Brain-derived Neurotrophic Factor Val66Met Polymorphism Research Articles

BDNF Val66Met moderates episodic memory decline and tau biomarker increases in early sporadic Alzheimer's disease.

Allelic variation in the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has been shown to moderate rates of cognitive decline in preclinical sporadic Alzheimer's disease (AD; i.e., Aβ + older adults), and pre-symptomatic autosomal dominant Alzheimer's disease (ADAD). In ADAD, Met66 was also associated with greater increases in CSF levels of total-tau (t-tau) and phosphorylated tau (p-tau181). This study sought to determine the extent to which BDNF Val66Met is associated with changes in episodic memory and CSF t-tau and p-tau181 in Aβ + older adults in early-stage sporadic AD. Aβ + Met66 carriers (n = 94) and Val66 homozygotes (n = 192) enrolled in the Alzheimer's Disease Neuroimaging Initiative who did not meet criteria for AD dementia, and with at least one follow-up neuropsychological and CSF assessment, were included. A series of linear mixed models were conducted to investigate changes in each outcome over an average of 2.8years, covarying for CSF Aβ42, APOE ε4 status, sex, age, baseline diagnosis, and years of education. Aβ + Met66 carriers demonstrated significantly faster memory decline (d = 0.33) and significantly greater increases in CSF t-tau (d = 0.30) and p-tau181 (d = 0.29) compared to Val66 homozygotes, despite showing equivalent changes in CSF Aβ42. These findings suggest that reduced neurotrophic support, which is associated with Met66 carriage, may increase vulnerability to Aβ-related tau hyperphosphorylation, neuronal dysfunction, and cognitive decline even prior to the emergence of dementia. Additionally, these findings highlight the need for neuropsychological and clinicopathological models of AD to account for neurotrophic factors and the genes which moderate their expression.

Potential role of APOE ɛ4 allele as a modifier for the association of BDNF Val66Met polymorphisms and cognitive impairment in community-dwelling older adults.

To determine whether the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with cognitive impairment (CI) in community-dwelling Chinese older adults, and to investigate whether this relationship is modified by the Apolipoprotein E (APOE) ɛ4 allele. The study is a secondary analysis of 703 participants aged ≥60 years randomly enrolled from the Beijing Longitudinal Study of Aging II prospective cohort. The education-adjusted Mini-Mental State Examination and the Clinical Dementia Rating Scale were used to measure the cognitive performance of the subjects. The main effects and interactions (additive and multiplicative) of the BDNF Met and the APOE ε4 alleles on CI were estimated by logistic regression models. In total, 84 out of 703 older adults aged ≥60 years old had CI. No significant difference was observed in the risk of CI between participants with the BDNF Met allele and that of subjects without the BDNF Met allele (p = 0.213; p = 0.164). Individuals carrying both the BDNF Met and APOE ε4 alleles had an almost 1.5-fold increased odds of CI compared with carriers of the BDNF Met allele but without the APOE ε4 allele. The additive association indicated a positive interaction of both BDNF Met and APOE ε4 alleles with wide CIs (p = 0.021; p = 0.018). The results suggest that the APOE ε4 allele may be a potential modifier for the association of the BDNF Val66Met polymorphism with CI in community-dwelling older adults.

Brain-derived Neurotrophic Factor Level and Gene Polymorphism as Risk Factors for Depression in Patients with type 2 Diabetes Mellitus- A Case-Controlled Study.

Diabetes mellitus and depression are comorbidities that can be caused by each other. Brain-derived neurotrophic factor (BDNF) functions as a neuronal growth factor. It maintains the functional integrity of the nervous system. To study the possible association between BDNF levels and gene polymorphism with depression in patients diagnosed with type 2 diabetes mellitus. The Elisa technique measured BDNF, and rs6265 gene polymorphism was detected using real-time PCR. Depression was assessed utilizing a clinical interview tool designed to establish the diagnosis of depression and differentiate it from other psychiatric diseases. BDNF levels were significantly lower in patients with type 2 diabetes mellitus and symptoms of depression than in patients with type 2 diabetes mellitus and no symptoms of depression (82.6±16.1. Vs 122± 17.47, p˂ 0.001). There was a statistically significant difference in BDNF levels in patients with diabetes among the three genotypes of the BDNF gene (p-value < 0.001). Val/ Val carriers had the highest serum BDNF levels, and Met/ Met carriers had the lowest serum BDNF levels. Subgroup analysis showed statistically significant genotype-related differences in serum BDNF levels among the three subgroups in the Depression group. Val/ Val carriers had the highest serum BDNF levels, and Met/ Met carriers had the lowest serum BDNF levels. BDNF Val66Met polymorphism had no significant association with the presence of depression, yet there was a trend towards significance (p = 0.05) Conclusion: In this pilot, Low levels of BDNF were associated with depression in patients with type 2 diabetes. Carriers of the Met/ Met allele have the lowest serum BDNF levels. Multicenter studies with more participants are required.

Dose-response effects of exercise on mental health in community-dwelling older adults: Exploration of genetic moderators

Background/Objective(1) Examine the role of exercise intensity on mental health symptoms in a community-based sample of older adults. (2) Explore the moderating role of genetic variation in brain-derived neurotrophic factor (BDNF) and apolipoprotein E (APOE) on the effects of exercise on mental health symptoms. MethodThis study is a secondary analysis of a three-arm randomized controlled trial, comparing the effects of 6 months of high-intensity aerobic training vs. moderate-intensity aerobic training vs. a no-contact control group on mental health symptoms assessed using the Depression, Anxiety, and Stress Scale (DASS). The BDNF Val66Met polymorphism and APOE ε4 carrier status were explored as genetic moderators of exercise effects on mental health symptoms. ResultsThe exercise intervention did not influence mental health symptoms. The BDNF Val66Met polymorphism did not moderate intervention effects on mental health symptoms. APOE ε4 carrier status moderated the effect of intervention group on perceived stress over 6 months, such that APOE ε4 carriers, but not non-carriers, in the high-intensity aerobic training group showed a decline in perceived stress over 6 months. ConclusionsAPOE ε4 carrier status may modify the benefits of high-intensity exercise on perceived stress such that APOE ε4 carriers show a greater decline in stress as a result of exercise relative to non-APOE ε4 carriers.

Day‐to‐day Sleep Variability in Val66Met BDNF Carriers: A Potential Biological Pathway Between BDNF Activity and Alzheimer’s Disease Pathology?

AbstractBackgroundWe previously showed that day‐to‐day sleep variability was associated with biomarkers of Alzheimer’s disease (AD) pathology. Given that brain‐derived neurotrophic factor (BDNF) activity has been involved in both AD and cognitive impacts of lifestyle risk factors, we sought to evaluate day‐to‐day sleep variability in those carrying the Met allele of the Val66Met BDNF polymorphism, which affects BDNF release. Additionally, we explored whether BDNF polymorphism modified the association between CSF AD pathology and day‐to‐day sleep variability.MethodThe PREVENT‐AD cohort enrolls dementia‐free persons with a parental history of sporadic AD. We characterized 203 dementia‐free participants from this cohort at the polymorphic BDNF locus, identifying 136 persons with genotype Val/Val (age 68.2±5.3y, 75%women), 67 Met heterozygotes/homozygotes (68.4±5.6y, 73% women, including six Met/Met homozygotes). After a week of actigraphy, we calculated these participants’ standard deviation of day‐to‐day sleep characteristics. We used t‐tests to compare day‐to‐day sleep variability in sleep characteristics between Val homozygotes and Met carriers. In a subsample of 101 participants, we assayed CSF Aβ42, t‐tau and p‐tau181, and used age‐ and sex‐adjusted linear regressions with an interaction term to test for moderation by BDNF genotype (36 Met carriers vs. 65 Val homozygotes) between sleep variability and CSF biomarker results.ResultAs compared to Val homozygotes, sleep was disturbed and unstable in BDNF Met carriers (heterozygotes/homozygotes). They had higher day‐to‐day variability in sleep fragmentation (activity counts, wake after sleep onset, fragmentation index), sleep onset latency, and sleep duration, resulting in weekly sleep patterns that were more fragmented and less efficient. Further, BDNF genotype moderated the association between CSF t‐tau and p‐tau181 with day‐to‐day sleep duration variability, such that only Met carriers showed an association between elevated tau concentration and sleep duration variability.ConclusionBDNF Met carriers had disturbed and unstable daily sleep patterns. Because the Met allele is known to decrease plasticity of neural mechanisms, the ability to achieve healthy and stable sleep may depend on such mechanisms. Thus, poorer sleep in Met carriers might be a biological mechanism by which altered BDNF activity affects tau pathology or, alternatively, accumulated AD pathology in Met carriers may disrupt sleep‐wake patterns.

54 The Differential Impact of Genetic Moderators on the Relationship Between Depression and Cognition

Objective:Depression has a well-established negative effect on cognitive functioning. Variations in the apolipoprotein e (APOE) and brain-derived neurotrophic factor (BDNF) genes likely contribute to this relationship. APOE4 and the BDNF Val66Met polymorphism are independently associated with late-life depression and cognitive dysfunction. The current study investigated the moderating effects of APOE4 and BDNFMet (i.e., the presence of the BDNF Val66Met polymorphism) on the relationship between depression and cognitive functioning in older adults.Participants and Methods:The sample included 103 older adults drawn from two clinical trials who were recruited from the VA Palo Alto Health Care System (VAPAHCS) and the Stanford/VA Alzheimer’s Disease Center. Depression was diagnosed using the Mini Neuropsychiatric Interview for the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV). The presence of an APOE4 and BDNFMet allele were dichotomized (i.e., yes/no) and determined using venipuncture. A comprehensive neuropsychological battery was used to assess attention (RAVLT Trial 1, WAIS-IV DSF), processing speed (TMTA, SDMT, Stroop Word, Stroop Color), working memory (WAIS-IV DSB, DSS), visuospatial functioning (JLO), language (VNT), memory (RAVLT Delayed Recall, WMS-IV Logical Memory II), and executive function (TMTB, Stroop Color-Word). Separate moderation analyses were conducted with depression as the predictor and APOE4 or BDNFMet status as the moderator using the SPSS PROCESS macro v4.0. Age was a covariate for models with processing speed, memory, language, and executive function as outcome variables.Results:Participants were largely male (93%) and White (75%). Ten percent met criteria for depression, 26% were APOE4 carriers, and 32% were BDNFMet carriers. The overall model examining depression, APOE4, and memory was significant (p &lt; .01, R2 = .14). Depression was associated with lower memory performance (p &lt; .05), however, APOE4 was not a significant moderator (p &gt; .05). Similarly, the overall model examining depression, APOE4, and language was also significant (p &lt; .05, R2 = .10). While the direct effects of depression and APOE4 on language were nonsignificant (p &gt; .05), there was a significant two-way interaction between APOE4 and depression (p = .03). The overall model with depression, BDNFMet, and memory was significant (p &lt; .001, R2 = .18). While neither depression nor BDNFMet had significant direct effects on memory (p &gt; .05), a two-way interaction emerged between depression and BDNFMet (p = .05). Simple slopes analyses were used to further investigate significant interactions. Depression, APOE4, and BDNFMet did not significantly impact attention, processing speed, working memory, visuospatial functioning, or executive function, and no significant interactions were noted among variables. BDNFMet had no direct impact on language.Conclusions:APOE4 and BDNFMet were found to differentially moderate the relationship between depression and cognition. Specifically, APOE4 carriers with depression had worse language performance compared to those who were healthy, depressed, or APOE4 carriers. BDNFMet carriers with depression performed worse on measures of memory compared to those who were healthy, depressed, or BDNFMet carriers. The treatment of depression in APOE4 and BDNFMet carriers may reduce associated cognitive impairments. Limitations and future implications are also discussed.

Influence of BDNF Val66Met genetic polymorphism in Major Depressive Disorder and Body Mass Index: Evidence from a meta-analysis of 6481 individuals

BackgroundMajor depressive disorder (MDD) and obesity are global health problems that frequently co-occur. Among shared etiological factors, genetic variation at the brain-derived neurotrophic factor (BDNF) gene is interesting since its implication in energy balance regulation, food intake and synaptic function. Thus, the aim of this study was to investigate the influence of the BDNF Val66Met polymorphism in relation to MDD and body mass index (BMI) in two large independent cohorts. MethodsThe sample consisted of 2646 individuals with MDD and 3835 controls from the PISMA-ep and Radiant studies. Linear regressions were performed to test the association between the polymorphism and BMI and the interaction between the polymorphism and MDD on BMI. A meta-analysis across cohorts was conducted. ResultsNo association was found between the polymorphism and BMI. However, we found an association with MDD, showing these individuals higher BMI than controls in both cohorts. No differences were found in BMI depending on Val66Met genotype and no interaction between this polymorphism and MDD in relation to BMI was found. Although a tendency towards an interaction was found in the Radiant sample, the results of the meta-analysis did not support this finding. LimitationsThe use of self-reported height and weight measures to calculate BMI values. ConclusionsWe provide evidence for an association between BMI and MDD confirming previous results. Our meta-analysis including two large cohorts showed no interaction between BDNF, BMI and MDD. Future studies will be needed to confirm the role of this polymorphism in the relationship between BMI and MDD.

The brain-derived neurotrophic factor Val66met polymorphism is associated with better attention and working memory performance and resilience to mild chronic stress.

The val66met polymorphism of the brain-derived neurotrophic factor (BDNF) gene has been identified as a potential moderator for the relationship between chronic stress and executive functioning. However, whether the presence of the met allele increases cognitive vulnerability or resilience to stress has yet to be determined. Given the established effects of autonomic activity and psychological arousal on executive functioning, in the present study, 56 healthy university students completed self-report measures of chronic stress, positive arousal (vigour) and negative arousal (anxiety) and measured heart-rate variability to quantify autonomic activity. Participants then completed a cognitive test battery that measured attention, decision-making, visual learning and working memory. Regression analyses demonstrated that Val/met participants performed better on attention and working memory tasks than Val/val participants, but no differences were seen in decision-making and visual learning. Further, Val/met participants were protected from stress-related differences in attention seen in Val/val participants. Val66met was not associated with physiological or psychological arousal. This study demonstrates that val66met plays an important but selective role in cognitive performance.

Enhanced methamphetamine sensitisation in a rat model of the brain-derived neurotrophic factor Val66Met variant: Sex differences and dopamine receptor gene expression

Brain-derived neurotrophic factor (BDNF) and the Val66Met polymorphism may play a role in the development of psychosis and schizophrenia. The aim of this study was to investigate long-term effects of methamphetamine (Meth) on psychosis-like behaviour and dopamine receptor and dopamine transporter gene expression in a novel rat model of the BDNF Val66Met polymorphism. At the end of a 7-day subchronic Meth treatment, female rats with the Met/Met genotype selectively showed locomotor hyperactivity sensitisation to the acute effect of Meth. Male rats showed tolerance to Meth irrespective of Val66Met genotype. Two weeks later, female Met/Met rats showed increased locomotor activity following both saline treatment or a low dose of Meth, a hyperactivity which was not observed in other genotypes or in males. Baseline PPI did not differ between the groups but the disruption of PPI by acute treatment with apomorphine was absent in Meth-pretreated Met/Met rats. Female Met/Met rats selectively showed down-regulation of dopamine D2 receptor gene expression in striatum. Behavioural effects of MK-801 or its locomotor sensitisation by prior Meth pretreatment were not influenced by genotype. These data suggest a selective vulnerability of female Met/Met rats to short-term and long-term effects of Meth, which could model increased vulnerability to psychosis development associated with the BDNF Val66Met polymorphism.

Association of the Brain-Derived Neurotrophic Factor Gene (BDNF) Val66Met Polymorphism with Individual Alpha Peak Frequency and Alpha Power in Adults

—A single nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene (Val66Met) functions to regulate activity-dependent secretion of (BDNF), which plays an important role in neuroprotection and synaptic plasticity. In several studies, the Met allele was associated with lower electroencephalogram (EEG) α-power values, calculated in the standard frequency range, in young subjects. In addition to α-power, one of the inherited EEG correlates of brain functioning is individual alpha peak frequency (IAPF). Although IAPF has a separate functional role, its association with BDNF Val66Met polymorphism has not been studied. IAPF is also used to determine the boundaries of individual frequency ranges, which, unlike the standard ones, are more consistent with functional rhythm characteristics. Using a sample of 192 subjects aged 18–78 years, the association between parietal-occipital IAPF and BDNF polymorphism, as well as the genotype differences in α-power calculated in standard (8–12 Hz) and individual frequency ranges (from (IAPF –2) to (IAPF +2) Hz) were examined. A decrease of IAPF in Val/Met compared to Val/Val was observed. For power calculated in the individual frequency range, genetic differences in both eyes-closed (Val/Met > homozygous genotypes) and eyes-open (Val-carriers > Met/Met) conditions were revealed. Analysis within the standard frequency range showed differences only in the eyes-open condition, which could be due to a shift of power indicators calculated in the α-rhythm functional range to the low frequency region among Val/Met carriers, which showed a decrease in IAPF. The results suggest that the inclusion of Val/Met in the pooled group of Met carriers in the analysis of genetic differences in brain activity may level out the differences between the Val/Val and Val/Met genotypes and show the advantage of using individual frequency bands in the analysis of BDNF Val66Met-associated EEG features.

Val66Met Polymorphism of Brain-Derived Neurotrophic Factor (BDNF) is Associated with Individual Alpha Peak Frequency and Alpha Power in Adults

Single-nucleotide polymorphism within the BDNF gene (Val66Met) influences activity-dependent secretion of the brain-derived neurotrophic factor (BDNF), which affects neuroprotection and synaptic plasticity. Several studies found associations between Met allele and lower power of the EEG α-rhythm determined in the standard frequency range in young adults. Along with the power, one of the highly heritable EEG correlates of brain functions is the individual α-peak frequency (IAPF). Although IAPF has independent functional significance, its association with the Val66Met BDNF polymorphism has not been studied. IAPF is also used to determine the boundaries of individual frequency ranges; in contrast to the standard ones, they reflect functional characteristics of rhythms to a greater extent. We explored in 192 subjects aged 18–78 years whether parieto-occipital IAPF is associated with BDNF polymorphism and tested genotypic differences in α-power calculated in standard (8−12 Hz) and individual (from (IAPF –2) to (IAPF +2) Hz) frequency ranges. IAPF was decreased in Val/Met in comparison to Val/Val. For individual frequency range, genetic differences were found in both eyes closed (Val/Met homozygous genotypes) and eyes open (Val-carriers Met/Met) condition. For standard frequency range – only in eyes open condition, which may be due to a shift of the α-functional range towards a region of low frequencies among Val/Met-carriers that showed a decrease in IAPF. The results indicate that the inclusion of Val/Met in the combined group of Met-carriers in the analysis of genetic differences in brain activity can eliminate the differences between Val/Val and Val/Met genotypes, as well as the advantage of using individual frequency bands in the analysis of BDNF-associated features of EEG.

Brain-derived neurotrophic factor Val66Met polymorphism moderates the relationship between impulsivity, negative emotions, and binge drinking intensity in university students.

Studies on the genetic factors involved in binge drinking (BD) and its associated traits are very rare. The aim of this cross-sectional study was to investigate differences in the association between impulsivity, emotion regulation and BD in a sample of young adults according to the rs6265/Val66Met variant in the brain-derived neurotrophic factor (BDNF) gene, a well-known candidate gene in alcohol use disorders. We recruited 226 university students (112 women), aged between 18 and 25years old, from two centers in France. The participants completed measures related to alcohol consumption, depression severity, state anxiety levels, impulsivity (UPPS-P), and difficulties in emotion regulation [Difficulty in Emotion Regulation Scale (DERS)]. The relationship between the BD score and the clinical characteristics in the BDNF genotype groups was assessed by partial correlation analyses and moderation analyses. The partial correlation analyses showed that, in the Val/Val genotype group, the BD score was positively related to UPPS-P Lack of Premeditation and Sensation Seeking scores. In the Met carriers group, the BD score was positively related to UPPS-P Positive Urgency, lack of Premeditation, lack of Perseverance and Sensation Seeking scores and to Clarity score of the DERS. Moreover, the BD score was positively associated with depression severity and state anxiety scores. The moderation analyses revealed that BDNF Val/Met genotype moderated the relationship between several clinical variables and BD. The results of the present study support the hypothesis of common and specific vulnerability factors regarding impulsivity and emotion regulation difficulties associated with BD according to this BDNF rs6265 polymorphism.

Impaired fear memory in a rat model of the brain-derived neurotrophic factor Val66Met polymorphism is reversed by chronic exercise

The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with reduced activity-dependent BDNF release in the brain and has been implicated in fear and anxiety disorders, including post-traumatic stress disorder. Exercise has been shown to have benefits in affective disorders but the role of BDNF Val66Met remains unclear. Male and female BDNF Val66Met rats were housed in automated running-wheel cages from weaning while controls were housed in standard cages. During adulthood, all rats underwent standard three-day fear conditioning testing, with three tone/shock pairings on day 1 (acquisition), and extinction learning and memory (40 tones/session) on day 2 and day 3. Expression of BDNF and stress-related genes were measured in the frontal cortex. Extinction testing on day 2 revealed significantly lower freezing in response to initial cue exposure in control Met/Met rats, reflecting impaired fear memory. This deficit was reversed in both male and female Met/Met rats exposed to exercise. There were no genotype effects on acquisition or extinction of fear, however chronic exercise increased freezing in all groups at every stage of testing. Exercise furthermore led to increased expression of Bdnf in the prefrontal cortex of females and its isoforms in both sexes, as well as increased expression of FK506 binding protein 51 (Fkpb5) in females and decreased expression of Serum/glucocorticoid-regulated kinase (Sgk1) in males independent of genotype. These results show that the Met/Met genotype of the Val66Met polymorphism affects fear memory, and that chronic exercise selectively reverses this genotype effect. Chronic exercise also led to an overall increase in freezing in all genotypes which may contribute to results.

A Rat Model of the Brain-Derived Neurotrophic Factor Val66Met Polymorphism Shows Attenuated Motivation for Alcohol Self-Administration and Diminished Propensity for Cue-Induced Relapse in Females.

Brain-derived neurotrophic factor (BDNF) has been implicated in alcohol use disorder. The Val66Met polymorphism is a common variant of the BDNF gene (rs6265) which reduces activity-dependent BDNF release, and has been suggested as a risk factor for psychiatric disorders and substance use. Using an operant self-administration paradigm, this study aimed to investigate ethanol preference and ethanol seeking in a novel rat model of the BDNF Val66Met polymorphism, Val68Met rats. Male and female BDNF Val68Met rats of three genotypes (Val/Val, Val/Met and Met/Met) were trained to lever press for a 10% ethanol solution. There was no effect of Val68Met genotype on acquisition of stable response to ethanol or its extinction. Met/Met rats of both sexes had a slight, but significantly lower breakpoint during progressive ratio sessions while female rats with the Met/Met genotype demonstrated a lower propensity for reinstatement of responding to cues. There were no effects of Val68Met genotype on anxiety-like behaviour or locomotor activity. In conclusion, Met/Met rats showed lower motivation to continue to press for a reward, and also a decreased propensity to relapse, suggesting a possible protective effect of the Met/Met genotype against alcohol use disorder, at least in females.

Association between chronic tinnitus and brain-derived neurotrophic factor antisense RNA polymorphisms linked to the Val66Met polymorphism in BDNF

Tinnitus is the sound heard in the ear or head of a person in the absence of external stimuli. Its etiopathogenesis is still not fully understood and the etiological causes responsible for tinnitus are quite variable. Brain-derived neurotrophic factor (BDNF) is one of the key neurotrophic factors in the growth, differentiation, and survival of neurons and in the developing auditory pathway, including the inner ear sensory epithelium. The regulation of BDNF gene is known to be managed by BDNF antisense (BDNF-AS) gene. BDNF-AS is located downstream of the BDNF gene and transcribes a long non-coding RNA. Inhibition of BDNF-AS upregulates BDNF mRNA, which increases protein levels and stimulates neuronal development and differentiation. Thus, BDNF and BDNF-AS both may play roles in the auditory pathway. Polymorphisms in both genes may have impact on hearing performance. A link was suggested between tinnitus and BDNF Val66Met polymorphism. However, there is no study questioning the relationship of tinnitus with BDNF-AS polymorphisms linked with BDNF Val66Met polymorphism. Therefore, this study aimed to scrutinize the role of BDNF-AS polymorphisms showing linkage with the BDNF Val66Met polymorphism in the course of tinnitus pathophysiology. Six BDNF-AS polymorphisms were analyzed on the tinnitus patients (n = 85) and the control subjects (n = 60) by Fluidigm Real-Time PCR using the Fluidigm Biomark microfluidic platform. When BDNF-AS polymorphisms were compared between the groups in terms of genotype and gender distribution, statistically significant differences were detected in rs925946, rs1519480, and rs10767658, polymorphisms (p less than 0.05). When the polymorphisms were compared by the duration of tinnitus, significant differences were found in rs925946, rs1488830, rs1519480, and rs10767658 polymorphisms (p less than 0.05). According to genetic inheritance model analysis, 2.33 and 1.53-fold risks were found for the rs10767658 polymorphism in the recessive and the additive models, respectively. For the rs1519480 polymorphism, a 2.25 fold risk was observed in the additive model. For the rs925946 polymorphism, 2.44 fold protective effect in dominant model, and 0.62 fold risk was found in the additive model. In conclusion, four of the polymorphisms in BDNF-AS gene (rs955946, rs1488830, rs1519480, and rs10767658) are potential gene loci that may play a role in the auditory pathway and affect auditory performance.

BDNF Val66Met polymorphism is associated with consolidation of episodic memory during sleep

The brain-derived neurotrophic factor (BDNF) is an essential regulator of synaptic plasticity, a candidate neurobiological mechanism underlying learning and memory. A functional polymorphism in the BDNF gene, Val66Met (rs6265), has been linked to memory and cognition in healthy individuals and clinical populations. Sleep contributes to memory consolidation, yet information about the possible role of BDNF in this process is scarce. To address this question, we investigated the relationship between the BDNF Val66Met genotype and consolidation of episodic declarative and procedural (motor) non-declarative memories in healthy adults. The carriers of Met66 allele, as compared with Val66 homozygotes, showed stronger forgetting overnight (24 h after encoding), but not over shorter time (immediately or 20 min after word list presentation). There was no effect of Val66Met genotype on motor learning. These data suggest that BDNF plays a role in neuroplasticity underlying episodic memory consolidation during sleep.

The influence of the BDNF Val66Met genotype on emotional recognition memory in post-traumatic stress disorder

Dysregulated consolidation of emotional memories is a core feature of posttraumatic stress disorder (PTSD). Brain Derived Neurotrophic Factor (BDNF) influences synaptic plasticity and emotional memory consolidation. The BDNF Val66Met polymorphism has been associated with PTSD risk and memory deficits respectively, although findings have been inconsistent, potentially due to a failure to control for important confounds such as sex, ethnicity, and the timing/extent of previous trauma experiences. Furthermore, very little research has examined the impact of BDNF genotypes on emotional memory in PTSD populations. This study investigated the interaction effects of Val66Met and PTSD symptomatology in an emotional recognition memory task in 234 participants divided into healthy control (n = 85), trauma exposed (TE: n = 105) and PTSD (n = 44) groups. Key findings revealed impaired negative recognition memory in PTSD compared to control and TE groups and in participants with the Val/Met compared to the Val/Val genotype. There was a group × genotype interaction showing no Met effect in the TE group despite significant effects in PTSD and controls. Results suggest that people previously exposed to trauma who do not develop PTSD may be protected from the BDNF Met effect, however more research is needed to replicate findings and to explore the epigenetic and neural processes involved.

The effect of brain-derived neurotrophic factor Val66Met polymorphism on adolescent activity and rest rhythms, circadian preferences and attentional performance

BackgroundVariations in circadian regulating mechanisms generate different individual preferences in respect of sleep and activity timing, which are known as chronotypes. In this sense, specifically during adolescence, there is a greater tendency for an eveningness chronotype. One factor that has been shown to have an impact on circadian rhythm patterns, as well as on some aspects of cognitive function, is the relatively common Val66Met (rs6265) polymorphism in the human brain-derived neurotrophic factor gene. ObjectiveThis study aimed to evaluate the effect of the BDNF Val66Met polymorphism on the performance of adolescents in attentional tests, circadian preferences and activity-rest rhythm. Methods85 healthy high school students completed the Morningness-Eveningness Questionnaire to assess their circadian preferences; were evaluated using the Psychological Battery for Attention Assessment; and were categorized as carriers and non-carriers of the rs6265 polymorphism using the TaqMan rt-PCR technique. A subsample of 42 students had their activity/rest rhythm recorded by actigraphy for nine days from which sleep parameters were estimated. ResultsCircadian preference did not affect attentional performance (p > 0.1), but the time that the students attended school had an impact on all types of attention with morning shift students scoring higher, regardless of chronotype (p < 0.05). The presence of the BDNF Val66Met polymorphism was associated only with alternate attention performance (p < 0.05). Regarding actigraphy evaluation, the carriers of the polymorphism demonstrated significantly higher total time in bed, total sleep time, social jetlag, and earlier sleep onset. ConclusionsThe results indicate some degree of adaptation in the students' attentional performance, according to their school schedules. The presence of BDNF polymorphism demonstrated a counterintuitive impact on attentional performance, comparing to previous findings. The findings reinforce the effect of genetic traits on sleep-wake rhythm parameters, when objectively evaluated.

Pathoclinical associations between panic disorders and the brain-derived neurotrophic factor Val66Met polymorphism: an updated meta-analysis.

Prior studies have indicated the pathological role of brain-derived neurotrophic factor (BDNF) gene polymorphism in panic disorders (PD). A functionally less active BDNF Val66Met mutant was previously detected in PD patients with different ethnic backgrounds. However, the results remain inconclusive or inconsistent. A meta-analysis was used to explore the consistency of the BDNF Val66Met mutant's association with PD irrespective of the subject's ethnicity. Relevant case-controlled full-length clinical and preclinical reports were retrieved by database searching, and 11 articles involving 2203 cases and 2554 controls were systematically selected per the standard inclusion criteria. Eleven articles were finally included that explored the relationship between the Val66Met polymorphism and PD risk susceptibility. Statistical analysis revealed a significant genetic association of the mutation, allele frequencies, and genotype distributions of BDNF with PD onset. Our findings demonstrated that the BDNF Val66Met is a susceptibility factor of PD.

Brain-derived neurotrophic factor Val66Met polymorphism modulates the effects of circadian desynchronization on activity and sleep in male mice.

Understanding how environmental interact challenges with genetic predispositions modulate health and wellbeing is an important area of biomedical research. Circadian rhythms play an important role in coordinating the multitude of cellular and tissue processes that organisms use to predict and adapt to regular changes in the environment, and robust circadian rhythms contribute to optimal physiological and behavioral responses to challenge. However, artificial lighting and modern round-the-clock lifestyles can disrupt the circadian system, leading to desynchronization of clocks throughout the brain and body. When coupled with genetic predispositions, circadian desynchronization may compound negative outcomes. Polymorphisms in the brain-derived neurotrophic (BDNF) gene contribute to variations in neurobehavioral responses in humans, including impacts on sleep, with the common Val66Met polymorphism linked to several negative outcomes. We explored how the Val66Met polymorphism modulates the response to environmental circadian desynchronization (ECD) in a mouse model. ECD was induced by housing adult male mice in a 20 h light-dark cycle (LD10:10; 10 h light, 10 h dark). Sleep and circadian activity were recorded in homozygous (Met) mice and their wild-type (Val) littermates in a standard 24 h LD cycle (LD12:12), then again after 20, 40, and 60 days of ECD. We found ECD significantly affected the sleep/wake timing in Val mice, however, Met mice maintained appropriate sleep timing after 20 days ECD, but not after 40 and 60 days of ECD. In addition, the rise in delta power at lights on was absent in Val mice but was maintained in Met mice. To elucidate the circadian and homeostatic contribution to disrupted sleep, mice were sleep deprived by gentle handling in LD12:12 and after 20 days in ECD. Following 6 h of sleep deprivation delta power was increased for both Val and Met mice in LD12:12 and ECD conditions. However, the time constant was significantly longer in the Val mice during ECD compared to LD12:12, suggesting a functioning but altered sleep homeostat. These data suggest the Val66Met mutation is associated with an ability to resist the effects of LD10:10, which may result in carriers suffering fewer negative impacts of ECD.