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.

[18F]GE-180-PET and Post Mortem Marker Characteristics of Long-Term High-Fat-Diet-Induced Chronic Neuroinflammation in Mice.

Obesity is characterized by immoderate fat accumulation leading to an elevated risk of neurodegenerative disorders, along with a host of metabolic disturbances. Chronic neuroinflammation is a main factor linking obesity and the propensity for neurodegenerative disorders. To determine the cerebrometabolic effects of diet-induced obesity (DIO) in female mice fed a long-term (24 weeks) high-fat diet (HFD, 60% fat) compared to a group on a control diet (CD, 20% fat), we used in vivo PET imaging with the radiotracer [18F]FDG as a marker for brain glucose metabolism. In addition, we determined the effects of DIO on cerebral neuroinflammation using translocator protein 18 kDa (TSPO)-sensitive PET imaging with [18F]GE-180. Finally, we performed complementary post mortem histological and biochemical analyses of TSPO and further microglial (Iba1, TMEM119) and astroglial (GFAP) markers as well as cerebral expression analyses of cytokines (e.g., Interleukin (IL)-1ß). We showed the development of a peripheral DIO phenotype, characterized by increased body weight, visceral fat, free triglycerides and leptin in plasma, as well as increased fasted blood glucose levels. Furthermore, we found obesity-associated hypermetabolic changes in brain glucose metabolism in the HFD group. Our main findings with respect to neuroinflammation were that neither [18F]GE-180 PET nor histological analyses of brain samples seem fit to detect the predicted cerebral inflammation response, despite clear evidence of perturbed brain metabolism along with elevated IL-1ß expression. These results could be interpreted as a metabolically activated state in brain-resident immune cells due to a long-term HFD.

The effect of different weight loss strategies to treat non-alcoholic fatty liver disease focusing on fibroblast growth factor 21.

Objective: Obesity, often associated with non-alcoholic fatty liver disease (NAFLD), is characterized by an imbalance between energy expenditure and food intake, which is also reflected by desensitization of fibroblast growth factor 21 (FGF21). FGF21 is strongly influenced, among others, by TNFα, which is known to be upregulated in obesity-induced inflammation. Successful long-term treatments of NAFLD might be dietary modification, exercise, or fasting. Materials and methods: Whether succeeded NAFLD recovery is linked with improved FGF21 sensitivity and finally reverted FGF21 resistance was the focus of the present study. For this purpose, mice received a high-fat diet (HFD) for 6 months to establish obesity. Afterward, the mice were subjected to three different weight loss interventions, namely, dietary change to low-fat diet (LFD), treadmill training, and/or time-restricted feeding for additional 6 months, whereas one group remained on HFD. Results: In addition to the expected decrease in NAFLD activity with dietary change, this was also observed in the HFD group with additional time-restricted feeding. There was also an associated decrease in hepatic TNFα and FGF21 expression and an increase in ß-klotho expression, demonstrated mainly by using principal component analysis. Pearson correlation analysis shows that independent of any intervention, TNFα expression decreased with improved NAFLD recovery. This was accompanied with higher FGF21 sensitivity, as expressed by an increase in ß-klotho and FGFR1c expression and concomitantly decreased FGF21 levels. Conclusion: In summary, we conclude that successful NAFLD therapy is associated with a reversion of the TNFα-triggered FGF21-resistant state or desensitization.

Interaction of childhood abuse and depressive symptoms on cortical thickness: a general population study.

Childhood abuse was inconsistently related to whole-brain cortical thickness in former studies. However, both childhood abuse and cortical thickness have been associated with depressive symptoms. We hypothesised that childhood abuse moderates the association between depressive symptoms and cortical thickness. In 1551 individuals of the general population, associations between whole-brain cortical thickness and the interaction of childhood abuse (emotional, physical, and sexual) and depressive symptoms were analysed using an ANCOVA. Linear regression analyses were used to estimate the same effect on the cortical thickness of 34 separate regions (Desikan-Killiany-atlas). A significant interaction effect of childhood abuse and depressive symptoms was observed for whole-brain cortical thickness (F(2, 1534) = 5.28, p = 0.007). A thinner cortex was associated with depressive symptoms in abused (t value = 2.78, p = 0.025) but not in non-abused participants (t value = - 1.50, p = 0.224). Focussing on non-depressed participants, a thicker whole-brain cortex was found in abused compared to non-abused participants (t value = - 2.79, p = 0.025). Similar interaction effects were observed in 12 out of 34 cortical regions. Our results suggest that childhood abuse is associated with reduced cortical thickness in subjects with depressive symptoms. In abused subjects without depressive symptoms, larger cortical thickness might act compensatory and thus reflect resilience against depressive symptoms.

The neurobiology of childhood trauma-aldosterone and blood pressure changes in a community sample.

OBJECTIVE: Childhood trauma is an important risk factor for the onset and course of psychiatric disorders and particularly major depression. Recently, the renin-angiotensin-aldosterone system, one of the core stress hormone systems, has been demonstrated to be modified by childhood trauma. METHODS: Childhood trauma was obtained using the Childhood Trauma Questionnaire (CTQ) in a community-dwelling sample (N = 2038). Plasma concentrations of renin and aldosterone were measured in subjects with childhood trauma (CT; N = 385) vs. subjects without this experience (NoCT; N = 1653). Multivariable linear regression models were calculated to assess the associations between CTQ, systolic and diastolic blood pressure, renin and aldosterone concentrations, and the ratio of aldosterone and systolic blood pressure (A/SBP). RESULTS: CT subjects demonstrated higher plasma aldosterone (A) concentrations, a lower systolic and diastolic blood pressure, and a higher A/SBP. In addition, both aldosterone concentrations, as well as A/SBP, correlated with the severity of childhood trauma. These findings could not be attributed to differences in concomitant medication. CONCLUSIONS: In conclusion, childhood trauma was associated with neurobiological markers, which may impact the risk for psychiatric disorders, primarily major depression. The altered A/SBP ratio points to a desensitisation of peripheral mineralocorticoid receptor function, which may be a target for therapeutic interventions.

Body mass index but not genetic risk is longitudinally associated with altered structural brain parameters.

Evidence from previous studies suggests that elevated body mass index (BMI) and genetic risk for obesity is associated with reduced brain volume, particularly in areas of reward-related cognition, e.g. the medial prefrontal cortex (AC-MPFC), the orbitofrontal cortex (OFC), the striatum and the thalamus. However, only few studies examined the interplay between these factors in a joint approach. Moreover, previous findings are based on cross-sectional data. We investigated the longitudinal relationship between increased BMI, brain structural magnetic resonance imaging (MRI) parameters and genetic risk scores in a cohort of n = 502 community-dwelling participants from the Study of Health in Pomerania (SHIP) with a mean follow-up-time of 4.9 years. We found that (1) increased BMI values at baseline were associated with decreased brain parameters at follow-up. These effects were particularly pronounced for the OFC and AC-MPFC. (2) The genetic predisposition for BMI had no effect on brain parameters at baseline or follow-up. (3) The interaction between the genetic score for BMI and brain parameters had no effect on BMI at baseline. Finding a significant impact of overweight, but not genetic predisposition for obesity on altered brain structure suggests that metabolic mechanisms may underlie the relationship between obesity and altered brain structure.

Fibroblast Growth Factor 21 as a Potential Biomarker for Improved Locomotion and Olfaction Detection Ability after Weight Reduction in Obese Mice.

Obesity is one of the most challenging diseases of the 21st century and is accompanied by behavioural disorders. Exercise, dietary adjustments, or time-restricted feeding are the only successful long-term treatments to date. Fibroblast growth factor 21 (FGF21) plays a key role in dietary regulation, but FGF21 resistance is prevalent in obesity. The aim of this study was to investigate in obese mice whether weight reduction leads to improved behaviour and whether these behavioural changes are associated with decreased plasma FGF21 levels. After establishing a model for diet-induced obesity, mice were subjected to three different interventions for weight reduction, namely dietary change, treadmill exercise, or time-restricted feeding. In this study, we demonstrated that only the combination of dietary change and treadmill exercise affected all parameters leading to a reduction in weight, fat, and FGF21, as well as less anxious behaviour, higher overall activity, and improved olfactory detection abilities. To investigate the interrelationship between FGF21 and behavioural parameters, feature selection algorithms were applied designating FGF21 and body weight as one of five highly weighted features. In conclusion, we concluded from the complementary methods that FGF21 can be considered as a potential biomarker for improved behaviour in obese mice after weight reduction.

Alexithymia is associated with reduced vitamin D levels, but not polymorphisms of the vitamin D binding-protein gene.

OBJECTIVE: Alexithymia is a personality trait characterized by difficulties in identifying and describing emotions, which is associated with various psychiatric disorders, including depression and posttraumatic stress disorder (PTSD). Its pathogenesis is incompletely understood but previous studies suggested that genetic as well as metabolic factors, are involved. However, no results on the role of vitamin D and the polymorphisms rs4588 and rs7041 of the vitamin D binding protein (VDBP) have been published so far. METHODS: Serum levels of total 25(OH)D were measured in two general-population samples (total n = 5733) of the Study of Health in Pomerania (SHIP). The Toronto Alexithymia Scale-20 (TAS-20) was applied to measure alexithymia. Study participants were genotyped for rs4588 and rs7041. Linear and logistic regression analyses adjusted for sex, age, waist circumference, physical activity, season and study and, when applicable, for the batch of genotyping and the first three genetic principal components, were performed. In sensitivity analyses, the models were additionally adjusted for depressive symptoms. RESULTS: 25(OH)D levels were negatively associated with TAS-20 scores (ß = -0.002; P < 0.001) and alexithymia according to the common cutoff of TAS-20>60 (ß = -0.103; P < 0.001). These results remained stable after adjusting for depressive symptoms. The tested genetic polymorphisms were not significantly associated with alexithymia. CONCLUSIONS: Our results suggest that low vitamin D levels may be involved in the pathophysiology of alexithymia. Given that no associations between alexithymia and rs4588 as well as rs7041 were observed, indicates that behavioral or nutritional features of alexithymic subjects could also explain this association.

[Medical education in psychosocial disciplines in times of the COVID-19 pandemic - first experiences]. / Lehre in den psychosozialen medizinischen Fächern in Zeiten der COVID-19-Pandemie ­ erste Erfahrungen.

AIM: In specialties that heavily rely on communication skills such as psychiatry, psychotherapy and psychosomatic medicine, teaching in times of the COVID-19 pandemic is especially challenging. In this overview, educators and course directors report their experiences in eteaching and share their innovative solutions. METHODS: We present a collection of methods that relate to teaching and assessment as well as student activation. RESULTS: A range of helpful tools for teaching were compiled. This includes instructional videos with simulated patients, structured homework to document a mental status examination, structured hand-offs, and practical examinations in video format. Motivational techniques include podcasts with interviews with clinicians and patients and teaching with the use of cinematic material. DISCUSSION: Switching to online formats creates opportunities and advantages for the advancement of time- and location-independent learning. A fast conversion in this direction might also pose some disadvantages. A direct patient-student interaction is critical for engaging with transference, countertransference and situational aspects for teaching in psychosocial disciplines. Empirical studies of the effectiveness of these newly developed formats and faculty development for digital teaching are necessary.

Alexithymia is associated with increased all-cause mortality risk in men, but not in women: A 10-year follow-up study.

OBJECTIVE: Alexithymia is associated with various mental as well as physical disorders. Some evidence also suggested high alexithymia to increase mortality risk, but these results are few and based on specific sample compositions. We aimed to investigate the impact of alexithymia on mortality risk in a large population based cohort. In addition, we sought to elucidate the effects of the subfactors of alexithymia and sex differences. METHODS: In a sample of N = 1380 individuals from the Study of Health in Pomerania (SHIP), we investigated the hazard-ratio (HR) of alexithymia as obtained by the Toronto Alexithymia Scale-20 (TAS-20) on all-cause mortality over an average observation time of 10 years. Sex-by-TAS-20-interactions as well as sex-stratified analyses were performed. RESULTS: Alexithymia was significantly associated with enhanced mortality risk (HR = 1.033; 95%-CI = 1.008-1.058); p = 0.009). While sex-by-TAS-20 interactions remained insignificant, sex-stratified analyses showed that this effect was only significant in men (HR = 1.050; 95%-CI = 1.022-1.079; p ≤ 0.001), but not in women (HR: 1.008; 95%-CI = 0.960-1.057; p = 0.76). The effect was validated for the "difficulties identifying feelings" (DIF) and "difficulties describing feelings" (DDF) subfactors of the TAS-20. CONCLUSION: Our study supports and extents previous findings by indicating that mortality risk enhancing effects of alexithymia are specific to male subjects and validated for the DIF and DDF facets. Socioeconomic, clinical and metabolic factors were associated with this relationship. Finding that the impact of alexithymia remains stable in the fully adjusted models suggests that yet unidentified additional factors must be considered.

Associations and interactions of the serotonin receptor genes 5-HT1A, 5-HT2A, and childhood trauma with alexithymia in two independent general-population samples.

Previous studies suggested that childhood trauma and a disturbed serotonergic neurotransmission are involved in the pathogenesis of alexithymia. Specifically, genetic polymorphisms of the serotonin receptors 5-HT1A and 5-HT2A were found to be associated with alexithymia. However, it is unclear whether these factors show main or interaction effects with childhood trauma on alexithymia. Data from two independent general-population cohorts of the Study of Health in Pomerania (SHIP-Trend: N=3,706, Age: range=20-83, 51.6% female, SHIP-LEGEND: N=2,162, Age: range=20-80, 52.5% female) were used. The Toronto Alexithymia Scale-20 (TAS-20) and the Childhood Trauma Questionnaire (CTQ) were applied. Genotypes of rs6295 of 5-HT1A and rs6311 of 5-HT2A were determined. Ordinary least-squared regression models with robust standard errors were applied to investigate associations of the main and interaction effects of childhood maltreatment and the polymorphisms with alexithymia. Childhood trauma, but none of the investigated polymorphisms showed main effects on alexithymia. However, childhood trauma showed significant CTQ sum score x rs6295 interactions in male subjects in both samples such that the presence of the G-allele diminished the CTQ associated increase in the TAS-20 sum scores. Our results support a strong role of early life stress and interactions with rs6295 on alexithymic personality features at least in male subjects.

Dietary-Induced Low-Grade Inflammation in the Liver.

The literature describes a close correlation between metabolic disorders and abnormal immune responses, like low-grade inflammation (LGI), which may be one mechanistic link between obesity and various comorbidities, including non-alcoholic fatty liver disease (NAFLD). In our study, we investigated the influence of dietary composition on obesity-derived LGI in the liver. We used a dietary induced obesity mouse model of C57BL/6J mice fed with high fat diet (HFD, 60% fat, 20% protein, 20% carbohydrates) and two different controls. One was rich in carbohydrates (10% fat, 20% protein, 70% carbohydrates), further referred to as the control diet (CD), and the other one is referred to as the standard diet (SD), with a more balanced macronutrient content (9% fat, 33% protein, 58% carbohydrates). Our results showed a significant increased NAFLD activity score in HFD compared to both controls, but livers of the CD group also differed in their macroscopic appearance from healthy livers. Hepatic fat content showed significantly elevated cholesterol concentrations in the CD group. Histologic analysis of the cellular immune response in the liver showed no difference between HFD and CD and expression analysis of immunologic mediators like interleukin (IL)-1ß, IL-6, IL-10 and tumor necrosis factor alpha also point towards a pro-inflammatory response to CD, comparable to LGI in HFD. Therefore, when studying diet-induced obesity with a focus on inflammatory processes, we encourage researchers to carefully select controls and not use a control diet disproportionally rich in carbohydrates.

Vitamin D moderates the interaction between 5-HTTLPR and childhood abuse in depressive disorders.

A complex interplay between genetic and environmental factors determines the individual risk of depressive disorders. Vitamin D has been shown to stimulate the expression of the tryptophan hydroxylase 2 (TPH2) gene, which is the rate-limiting enzyme for serotonin production in the brain. Therefore, we investigate the hypothesis that serum vitamin D levels moderate the interaction between the serotonin transporter promotor gene polymorphism (5-HTTLPR) and childhood abuse in depressive disorders. Two independent samples from the Study of Health in Pomerania (SHIP-LEGEND: n = 1 997; SHIP-TREND-0: n = 2 939) were used. Depressive disorders were assessed using questionnaires (BDI-II, PHQ-9) and interview procedures (DSM-IV). Besides serum vitamin D levels (25(OH)D), a functional polymorphism (rs4588) of the vitamin D-binding protein is used as a proxy for 25(OH)D. S-allele carriers with childhood abuse and low 25(OH)D levels have a higher mean BDI-II score (13.25) than those with a higher 25(OH)D level (9.56), which was not observed in abused LL-carriers. This significant three-way interaction was replicated in individuals with lifetime major depressive disorders when using the rs4588 instead of 25(OH)D (p = 0.0076 in the combined sample). We conclude that vitamin D relevantly moderates the interaction between childhood abuse and the serotonergic system, thereby impacting vulnerability to depressive disorders.

Simvastatin add-on to escitalopram in patients with comorbid obesity and major depression (SIMCODE): study protocol of a multicentre, randomised, double-blind, placebo-controlled trial.

INTRODUCTION: Major depressive disorder (MDD) and obesity are both common disorders associated with significant burden of disease worldwide. Importantly, MDD and obesity often co-occur, with each disorder increasing the risk for developing the other by about 50%-60%. Statins are among the most prescribed medications with well-established safety and efficacy. Statins are recommended in primary prevention of cardiovascular disease, which has been linked to both MDD and obesity. Moreover, statins are promising candidates to treat MDD because a meta-analysis of pilot randomised controlled trials has found antidepressive effects of statins as adjunct therapy to antidepressants. However, no study so far has tested the antidepressive potential of statins in patients with MDD and comorbid obesity. Importantly, this is a difficult-to-treat population that often exhibits a chronic course of MDD and is more likely to be treatment resistant. Thus, in this confirmatory randomised controlled trial, we will determine whether add-on simvastatin to standard antidepressant medication with escitalopram is more efficacious than add-on placebo over 12 weeks in 160 patients with MDD and comorbid obesity. METHODS AND ANALYSIS: This is a protocol for a randomised, placebo-controlled, double-blind multicentre trial with parallel-group design (phase II). One hundred and sixty patients with MDD and comorbid obesity will be randomised 1:1 to simvastatin or placebo as add-on to standard antidepressant medication with escitalopram. The primary outcome is change in the Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to week 12. Secondary outcomes include MADRS response (defined as 50% MADRS score reduction from baseline), MADRS remission (defined as MADRS score <10), mean change in patients' self-reported Beck Depression Inventory (BDI-II) and mean change in high-density lipoprotein, low-density lipoprotein and total cholesterol from baseline to week 12. ETHICS AND DISSEMINATION: This protocol has been approved by the ethics committee of the federal state of Berlin (Ethik-Kommission des Landes Berlin, reference: 19/0226-EK 11) and by the relevant federal authority (Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), reference: 4043387). Study findings will be published in peer-reviewed journals and will be presented at (inter)national conferences. TRIAL REGISTRATION NUMBERS: NCT04301271, DRKS00021119, EudraCT 2018-002947-27.

Vitamin D levels are associated with trait resilience but not depression in a general population sample.

INTRODUCTION: Insufficient vitamin D levels were found to be related to various psychiatric disorders and particularly depression. The functional polymorphisms rs4588 and rs7041 of the vitamin D-binding protein (also group-specific component or Gc) influence vitamin D level and activity. Resilience is considered the individual predisposition to maintain psychological functioning in the face of adversities. We sought to investigate whether associations of vitamin D levels and genotypes of rs4588 and rs7041 were associated with trait resilience and symptoms of depression. METHODS: Serum levels of total 25(OH)D were measured in a general population sample (n = 1,908) of the Study of Health in Pomerania (SHIP-1). The Resilience Scale-25 (RS-25) was applied to assess trait resilience. Lifetime depressive symptoms were assessed using the CID-S, while current depressive symptoms were measured using the Beck Depression Inventory II (BDI-II). Study participants were genotyped for rs4588 and rs7041. RESULTS: Participants with vitamin D insufficiency had lower adjusted mean RS-25 scores as compared to vitamin D replete subjects (p = .002). Linear regression analyses revealed a positive association between 25(OH)D and RS-25 scores (ß = 2.782, p = .002). Additional adjustment for BDI-II scores slightly attenuated this result (ß = 1.830 and p = .026). Symptoms of depression and the lifetime diagnosis of MDD were not significantly associated with vitamin D concentrations. rs4588 and rs7041 showed strong associations with vitamin D concentrations (both p < .001), but not RS-25 scores. CONCLUSIONS: In contrast with previous studies, our findings do not provide evidence for a strong role of vitamin D in the psychopathology of depression. However, considering the role of trait resilience as a common protective factor to different psychiatric disorders, our results support the concept of low vitamin D as a general risk factor to stress-related psychopathologies.

Functional polymorphisms of the mineralocorticoid receptor gene NR3C2 are associated with diminished memory decline: Results from a longitudinal general-population study.

BACKGROUND: The mineralocorticoid receptor (MR) in the brain has a key role in the regulation of the central stress response and is associated with memory performance. We investigated whether the genetic polymorphisms rs5522 and rs2070951 of NR3C2 showed main and interactive effects with childhood trauma on memory decline. METHODS: Declarative memory was longitudinally assessed in 1,318 participants from the community-dwelling Study of Health in Pomerania using the Verbal Learning and Memory Test (VLMT). In a subsample of 377 participants aged 60 and older, the Mini-Mental Status Examination (MMSE) was additionally applied. Mean follow-up time for the VLMT and MMSE were 6.4 and 10.7 years, respectively. RESULTS: Homozygous carriers of the G allele of rs2070951 (p < .01) and of the A allele of rs5522 (p < .001) showed higher immediate recall of words as compared to carriers of C allele (rs2070951) or the G allele (rs5522). The CG haplotype was associated with decreased recall (p < .001). Likewise, in the subsample of older patients, the AA genotype of rs5522 was associated with higher MMSE scores (p < .05). CG haplotypes showed significantly reduced MMSE scores in comparison to the reference haplotype (ß = -0.60; p < .01). CONCLUSIONS: Our results indicate that the GG genotype of rs2070951 as well as the AA genotype of rs5522 are associated with diminished memory decline.

Alexithymia Is Associated with Altered Cortical Thickness Networks in the General Population.

BACKGROUND: Alexithymia is a personality trait characterized by difficulties in identifying and describing emotions and associated with various psychiatric disorders. Neuroimaging studies found evidence for morphological and functional brain alterations in alexithymic subjects. However, the neurobiological mechanisms underlying alexithymia remain incompletely understood. METHODS: We study the association of alexithymia with cortical correlation networks in a large community-dwelling sample of the Study of Health in Pomerania. Our analysis includes data of n = 2,199 individuals (49.4% females, age = 52.1 ± 13.6 years) which were divided into a low and high alexithymic group by a median split of the Toronto Alexithymia Scale. Cortical correlation networks were constructed based on the mean thicknesses of 68 regions, and differences in centralities were investigated. RESULTS: We found a significantly increased centrality of the right paracentral lobule in the high alexithymia network after correction for multiple testing. Several other regions with motoric and sensory functions showed altered centrality on a nominally significant level. CONCLUSIONS: Finding increased centrality of the paracentral lobule, a brain area with sensory as well as motoric features and involvement in bowel and bladder voiding, may contribute to explain the association of alexithymia with functional somatic disorders and chronic pain syndromes.

Cardiorespiratory Fitness and Gray Matter Volume in the Temporal, Frontal, and Cerebellar Regions in the General Population.

OBJECTIVE: To analyze the association between cardiorespiratory fitness (CRF) and global and local brain volumes. PARTICIPANTS AND METHODS: We studied 2103 adults (21-84 years old) from 2 independent population-based cohorts (Study of Health in Pomerania, examinations from June 25, 2008, through September 30, 2012). Cardiorespiratory fitness was measured using peak oxygen uptake (VO2peak), oxygen uptake at the anaerobic threshold (VO2@AT), and maximal power output from cardiopulmonary exercise testing on a bicycle ergometer. Magnetic resonance imaging brain data were analyzed by voxel-based morphometry using regression models with adjustment for age, sex, education, smoking, body weight, systolic blood pressure, glycated hemoglobin level, and intracranial volume. RESULTS: Volumetric analyses revealed associations of CRF with gray matter (GM) volume and total brain volume. After multivariable adjustment, a 1-standard deviation increase in VO2peak was related to a 5.31 cm³ (95% CI, 3.27 to 7.35 cm³) higher GM volume. Whole-brain voxel-based morphometry analyses revealed significant positive relations between CRF and local GM volumes. The VO2peak was strongly associated with GM volume of the left middle temporal gyrus (228 voxels), the right hippocampal gyrus (146 voxels), the left orbitofrontal cortex (348 voxels), and the bilateral cingulate cortex (68 and 43 voxels). CONCLUSION: Cardiorespiratory fitness was positively associated with GM volume, total brain volume, and specific GM and white matter clusters in brain areas not primarily involved in movement processing. These results, from a representative population sample, suggest that CRF might contribute to improved brain health and might, therefore, decelerate pathology-specific GM decrease.

Interactive impact of childhood maltreatment, depression, and age on cortical brain structure: mega-analytic findings from a large multi-site cohort.

BACKGROUND: Childhood maltreatment (CM) plays an important role in the development of major depressive disorder (MDD). The aim of this study was to examine whether CM severity and type are associated with MDD-related brain alterations, and how they interact with sex and age. METHODS: Within the ENIGMA-MDD network, severity and subtypes of CM using the Childhood Trauma Questionnaire were assessed and structural magnetic resonance imaging data from patients with MDD and healthy controls were analyzed in a mega-analysis comprising a total of 3872 participants aged between 13 and 89 years. Cortical thickness and surface area were extracted at each site using FreeSurfer. RESULTS: CM severity was associated with reduced cortical thickness in the banks of the superior temporal sulcus and supramarginal gyrus as well as with reduced surface area of the middle temporal lobe. Participants reporting both childhood neglect and abuse had a lower cortical thickness in the inferior parietal lobe, middle temporal lobe, and precuneus compared to participants not exposed to CM. In males only, regardless of diagnosis, CM severity was associated with higher cortical thickness of the rostral anterior cingulate cortex. Finally, a significant interaction between CM and age in predicting thickness was seen across several prefrontal, temporal, and temporo-parietal regions. CONCLUSIONS: Severity and type of CM may impact cortical thickness and surface area. Importantly, CM may influence age-dependent brain maturation, particularly in regions related to the default mode network, perception, and theory of mind.

Inflammatory markers and imaging patterns of advanced brain aging in the general population.

Inflammaging describes the complexity between low-grade chronic inflammation with the pathogenesis of brain aging and Alzheimer´s disease (AD). We aimed to find associations of inflammatory markers: i) white blood cell count (WBC), ii) high-sensitivity C-reactive protein (hs-CRP), and iii) fibrinogen with brain structures, sensitive neuroimaging markers of advanced brain aging and AD-like atrophy, and cognitive aging scores. We analyzed magnetic resonance imaging (MRI) scans of 2204 participants from the Study of Health in Pomerania-2 (SHIP-2) and SHIP-Trend (55.6% women, mean age 52.4±13.7 years). Associations of the inflammatory markers with specific brain signatures of brain aging (SPARE-BA), AD-like brain atrophy (SPARE-AD) and white matter disease (white matter hyperintensities volume (WMHV)) were investigated. Furthermore we explored their association with general brain structures including total brain volume (TBV), gray matter volume (GMV), and white matter volume (WMV), as well as cognitive scores (Nurnberger Age Inventory (NAI); Verbal Learning and Memory Test (VLMT). We adjusted for multiple vascular risk factors (VRF; e.g. smoking and blood pressure) and corresponding medication use to take their brain aging effects into account and corrected for false-discovery rate (FDR). Results:WBC was inversely associated with SPARE-BA (FDR-adjusted p=0.003), TBV (FDR-adjusted p=0.019) and GMV (FDR-adjusted p= 0.017). GMV was also inversely associated with hs-CRP (FDR-adjusted p=0.039) and fibrinogen (FDR-adjusted p=0.039). None of the inflammatory markers was associated with WMHV. Regression analysis also revealed a trend-level interaction between intake of antiinflammatory medication and hs-CRP with brain aging (SPARE-BA; FDR-adjusted p=0.062). Inflammatatory markers are associated with neuroimaging markers, with elevated WBC leading to significant acceleration in brain aging patterns but not with AD-like imaging structural changes. Given the overlap between accelerated brain aging and AD-like atrophy, increased WBC might be associated with global dementia symptoms due to this overlap in atrophy patterns. Elevated WBC may be not causal to preclinical AD dementia, but an accessory symptom of inflammaging. At population level, our results support the relevant roles of inflammatory markers on brain aging related atrophy.