Brain-derived Neurotrophic Factor Met Research Articles

APOE & BDNF polymorphisms interact to affect memory performance at baseline in adolescent athletes

ABSTRACT Although several single-nucleotide polymorphisms have been associated with cognitive functioning in a variety of healthy and clinical samples, the influence of gene × gene interactions on cognition is poorly understood. The purpose of this study was to examine interactive relationships between apolipoprotein E (APOE) and brain-derived neurotrophic factor (BDNF) polymorphisms on cognitive functioning in a sample of healthy adolescent athletes. Participants of this cross-sectional study included 78 student-athletes (52.6% male; age: M = 13.31, SD = 1.23). Athletes completed the Immediate Post-Concussion and Cognitive Testing (ImPACT) computerized battery at baseline. APOE and BDNF genotypes were determined with buccal samples (APOE ε4+: n = 26; APOE ε4-: n = 52; BDNF Met+: n = 23; BDNF Met-: n = 55). Two-way analyses of variance (ANOVAs) were used to evaluate the associations among APOE (ε4+ vs. ε4-) and BDNF (Met+ vs. Met-) genotypes and the ImPACT cognitive composites and two-factor model. No main effects were observed for either APOE or BDNF genotypes across the cognitive outcomes. However, there was a significant APOE × BDNF genotype interaction for the verbal (p=.009, η p 2 =.091) and visual (p = .012, η p 2 =.082) memory composites and the memory factor (p = .001, η p 2 =.133), such that ε4+/Met+ carriers demonstrated poorer performance relative to other allele combinations. No significant interactions were observed for the visual motor speed (p = .263, η p 2 =.017) or reaction time (p = .825, η p 2 =.001) composites or the speed factor (p = .205, η p 2 =.022). Our findings suggest an important relationship between APOE and BDNF genotypes on verbal and visual memory performance in healthy adolescent athletes. Clinicians may use this information to offer individualized concussion management based on individual athlete characteristics related to genetics and cognition.

Association of BDNF Val66Met With Tau Hyperphosphorylation and Cognition in Dominantly Inherited Alzheimer Disease

Allelic variation in the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism moderates increases in cerebrospinal fluid (CSF) levels of tau and phosphorylated tau 181 (p-tau181), measured using immunoassay, and cognitive decline in presymptomatic dominantly inherited Alzheimer disease (DIAD). Advances in mass spectrometry show that CSF tau phosphorylation occupancy at threonine 181 and 217 (p-tau181/tau181, p-tau217/tau217) increases with initial β-amyloid (Aβ) aggregation, while phosphorylation occupancy at threonine 205 (p-tau205/tau205) and level of total tau increase when brain atrophy and clinical symptoms become evident. To determine whether site-specific tau phosphorylation occupancy (ratio of phosphorylated to unphosphorylated tau) is associated with BDNF Val66Met in presymptomatic and symptomatic DIAD. This cross-sectional cohort study included participants from the Dominantly Inherited Alzheimer Network (DIAN) and Aβ-positive cognitively normal older adults in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Data were collected from 2009 through 2018 at multicenter clinical sites in the United States, United Kingdom, and Australia, with no follow-up. DIAN participants provided a CSF sample and completed clinical and cognitive assessments. Data analysis was conducted between March 2020 and March 2021. Mass spectrometry analysis was used to determine site-specific tau phosphorylation level; tau levels were also measured using immunoassay. Episodic memory and global cognitive composites were computed. Of 374 study participants, 144 were mutation noncarriers, 156 were presymptomatic mutation carriers, and 74 were symptomatic carriers. Of the 527 participants in the network, 153 were excluded because their CSF sample, BDNF status, or both were unavailable. Also included were 125 Aβ-positive cognitively normal older adults in the ADNI. The mean (SD) age of DIAD participants was 38.7 (10.9) years; 43% were women. The mean (SD) age of participants with preclinical sporadic AD was 74.8 (5.6) years; 52% were women. In presymptomatic mutation carriers, compared with Val66 homozygotes, Met66 carriers showed significantly poorer episodic memory (d = 0.62; 95% CI, 0.28-0.95), lower hippocampal volume (d = 0.40; 95% CI, 0.09-0.71), and higher p-tau217/tau217 (d = 0.64; 95% CI, 0.30-0.97), p-tau181/tau181 (d = 0.65; 95% CI, 0.32-0.99), and mass spectrometry total tau (d = 0.43; 95% CI, 0.10-0.76). In symptomatic mutation carriers, Met66 carriers showed significantly poorer global cognition (d = 1.17; 95% CI, 0.65-1.66) and higher p-tau217/tau217 (d = 0.53; 95% CI, 0.05-1.01), mass spectrometry total tau (d = 0.78; 95% CI, 0.28-1.25), and p-tau205/tau205 (d = 0.97; 95% CI, 0.46-1.45), when compared with Val66 homozygotes. In preclinical sporadic AD, Met66 carriers showed poorer episodic memory (d = 0.39; 95% CI, 0.00-0.77) and higher total tau (d = 0.45; 95% CI, 0.07-0.84) and p-tau181 (d = 0.46; 95% CI, 0.07-0.85). In DIAD, clinical disease stage and BDNF Met66 were associated with cognitive impairment and levels of site-specific tau phosphorylation. This suggests that pharmacological strategies designed to increase neurotrophic support in the presymptomatic stages of AD may be beneficial.

Psychiatric risk and resilience: Plasticity genes and positive mental health.

ObjectiveThe at‐risk mental state (ARMS) for psychosis has long played a key role in diathesis‐stress models of schizophrenia. More recent studies, however, have called for extending the boundaries of the ARMS construct beyond attenuated psychosis in nonhelp‐seeking samples to include not only other vulnerability indicators but also protective factors related to genotype, mental health, personality, and cognition.MethodAccordingly, we assessed in a sample of 100 college students, the ARMS construct with the Brief Prodromal Questionnaire (PQ‐B) for psychosis, in conjunction with measures of positive mental health, childhood adversity, psychiatric symptoms, personality traits, social cognition, and genetic variables derived from assays of the serotonin transporter (5‐HTTLPR) and the brain‐derived neurotrophic factor (BDNF).ResultsHigher PQ‐B scores correlated positively with vulnerability indicators of childhood adversity and heightened levels of a wide variety of psychiatric symptoms but correlated negatively with protective factors of better overall mental health, social cognition as well as with a distinct NEO profile marked by reduced neuroticism and elevated agreeableness and conscientiousness. Multivariate analyses indicated that a composite ARMS measure comprised of PQ‐B scores plus anxiety and depression symptoms revealed significant genotype differences, with lowest risk and highest resilience for allelic carriers of 5‐HTTLPR‐short and BDNF Met polymorphisms.ConclusionsResults provided support for extending the ARMS construct, pointing to important contributions of personality, social cognition, and genes that support neural plasticity in mitigating vulnerability and enhancing resilience and well‐being.

Associations between APOE-, COMT Val108/158Met- and BDNF Val66Met polymorphisms and variations in depressive and anxiety symptoms, sense of coherence and vital exhaustion in the real-life setting of mandatory basic military training.

Apolipoprotein E (APOE) ε, catechol-O-methytranferase (COMT) Val108/158Met and brain-derived neurotrophic factor (BDNF) Val66Met single nucleotide polymorphisms (SNPs) were shown to affect stress perception and response. The present study explored possible associations between these SNPs and changes in subclinical anxiety- and depressive symptoms, sense of coherence (SOC) and vital exhaustion (VE) during compulsory basic military training. The study encompassed 179 conscripts of a training base in Greece. The neuropsychiatric assessment was based on the Beck Depression Inventory, the State-Trait Anxiety Inventory, the Antonovsky SOC scale and the Maastricht Questionnaire. It was conducted at three time points of the 19-day basic military training: on day one (baseline), day six (follow-up I) and day 13 (follow-up II). Statistical analyses included Mann-Whitney test, Chi-square test and cross-sectional time series regression models based on the Skillings-Mack statistic. APOE ε4 non-carriers encountered significant changes in anxiety- and depressive symptoms and SOC (in all cases P < 0.001) over the observation period, whilst ε4 carriers did not. The changes in anxiety, depressive symptoms and SOC attained statistical significance in both BDNF Met66 carriers (in all cases P < 0.001) and non-carriers (P = 0.036; < 0.001; < 0.001, respectively) as well as in COMT Met108/158 carriers (P = 0.004; < 0.001; < 0.001, respectively) and non-carriers (P = 0.02; 0.01; 0.021, respectively. Changes over time in VE were not significant (P > 0.05). The observed resistance of APOE ε4 carriers vs non-carriers to changes in anxiety- and depressive symptoms and SOC when exposed to a stressful environment may point to superior coping capacities of healthy young men carrying the ε4 allele.

Sex-specific BDNF and APOE ε4 genotype interactions on white matter hyperintensity volume

The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). One variant of the brain-derived neurotrophic factor (BDNF) gene also confers higher risk of AD. APOE and BDNF genotypes may have interactive effects on AD pathology. The aim of this study was to determine whether APOE and BDNF genotype differentially impact white matter hyperintensity volume (WMHV). We used data from 212 cognitively unimpaired individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) We used generalized linear models to predict WMHV from BDNF genotype and an interaction with APOE. Sex, age, education, vascular risk, and imaging-based amyloid load (Florbetapir SUVR) were used as covariates. . WMHV was derived by using the Lesion Segmentation Toolbox (LST) in SPM12 with a threshold of k = 0.15. We used the Hachinski Ischemic Scale to measure for vascular risk. We found no significant interaction of BDNF-APOE on WMHV (β = 0.40, 95% CI: (-0.39, 1.20), p = 0.32). In sex-stratified analyses the BNDF-APOE interaction was significantly associated with WMHV in males (β = 1.14, 95% CI:(0.17, 2.11), p = 0.02), but not in females (β = -0.37, 95% CI: (-1.47, 0.76), p = 0.50). For males, carriers of both BDNF Met and APOE ε4 alleles had the highest WMHV. Sex-specific differences in BDNF expression may be related to hormonal differences, and BDNF genotype might underlie these differences. Given the continued interest in using BDNF as a treatment target for AD, understanding complex genotype interactions may aid in future therapeutic studies.

The Combined Effect of APOE and BDNF Val66Met Polymorphisms on Spatial Navigation in Older Adults.

Background:The apolipoprotein E (APOE) ɛ4 allele is associated with episodic memory and spatial navigation deficits. The brain-derived neurotrophic factor (BDNF) Met allele may further worsen memory impairment in APOE ɛ4 carriers but its role in APOE ɛ4-related spatial navigation deficits has not been established.Objective:We examined influence of APOE and BDNF Val66Met polymorphism combination on spatial navigation and volumes of selected navigation-related brain regions in cognitively unimpaired (CU) older adults and those with amnestic mild cognitive impairment (aMCI).Methods:187 participants (aMCI [n = 116] and CU [n = 71]) from the Czech Brain Aging Study were stratified based on APOE and BDNF Val66Met polymorphisms into four groups: ɛ4–/BDNFVal/Val, ɛ4–/BDNFMet, ɛ4+/BDNFVal/Val, and ɛ4+/BDNFMet. The participants underwent comprehensive neuropsychological examination, brain MRI, and spatial navigation testing of egocentric, allocentric, and allocentric delayed navigation in a real-space human analogue of the Morris water maze.Results:Among the aMCI participants, the ɛ4+/BDNFMet group had the least accurate egocentric navigation performance (p < 0.05) and lower verbal memory performance than the ɛ4–/BDNFVal/Val group (p = 0.007). The ɛ4+/BDNFMet group had smaller hippocampal and entorhinal cortical volumes than the ɛ4–/BDNFVal/Val (p≤0.019) and ɛ4–/BDNFMet (p≤0.020) groups. Among the CU participants, the ɛ4+/BDNFMet group had less accurate allocentric and allocentric delayed navigation performance than the ɛ4–/BDNFVal/Val group (p < 0.05).Conclusion:The combination of APOE ɛ4 and BDNF Met polymorphisms is associated with more pronounced egocentric navigation impairment and atrophy of the medial temporal lobe regions in individuals with aMCI and less accurate allocentric navigation in CU older adults.

Interaction Between BDNF Val66Met and APOE4 on Biomarkers of Alzheimer's Disease and Cognitive Decline.

Whether brain-derived neurotrophic factor (BDNF) Met carriage impacts the risk or progression of Alzheimer's disease (AD) is unknown. To evaluate the interaction of BDNF Met and APOE4 carriage on cerebral metabolic rate for glucose (CMRgl), amyloid burden, hippocampus volume, and cognitive decline among cognitively unimpaired (CU) adults enrolled in the Arizona APOE cohort study. 114 CU adults (mean age 56.85 years, 38% male) with longitudinal FDG PET, magnetic resonance imaging, and cognitive measures were BDNF and APOE genotyped. A subgroup of 58 individuals also had Pittsburgh B (PiB) PET imaging. We examined baseline CMRgl, PiB PET amyloid burden, CMRgl, and hippocampus volume change over time, and rate of change in cognition over an average of 15 years. Among APOE4 carriers, BDNF Met carriers had significantly increased amyloid deposition and accelerated CMRgl decline in regions typically affected by AD, but without accompanying acceleration of cognitive decline or hippocampal volume changes and with higher baseline frontal CMRgl and slower frontal decline relative to the Val/Val group. The BDNF effects were not found among APOE4 non-carriers. Our preliminary studies suggest that there is a weak interaction between BDNF Met and APOE4 on amyloid-β plaque burden and longitudinal PET measurements of AD-related CMRgl decline in cognitively unimpaired late-middle-aged and older adults, but with no apparent effect upon rate of cognitive decline. We suggest that cognitive effects of BDNF variants may be mitigated by compensatory increases in frontal brain activity-findings that would need to be confirmed in larger studies.

Zinc induced structural changes in the intrinsically disordered BDNF Met prodomain confer synaptic elimination.

Human brain derived neurotrophic factor (BDNF) encodes a protein product consisting of a C-terminal mature domain (mature BDNF) and an N-terminal prodomain, which is an intrinsically disordered protein. A common single nucleotide polymorphism in humans results in a methionine substitution for valine at position 66 of the prodomain, and is associated with memory deficits, depression and anxiety disorders. The BDNF Met66 prodomain, but not the Val66 prodomain, promotes rapid structural remodeling of hippocampal neurons' growth cones and dendritic spines by interacting directly with the SorCS2 receptor. While it has been reported that the Met66 and Val66 prodomains exhibit only modest differences in structural propensities in the apo state, here we show that Val66 and Met66 prodomains differentially bind zinc (Zn). Zn2+ binds with higher affinity and more broadly impacts residues on the Met66 prodomain compared to the Val66 prodomain as shown by NMR and ITC. Zn2+ binding to the Met66 and Val66 prodomains results in distinct conformational and macroscopic differences observed by NMR, light scattering and cryoEM. To determine if Zn2+ mediated conformational change in the Met66 prodomain is required for biological effect, we mutated His40, a Zn2+ binding site, and observed a loss of Met66 prodomain bioactivity. As the His40 site is distant from the known region of the prodomain involved in receptor binding, we suggest that Met66 prodomain bioactivity involves His40 mediated stabilization of the multimeric structure. Our results point to the necessity of a Zn2+-mediated higher order molecular assembly of the Met66 prodomain to mediate neuronal remodeling.

A-27 APOE & BDNF Polymorphisms Interact to Affect Memory Performance at Baseline in Adolescent Athletes

Abstract Objective Although several single-nucleotide polymorphisms have been associated with cognitive functioning in a variety of healthy and clinical samples, the influence of gene x gene interactions on cognition is poorly understood. The purpose of this study was to examine interactive relationships between apolipoprotein E (APOE) and brain-derived neurotrophic factor (BDNF) polymorphisms on cognitive functioning in a sample of healthy adolescent athletes. Method Participants of this cross-sectional study included 82 athletes (53.7% male, age, M = 12.85, SD = 1.13) who completed the Immediate Post-Concussion and Cognitive Testing (ImPACT) computerized battery at baseline as part of a school-based sports-concussion management program. Athletes also provided a buccal sample for determination of their APOE and BDNF genotypes. Two-way analyses of variance (ANOVAs) were used to evaluate the effect of APOE (ε4+ vs. ε4-) and BDNF (Met+ vs. Met-) genotypes on the ImPACT cognitive composites. Results ANOVAs showed non-significant main effects for both APOE and BDNF genotypes across the four cognitive composites. However, there was a significant APOE x BDNF genotype interaction for the verbal (p = .01; ηp2 = .08) and visual (p = .013; ηp2 = .08) memory composites, such that ε4+/Met+ carriers demonstrated poorer performance relative to the other allele combinations (ε4+/Met-, ε4−/Met+, ε4−/Met-). No significant interactions were observed for the visual motor speed (p = .20; ηp2 = .02) or reaction time (p = .87; ηp2 &amp;lt; .001) composites. Conclusions Our findings suggest a meaningful relationship between APOE and BDNF genotypes on verbal and visual memory performance in healthy adolescent athletes. These findings will need to be replicated using much larger samples, and future studies will need to explore these associations following sports-related concussion.

Risk and protective effects of serotonin and BDNF genes on stress-related adult psychiatric symptoms

We focused on individual risk by examining childhood adversity and current psychiatric symptoms in a sample of 100 college students genotyped for both the serotonin transporter (5-HTTLPR) and the brain-derived neurotrophic factor (BDNF). Naturally occurring allelic variation in 5-HTTLPR (short/long) and BDNF (valine/methionine) have been strongly implicated in stress-related psychiatric risk, but the combined effects of these alleles on psychological functioning have yet to be fully elucidated. Univariate analysis revealed gene-environment correlations linking heightened psychiatric risk with past childhood adversity for short but not long 5-HTTLPR allelic carriers and for valine (Val) but not methionine (Met) BDNF allelic carriers. Multivariate analyses revealed a significant gene x gene interaction with results showing that risk varied systematically depending on both 5-HTTLPR and BDNF alleles, independent of childhood adversity. Hierarchical regression analyses indicated that approximately 11% of the variance in symptoms of depression could be specifically accounted for by the epistatic interaction of 5-HTTLPR and BDNF val66Met polymorphisms. Allelic group analyses indicated lowest risk, as measured by depression and anxiety, for allelic carriers of 5-HTTLPR-short and BDNF Met, followed by 5-HTTLPR-long and BDNF-Val, 5-HTTLPR-short and BDNF-Val, and 5-HTTLPR-long and BDNF-Met. Results suggest that protective or risk-enhancing effects on stress-related psychiatric functioning may depend on specific allelic combinations of 5-HTTLPR and BDNF.

BDNF VAL66MET INCREASES RATE OF MEMORY DECLINE, HIPPOCAMPAL VOLUME LOSS AND TAU ACCUMULATION IN AUTOSOMAL DOMINANT ALZHEIMER’S DISEASE

The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (rs6265) is implicated in synaptic excitation and neuronal integrity. In autosomal dominant Alzheimer's disease (ADAD), mutation carriers (MC) who also carry the Met66 allele show worse memory and higher levels of cerebrospinal fluid (CSF) tau, but equivalent amyloid levels compared to MC Val66 homozygotes at baseline. The aim of this study was to determine the extent to which the BDNF Val66Met polymorphism affects changes in memory, brain volume, tau and Aβ in ADAD prospectively. Prospective neuropsychological, biomarker and neuroimaging data collected from the Dominantly Inherited Alzheimer Network (DIAN) over ∼2 years were analyzed in 81 preclinical mutation carriers (MC), all with a clinical dementia rating (CDR) score of 0 and estimated to be 11 years prior to clinical symptom onset, and 78 matched mutation non-carriers (NC). BDNF genotype was obtained for MCs (58 Val66 homozygotes, 23 Met66 carriers). Compared to MC Val66 homozygotes, MC Met66 carriers showed greater decline in episodic memory (p<.001), loss of hippocampal volume (p=.005), and increase of CSF tau (p<.001) (Figure 1). Cortical Aβ accumulation was equivalent between MC Val66 homozygotes and MC Met66 carriers (p=.427) (Figure 1). Compared to NCs, MC Val66 homozygotes showed greater increase in cortical Aβ accumulation (p<.001) but equivalent rates of change in episodic memory decline (p=.700), loss of hippocampal volume (p=.215), and accumulation of CSF tau (p=.266) (Figure 1). ADAD is associated with pathologically increased rates of Aβ and tau accumulation, loss of hippocampal volume and decline in episodic memory. The results of the current study show that for MCs who also carry the BDNF Met66 allele, decline in episodic memory, loss of hippocampal volume and increase in CSF tau is substantially greater than for MCs who are Val66 homozygotes, despite equivalent rates of Aβ accumulation. This is consistent with findings in preclinical sporadic AD, where amyloid positive Met66 carriers also show faster deterioration in episodic memory and hippocampal volume, but not Aβ accumulation, when compared to Aβ+ Val66 homozygotes. Together, these data suggest that the BDNF Val66Met polymorphism modifies the contributions to the neurodegenerative process in ADAD. Episodic memory performance, hippocampal volume, Aβ, and tau in preclinical MC Val66 homozygotes (blue lines) and preclinical MC Met66 carriers (red lines) when compared to mutation non-carriers (black lines).

Association of DISC1, BDNF, and COMT polymorphisms with exploratory eye movement of schizophrenia in a Chinese Han population.

Previous studies suggested that exploratory eye movement (EEM) dysfunction appears to be a biological marker specific to schizophrenia, with an unknown molecular mechanism. Genetic studies indicate that disrupted-in-schizophrenia-1 (DISC1), brain-derived neurotrophic factor (BDNF), and catechol-O-methyl transferase (COMT) genes might be implicated in the etiology of schizophrenia, but not in all populations. The present study aimed to explore associations between these candidate genes and EEM endophenotypes for schizophrenia in a Chinese Han population. EEM recordings were examined in 139 patients with schizophrenia and 143 healthy control participants. All five EEM parameters, responsive search score, cognitive search score, number of eye fixations, total eye scanning length, and mean eye scanning length, of schizophrenic patients differed significantly from those of healthy controls (P<0.001). The DISC1 SerCys, BDNF ValMet, and COMT ValMet were genotyped in a total sample of 818 schizophrenic patients and 827 healthy control participants, including the above EEM samples. We found that DISC1 Cys and BDNF Met were associated with an increased risk of developing schizophrenia (P<0.001). Furthermore, responsive search score scores of BDNF Met/Met carriers were significantly lower than those of Val allele carriers (P=0.022), which remained modest after Bonferroni correction. The BDNF MetMet polymorphism might be associated with the EEM dysfunction of schizophrenia.

Lack of an association of BDNF Val66Met polymorphism and plasma BDNF with hippocampal volume and memory.

Brain-derived neurotrophic factor (BDNF) has been shown to be important for neuronal survival and synaptic plasticity in the hippocampus in nonhuman animals. The Val66Met polymorphism in the BDNF gene, involving a valine (Val) to methionine (Met) substitution at codon 66, has been associated with lower BDNF secretion in vitro. However, there have been mixed results regarding associations between either circulating BDNF or the BDNF Val66Met polymorphism with hippocampal volume and memory in humans. The current study examined the association of BDNF genotype and plasma BDNF with hippocampal volume and memory in two large independent cohorts of middle-aged and older adults (both cognitively normal and early-stage dementia). Sample sizes ranged from 123 to 649. Measures of the BDNF genotype, plasma BDNF, MRI-based hippocampal volume, and memory performance were obtained from the Knight Alzheimer Disease Research Center (ADRC) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). There were no significant differences between BDNF Met+ and Met- groups on either hippocampal volume or memory in either cohort. In addition, plasma BDNF was not significantly associated with either hippocampal volume or memory in either cohort. Neither age, cognitive status, nor gender moderated any of the relationships. Overall, current findings suggest that BDNF genotype and plasma BDNF may not be robust predictors for variance in hippocampal volume and memory in middle age and older adult cohorts.

EEG Alpha Power as an Intermediate Measure Between Brain-Derived Neurotrophic Factor Val66Met and Depression Severity in Patients With Major Depressive Disorder

Major depressive disorder has a large impact on patients and society and is projected to be the second greatest global burden of disease by 2020. The brain-derived neurotrophic factor (BDNF) gene is considered to be one of the important factors in the etiology of major depressive disorder. In a recent study, alpha power was found to mediate between BDNF Met and subclinical depressed mood. The current study looked at a population of patients with major depressive disorder (N = 107) to examine the association between the BDNF Val66Met polymorphism, resting state EEG alpha power, and depression severity. For this purpose, repeated-measures analysis of variance, partial correlation, and multiple linear models were used. Results indicated a negative association between parietal-occipital alpha power in the eyes open resting state and depression severity. In addition, Met/Met patients showed lower global absolute alpha power in the eyes closed condition compared with Val-carriers. These findings are in accordance with the previously uncovered pathway between BDNF Val66Met, resting state EEG alpha power, and depression severity. Additional research is needed for the clarification of this tentative pathway and its implication in personalized treatment of major depressive disorder.

BDNF Val66Met and DRD2 Taq1A polymorphisms interact to influence PTSD symptom severity: A preliminary investigation in a South African population

We evaluated the role that selected variants in serotonin transporter (5-HTT), dopamine receptor 2 (DRD2) and brain-derived neurotrophic factor (BDNF) genes play in PTSD symptom severity in an at-risk population. We also investigated the interaction between the genetic variants to determine whether these variables and the interactions between the variables influenced the severity of PTSD symptoms. PTSD symptoms were quantitatively assessed using the Davidson Trauma Scale (DTS) in 150 participants from an at-risk South African population. All participants were genotyped for the 5-HTTLPR, DRD2 Taq1A and BDNF Val66Met polymorphisms. Gene-gene interactions were investigated using various linear models. All analyses were adjusted for age, gender, major depressive disorder diagnosis, level of resilience, level of social support and alcohol dependence. A significant interaction effect between DRD2 Taq1A and BDNF Val66Met variants on DTS score was observed. On the background of the BDNF Val66Val genotype, DTS score increased significantly with the addition of a DRD2 Taq1A A1 allele. However, on the BDNF Met66 allele background, the addition of an A1 allele was found to reduce total DTS score. This study provides preliminary evidence for an epistatic interaction between BDNF Val66Met and DRD2 Taq1A polymorphisms on the severity of PTSD symptoms, where both too little and too much dopamine can result in increased PTSD symptom severity.

Bipolar Disorder, Brain-Derived Neurotrophic Factor (BDNF) Val66Met Polymorphism and Brain Morphology

In this study of the effect of bipolar status and presence of BDNF Val66Met polymorphism on differences in regional brain volumes, we hypothesized based on previous studies that 1) bipolar subjects will have smaller regional brain volumes than healthy controls; 2) BDNF Met66 allele carriers within the same population are likely to have smaller regional brain volumes as compared to Val66 homozygyotes. In our Caucasian sample of 166 bipolar subjects and 64 gender-matched healthy controls, we found significant decreases in total (p = 0.005) and regional gray matter volumes in bipolar patients compared to healthy controls, more pronounced in the inferior and posterior parts of the brain, together with a concomitant increase in total CSF (p = 0.012) particularly in the lateral ventricles (p = 0.023). However, there was no difference in white matter volumes noted by other studies. Furthermore we did not find significant differences in other brain regions that have been reported by other authors. Nor did we find a significant effect of BDNF on these measurements.

Postpartum depressive symptoms and the BDNF Val66Met functional polymorphism: effect of season of delivery

Postpartum depression (PPD) is an often underdiagnosed and undertreated mood disorder, with negative impact on the mother's and infant's health. Seasonal variation has been discussed as a risk factor for PPD. Candidate genes, such as those encoding for the brain-derived neurotrophic factor (BDNF), serotonin transporter (5-HTT), and Period2 (PER2), have been associated with depression and seasonal disorders. The present study is aimed to examine whether functional polymorphic variants, BDNF Val66Met, 5-HTTLPR, or PER2 SNP 10870, are associated with PPD symptoms and whether these genetic polymorphisms interact with season in predicting PPD symptoms. This case-control study comprised of 275 women from a population-based cohort of delivering women in Sweden, who completed a questionnaire containing the Edinburgh postnatal depression scale (EPDS) at 6weeks and 6months postpartum. Stressful life events (SLEs) and maternity stressors were also assessed. The results did not reveal any statistically significant overall association between the studied genetic polymorphisms and PPD symptoms. However, a significant association between BDNF Met66 carrier status and development of PPD symptoms at 6weeks postpartum, even when controlling for prepartum and postpartum environmental risk factors, was evident among mothers delivering during autumn/winter. No gene-gene interactions were found but a cumulative effect was detected with carriers of a greater number of 5-HTTLPR S and BDNFVal66Met Met alleles reporting higher EPDS scores, if delivered during autumn/winter. Our findings propose a role of the BDNF gene in the development of PPD symptoms, potentially mediated by season of delivery.

Additive effect of BDNF and REST polymorphisms is associated with improved general cognitive ability

Brain-derived neurotrophic factor (BDNF) is a pleiotropic protein involved in neuronal proliferation, differentiation, synaptic plasticity and survival. Independent studies investigating association between the functional BDNF Val66Met polymorphism and cognitive abilities have reported some conflicting findings, which may reflect inadequate sample size, variation in testing methods, population stratification or the confounding effects of other genes. To test the latter hypothesis, we screened and genotyped polymorphisms in the RE1-silencing transcription factor (REST) gene whose function includes the downregulation of BDNF expression. We identified an exon 4 hexadecapeptide variable number tandem repeat (VNTR) with either four or five copies that was located within a proline-rich domain and investigated a further five single nucleotide polymorphisms (SNPs). Using a cohort of 746 community-dwelling older volunteers, we analysed REST genotype data both independently and in combination with the BDNF Val66Met polymorphism. A haplotype within the REST gene containing the four copy VNTR and a non-synonymous SNP showed a weak but significant association with a higher score of general intelligence (P = 0.05). Analysis of this haplotype and the BDNF Val66Met polymorphism in combination showed a significant interaction (global P-value = 0.0003) with an additive increase in cognitive performance for those possessing the BDNF Val66 allele and the REST haplotype containing the four copy repeat (P = 0.004). The REST haplotypes in combination with the BDNF Met66 polymorphism did not reduce cognitive performance more than the independent influence of the Met66 allele. Our results suggest that investigation of a common REST polymorphism may be necessary to help reduce contrasting reports based around BDNF Val66Met and cognition.

The p.Val66Met polymorphism in the BDNF gene protects against early seizures in Rett syndrome

X chromosome inactivation and the MECP2 genotype do not provide the full explanations for the clinical differences between patients with Rett syndrome (RTT), suggesting the involvement of other factors. One MeCP2 target is the brain-derived neurotrophic factor (BDNF) gene. We investigated, according to the MECP2 genotype, the role of the BDNF functional polymorphism (Val66Met) on the severity of RTT. This polymorphism in BDNF was analyzed by PCR and dHPLC in 81 patients with RTT. We studied the association between the MECP2 and BDNF genotypes and the clinical features in each patient. We found that some RTT features can be correlated with MECP2 genotypes. Missense mutations are associated with a more severe epileptic phenotype (early onset and drug resistance) than other mutations. Non-sense and late truncating mutations lead to a less severe phenotype regarding walking. The distribution of the Val66Met polymorphism was not significantly different between the different groups in regard to the severity of all tested symptoms. However, girls with RTT bearing the Val66Val genotype tend to present earlier seizures than girls with RTT bearing the Met66 allele. No girls with RTT with the Met66 allele presented early seizures. Early onset of seizures is linked to the combined MECP2 and BDNF genotypes. The BDNF Met66 allele may protect against seizures, whereas missense mutations in the MBD of MECP2 are more frequently associated with early seizures.

The Brain-Derived Neurotrophic Factor VAL66MET Polymorphism and Cerebral White Matter Hyperintensities in Late-Life Depression

In animal models, brain-derived neurotrophic factor (BDNF) appears to protect against cerebral ischemia. The authors examined whether the BDNF Val66Met polymorphism, which affects BDNF distribution, was associated with greater volumes of hyperintense lesions as detected on magnetic resonance imaging in a cohort of depressed and nondepressed elders. Subjects completed cross-sectional assessments, including clinical evaluation and a brain magnetic resonance imaging scan, and provided blood samples for Val66Met genotyping. The study was conducted at a university-based academic hospital. Participants included 199 depressed and 113 nondepressed subjects aged 60 years or older. Hyperintensity lesion volumes were measured using a semiautomated segmentation procedure. Statistical models examined the relationship between genotype and lesion volume while controlling for depression, presence of hypertension, age, and sex. After controlling for covariates, Met66 allele carriers exhibited significantly greater white matter hyperintensity volumes (F(1,311) = 4.09, p = 0.0442). This effect was independent of a diagnosis of depression or report of hypertension. Genotype was not significantly related to gray matter hyperintensity volume (F(1,311) = 1.14, p = 0.2871). The BDNF Met66 allele is associated with greater white matter hyperintensity volumes in older individuals. Further work is needed to determine how this may be associated with other clinically relevant findings in late-life depression.