From the reward network to whole-brain metrics: structural connectivity in adolescents and young adults according to body mass index and genetic risk of obesity.

BACKGROUND: Obesity is a multifactorial condition. Genetic variants, such as the fat mass and obesity related gene (FTO) polymorphism, may increase the vulnerability of developing obesity by disrupting dopamine signaling within the reward network. Yet, the association of obesity, genetic risk of obesity, and structural connectivity of the reward network in adolescents and young adults remains unexplored. We investigate, in adolescents and young adults, the structural connectivity differences in the reward network and at the whole-brain level according to body mass index (BMI) and the FTO rs9939609 polymorphism. METHODS: One hundred thirty-two adolescents and young adults (age range: [10, 21] years, BMI z-score range: [-1.76, 2.69]) were included. Genetic risk of obesity was determined by the presence of the FTO A allele. Whole-brain and reward network structural connectivity were analyzed using graph metrics. Hierarchical linear regression was applied to test the association between BMI-z, genetic risk of obesity, and structural connectivity. RESULTS: Higher BMI-z was associated with higher (B = 0.76, 95% CI = [0.30, 1.21], P = 0.0015) and lower (B = -0.003, 95% CI = [-0.006, -0.00005], P = 0.048) connectivity strength for fractional anisotropy at the whole-brain level and of the reward network, respectively. The FTO polymorphism was not associated with structural connectivity nor with BMI-z. CONCLUSIONS: We provide evidence that, in healthy adolescents and young adults, higher BMI-z is associated with higher connectivity at the whole-brain level and lower connectivity of the reward network. We did not find the FTO polymorphism to correlate with structural connectivity. Future longitudinal studies with larger sample sizes are needed to assess how genetic determinants of obesity change brain structural connectivity and behavior.

Physical activity and mental health: the connection between step count and depression, anxiety and quality of sleep.

While there are studies connecting everyday physical activity (PA) to mental health, they mostly use self-report measures for PA which are biased in multiple ways. Nevertheless, a realistic assessment of everyday PA is important for the development and implementation of low-threshold public health interventions. Therefore, we want to analyze the relationship between objectively measured daily steps and mental health. We included 1451 subjects from a subsample of the population-based LIFE-Adult-Study (2011-2014) with an average age of 55.0 years, 52.1% were female. We analyzed the effects of PA (step count measured via SenseWear Pro 3) on depression (CES-D), anxiety (GAD-7), and quality of sleep (PSQI). The regression analysis showed a significant negative association between low to moderate PA [Incidence rate ratio: 0.87 (0.77; 0.98)] as well as high to very high PA [0.84 (0.74; 0.95)] and depression and no significant associations between PA and anxiety [l-m: 0.98 (0.81; 1.18)/h-vh: 1.00 (0.82; 1.21)] or quality of sleep [l-m: 0.94 (0.84, 1.06)/h-vh: 0.92 (0.82, 1.03)], controlling for sociodemographic variables and personality. Low-threshold interventions that increase daily step count could be a useful approach for the prevention of depression. The use of objective PA measurement for research is highly encouraged.

Early volumetric changes of hippocampus and medial prefrontal cortex following medial temporal lobe resection.

Previous studies have shown that cognitive demands and physical exercise stimulate adult neurogenesis in the dentate gyrus and hippocampus. Recent observations in healthy humans and patients with mild cognitive impairment moreover suggest that training-induced increases in hippocampal volume may be associated with improved memory performance. The corresponding plasticity processes in hippocampal volume may occur on timescales of months to years. For patients with focal lesions in this region, previous functional imaging studies suggest that increased recruitment of the contralateral hippocampus and extratemporal regions may be an important part of the reorganization of episodic memory. However, it is currently unclear whether focal damage to the medial temporal lobe (MTL) induces gray matter (GM) volume changes in the intact contralateral hippocampus and in connected network regions on a shorter timescale. We therefore investigated whether unilateral resection of the MTL, including the hippocampus, induces measurable volumetric changes in the contralateral hippocampus and in the default mode network (DMN). We recruited 31 patients with unilateral left (N = 19) or right (N = 12) hippocampal sclerosis undergoing MTL resection for treatment of drug-resistant epilepsy. Structural MRI was acquired immediately before and 3 months after surgery. Longitudinal voxel-based morphometry (VBM) analysis revealed a significant increase of right hippocampal volume following resection of the left anterior MTL. Furthermore, this patient group showed GM volume increases in the DMN. These results demonstrate significant structural plasticity of the contralateral hippocampus, even in patients with a long-standing unilateral hippocampal dysfunction and structural reorganization processes extending to distant, but functionally connected brain regions.

Prevalence of DSM-5 Mild Neurocognitive Disorder in Dementia-Free Older Adults: Results of the Population-Based LIFE-Adult-Study.

OBJECTIVE: The DSM-5 introduces mild neurocognitive disorder (miNCD) as a syndrome that recognizes the potential clinical importance of acquired cognitive deficits being too mild to qualify for diagnosis of dementia. We provide new empirical data on miNCD including total, age-, and sex-specific prevalence rates; number and types of neurocognitive domains being impaired; and diagnostic overlap with the well-established mild cognitive impairment (MCI) concept. DESIGN: Cross-sectional results of an observational cohort study (LIFE-Adult-Study). SETTING: General population. PARTICIPANTS: A total of 1,080 dementia-free individuals, aged 60-79 years. MEASUREMENTS: We calculated weighted point prevalence rates with confidence intervals (95% CI) for miNCD and analyzed diagnostic overlap between miNCD and MCI by calculating overall percentage agreement and Cohen's kappa coefficient. RESULTS: Weighted total prevalence of miNCD was 20.3% (95% CI: 17.8-23.0). Prevalence was similar in both sexes, but significantly higher in older age. Two-thirds (66.2%) of the individuals with miNCD showed impairment restricted to only one out of six possible neurocognitive domains. Learning and memory was the most frequently (38.3%) impaired domain in all miNCD-cases, followed by social cognition (26.1%). Analysis of diagnostic overlap with MCI yielded an overall agreement of 98.6% and a kappa of 0.959. CONCLUSIONS: By considering all six predefined neurocognitive domains, our study observed a substantial proportion of dementia-free older adults having miNCD. Provision of information on the underlying etiology/ies may be of prime importance in future studies aiming at evaluating the clinical relevance of the miNCD syndrome.

Suggestion of a new standard in measuring the mandible via MRI and an overview of reference values in young women.

PURPOSE: Adult idiopathic condylar resorption (AICR) mainly affects young women, but generally accepted diagnostic standards are lacking. Patients often need temporomandibular joint (TMJ) surgery, and often jaw anatomy is assessed by CT as well as MRI to observe both bone and soft tissue. This study aims to establish reference values for mandible dimensions in women from MRI only and correlate them to, e.g., laboratory parameters and lifestyle, to explore new putative parameters relevant in AICR. MRI-derived reference values could reduce preoperative effort by allowing physicians to rely on only the MRI without additional CT scan. METHODS: We analyzed MRI data from a previous study (LIFE-Adult-Study, Leipzig, Germany) of 158 female participants aged 15-40 years (as AICR typically affects young women). The MR images were segmented, and standardized measuring of the mandibles was established. We correlated morphological features of the mandible with a large variety of other parameters documented in the LIFE-Adult study. RESULTS: We established new reference values for mandible morphology in MRI, which are consistent with previous CT-based studies. Our results allow assessment of both mandible and soft tissue without radiation exposure. Correlations with BMI, lifestyle, or laboratory parameters could not be observed. Of note, correlation between SNB angle, a parameter often used for AICR assessment, and condylar volume, was also not observed, opening up the question if these parameters behave differently in AICR patients. CONCLUSION: These efforts constitute a first step towards establishing MRI as a viable method for condylar resorption assessment.

Relationship between excitability, plasticity and thickness of the motor cortex in older adults.

The relationship between brain structure, cortical physiology, and learning ability in older adults is of particular interest in understanding mechanisms of age-related cognitive decline. Only a few studies addressed this issue so far, yielding mixed results. Here, we used comprehensive multiple regression analyses to investigate associations between brain structure on the one hand, i.e., cortical thickness (CT), fractional anisotropy (FA) of the pyramidal tract and individual coil-to-cortex distance, and cortical physiology on the other hand, i.e. motor cortex excitability and long-term potentiation (LTP)-like cortical plasticity, in healthy older adults (mean age 64 years, 14 women). Additional exploratory analyses assessed correlations between cortical physiology and learning ability in the verbal domain. In the regression models, we found that cortical excitability could be best predicted by CT of the hand knob of the primary motor cortex (CT-M1HAND) and individual coil-to-cortex distance, while LTP-like cortical plasticity was predicted by CT-M1HAND and FA of the pyramidal tract. Exploratory analyses revealed a significant inverse correlation between cortical excitability and learning ability. In conclusion, higher cortical excitability was associated with lower CT and lower learning ability in a cohort of healthy older adults, in line with previous reports of increased cortical excitability in patients with cortical atrophy and cognitive deficits due to Alzheimer's Disease. Cortical excitability may thus be a parameter to identify individuals at risk for cognitive decline and gray matter atrophy, a hypothesis to be explored in future longitudinal studies.

The Association Between Depth of the Olfactory Sulcus, Age, Gender and Olfactory Function: An MRI-based Investigation in More Than 1000 Participants.

OBJECTIVE: The present study aimed to investigate the relationship between olfactory sulcus (OS) depth and olfactory function considering age and gender and to provide normative data on OS depth in a population with normal olfactory function. MATERIALS AND METHODS: OS depth was obtained using T1 magnetic resonance imaging scans. Participants (mean age ± sd = 57 ± 16 years, ranging from 20 to 80 years) were screened for olfactory function using the Sniffin' Sticks Screening 12 test. They were divided into an olfactory dysfunction group (n = 604) and a normosmia group (n = 493). Participants also completed questionnaires measuring depression, anxiety and quality of life. RESULTS: The right OS was deeper than the left side in all age groups. On the left side, women had deeper OS compared with men, exhibiting a higher degree of symmetry in left and right OS depth in women. Variance of olfactory function was largely determined by age, OS depth explained only minor portions of this variance. Normative data for minimum OS depth was 7.55 mm on the left and 8.78 mm on the right for participants aged between 18 and 35 years (n = 144), 6.47 mm on the left and 6.99 mm on the right for those aged 36-55 years (n = 120), and 5.28 mm on the left and 6.19 mm on the right for participants older than 55 years (n = 222). CONCLUSION: Considering the limited resolution of the presently used T1 weighted MR scans and the nature of the olfactory screening test, OS depth explained only minor portions of the variance of olfactory function, which was largely determined by age. Age-related normative data of OS depth are presented as a reference for future work.

Perceived stress of mental demands at work, objective stress and resilience - an analysis of the LIFE-Adult-study.

BACKGROUND: So far, previous research suggests positive effects of mental demands at the workplace. However, it may depend on how stressfull these demands are perceived on an individual level. OBJECTIVE: The aim was to build on previous research by investigating how mental demands are related to stress, overload, and work discontent and whether this relationship is mediated by individuals resources, such as resilience. METHOD: A sub-sample of the LIFE Adult Cohort (n = 480) was asked to answer questions on sociodemographic characteristics, objective stress (using the Trier Inventory of Chronic Stress (TICS)), and perceptions of stress with regard to verbal and executive mental demands at work. RESULTS: According to generalized linear regression models, higher verbal as well as executive mental demands were associated with higher levels of chronic stress, work overload and discontent. Higher levels of resilience were associated with lower levels of these outcomes. Analyses regarding interaction effects revealed that the interaction between resilience and perceived stress of verbal mental demands was significant only in terms of work overload. CONCLUSION: Higher perceived stressfulness of mental demands was associated with higher chronic stress, work overload and work discontent. Therefore, mental demands should be targeted by occupational interventions that aim to improve job conditions and employees' overall well-being. Besides resilience, other potential influencers or personal resources should be focused on in future studies to develop interventions.

The different areas of chronic stress and food addiction: Results from the LIFE-Adult-Study.

There is an empirical association between stress and symptoms of food addiction (FA), but it is still not clear which domains of stress are the most relevant when it comes to FA, limiting the ability of researchers and practitioners to address problematic eating-related health outcomes. In order to address this gap in the literature, we analysed how different domains of chronic stress are related to FA. We used data from a subsample of the LIFE-Adult-Study (N = 1172), a German cohort study. We conducted a linear regression analysis with stress domains (Trier Inventory for Chronic Stress, TICS) as predictors of FA (Yale Food Addiction Scale, YFAS). In the second regression analysis we included sociodemographic variables, personality, and smoking as control variables. There was a significant and positive association between Social Overload, Work Discontent, Excessive Demands from Work, and Chronic Worrying and FA. After adding control variables, only Social Overload, Excessive Demands from Work, and Chronic Worrying remained significant predictors. Connections between stress domains and FA can serve as starting points for the development of meaningful interventions that support individuals self-care strategies (Social Overload), complexity management (Excessive Demands from Work), and coping with negative emotions (Chronic Worrying).

Development of the Hedonic Overeating-Questionnaire (HEDO-Q).

Addictive-like eating is prevalent, but a clear conceptualization and operationalization outside of an addiction framework is lacking. By adopting a biopsychological framework of food reward, this study sought to develop and evaluate a brief self-report questionnaire for the trait assessment of hedonic overeating and dyscontrol. Items in the Hedonic Overeating-Questionnaire (HEDO-Q) were constructed following a rational approach and psychometrically evaluated in a large random sample from the German population (N = 2531). A confirmatory factor analysis supported the unidimensional nature of the six-item HEDO-Q with the three postulated components of wanting, liking, and dyscontrol. Psychometric properties were favorable with good corrected item-total correlations, acceptable item difficulty and homogeneity, and high internal consistency. Population norms were provided. The HEDO-Q revealed strict measurement invariance for sex and partial invariance for age and weight status. Discriminant validity was demonstrated in distinguishing participants with versus without eating disturbances or obesity. Associations with the established measures of eating disorder and general psychopathology supported the convergent and divergent validity of the HEDO-Q. This first evaluation indicates good psychometric properties of the HEDO-Q in the general population. Future validation work is warranted on the HEDO-Q's stability, sensitivity to change, and predictive and construct validity.

Anxiety and Food Addiction in Men and Women: Results From the Longitudinal LIFE-Adult-Study.

Background: Anxiety is a widespread phenomenon, and it is connected to disordered eating and obesity. We want to analyze the connection between anxiety and food addiction (FA) over two points in time to better understand the directionality of the association. Since there are gender differences with regard to anxiety and eating, we are also interested in differences between men and women. Methods: We used data from the population-based LIFE-Adult-Study (N = 1,474) at time 1 (baseline) and time 2 (first follow-up) to analyze the connections between anxiety (GAD-7) and FA (YFAS) using a multiple group latent cross-lagged panel model with female and male participants as groups. We controlled for age, marital status, socioeconomic status and social support. Results: Anxiety (women: ß = 0.50, p ≤ 0.001; men: ß = 0.59, p ≤ 0.001) as well as FA (women: ß = 0.37, p ≤ 0.001; men: ß = 0.58, p ≤ 0.001) exhibited stability over time for both genders. We found a significant association between anxiety at time 1 and FA at time 2 for women (ß = 0.25, p ≤ 0.001) but not for men (ß = 0.04, p = 0.10), and significant associations between FA at time 1 and anxiety at time 2 for women (ß = 0.23, p ≤ 0.001) as well as men (ß = 0.21, p ≤ 0.001). Conclusion: Food addiction longitudinally affects anxiety, independent of gender and other sociodemographic variables. In addition, anxiety affects subsequent FA as well, but only in women. Interventions that address FA could reduce anxiety in men and women, while interventions that mitigate anxiety could help prevent FA in women.

Different Areas of Chronic Stress and Their Associations with Depression.

BACKGROUND: Research shows a connection between stress and depression, but there is little differentiation between areas of stress, making it difficult to identify and address specific areas in the context of public health measures. We utilized a multi-dimensional approach to chronic stress to better understand the relationship between different areas of stress and depression. METHODS: We conducted linear regression analyses and used data from a sub-sample of the LIFE-Adult-Study (N = 1008) to analyze the connection between nine different areas of chronic stress (TICS) and depression (CES-D). In the second analysis, we controlled for sociodemographic variables, personality, physical activity, and social support. RESULTS: There was a significant positive association between the stress domains Excessive Demands from Work, Lack of Social Recognition, Social Isolation, and Chronic Worrying and depression and a significant negative association between Pressure to Perform and depression. After adding control variables, only Pressure to Perform, Social Isolation, and Chronic Worrying remained significant predictors. CONCLUSIONS: By focusing on the connections between chronic stress and depression, researchers can help identify the areas that matter most and contribute to the creation of meaningful and efficient interventions. On the basis of our results, measures for the prevention of depression that focus on the reduction of worrying and social isolation are recommended.

The effect of a high-polyphenol Mediterranean diet (Green-MED) combined with physical activity on age-related brain atrophy: the Dietary Intervention Randomized Controlled Trial Polyphenols Unprocessed Study (DIRECT PLUS).

BACKGROUND: The effect of diet on age-related brain atrophy is largely unproven. OBJECTIVES: We aimed to explore the effect of a Mediterranean diet (MED) higher in polyphenols and lower in red/processed meat (Green-MED diet) on age-related brain atrophy. METHODS: This 18-mo clinical trial longitudinally measured brain structure volumes by MRI using hippocampal occupancy score (HOC) and lateral ventricle volume (LVV) expansion score as neurodegeneration markers. Abdominally obese/dyslipidemic participants were randomly assigned to follow 1) healthy dietary guidelines (HDG), 2) MED, or 3) Green-MED diet. All subjects received free gym memberships and physical activity guidance. Both MED groups consumed 28 g walnuts/d (+440 mg/d polyphenols). The Green-MED group consumed green tea (3-4 cups/d) and Mankai (Wolffia-globosa strain, 100 g frozen cubes/d) green shake (+800 mg/d polyphenols). RESULTS: Among 284 participants (88% men; mean age: 51 y; BMI: 31.2 kg/m2; APOE-ε4 genotype = 15.7%), 224 (79%) completed the trial with eligible whole-brain MRIs. The pallidum (-4.2%), third ventricle (+3.9%), and LVV (+2.2%) disclosed the largest volume changes. Compared with younger participants, atrophy was accelerated among those ≥50 y old (HOC change: -1.0% ± 1.4% compared with -0.06% ± 1.1%; 95% CI: 0.6%, 1.3%; P < 0.001; LVV change: 3.2% ± 4.5% compared with 1.3% ± 4.1%; 95% CI: -3.1%, -0.8%; P = 0.001). In subjects ≥ 50 y old, HOC decline and LVV expansion were attenuated in both MED groups, with the best outcomes among Green-MED diet participants, as compared with HDG (HOC: -0.8% ± 1.6% compared with -1.3% ± 1.4%; 95% CI: -1.5%, -0.02%; P = 0.042; LVV: 2.3% ± 4.7% compared with 4.3% ± 4.5%; 95% CI: 0.3%, 5.2%; P = 0.021). Similar patterns were observed among younger subjects. Improved insulin sensitivity over the trial was the parameter most strongly associated with brain atrophy attenuation (P < 0.05). Greater Mankai, green tea, and walnut intake and less red and processed meat were significantly and independently associated with reduced HOC decline (P < 0.05). Elevated urinary concentrations of the polyphenols urolithin-A (r = 0.24; P = 0.013) and tyrosol (r = 0.26; P = 0.007) were significantly associated with lower HOC decline. CONCLUSIONS: A Green-MED (high-polyphenol) diet, rich in Mankai, green tea, and walnuts and low in red/processed meat, is potentially neuroprotective for age-related brain atrophy.This trial was registered at clinicaltrials.gov as NCT03020186.

Genome-wide association and transcriptome analysis suggests total serum ghrelin to be linked with GFRAL.

OBJECTIVE: Ghrelin is an orexigenic peptide hormone involved in the regulation of energy homeostasis, food intake and glucose metabolism. Serum levels increase anticipating a meal and fall afterwards. Underlying genetic mechanisms of the ghrelin secretion are unknown. METHODS: Total serum ghrelin was measured in 1501 subjects selected from the population-based LIFE-ADULT-sample after an overnight fast. A genome-wide association study (GWAS) was performed. Gene-based expression association analyses (transcriptome-wide association study (TWAS)) are statistical tests associating genetically predicted expression to a certain trait and were done using MetaXcan. RESULTS: In the GWAS, three loci reached genome-wide significance: the WW-domain containing the oxidoreductase-gene (WWOX; P = 1.80E-10) on chromosome 16q23.3-24.1 (SNP: rs76823993); the contactin-associated protein-like 2 gene (CNTNAP2; P = 9.0E-9) on chromosome 7q35-q36 (SNP: rs192092592) and the ghrelin And obestatin prepropeptide gene (GHRL; P = 2.72E-8) on chromosome 3p25.3 (SNP: rs143729751). In the TWAS, the three genes where the expression was strongest associated with serum ghrelin levels was the ribosomal protein L36 (RPL36; P = 1.3E-06, FDR = 0.011, positively correlated), AP1B1 (P = 1.1E-5, FDR = 0.048, negatively correlated) and the GDNF family receptor alpha like (GFRAL), receptor of the anorexigenic growth differentiation factor-15 (GDF15), (P = 1.8E-05, FDR = 0.15, also negatively correlated). CONCLUSIONS: The three genome-wide significant genetic loci from the GWA and the genes identified in the TWA are functionally plausible and should initiate further research.

Gastrointestinal Hormones in Healthy Adults: Reliability of Repeated Assessments and Interrelations with Eating Habits and Physical Activity.

Background: Gastrointestinal hormones (GIHs) are crucial for the regulation of a variety of physiological functions and have been linked to hunger, satiety, and appetite control. Thus, they might constitute meaningful biomarkers in longitudinal and interventional studies on eating behavior and body weight control. However, little is known about the physiological levels of GIHs, their intra-individual stability over time, and their interaction with other metabolic and lifestyle-related parameters. Therefore, the aim of this pilot study is to investigate the intra-individual stability of GIHs in normal-weight adults over time. Methods: Plasma concentrations of ghrelin, leptin, GLP-1 (glucagon-like-peptide), and PP (pancreatic polypeptide) were assessed by enzyme-linked immunosorbent assay (ELISA) in 17 normal-weight, healthy adults in a longitudinal design at baseline and at follow-up six months later. The reliability of the measurements was estimated using intra-class correlation (ICC). In a second step, we considered the stability of GIH levels after controlling for changes in blood glucose and hemoglobin A1 (HbA1c) as well as self-reported physical activity and dietary habits. Results: We found excellent reliability for ghrelin, good reliability for GLP1 and PP, and moderate reliability for leptin. After considering glucose, HbA1c, physical activity, and dietary habits as co-variates, the reliability of ghrelin, GLP1, and PP did not change significantly; the reliability of leptin changed to poor reliability. Conclusions: The GIHs ghrelin, GLP1, and PP demonstrated good to excellent test-retest reliability in healthy individuals, a finding that was not modified after adjusting for glucose control, physical activity, or dietary habits. Leptin showed only moderate to poor reliability, which might be linked to weight fluctuations, albeit small, between baseline and follow-up assessment in our study sample. Together, these findings support that ghrelin, GLP1, and PP might be further examined as biomarkers in studies on weight control, with GLP1 and PP serving as anorexic markers and ghrelin as an orexigenic marker. Additional reliability studies in obese individuals are necessary to verify or refute our findings for this cohort.

Heart failure is independently associated with white matter lesions: insights from the population-based LIFE-Adult Study.

AIMS: White matter lesions (WML) are common structural alterations in the white matter of the brain and their prevalence increases with age. They are associated with cerebral ischaemia and cognitive dysfunction. Patients with heart failure (HF) are at risk for cognitive decline. We hypothesized that the presence and duration of HF are associated with WML. METHODS AND RESULTS: The LIFE-Adult Study is a population-based study of 10 000 residents of Leipzig, Germany. WML were quantitated in 2490 participants who additionally underwent cerebral MRI using the Fazekas score. Mean age was 64 years, and 46% were female; 2156 (86.6%) subjects had Fazekas score of 0-1, and 334 (13.4%) had Fazekas score of 2-3. Thirty participants had a medical history of HF, 1019 had hypertension, and 51 had a history of stroke. Median left ventricular ejection fraction of the participants with HF was 57% (interquartile ranges 54-62). Age, troponin T, NT-proBNP, body mass index, history of acute myocardial infarction, stroke, HF, and diabetes were positively associated with WML in univariate analysis. On multivariate analysis, age, hypertension, stroke, and HF were independently associated with WML. The odd's ratio for the association of WML (Fazekas 2-3) with HF was 2.8 (95% CI 1.2-6.5; P = 0.019). WML increased with longer duration of HF (P = 0.036 for trend). CONCLUSIONS: In addition to age, hypertension, and stroke, the prevalence and duration of HF are independently associated with WML. This observation sets the stage to investigate the prognostic value of WML in HF and the impact of HF therapies on WML.

Age-, sex-, and education-specific norms for an extended CERAD Neuropsychological Assessment Battery-Results from the population-based LIFE-Adult-Study.

OBJECTIVE: To provide new age-, sex-, and education-specific reference values for an extended version of the well-established Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Assessment Battery (CERAD-NAB) that additionally includes the Trail Making Test and the Verbal Fluency Test-S-Words. METHOD: Norms were calculated based on the cognitive performances of n = 1,888 dementia-free participants (60-79 years) from the population-based German LIFE-Adult-Study. Multiple regressions were used to examine the association of the CERAD-NAB scores with age, sex, and education. In order to calculate the norms, quantile and censored quantile regression analyses were performed estimating marginal means of the test scores at 2.28, 6.68, 10, 15.87, 25, 50, 75, and 90 percentiles for age-, sex-, and education-specific subgroups. RESULTS: Multiple regression analyses revealed that younger age was significantly associated with better cognitive performance in 15 CERAD-NAB measures and higher education with better cognitive performance in all 17 measures. Women performed significantly better than men in 12 measures and men than women in four measures. The determined norms indicate ceiling effects for the cognitive performances in the Boston Naming, Word List Recognition, Constructional Praxis Copying, and Constructional Praxis Recall tests. CONCLUSIONS: The new norms for the extended CERAD-NAB will be useful for evaluating dementia-free German-speaking adults in a broad variety of relevant cognitive domains. The extended CERAD-NAB follows more closely the criteria for the new DSM-5 Mild and Major Neurocognitive Disorder. Additionally, it could be further developed to include a test for social cognition. (PsycINFO Database Record

VEGF and GLUT1 are highly heritable, inversely correlated and affected by dietary fat intake: Consequences for cognitive function in humans.

OBJECTIVE: Reduction of brain glucose transporter GLUT1 results in severe neurological dysfunction. VEGF is required to restore and maintain brain glucose uptake across the blood brain barrier via GLUT1, which was shown to be acutely diminished in response to a high fat diet (HFD) in mice. The genetic and HFD-related regulation and association of VEGF and GLUT1 (SLC2A1) in humans was investigated in the NUtriGenomic Analysis in Twins (NUGAT) study. METHODS: 92 healthy and non-obese twins were standardized to a high-carbohydrate low-fat diet for 6 weeks before switched to a 6-week HFD under isocaloric conditions. Three clinical investigation days were conducted: after 6 weeks of low-fat diet and after 1 and 6 weeks of HFD. Serum VEGF and other cytokine levels were measured using ELISA. Gene expression in subcutaneous adipose tissue was assessed by quantitative Real-Time PCR. Genotyping was performed using microarray. The Auditory Verbal Learning Task was conducted to measure cognitive performance. RESULTS: In this human study, we showed that the environmental regulation of SLC2A1 expression and serum VEGF by HFD was inversely correlated and both factors showed strong heritability (>90%). In response to the HFD containing 45% fat, serum VEGF levels increased (P = 0.002) while SLC2A1 mRNA expression in adipose tissue decreased (P = 0.001). Higher BMI was additionally associated with lower SLC2A1 expression. AA-genotypes of the rs9472159 polymorphism, which explained ∼39% of the variation in circulating VEGF concentrations, showed significantly reduced serum VEGF levels (P = 6.4 × 10-11) but higher SLC2A1 expression (P = 0.009) in adipose tissue compared to CC/CA-genotypes after 6 weeks of HFD. Memory performance in AA-genotypes declined in response to the HFD compared to CC- and CA-genotypes. CONCLUSIONS: The results provide evidence to suggest the translatability of the dietary regulation of VEGF and GLUT1 from mouse models to humans. Our data demonstrate that HFD induces a genetically determined and correlated decrease of GLUT1 and increase of VEGF which may affect memory performance. CLINICAL TRIAL REGISTRATION NUMBER: NCT01631123.

Postnatal development of GABA and calbindin cells and fibers in the prefrontal cortex and basolateral amygdala of gerbils (Meriones unguiculatus).

The postnatal maturation of immunohistochemically stained gamma-amino-butyric acid (GABA) and calbindin (CB) cells and fibers were quantitatively examined in the prefrontal cortex (PFC) and the basolateral amygdala (BLA) of the Mongolian gerbil (Meriones unguiculatus). Animals of different ages, ranging from juvenile (postnatal day (PD)14, PD20, PD30), to adolescent (PD70), adult (PD180, PD540) and aged (PD720) were analyzed. Results reveal an increase in GABAergic fiber densities between PD14-20 in the PFC and the BLA with a concomitant decrease in cell density. After PD70 GABA fiber density slightly decreases again in the BLA, while there is a further slow but significant increase in the PFC between PD70 and PD540. Fibers immunoreactive for the calcium binding-protein CB, which is predominantly localized in particular GABAergic subpopulations, also accumulate between PD14 and PD20 in the PFC and BLA, while a concomitant decrease in cell density is only seen in the BLA. Both areas reveal a decrease of CB cells between PD30 and PD70, which parallels with a decrease of CB fibers in the PFC. However, there is no particular 'aging-effect' in the fiber or cell densities of GABA or CB in any of the investigated areas in old animals. In conclusion, we here demonstrate long-term dynamics in cell and fiber densities of the GABAergic system until late in development which might correspond to the prolonged maturation of other neuroanatomical and functional systems.