Met Carriers Research Articles

Sex Differences in the Effect of Brain-derived Neurotrophic Factor (BDNF) Val66Met Polymorphism on Baseline EEG Connectivity

Dependent on Val66Met polymorphism in BDNF gene secretion of neurotrophin affects morphological and functional changes in the developing and mature nervous system, in particular, may contribute to associated with white matter degradation changes in connectivity observed with aging. It was also shown that the associated with Val66Met polymorphism differences in connectivity between cortical structures are moderated by the sex of the subjects. However, there are no studies examining the effect of polymorphism on connectivity, taking into account age and gender differences. In this regard, the present study examined the associations of the Val66Met polymorphism of the BDNF gene with the characteristics of delayed phase synchronization based on EEG data in 223 younger (from 18 to 35 years old) and 134 older (over 55 years old) men and women. The analysis included connections between 84 cortical areas, identified on the basis of 42 Brodmann areas located in the left and right hemispheres. A statistically significant effect, including the factor of polymorphism, was the SEX × GENOTYPE interaction when considering associations at the frequency of the α1-rhythm: in Val/Met men, the strength of thirty-three connections was higher compared to Val/Val. Strengthening of connections was observed mainly between the parahippocampal regions of different hemispheres. At the frequency of the gamma rhythm, associated with the genotype differences in connectivity depended on gender and age. In young subjects, the scores of connectivity in Val/Val women were lower in comparison with men, however, no differences between Val/Val and Met carriers were found in any age group. The combined effect of sex and BDNF genotype on the baseline EEG parameters of brain connectivity may be a background for further study of the role of these factors in the formation of basic characteristics of brain activity.

A pilot study of the role of the BDNF Val66Met polymorphism in response to exercise-augmented exposure therapy for posttraumatic stress disorder

Brain-Derived Neurotrophic Factor (BDNF) is implicated in extinction learning, which is a primary mechanism of exposure therapy for posttraumatic stress disorder (PTSD). Brief aerobic exercise has been shown to promote BDNF release and augment extinction learning. On the premise that the Val allele of the BDNF Val66Met polymorphism facilitates greater release of BDNF, this study examined the extent to which the Val allele of the BDNF polymorphism predicted treatment response in PTSD patients who underwent exposure therapy combined with aerobic exercise or passive stretching. PTSD patients (N = 85) provided saliva samples in order to extract genomic DNA to identify Val/Val and Met carriers of the BDNF Val66Met genotype, and were assessed for PTSD severity prior to and following a 9-week course of exposure therapy combined with aerobic exercise or stretching. The sample comprised 52 Val/Val carriers and 33 Met carriers. Patients with the BDNF high-expression Val allele display greater reduction of PTSD symptoms at posttreatment than Met carriers. Hierarchical regression analysis indicated that greater PTSD reduction was specifically observed in Val/Val carriers who received exposure therapy in combination with the aerobic exercise. This finding accords with animal and human evidence that the BDNF Val allele promotes greater extinction learning, and that these individuals may benefit more from exercise-augmented extinction. Although preliminary, this result represents a possible avenue for augmented exposure therapy in patients with the BDNF Val allele.

Mild behavioral impairment in early Alzheimer’s disease and its association with APOE and BDNF risk genetic polymorphisms

BackgroundMild behavioral impairment (MBI) has been commonly reported in early Alzheimer’s disease (AD) but rarely using biomarker-defined samples. It is also unclear whether genetic polymorphisms influence MBI in such individuals. We thus aimed to examine the association between the cognitive status of participants (amnestic mild cognitive impairment (aMCI-AD) vs cognitively normal (CN) older adults) and MBI severity. Within aMCI-AD, we further examined the association between APOE and BDNF risk genetic polymorphisms and MBI severity.MethodsWe included 62 aMCI-AD participants and 50 CN older adults from the Czech Brain Aging Study. The participants underwent neurological, comprehensive neuropsychological examination, APOE and BDNF genotyping, and magnetic resonance imaging. MBI was diagnosed with the Mild Behavioral Impairment Checklist (MBI-C), and the diagnosis was based on the MBI-C total score ≥ 7. Additionally, self-report instruments for anxiety (the Beck Anxiety Inventory) and depressive symptoms (the Geriatric Depression Scale-15) were administered. The participants were stratified based on the presence of at least one risk allele in genes for APOE (i.e., e4 carriers and non-carriers) and BDNF (i.e., Met carriers and non-carriers). We used linear regressions to examine the associations.ResultsMBI was present in 48.4% of the aMCI-AD individuals. Compared to the CN, aMCI-AD was associated with more affective, apathy, and impulse dyscontrol but not social inappropriateness or psychotic symptoms. Furthermore, aMCI-AD was related to more depressive but not anxiety symptoms on self-report measures. Within the aMCI-AD, there were no associations between APOE e4 and BDNF Met and MBI-C severity. However, a positive association between Met carriership and self-reported anxiety appeared.ConclusionsMBI is frequent in aMCI-AD and related to more severe affective, apathy, and impulse dyscontrol symptoms. APOE and BDNF polymorphisms were not associated with MBI severity separately; however, their combined effect warrants further investigation.

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.

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.

Aerobic exercise improves executive functions in females, but not males, without the BDNF Val66Met polymorphism

BackgroundAerobic exercise promotes cognitive function in older adults; however, variability exists in the degree of benefit. The brain-derived neurotropic factor (BDNF) Val66Met polymorphism and biological sex are biological factors that have been proposed as important modifiers of exercise efficacy. Therefore, we assessed whether the effect of aerobic exercise on executive functions was dependent on the BDNFval66met genotype and biological sex.MethodsWe used data from a single-blind randomized controlled trial in older adults with subcortical ischemic vascular cognitive impairment (NCT01027858). Fifty-eight older adults were randomly assigned to either the 6 months, three times per week progressive aerobic training (AT) group or the usual care plus education control (CON) group. The secondary aim of the parent study included executive functions which were assessed with the Trail Making Test (B–A) and the Digit Symbol Substitution Test at baseline and trial completion at 6 months.ResultsAnalysis of covariance, controlling for baseline global cognition and baseline executive functions performance (Trail Making Test or Digit Symbol Substitution Test), tested the three-way interaction between experimental group (AT, CON), BDNFval66met genotype (Val/Val carrier, Met carrier), and biological sex (female, male). Significant three-way interactions were found for the Trail Making Test (F(1,48) = 4.412, p < 0.04) and Digit Symbol Substitution Test (F(1,47) = 10.833, p < 0.002). Posthoc analyses showed female Val/Val carriers benefited the most from 6 months of AT compared with CON for Trail Making Test and Digit Symbol Substitution Test performance. Compared with CON, AT did not improve Trail Making Test performance in male Val/Val carriers or Digit Symbol Substitution Test performance in female Met carriers.ConclusionsThese results suggest that future randomized controlled trials should take into consideration BDNF genotype and biological sex to better understand the beneficial effects of AT on cognitive function in vascular cognitive impairment to maximize the beneficial effects of exercise and help establish exercise as medicine for cognitive health.

Relationship of APOE ε4 allele and BDNF Val66Met polymorphism to retinal structural and vascular OCTA parameters in aging cohort: Optic nerve decline and cognitive change study

AbstractPurpose: To investigate the relationship between the APOE (Apolipoprotein ε4) allele and brain‐derived neurotrophic factor (BDNF) Val66Met polymorphism on retinal structural and vascular characteristics in healthy aging subjects.Methods: 109 healthy participants (mean age 67.1 (±9.0) years) were recruited. Participants were classified as either APOE carriers or non‐carriers based on the presence or absence of the ε4 allele and cohorts established based on their BDNF genotype (Val/Val, Met/Met and Val/Met). Baseline assessment included ophthalmological examination and retinal imaging including OCT (optical coherence tomography) and OCTA (optical coherence tomography angiography) with 3 T Wide Bore MRI imaging to assess brain volumetric measures. Cognitive function was evaluated using a battery of neuropsychological assessments. The relationship between carriers of APOE ε4 allele and Met carriers between these ocular parameters were analysed using the generalized estimating equation (GEE) models and data adjusted for age, sex and inter‐eye differences as within‐subject variables (p &lt; 0.05).Results: 20 subjects (22%) were identified as APOE ε4 carriers and 44 subjects (41%) were identified as Met Carriers. Temporal RNFL thickness was decreased in APOE ε4 carriers (p &lt; 0.01). Vessel density between carriers and non‐carriers was not significantly different at either the superficial or deep level, however, the FAZ (foveal avascular zone) area was found to be smaller in ε4 carriers in both superficial (p &lt; 0.01) and deep layers (p &lt; 0.003). The BDNF Met allele carriage had significant association with reduction of the entorhinal cortex volume in the healthy aging cohort (p = 0.012). No association was found with cognitive performances.Conclusions: Our results indicate possible associations between reduced FAZ area and reduced temporal RNFL thickness with the APOE ε4 allele, and that carriage of BDNF Val66Met polymorphism may be associated with some specific regions of cortical volume loss. Further studies could further characterize this association.

Catechol-O-Methyltransferase Effects on Smoking: A Review and Proof of Concept of Sex-Sensitive Effects.

This article reviews recent research on how catechol-O-methyltransferase (COMT) may impact cigarette smoking behavior, and how effects may be sex-sensitive. Preliminary data are presented on sex-sensitive effects of COMT on response to short-term abstinence in individuals who smoke. Although research is mixed, functional variants in the COMT gene have been linked with smoking behavior, cessation outcomes and nicotine abstinence-related symptoms. Our proof-of-concept preliminary data from a human laboratory study of individuals who smoke cigarettes found that those with the high COMT enzyme activity genotype (Val/Val) reported more severe smoking urges and withdrawal symptoms following overnight abstinence than Met carriers. These effects were present in women, but not in men and were abstinent-dependent, in that they dissipated following nicotine administration. The preliminary data showing sex-sensitive pharmacogenetic effects may shed light on mechanisms contributing to sex differences in barriers to smoking cessation or potential sex-specific treatment options.

The inconsistent mediating effect of catechol O methyl transferase Val158Met polymorphism on the sex difference of cognitive impairment in schizophrenia patients.

ObjectiveSchizophrenia is a multifaceted mental disorder characterized by heterogeneous positive/negative symptoms and cognitive deficits. Sex differences have been reported in various aspects of the disease. However, the underlying genetic reasons remain unelucidated. Recent studies show that the influence of COMT Val158Met (rs4680) variation is sexually dimorphic. Thus, this study aims to explore whether there is an effect of the interaction between COMT Val158Met (rs4680) polymorphism and sex on patients’ clinical characteristics and cognitive function.Materials and methodsWe recruited 367 in patients with chronic schizophrenia (246 males and 121 females) and 419 healthy controls (172 males and 247 females). The cognitive performance was assessed by Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and the COMT Val158Met (rs4680) polymorphism is genotyped. The psychopathological symptoms of the patients were assessed by the Positive and Negative Syndrome Scale (PANSS).ResultsWe find that male patients had a significantly higher proportion of carrying the Val allele and Val/Val carriers exhibited more severe positive symptoms and cognitive impairment than Met carriers. COMT Val158Met (rs4680) polymorphism inconsistently mediated the relationship between sex and cognitive performance in schizophrenia patients.ConclusionThese findings suggest that COMT Val158Met (rs4680) polymorphism is associated with the risk and severity of schizophrenia in a sexually dimorphic way and contributes more to the clinical symptoms and cognitive impairment in male patients with schizophrenia.

Different Exercise Types Produce the Same Acute Inhibitory Control Improvements When the Subjective Intensity Is Equal.

Twenty-eight active older people (67.19 ± 4.91 years) who engaged in physical exercise activity twice a week were recruited to participate in a counterbalanced experimental protocol. The participants performed three different exercise sessions on three different days, one based on aerobic activities, one based on strength exercises with elastic bands, and one based on stationary balance games. During all three sessions, they were encouraged to maintain a moderate subjective intensity (5–6 on the RPE10 scale), and their heart rate was recorded. In addition, all of the participants took a digital version of the Stroop test before and after each session. The study aimed to compare the acute cognitive impacts of different types of exercise sessions in older adults. The participants’ heart rate differed between the exercise sessions, but they maintained the RPE intensity. There was a significant improvement in inhibitory control (Stroop test) after all sessions, with no differences between exercise sessions. Moreover, some participants agreed to be genotyped to record the single nucleotide polymorphism of BDNF rs6265. There were no differences between Val/Val and Met carriers at the beginning or end of the exercise sessions. The present study showed similar cognitive improvements with different exercise type sessions when the subjective intensity was maintained.

The effects of catechol-O-methyltransferase single nucleotide polymorphisms on positive and negative symptoms of schizophrenia: A systematic review and meta-analysis.

The catechol-O-methyltransferase (COMT) gene is thought to have an important role in the etiopathogenesis of schizophrenia, but there are conflicting results regarding its role in clinical presentation. We aimed to elucidate the relationship between the single nucleotide polymorphisms (SNPs) in the COMT gene and the severity of positive and negative symptoms. In order to investigate the relationship, the PubMed, PubMed Central, Scopus, and Cochrane CENTRAL databases were screened for eligible articles. Thirty-eight studies, including 4443 adult patients with schizophrenia, were included in the quantitative analyses, and four studies were qualitatively assessed. Quantitative analyses were performed for acutely ill and clinically stable patient subgroups regarding the different genotypes of rs4680 SNP. Our results showed that the severity of negative symptoms was higher in patients who were rs4680 Met homozygous compared to Val/Met heterozygotes only in acutely ill samples. There was no other significant difference between genotypes. Meta-regression did not reveal any significant moderator effect on the difference in negative symptoms. General psychopathology, positive, negative, and total psychotic symptom levels also were similar between Val homozygotes and Met carriers. Nonetheless, there are some limitations in the study. First, SNPs except for rs4680 were under-researched because of the limited number of studies. Second, high heterogeneity across studies was the main concern. Our results suggested that the COMT rs4680 Met allele was associated with higher levels of negative symptoms within acutely ill patients. Future studies should focus on specific patient subgroups to reveal the moderating effects of SNPs.

White-Matter Integrity and Working Memory: Links to Aging and Dopamine-Related Genes.

Working memory, a core function underlying many higher-level cognitive processes, requires cooperation of multiple brain regions. White matter refers to myelinated axons, which are critical to interregional brain communication. Past studies on the association between white-matter integrity and working memory have yielded mixed findings. Using voxelwise tract-based spatial statistics analysis, we investigated this relationship in a sample of 328 healthy adults from 25 to 80 years of age. Given the important role of dopamine (DA) in working-memory functioning and white matter, we also analyzed the effects of dopamine-related genes on them. There were associations between white-matter integrity and working memory in multiple tracts, indicating that working-memory functioning relies on global connections between different brain areas across the adult life span. Moreover, a mediation analysis suggested that white-matter integrity contributes to age-related differences in working memory. Finally, there was an effect of the COMT Val158Met polymorphism on white-matter integrity, such that Val/Val carriers had lower fractional anisotropy values than any Met carriers in the internal capsule, corona radiata, and posterior thalamic radiation. As this polymorphism has been associated with dopaminergic tone in the prefrontal cortex, this result provides evidence for a link between DA neurotransmission and white matter. Together, the results support a link between white-matter integrity and working memory, and provide evidence for its interplay with age- and DA-related genes.

Looking for factors affecting functioning in euthymic patients with bipolar I disorder: the importance of cognitive complaints and BDNF‘s Val66Met polymorphism

IntroductionFunctioning in Bipolar Disorder (BD) is affected in a substantial proportion of patients. The impact of demographic, clinical, cognitive, and genetic factors on functioning has been shown individually; however, as a complex phenomenon, a global approach to identify the most relevant as well as possible interactions is needed. Methods102 patients with type I BD in euthymia were invited for evaluation of demographic, clinical, and cognitive characteristics as well as genotype for Val66Met polymorphism of BDNF gene to determine those associated with poor functioning according to the FAST scale cut-off score. Clinical evaluation included assessment of residual affective symptoms and anxiety. Cognitive evaluation included the COBRA scale, verbal memory, and executive functions testing. ResultsResidual depressive symptoms, anxiety, cognitive complaints and being a Met carrier were more frequent in the poor functioning group and were entered in a logistic regression model. Being a Met carrier (OR=4.46, CI=1.19–16.67) and cognitive complaints (OR=1.29, CI= 1.13–1.46) were the most important predictors of poor functioning in type I BD. LimitationsCross-sectional study, with select population limiting generalizability of findings. ConclusionsA better understanding of underlying factors affecting cognition, including the possible involvement of BDNF Val66Met polymorphism, its systematic evaluation and a continued search for targeted treatment, along with recognition and attention of residual affective and anxious symptoms might improve psychosocial outcomes such as functioning in this population.

The Brain-Derived Neurotrophic Factor Functional Polymorphism and Hand Grip Strength Impact the Association between Brain-Derived Neurotrophic Factor Levels and Cognition in Older Adults in the United States.

Aging is associated with subtle cognitive decline in attention, memory, executive function, processing speed, and reasoning. Although lower brain-derived neurotrophic factor (BDNF) has been linked to cognitive decline among older adults, it is not known if the association differs among individuals with various BDNF Val66Met (rs6265) genotypes. In addition, it is not clear whether these associations vary by hand grip strength or physical activity (PA). A total of 2904 older adults were included in this study using data from the Health and Retirement Study. Associations between serum BDNF and measures of cognitive function were evaluated using multivariable linear regression models stratified by Met allele status. PA and hand grip strength were added to the model to evaluate whether including these variables altered associations between serum BDNF and cognition. Mean age was 71.4years old, and mean body mass index was 28.3kg/m2. Serum BDNF levels were positively associated with higher total cognitive score (beta = 0.34, p = .07), mental status (beta = 0.16, p = .07), and word recall (beta = 0.22, p =.04) among Met carriers, while serum BDNF levels were negatively associated with mental status (beta = -0.09, p = .07) among non-Met carriers. Furthermore, associations changed when hand grip strength was added to the model but not when PA was added to the model. The BDNF Val66Met variant may moderate the association between serum BDNF levels and cognitive function in older adults. Furthermore, such associations differ according to hand grip strength but not PA.

BDNF polymorphism and interhemispheric balance of motor cortex excitability: a preliminary study.

Preclinical studies have demonstrated that brain-derived neurotrophic factor (BDNF) plays a crucial role in the homeostatic regulation of cortical excitability and excitation/inhibition balance. Using transcranial magnetic stimulation techniques, we investigated whether BDNF polymorphism could influence cortical excitability of the left and right primary motor cortex in healthy humans. Twenty-nine participants were recruited and genotyped for the presence of the BDNF Val66Met polymorphism, namely homozygous for the valine allele (Val/Val), heterozygotes (Val/Met), and homozygous for the methionine allele (Met/Met). Blinded to the latter, we evaluated inhibitory and facilitatory circuits of the left (LH) and right motor cortex (RH) by measuring resting (RMT) and active motor threshold (AMT), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF). For each neurophysiological metric, we also considered the interhemispheric balance expressed by the laterality index (LI). Val/Val participants (n = 21) exhibited an overall higher excitability of the LH compared with the RH, as probed by lower motor thresholds, lower SICI, and higher ICF. Val/Val participants displayed positive LI, especially for AMT and ICF (all P < 0.05), indicating higher LH excitability and more pronounced interhemispheric excitability imbalance as compared with Met carriers. Our preliminary results suggest that BDNF Val66Met polymorphism might influence interhemispheric balance of motor cortex excitability.NEW & NOTEWORTHY BDNF Val66Met polymorphism might influence interhemispheric balance of motor cortex excitability. Specifically, Val/Val carriers display higher excitability of the left compared with the right primary motor cortex, whereas Met carriers do not show any significant corticomotor excitability imbalance. These preliminary results are relevant to understanding aberrant interhemispheric excitability and excitation/inhibition balance in neurological disorders.

Influence of Catechol-O-Methyltransferase Gene Polymorphism on the Correlation between Alexithymia and Hypervigilance to Pain

The psychological characteristic of having difficulty expressing emotions, known as alexithymia, is associated with hypervigilance to pain and is considered one of the risk factors for chronic pain. The correlation between alexithymia and hypervigilance to pain can be observed even in healthy individuals. However, the factors influencing this correlation remain unknown. We explored the dopamine system, which is known to be involved in emotion and pain. The dopamine-degrading enzyme catechol-O-methyltransferase (COMT) has a genetic polymorphism known to influence dopamine metabolism in the prefrontal cortex. COMT polymorphism reportedly affects various aspects of pain and increases pain sensitivity in Met allele carriers. Therefore, we investigated whether the correlation between alexithymia and hypervigilance to pain is influenced by COMT polymorphism in healthy individuals. The results revealed a significant positive correlation between the “difficulty describing feelings” of the 20-item Toronto Alexithymia Scale and the “attention to changes in pain” of the pain vigilance and awareness questionnaire in COMT Met carriers but not in Val/Val individuals. This finding suggests that the correlation between alexithymia and hypervigilance to pain is influenced by COMT polymorphism.

Predictive roles of brain-derived neurotrophic factor Val66Met polymorphism on antidepressant efficacy of different forms of prefrontal brain stimulation monotherapy: A randomized, double-blind, sham-controlled study

BackgroundAlthough repetitive transcranial magnetic stimulation (rTMS) and prolonged intermittent theta-burst stimulation (piTBS) can induce changes in synaptic plasticity, the influence of brain-derived neurotrophic factor (BDNF) genotypes on their antidepressant effects remain unknown. Hence, we investigated the BDNF polymorphism contribution to the antidepressant effect of different forms left-sided prefrontal stimulations in a randomized, sham-controlled study MethodsSeventy-five patients with medication-resistant depression were randomly assigned into three monotherapy groups: piTBS, high-frequency(HF) rTMS, or sham. The acute treatment period was two weeks. 17-item Hamilton Depression Rating scale (HDRS-17) were applied at baseline, week-1, and week-2. The primary outcome was percentage changes of HDRS-17 (%HDRS-17 changes) analyzed by generalized estimating equation (GEE) model. ResultsThe GEE analysis revealed a significant interaction between group, time, and BDNF genotypes effects on %HDRS-17 changes over time. In patients carrying Val homozygotes, piTBS and HF-rTMS both exhibited significantly greater %HDRS reduction than sham at week-2. In Met carriers, only piTBS showed better efficacy than sham at week-2 (piTBS vs. sham, -41.1% vs.-18.9%, p=0.004). Regarding the influence of different BDNF genotypes on antidepressant efficacy in each intervention, only HF-rTMS exhibited significantly different degrees of %HDRS-17 changes between Val homozygotes and Met carriers (-68.5% vs. -26.4%, p=0.012, respectively), but piTBS delivered the consistent efficacy regardless of the BDNF polymorphism. ConclusionsThis is the first study to confirm the different impacts of BDNF genotypes on the effect of different left-sided prefrontal brain stimulation. BDNF Val66Met polymorphism may play a role in the antidepressant response of piTBS and HF-rTMS. (Trial Registration Number UMIN-CTR:UMIN000020892: Registration date: Feb.4, 2016)

Investigating interactive effects of worry and the catechol-o-methyltransferase gene (COMT) on working memory performance.

Extant research indicates that worry is associated with reduced working memory. It remains unclear, however, what mechanisms contribute to impaired performance in worriers. Critically, dopamine in the prefrontal cortex heavily influences the stability of mental representations during working memory tasks, yet no research has probed its role in associations between worry and working memory. To address this gap, the current study was designed to examine the moderating role of dopamine on the association between worry and working memory, using the catechol-o-methyltransferase (COMT) gene as a proxy for basal levels of dopamine. Across four assessments, we examined within- and between-person variation in worry and its interactive effects with COMT to predict working memory performance. Within-person variation in worry interacted with COMT to predict accuracy, such that higher worry across time predicted less accuracy for homozygous Val carriers but not Met carriers. Our findings demonstrate that basal dopamine plays an important role in how increases in worry across time for an individual negatively impact working memory performance.

Met carriers of the BDNF Val66Met polymorphism show reduced Glx/NAA in the pregenual ACC in two independent cohorts

The Met allele of the Val66Met SNP of the BDNF gene (rs6265) is associated with impaired activity-dependent release of brain-derived neurotrophic factor (BDNF), resulting in reduced synaptic plasticity, impaired glutamatergic neurotransmission, and morphological changes. While previous work has demonstrated Val66Met effects on magnetic resonance spectroscopy (MRS) markers of either glutamatergic metabolism (Glx) or neuronal integrity (NAA), no study has investigated Val66Met effects on these related processes simultaneously. As these metabolites share a metabolic pathway, the Glx/NAA ratio may be a more sensitive marker of changes associated with the Val66Met SNP. This ratio is increased in psychiatric disorders linked to decreased functioning in the anterior cingulate cortex (ACC). In this study, we investigated the correlation of the Val66Met polymorphism of the BDNF gene with Glx/NAA in the pregenual anterior cingulate cortex (pgACC) using MRS at 3 Tesla (T) (n = 30, all males) and 7 T (n = 98, 40 females). In both cohorts, Met carriers had lower Glx/NAA compared to Val homozygotes. Follow-up analyses using absolute quantification revealed that the Met carriers do not show decreased pgACC glutamate or glutamine levels, but instead show increased NAA compared to the Val homozygotes. This finding may in part explain conflicting evidence for Val66Met as a risk factor for developing psychiatric illnesses.

Catechol-O-Methyltransferase Gene Val158Met Polymorphism Moderates the Effect of Social Exclusion and Inclusion on Aggression in Men: Findings From a Mixed Experimental Design.

Accumulating research has identified the interactive effects of catechol-O-methyltransferase (COMT) gene Val158Met polymorphism and environmental factors on aggression. However, available evidence was mainly based upon correlational design, which yields mixed findings concerning who (Val vs. Met carriers) are more affected by environmental conditions and has been challenged for the low power of analyses on gene–environment interaction. Drawing on a mixed design, we scrutinized how COMT Val158Met polymorphism (between-group variable) impacts on aggression, assessed by hostility, aggressive motivation, and aggressive behavior, under different social conditions (exclusion vs. inclusion, within-group variable) in a sample of 70 Chinese male undergraduate students. We found that both Val/Val homozygote and Met alleles carriers showed differences in the feelings of hostility and aggressive motivation under conditions of exclusion versus inclusion, but these differences were more pronounced for Met allele carriers. These findings implied that COMT Val158Met polymorphism did not respond to environmental stimuli in an all-or-none way and shed light on the importance of examining the gene–environment interaction using a mixed design.