Cerebrospinal Fluid Concentration of Brain-Derived Neurotrophic Factor and Cognitive Function in Non-Demented Subjects

Brain-derived neurotrophic factor (BDNF) is an activity-dependent secreted protein that is critical to organization of neuronal networks and synaptic plasticity, especially in the hippocampus. We tested hypothesis that reduced CSF BDNF is associated with age-related cognitive decline.CSF concentration of BDNF, Abeta(42) and total tau were measured in 128 cognitively normal adults (Normals), 21 patients with Alzheimer's disease (AD), and nine patients with Mild Cognitive Impairment. Apolipoprotein E and BDNF SNP rs6265 genotype were determined. Neuropsychological tests were performed at baseline for all subjects and at follow-up visits in 50 Normals. CSF BDNF level was lower in AD patients compared to age-matched Normals (p = 0.02). CSF BDNF concentration decreased with age among Normals and was higher in women than men (both p<0.001). After adjusting for age, gender, education, CSF Abeta(42) and total tau, and APOE and BDNF genotypes, lower CSF BDNF concentration was associated poorer immediate and delayed recall at baseline (both p<0.05) and in follow up of approximately 3 years duration (both p<0.01).Reduced CSF BDNF was associated with age-related cognitive decline, suggesting a potential mechanism that may contribute in part to cognitive decline in older individuals

Interaction between CRHR1 and BDNF Genes Increases the Risk of Recurrent Major Depressive Disorder in Chinese Population

BACKGROUND: An important etiological hypothesis about depression is stress has neurotoxic effects that damage the hippocampal cells. Corticotropin-releasing hormone (CRH) regulates brain-derived neurotrophic factor (BDNF) expression through influencing cAMP and Ca2+ signaling pathways during the course. The aim of this study is to examine the single and combined effects of CRH receptor 1 (CRHR1) and BDNF genes in recurrent major depressive disorder (MDD). METHODOLOGY/PRINCIPAL FINDING: The sample consists of 181 patients with recurrent MDD and 186 healthy controls. Whether genetic variations interaction between CRHR1 and BDNF genes might be associated with increased susceptibility to recurrent MDD was studied by using a gene-based association analysis of single-nucleotide polymorphisms (SNPs). CRHR1 gene (rs1876828, rs242939 and rs242941) and BDNF gene (rs6265) were identified in the samples of patients diagnosed with recurrent MDD and matched controls. Allelic association between CRHR1 rs242939 and recurrent MDD was found in our sample (allelic: p = 0.018, genotypic: p = 0.022) with an Odds Ratio 0.454 (95% CI 0.266-0.775). A global test of these four haplotypes showed a significant difference between recurrent MDD group and control group (chi-2 = 13.117, df = 3, P = 0.016. Furthermore, BDNF and CRHR1 interactions were found in the significant 2-locus, gene-gene interaction models (p = 0.05) using a generalized multifactor dimensionality reduction (GMDR) method. CONCLUSION: Our results suggest that an interaction between CRHR1 and BDNF genes constitutes susceptibility to recurrent MDD

The impact of childhood abuse and recent stress on serum brain-derived neurotrophic factor and the moderating role of BDNF Val66Met

Contains fulltext : 98431.pdf (publisher's version ) (Open Access)RATIONALE: Recent findings show lowered brain-derived neurotrophic factor (BDNF) levels in major depressive disorder (MDD). Exposure to stressful life events may (partly) underlie these BDNF reductions, but little is known about the effects of early or recent life stress on BDNF levels. Moreover, the effects of stressful events on BDNF levels may in part be conditional upon a common variant on the BDNF gene (Val(66)Met; RS6265), with the Met allele being associated with a decrease in activity-dependent secretion of BDNF compared to the Val allele. METHODS: We investigated cross-sectionally in 1,435 individuals with lifetime MDD the impact of childhood abuse (CA) and recent life events on serum BDNF levels and assessed whether the impact of these events was moderated by the BDNF Val(66)Met polymorphism. RESULTS: Overall, BDNF Met carriers had reduced serum BDNF levels when exposed to CA in a dose-dependent way. Moreover, exposure to recent life events was also associated with decreases in BDNF levels, but this was independent of BDNF Val(66)Met. Moreover, when not exposed to CA, Met carriers had higher BDNF levels than the Val/Val individuals, who did not show decreases in BDNF associated with CA. Finally, these findings were only apparent in the MDD group without comorbid anxiety. CONCLUSIONS: These gene-environment interactions on serum BDNF levels suggest that Met carriers are particularly sensitive to (early) stressful life events, which extends previous findings on the moderating role of the BDNF Val(66)Met polymorphism in the face of stressful life events

Impact of Brain-Derived Neurotrophic Factor Val66Met Polymorphism on Cortical Thickness and Voxel-Based Morphometry in Healthy Chinese Young Adults

BACKGROUND: Following voxel-based morphometry (VBM), brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (rs6265) has been shown to affect human brain morphology in Caucasians. However, little is known about the specific role of the Met/Met genotype on brain structure. Moreover, the relationship between BDNF Val66Met polymorphism and Chinese brain morphology has not been studied. METHODOLOGY/PRINCIPAL FINDINGS: The present study investigated brain structural differences among three genotypes of BDNF (rs6265) for the first time in healthy young Chinese adults via cortical thickness analysis and VBM. Brain differences in Met carriers using another grouping method (combining Val/Met and Met/Met genotypes into a group of Met carriers as in most previous studies) were also investigated using VBM. Dual-approach analysis revealed less gray matter (GM) in the frontal, temporal, cingulate and insular cortices in the Met/Met group compared with the Val/Val group (corrected, P<0.05). Areas with less GM in the Val/Met group were included in the Met/Met group. VBM differences in Met carriers were only found in the middle cingulate cortex. CONCLUSIONS/SIGNIFICANCE: The current results indicated a unique pattern of brain morphologic differences caused by BDNF (rs6265) in young Chinese adults, in which the Met/Met genotype markedly affected the frontal, temporal, cingulate, and insular regions. The grouping method with Met carriers was not suitable to detect the genetic effect of BDNF Val66Met polymorphism on brain morphology, at least in the Chinese population, because it may hide some specific roles of Met/Met and Val/Met genotypes on brain structure

Neurotrophic gene polymorphisms and response to psychological therapy

Therapygenetics, the study of genetic determinants of response to psychological therapies, is in its infancy. Here, we investigate whether single-nucleotide polymorphisms in nerve growth factor (NGF) (rs6330) and brain-derived neutrotrophic factor (BDNF) (rs6265) genes predict the response to cognitive behaviour therapy (CBT). Neurotrophic genes represent plausible candidate genes: they are implicated in synaptic plasticity, response to stress, and are widely expressed in brain areas involved in mood and cognition. Allelic variation at both loci has shown associations with anxiety-related phenotypes. A sample of 374 anxiety-disordered children with white European ancestry was recruited from clinics in Reading, UK, and in Sydney, Australia. Participants received manualised CBT treatment and DNA was collected from buccal cells using cheek swabs. Treatment response was assessed at post-treatment and follow-up time points. We report first evidence that children with one or more copies of the T allele of NGF rs6330 were significantly more likely to be free of their primary anxiety diagnosis at follow-up (OR=0.60 (0.42–0.85), P=0.005). These effects remained even when other clinically relevant covariates were accounted for (OR=0.62 (0.41–0.92), P=0.019). No significant associations were observed between BDNF rs6265 and response to psychological therapy. These findings demonstrate that knowledge of genetic markers has the potential to inform clinical treatment decisions for psychotherapeutic interventions

BDNF polymorphism predicts the rate of decline in skilled task performance and hippocampal volume in healthy individuals

Numerous studies have indicated a link between the presence of polymorphism in brain-derived neurotrophic factor (BDNF) and cognitive and affective disorders. However, only a few have studied these effects longitudinally along with structural changes in the brain. This study was carried out to investigate whether valine-to-methionine substitution at position 66 (val66met) of pro-BDNF could be linked to alterations in the rate of decline in skilled task performance and structural changes in hippocampal volume. Participants consisted of 144 healthy Caucasian pilots (aged 40–69 years) who completed a minimum of 3 consecutive annual visits. Standardized flight simulator score (SFSS) was measured as a reliable and quantifiable indicator for skilled task performance. In addition, a subset of these individuals was assessed for hippocampal volume alterations using magnetic resonance imaging. We found that val66met substitution in BDNF correlated longitudinally with the rate of decline in SFSS. Structurally, age-dependent hippocampal volume changes were also significantly altered by this substitution. Our study suggests that val66met polymorphism in BDNF can be linked to the rate of decline in skilled task performance. Furthermore, this polymorphism could be used as a predictor of the effects of age on the structure of the hippocampus in healthy individuals. Such results have implications for understanding possible disabilities in older adults performing skilled tasks who are at a higher risk for cognitive and affective disorders

Genetic and behavioral determinants of hippocampal volume recovery during abstinence from alcohol

Alcohol-dependent individuals (ALC) have smaller hippocampi and poorer neurocognition than healthy controls. Results from studies on the association between alcohol consumption and hippocampal volume have been mixed, suggesting that comorbid or premorbid factors (i.e., those present prior to the initiation of alcohol dependence) determine hippocampal volume in ALC. We aimed to characterize the effects of select comorbid (i.e., cigarette smoking) and premorbid factors (brain-derived neurotrophic factor [BDNF] genotype [Val66Met rs6265]) on hippocampal volume in an ALC cohort followed longitudinally into extended abstinence. One hundred twenty-one adult ALC in treatment (76 smokers, 45 non-smokers) and 35 non-smoking light-drinking controls underwent quantitative magnetic resonance imaging, BDNF genotyping, and neurocognitive assessments. Representative subgroups were studied at 1 week, 1 month, and at an average of 7 months of abstinence. ALC had smaller hippocampi than healthy controls at all time points. Hippocampal volume at 1 month of abstinence correlated with lower visuospatial function. Smoking status did not influence hippocampal volume or hippocampal volume recovery during abstinence. However, only BDNF Val homozygotes tended to have hippocampal volume increases over 7 months of abstinence, and Val homozygotes had significantly larger hippocampi than Met carriers at 7 months of abstinence. These findings suggest that BDNF genotype, but not smoking status or measures of drinking severity, regulate functionally relevant hippocampal volume recovery in abstinent ALC. Future studies aimed at exploring genetic determinants of brain morphometry in ALC may need to evaluate individuals during extended abstinence after the acute environmental effects of chronic alcohol consumption have waned

Travel and venous thrombosis: a systematic review

In the past decade, numerous publications on the association between venous thrombosis (VT) and travel have been published. Relative and absolute risks of VT after travel, and particularly after travel by air, have been studied in case-control and observational follow-up studies, whereas the effect of prophylaxis has been studied through intervention trials of asymptomatic clots. The mechanism responsible for the association between travel and VT was addressed in pathophysiologic studies. Here, we systematically reviewed the epidemiologic and pathophysiologic studies about the association between travel and VT. We conclude that long-distance travel increases the risk of VT approximately two to fourfold. The absolute risk of a symptomatic event within 4 weeks of flights longer than 4 h is 1/4600 flights. The risk of severe pulmonary embolism (PE) occurring immediately after air travel increases with duration of travel, up to 4.8 per million in flights longer than 12 h. The mechanism responsible for the increased risk of VT after (air) travel has insufficiently been studied to draw solid conclusions, but one controlled-study showed evidence for an additional mechanism to immobilization that could lead to coagulation activation after air trave