novel genes influencing white matter hyperintensity burden, which converged on pathways related to the immune response and to a compromised blood-brain barrier possibly due to disrupted cell-cell and cell-extracellular matrix interactions. The results also suggest that antihyperlipidaemic therapy may contribute to lowering risk for white matter hyperintensities possibly through protection against blood-brain barrier disruption.

Value-related attitudes towards mental health problems and help-seeking barriers: a sequential mixed-methods design investigating participants with reported depressive episodes in rural Northern Germany with and without treatment experience.

BACKGROUND: Seeking help for severe depressive symptoms remains a major obstacle for particular groups within the general population. Value-related attitudes might contribute to this treatment gap, particularly in rural regions with a low density of psychiatric-psychotherapeutic services. We aimed to investigate narratives of socialization, value systems, and barriers of help-seeking to better understand social milieus at increased risk for underuse of psychiatric-psychotherapeutic services in a rural area in East Germany. This could complement the explanatory power of classical socio-demographic determinants and provide guidance for possible interventions. METHOD: Based on results of an analysis of a population-based German cohort study (SHIP-TREND-1), 20 individual semi-structured interviews were conducted with participants who met criteria for having been moderately or severely depressed at least once in their life. Qualitative analyses of interview data were guided by grounded theory methodology. RESULTS: Participants with severe symptoms of depression were more frequent among non-responders of this study. We identified key aspects that influence help-seeking for mental health problems and seem to be characteristic for rural regions: family doctors serve as initial contact points for mental health problems and are considered as alternatives for mental health professionals; norms of traditional masculinity such as being more rational than emotional, needing to endure hardships, embodying strength, and being independent were frequently mentioned as inhibiting help-seeking by middle-aged men; anticipated adverse side-effects of therapy such as worsening of symptoms; a frequently expressed desire for less pathologically perceived treatment options. CONCLUSIONS: Our results suggest that barriers regarding help-seeking in rural regions are multifaceted and seem to be influenced by traditional norms of masculinity. We believe it is critical to strengthen existing and already utilized services such as family doctors and to implement and evaluate tailored interventions targeting the needs of the rural milieu.

Association between maternal pre-pregnancy body mass index and offspring's outcomes at 9 to 15 years of age.

OBJECTIVE: Maternal pre-pregnancy underweight, overweight and obesity might increase the risk for worse short- and long-term outcome in the offspring. There is a need for further study into the relationship between maternal pre-pregnancy body mass index (BMI) and the combined outcome of physical development, state of health and social behavior in children. QUESTION: Is maternal pre-pregnancy BMI associated with the child outcome in terms of physical development, state of health and social behavior (school and leisure time behavior) at the age of 9 to 15 years? METHODS: In the population-based birth cohort study Survey of Neonates in Pomerania (SNIP) children at the age 9-15 years and their families were re-examined by questionnaire-based follow-up. 5725 mother-child pairs were invited to SNiP-follow-up. This analysis is based on the recall fraction of 24.1% (n = 1379). Based on the maternal pre-pregnancy BMI (ppBMI), 4 groups were formed: underweight (ppBMI < 19 kg/m2, n = 117), normal weight (ppBMI 19-24.99 kg/m2, n = 913, reference), overweight (ppBMI 25-30 kg). /m2, n = 237) and obesity (ppBMI > 30 kg/m2, n = 109). RESULTS: In the multiple regression model, the BMI-z-score for children of mothers in the underweight group was -0.50 lower, and 0.50/1.07 higher in the overweight/obese group (p < 0.001) compared to reference at median age of 12 years. No differences were found in children of underweight mothers with regard to social behavior (interaction with friends and family), school and sports performance (coded from "very good" to "poor"), other leisure activities (watching television, using mobile phones, gaming), and health (occurrence of illnesses) compared to children of normal weight mothers. In contrast, maternal pre-pregnancy overweight and obesity were associated with lower school and sports performance, and higher screen time (smart phone, gaming, television) compared to children of normal weight mothers. CONCLUSION: Maternal pre-pregnancy overweight and obesity but not underweight was negatively associated with school performance and leisure time behavior in the offspring at 9-15 years of age.

Circulating microRNA miR-425-5p Associated with Brain White Matter Lesions and Inflammatory Processes.

White matter lesions (WML) emerge as a consequence of vascular injuries in the brain. While they are commonly observed in aging, associations have been established with neurodegenerative and neurological disorders such as dementia or stroke. Despite substantial research efforts, biological mechanisms are incomplete and biomarkers indicating WMLs are lacking. Utilizing data from the population-based Study of Health in Pomerania (SHIP), our objective was to identify plasma-circulating micro-RNAs (miRNAs) associated with WMLs, thus providing a foundation for a comprehensive biological model and further research. In linear regression models, direct association and moderating factors were analyzed. In 648 individuals, we identified hsa-miR-425-5p as directly associated with WMLs. In subsequent analyses, hsa-miR-425-5p was found to regulate various genes associated with WMLs with particular emphasis on the SH3PXD2A gene. Furthermore, miR-425-5p was found to be involved in immunological processes. In addition, noteworthy miRNAs associated with WMLs were identified, primarily moderated by the factors of sex or smoking status. All identified miRNAs exhibited a strong over-representation in neurodegenerative and neurological diseases. We introduced hsa-miR-425-5p as a promising candidate in WML research probably involved in immunological processes. Mir-425-5p holds the potential as a biomarker of WMLs, shedding light on potential mechanisms and pathways in vascular dementia.

Methylation Patterns of the FKBP5 Gene in Association with Childhood Maltreatment and Depressive Disorders.

Childhood maltreatment is an important risk factor for adult depression and has been associated with changes in the hypothalamic pituitary adrenal (HPA) axis, including cortisol secretion and methylation of the FKBP5 gene. Furthermore, associations between depression and HPA changes have been reported. This study investigated the associations of whole-blood FKBP5 mRNA levels, serum cortisol levels, childhood maltreatment, and depressive symptoms with the whole-blood methylation status (assessed via target bisulfite sequencing) of 105 CpGs at the FKBP5 locus using data from the general population-based Study of Health in Pomerania (SHIP) (N = 203). Both direct and interaction effects with the rs1360780 single-nucleotide polymorphism were investigated. Nominally significant associations of main effects on methylation of a single CpG site were observed at intron 3, intron 7, and the 3'-end of the gene. Additionally, methylation at two clusters at the 3'-end and intron 7 were nominally associated with childhood maltreatment × rs1360780 and depressive symptoms × rs1360780, respectively. The results add to the understanding of molecular mechanisms underlying the emergence of depression and could aid the development of personalised depression therapy and drug development.

Proposing a communication module to enhance dental students' attitudes towards people with dementia: Phase 1 of a curriculum revision study.

INTRODUCTION: The number of mentally altered patients a dentist meets in practice is increasing and interaction with them can be very challenging. As a baseline for an interventional study, we want to assess the attitude of dental students and identify areas of improvement in patient communication. This work compares the attitude of dental students towards people suffering from dementia to the attitudes of trained medical caregivers and the general population. Our aim is to use the results to assess the need for training in communicating with mentally altered patients. MATERIALS AND METHODS: Fourth-year dental students attended two lectures on dementia given by a psychiatrist as part of the geriatric dentistry lecture and were questioned afterwards using the Dementia Attitude Scale. In 2016 and 2017, 73 students at the University of Greifswald were interviewed. The response rate was 84%. Using a factor analysis, the Dementia Attitude Scale's validated questions were interpreted and compared with data from nursing staff from Switzerland and the USA. RESULTS: The factor analysis of the data showed the same two-factor loadings as the comparative groups, and that dental students' attitude is more comparable to the general population than to medically trained nursing staff. CONCLUSION: Given the results, we conclude that the implementation of a communication module can serve in improving the attitude of dental students towards patients with dementia.

Circulating Metabolome and White Matter Hyperintensities in Women and Men.

BACKGROUND: White matter hyperintensities (WMH), identified on T2-weighted magnetic resonance images of the human brain as areas of enhanced brightness, are a major risk factor of stroke, dementia, and death. There are no large-scale studies testing associations between WMH and circulating metabolites. METHODS: We studied up to 9290 individuals (50.7% female, average age 61 years) from 15 populations of 8 community-based cohorts. WMH volume was quantified from T2-weighted or fluid-attenuated inversion recovery images or as hypointensities on T1-weighted images. Circulating metabolomic measures were assessed with mass spectrometry and nuclear magnetic resonance spectroscopy. Associations between WMH and metabolomic measures were tested by fitting linear regression models in the pooled sample and in sex-stratified and statin treatment-stratified subsamples. Our basic models were adjusted for age, sex, age×sex, and technical covariates, and our fully adjusted models were also adjusted for statin treatment, hypertension, type 2 diabetes, smoking, body mass index, and estimated glomerular filtration rate. Population-specific results were meta-analyzed using the fixed-effect inverse variance-weighted method. Associations with false discovery rate (FDR)-adjusted P values (PFDR)<0.05 were considered significant. RESULTS: In the meta-analysis of results from the basic models, we identified 30 metabolomic measures associated with WMH (PFDR<0.05), 7 of which remained significant in the fully adjusted models. The most significant association was with higher level of hydroxyphenylpyruvate in men (PFDR.full.adj=1.40×10-7) and in both the pooled sample (PFDR.full.adj=1.66×10-4) and statin-untreated (PFDR.full.adj=1.65×10-6) subsample. In men, hydroxyphenylpyruvate explained 3% to 14% of variance in WMH. In men and the pooled sample, WMH were also associated with lower levels of lysophosphatidylcholines and hydroxysphingomyelins and a larger diameter of low-density lipoprotein particles, likely arising from higher triglyceride to total lipids and lower cholesteryl ester to total lipids ratios within these particles. In women, the only significant association was with higher level of glucuronate (PFDR=0.047). CONCLUSIONS: Circulating metabolomic measures, including multiple lipid measures (eg, lysophosphatidylcholines, hydroxysphingomyelins, low-density lipoprotein size and composition) and nonlipid metabolites (eg, hydroxyphenylpyruvate, glucuronate), associate with WMH in a general population of middle-aged and older adults. Some metabolomic measures show marked sex specificities and explain a sizable proportion of WMH variance.

Depression, cardiometabolic disease, and their co-occurrence after childhood maltreatment: an individual participant data meta-analysis including over 200,000 participants.

BACKGROUND: Childhood maltreatment is associated with depression and cardiometabolic disease in adulthood. However, the relationships with these two diseases have so far only been evaluated in different samples and with different methodology. Thus, it remains unknown how the effect sizes magnitudes for depression and cardiometabolic disease compare with each other and whether childhood maltreatment is especially associated with the co-occurrence ("comorbidity") of depression and cardiometabolic disease. This pooled analysis examined the association of childhood maltreatment with depression, cardiometabolic disease, and their comorbidity in adulthood. METHODS: We carried out an individual participant data meta-analysis on 13 international observational studies (N = 217,929). Childhood maltreatment comprised self-reports of physical, emotional, and/or sexual abuse before 18 years. Presence of depression was established with clinical interviews or validated symptom scales and presence of cardiometabolic disease with self-reported diagnoses. In included studies, binomial and multinomial logistic regressions estimated sociodemographic-adjusted associations of childhood maltreatment with depression, cardiometabolic disease, and their comorbidity. We then additionally adjusted these associations for lifestyle factors (smoking status, alcohol consumption, and physical activity). Finally, random-effects models were used to pool these estimates across studies and examined differences in associations across sex and maltreatment types. RESULTS: Childhood maltreatment was associated with progressively higher odds of cardiometabolic disease without depression (OR [95% CI] = 1.27 [1.18; 1.37]), depression without cardiometabolic disease (OR [95% CI] = 2.68 [2.39; 3.00]), and comorbidity between both conditions (OR [95% CI] = 3.04 [2.51; 3.68]) in adulthood. Post hoc analyses showed that the association with comorbidity was stronger than with either disease alone, and the association with depression was stronger than with cardiometabolic disease. Associations remained significant after additionally adjusting for lifestyle factors, and were present in both males and females, and for all maltreatment types. CONCLUSIONS: This meta-analysis revealed that adults with a history of childhood maltreatment suffer more often from depression and cardiometabolic disease than their non-exposed peers. These adults are also three times more likely to have comorbid depression and cardiometabolic disease. Childhood maltreatment may therefore be a clinically relevant indicator connecting poor mental and somatic health. Future research should investigate the potential benefits of early intervention in individuals with a history of maltreatment on their distal mental and somatic health (PROSPERO CRD42021239288).

Identification of candidate metabolite biomarkers for metabolic syndrome and its five components in population-based human cohorts.

BACKGROUND: Metabolic Syndrome (MetS) is characterized by risk factors such as abdominal obesity, hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C), hypertension, and hyperglycemia, which contribute to the development of cardiovascular disease and type 2 diabetes. Here, we aim to identify candidate metabolite biomarkers of MetS and its associated risk factors to better understand the complex interplay of underlying signaling pathways. METHODS: We quantified serum samples of the KORA F4 study participants (N = 2815) and analyzed 121 metabolites. Multiple regression models adjusted for clinical and lifestyle covariates were used to identify metabolites that were Bonferroni significantly associated with MetS. These findings were replicated in the SHIP-TREND-0 study (N = 988) and further analyzed for the association of replicated metabolites with the five components of MetS. Database-driven networks of the identified metabolites and their interacting enzymes were also constructed. RESULTS: We identified and replicated 56 MetS-specific metabolites: 13 were positively associated (e.g., Val, Leu/Ile, Phe, and Tyr), and 43 were negatively associated (e.g., Gly, Ser, and 40 lipids). Moreover, the majority (89%) and minority (23%) of MetS-specific metabolites were associated with low HDL-C and hypertension, respectively. One lipid, lysoPC a C18:2, was negatively associated with MetS and all of its five components, indicating that individuals with MetS and each of the risk factors had lower concentrations of lysoPC a C18:2 compared to corresponding controls. Our metabolic networks elucidated these observations by revealing impaired catabolism of branched-chain and aromatic amino acids, as well as accelerated Gly catabolism. CONCLUSION: Our identified candidate metabolite biomarkers are associated with the pathophysiology of MetS and its risk factors. They could facilitate the development of therapeutic strategies to prevent type 2 diabetes and cardiovascular disease. For instance, elevated levels of lysoPC a C18:2 may protect MetS and its five risk components. More in-depth studies are necessary to determine the mechanism of key metabolites in the MetS pathophysiology.

Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning.

Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.

Lack of structural brain alterations associated with insomnia: findings from the ENIGMA-Sleep Working Group.

Existing neuroimaging studies have reported divergent structural alterations in insomnia disorder (ID). In the present study, we performed a large-scale coordinated meta-analysis by pooling structural brain measures from 1085 subjects (mean [SD] age 50.5 [13.9] years, 50.2% female, 17.4% with insomnia) across three international Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA)-Sleep cohorts. Two sites recruited patients with ID/controls: Freiburg (University of Freiburg Medical Center, Freiburg, Germany) 42/43 and KUMS (Kermanshah University of Medical Sciences, Kermanshah, Iran) 42/49, while the Study of Health in Pomerania (SHIP-Trend, University Medicine Greifswald, Greifswald, Germany) recruited population-based individuals with/without insomnia symptoms 75/662. The influence of insomnia on magnetic resonance imaging-based brain morphometry using an insomnia brain score was then assessed. Within each cohort, we used an ordinary least-squares linear regression to investigate the link between the individual regional cortical and subcortical volumes and the presence of insomnia symptoms. Then, we performed a fixed-effects meta-analysis across cohorts based on the first-level results. For the insomnia brain score, weighted logistic ridge regression was performed on one sample (Freiburg), which separated patients with ID from controls to train a model based on the segmentation measurements. Afterward, the insomnia brain scores were validated using the other two samples. The model was used to predict the log-odds of the subjects with insomnia given individual insomnia-related brain atrophy. After adjusting for multiple comparisons, we did not detect any significant associations between insomnia symptoms and cortical or subcortical volumes, nor could we identify a global insomnia-related brain atrophy pattern. Thus, we observed inconsistent brain morphology differences between individuals with and without insomnia across three independent cohorts. Further large-scale cross-sectional/longitudinal studies using both structural and functional neuroimaging are warranted to decipher the neurobiology of insomnia.

Mental health-related telemedicine interventions for pregnant women and new mothers: a systematic literature review.

BACKGROUND: Pregnancy and the postpartum period are times when women are at increased risk for depression and mental problems. This may also negatively affect the foetus. Thus, there is a need for interventions with low-threshold access and care. Telemedicine interventions are a promising approach to address these issues. This systematic literature review examined the efficacy of telemedicine interventions for pregnant women and/or new mothers to address mental health-related outcomes. The primary objective was to analyse whether telemedicine interventions can reduce mental health problems in pregnant women and new mothers. The secondary aim was to clarify the impact of type of interventions, their frequency and their targets. METHODS: Inclusion criteria: randomized controlled trials, with participants being pregnant women and/or new mothers (with infants up to twelve months), involving telemedicine interventions of any kind (e.g. websites, apps, chats, telephone), and addressing any mental health-related outcomes like depression, postnatal depression, anxiety, stress and others. Search terms were pregnant women, new mothers, telemedicine, RCT (randomised controlled trials), mental stress as well as numerous synonyms including medical subject headings. The literature search was conducted within the databases PubMed, Cochrane Library, Web of Science and PsycINFO. Screening, inclusion of records and data extraction were performed by two researchers according to the PRISMA guidelines, using the online tool CADIMA. RESULTS: Forty four articles were included. A majority (62%) reported significantly improved mental health-related outcomes for participants receiving telemedicine interventions compared to control. In particular (internet-delivered) Cognitive Behavioural Therapy was successful for depression and stress, and peer support improved outcomes for postnatal depression and anxiety. Interventions with preventive approaches and interventions aimed at symptom reduction were largely successful. For the most part there was no significant improvement in the symptoms of anxiety. CONCLUSION: Telemedicine interventions evaluated within RCTs were mostly successful. However, they need to be designed to specifically target a certain mental health issue because there is no one-size-fits-all approach. Further research should focus on which specific interventions are appropriate for which mental health outcomes in terms of intervention delivery modes, content, target approaches, etc. Further investigation is needed, in particular with regard to anxiety.

Prevalence of COVID-19 and Psychotropic Drug Treatment in Psychiatric In-patients in Germany in 2020: Results from a Nationwide Pilot Survey.

INTRODUCTION: In patients with a pre-existing mental disorder, an increased risk for a first manifestation of a psychiatric disorder in COVID-19 patients, a more severe course of COVID-19 and an increased mortality have been described. Conversely, observations of lower COVID-19 incidences in psychiatric in-patients suggested protective effects of psychiatric treatment and/or psychotropic drugs against COVID-19. METHODS: A retrospective multi-center study was conducted in 24 German psychiatric university hospitals. Between April and December 2020 (the first and partly second wave of COVID-19), the effects of COVID-19 were assessed on psychiatric in-patient care, the incidence and course of a SARS-CoV-2 infection, and treatment with psychotropic drugs. RESULTS: Patients (n=36,322) were admitted to the hospitals. Mandatory SARS-CoV-2 tests before/during admission were reported by 23 hospitals (95.8%), while 18 (75%) conducted regular testing during the hospital stay. Two hundred thirty-two (0.6%) patients were tested SARS-CoV-2-positive. Thirty-seven (16%) patients were receiving medical treatment for COVID-19 at the psychiatric hospital, ten (4.3%) were transferred to an intermediate/intensive care unit, and three (1.3%) died. The most common prescription for SARS-CoV-2-positive patients was for second-generation antipsychotics (n=79, 28.2%) and antidepressants (SSRIs (n=38, 13.5%), mirtazapine (n=36, 12.9%) and SNRIs (n=29, 10.4%)). DISCUSSION: Contrary to previous studies, our results showed a low number of infections and mortality in SARS-CoV-2-positive psychiatric patients. Several preventive measures seem effective to protect this vulnerable group. Our observations are compatible with the hypothesis of a protective effect of psychotropic drugs against COVID-19 as the overall mortality and need for specific medical treatment was low.

Association of spermidine plasma levels with brain aging in a population-based study.

INTRODUCTION: Supplementation with spermidine may support healthy aging, but elevated spermidine tissue levels were shown to be an indicator of Alzheimer's disease (AD). METHODS: Data from 659 participants (age range: 21-81 years) of the population-based Study of Health in Pomerania TREND were included. We investigated the association between spermidine plasma levels and markers of brain aging (hippocampal volume, AD score, global cortical thickness [CT], and white matter hyperintensities [WMH]). RESULTS: Higher spermidine levels were significantly associated with lower hippocampal volume (ß = -0.076; 95% confidence interval [CI]: -0.13 to -0.02; q = 0.026), higher AD score (ß = 0.118; 95% CI: 0.05 to 0.19; q = 0.006), lower global CT (ß = -0.104; 95% CI: -0.17 to -0.04; q = 0.014), but not WMH volume. Sensitivity analysis revealed no substantial changes after excluding participants with cancer, depression, or hemolysis. DISCUSSION: Elevated spermidine plasma levels are associated with advanced brain aging and might serve as potential early biomarker for AD and vascular brain pathology.

Deciphering the Effect of Different Genetic Variants on Hippocampal Subfield Volumes in the General Population.

The aim of this study was to disentangle the effects of various genetic factors on hippocampal subfield volumes using three different approaches: a biologically driven candidate gene approach, a hypothesis-free GWAS approach, and a polygenic approach, where AD risk alleles are combined with a polygenic risk score (PRS). The impact of these genetic factors was investigated in a large dementia-free general population cohort from the Study of Health in Pomerania (SHIP, n = 1806). Analyses were performed using linear regression models adjusted for biological and environmental risk factors. Hippocampus subfield volume alterations were found for APOE ε4, BDNF Val, and 5-HTTLPR L allele carriers. In addition, we were able to replicate GWAS findings, especially for rs17178139 (MSRB3), rs1861979 (DPP4), rs7873551 (ASTN2), and rs572246240 (MAST4). Interaction analyses between the significant SNPs as well as the PRS for AD revealed no significant results. Our results confirm that hippocampal volume reductions are influenced by genetic variation, and that different variants reveal different association patterns that can be linked to biological processes in neurodegeneration. Thus, this study underlines the importance of specific genetic analyses in the quest for acquiring deeper insights into the biology of hippocampal volume loss, memory impairment, depression, and neurodegenerative diseases.