Brain-derived Neurotrophic Factor Genotype Research Articles

Association between the Val66Met (rs6265) polymorphism of the brain-derived neurotrophic factor (BDNF) gene, BDNF protein level in the blood and the risk of developing early‑onset Parkinson's disease.

Brain-derived neurotrophic factor (BDNF) is involved in the maintenance of dopamine level and the survival of dopaminergic neurons, which may affect the functionality of brain structures responsible for motor and cognitive function. The aim of the study was to assess the association of individual and combined single nucleotide polymorphism (SNP) in the rs6265 BDNF (Val66Met), rs397595 DAT (SLC6A3), and rs4680 COMT (Val158Met) genes with early‑onset of Parkinson's disease (PD) patients. Moreover, we assessed the association between the BDNF Val66Met polymorphism and the level of BDNF protein in the serum of patients with PD and controls. The study involved 163 patients with idiopathic PD divided into early onset (<55 years) and late‑onset (>55 years) groups and 91 healthy age‑matched people (Control). The SNP were determined using the TaqMan Real‑Time PCR method. Serum BDNF levels were determined by ELISA assay. The risk of developing early PD in people with the BDNF genotype AG increases threefold in comparison with the carriers of the BDNF genotype GG. In PD patients and healthy people with the BDNF genotypes AG and AA, a lower serum BDNF level was found compared to those with the BDNF genotype GG in both groups. The results of our study indicate that the presence of the Val66Met BDNF gene polymorphism is associated with reduced blood BDNF levels and an elevated risk of developing early‑onset PD. This effect appears to be more pronounced in men.

8245 Estradiol Interacts with the Val66Met Single Nucleotide Polymorphism in the Brain-Derived Neurotrophic Factor Gene to Alter Endometrial Thickness in a Rat Model

Abstract Disclosure: S. Moosa: None. E. Kohlmeir: None. S. Kujawa: None. D. Korol: None. A. Prakapenka: None. Brain derived neurotrophic factor (BDNF) is most known for its involvement in cell development, survival, and plasticity in the nervous system. BDNF and its cognate receptors can also be found in non-neural tissue including the ovary and uterus in humans and in animal models, suggesting that BDNF signaling may regulate reproductive functions. Indeed, disruptions in BDNF signaling are associated with health conditions related to the reproductive system, such as endometriosis. Studies show that treatment with estradiol increases expression of uterine BDNF and its cognate receptors, suggesting that estradiol can modulate BDNF signaling and its effects in the reproductive system. A common human functional single nucleotide polymorphism (SNP) in the BDNF gene, Val66Met (rs6265), is thought to decrease activity-dependent release of BDNF, altering BDNF signaling. Using a CRISPR/cas9 rat model of the human Val66Met BDNF SNP, we investigated the interacting role of estradiol and this variation in the BDNF gene on female uterine structure. Middle-aged (11-14-months-old) female rats were either homozygous for the Val allele (Val/Val; control) or the Met allele (Met/Met; BDNF SNP). All rats were ovariectomized and after three weeks randomly assigned to receive subcutaneous treatment of vehicle (sesame oil) or estradiol (17beta-estradiol benzoate) for two consecutive days. Twenty-four hours after the second injection, rats were euthanized and tissue collected, weighed, and placed in fixative. Uterine tissue weights differed significantly by treatment and by genotype such that uterine horns were heavier in estradiol-treated compared to vehicle-treated rats within each genotype and uterine horns were heavier in Met/Met compared to Val/Val rats within each treatment condition. To determine which uterine layer contributed to the weight differences, uterine horns were sectioned and stained with hematoxylin and eosin. Thickness of myometrium, endometrium, and lumen were individually measured. Although there were no treatment and no genotype effects on myometrial thickness, there were significant treatment and genotype effects on endometrial thickness. Of note, the endometrium of estradiol-treated Met/Met rats was thicker compared to vehicle-treated Met/Met rats and compared to estradiol-treated Val/Val rats, suggesting that estradiol and the BDNF gene variation interact to modulate endometrial size. Lumen circumference did not differ between genotypes but did increase with estradiol compared to vehicle treatment within each genotype. Altogether, findings suggest that BDNF genotype affects uterine structure, notably the endometrium. Differences with BDNF gene variation emerged with estradiol exposure, implicating the hormone’s role in modulating BDNF signaling and warranting future research on the interactive effects of estradiol and BDNF genotype on the endometrium. Presentation: 6/2/2024

8245 Estradiol Interacts with the Val66Met Single Nucleotide Polymorphism in the Brain-Derived Neurotrophic Factor Gene to Alter Endometrial Thickness in a Rat Model

Abstract Disclosure: S. Moosa: None. E. Kohlmeir: None. S. Kujawa: None. D. Korol: None. A. Prakapenka: None. Brain derived neurotrophic factor (BDNF) is most known for its involvement in cell development, survival, and plasticity in the nervous system. BDNF and its cognate receptors can also be found in non-neural tissue including the ovary and uterus in humans and in animal models, suggesting that BDNF signaling may regulate reproductive functions. Indeed, disruptions in BDNF signaling are associated with health conditions related to the reproductive system, such as endometriosis. Studies show that treatment with estradiol increases expression of uterine BDNF and its cognate receptors, suggesting that estradiol can modulate BDNF signaling and its effects in the reproductive system. A common human functional single nucleotide polymorphism (SNP) in the BDNF gene, Val66Met (rs6265), is thought to decrease activity-dependent release of BDNF, altering BDNF signaling. Using a CRISPR/cas9 rat model of the human Val66Met BDNF SNP, we investigated the interacting role of estradiol and this variation in the BDNF gene on female uterine structure. Middle-aged (11-14-months-old) female rats were either homozygous for the Val allele (Val/Val; control) or the Met allele (Met/Met; BDNF SNP). All rats were ovariectomized and after three weeks randomly assigned to receive subcutaneous treatment of vehicle (sesame oil) or estradiol (17beta-estradiol benzoate) for two consecutive days. Twenty-four hours after the second injection, rats were euthanized and tissue collected, weighed, and placed in fixative. Uterine tissue weights differed significantly by treatment and by genotype such that uterine horns were heavier in estradiol-treated compared to vehicle-treated rats within each genotype and uterine horns were heavier in Met/Met compared to Val/Val rats within each treatment condition. To determine which uterine layer contributed to the weight differences, uterine horns were sectioned and stained with hematoxylin and eosin. Thickness of myometrium, endometrium, and lumen were individually measured. Although there were no treatment and no genotype effects on myometrial thickness, there were significant treatment and genotype effects on endometrial thickness. Of note, the endometrium of estradiol-treated Met/Met rats was thicker compared to vehicle-treated Met/Met rats and compared to estradiol-treated Val/Val rats, suggesting that estradiol and the BDNF gene variation interact to modulate endometrial size. Lumen circumference did not differ between genotypes but did increase with estradiol compared to vehicle treatment within each genotype. Altogether, findings suggest that BDNF genotype affects uterine structure, notably the endometrium. Differences with BDNF gene variation emerged with estradiol exposure, implicating the hormone’s role in modulating BDNF signaling and warranting future research on the interactive effects of estradiol and BDNF genotype on the endometrium. Presentation: 6/2/2024

APOE×BDNF Interaction and Poorer Cognitive Outcomes Among Veterans With Mild Traumatic Brain Injury: An Exploratory Study.

The authors examined the interaction between apolipoprotein E (APOE) ε4 and brain-derived neurotrophic factor (BDNF) Val66Met alleles on neuropsychological functioning among veterans with histories of mild traumatic brain injury (mTBI). Participants were 78 veterans with mTBI (85% males; mean±SD age=32.95±7.00 years; mean time since injury=67.97±34.98 months) who completed a structured clinical interview and underwent a comprehensive neuropsychological assessment. Participants also provided a buccal swab for determination of their APOE and BDNF genotypes. Three cognitive composite scores were calculated from the neuropsychological assessment, reflecting visuospatial speed (seven variables), executive functioning (10 variables), and memory (eight variables). Two-way analyses of covariance (ANCOVAs) adjusted for age, sex, and race-ethnicity were used to assess the effects of APOE (ε4+ vs. ε4-) and BDNF (Met+ vs. Met-) on cognitive functioning. ANCOVAs revealed no significant main effects of APOE or BDNF genotypes on cognitive functioning; however, there was a significant APOE-by-BDNF genotype interaction for all three cognitive composite measures (visuospatial speed: ηp2=0.055; executive functioning: ηp2=0.064; and memory: ηp2=0.068). Specifically, the ε4+/Met+ (N=8) subgroup demonstrated the poorest cognitive functioning relative to all other allele subgroups (ε4+/Met-: N=12, ε4-/Met+: N=23, and ε4-/Met-: N=35). This exploratory study is the first to show that, compared with other allele subgroups assessed, veterans with both ε4 and Met alleles demonstrated the poorest cognitive functioning across several cognitive domains known to be negatively affected in the context of mTBI. Further research with larger sample sizes is needed to replicate these findings.

Effects of a 6-month dual-task, power-based exercise program on cognitive function, neurological and inflammatory markers in older adults: secondary analysis of a cluster randomised controlled trial.

Functional power-based exercise training can improve physical performance in older adults and cognitive training can improve measures of cognition, but their combined effects on cognition and related risk factors (neurological and inflammatory markers) remains uncertain. This 6-month cluster randomised controlled trial evaluated the effectiveness of dual-task functional power training (DT-FPT) on cognition and circulating neurological and inflammatory markers in older adults at increased falls risk, and whether intervention responses varied by apolipoprotein-E (ApoE) and brain derived neurotrophic factor (BDNF) polymorphisms. Three hundred residents aged ≥ 65 years at increased falls risk residing in 22 independent-living retirement communities, were randomised by village, to DT-FPT (n = 156, 11 villages) involving a multi-component power-based training program performed simultaneously with cognitive and/or motor tasks (45-60 min, 2/week), or a usual care control (CON) group (n = 144, 11 villages). Cognition (computerized CogState battery), inflammatory cytokines, BDNF, insulin-like growth factor-1, vascular endothelial growth factor, amyloid β (1-40) and (1-42) were assessed at baseline and 6-months. Overall, 233 (78%) participants completed the intervention and adherence averaged 50.1%. DT-FPT led to a net 0.18-0.20 SD benefit versus CON in psychomotor ability/attention and reaction time/attention (both P < 0.05). There were no significant intervention effects on circulating markers, except for a net 10.5% benefit in amyloid β (1-40) in DT-FPT versus CON (P < 0.05). Responses were not influenced by APOE or BDNF genotype. In conclusion, DT-FPT in older adults at increased falls risk can provide some cognitive benefits, but these were not related to corresponding changes in inflammatory or neurological markers or influenced by genotype. Australian New Zealand Clinical Trials Registry (ACTRN12613001161718). http://www.anzctr.org.au/ This project was funded by a grant from the National Health and Medical Research Council (NHMRC) Project (APP1046267).

Interaction between BDNF Val66Met polymorphism and mismatch negativity for working memory capacity in schizophrenia

Both the brain-derived neurotrophic factor (BDNF) valine (Val)/methionine (Met) polymorphism and mismatch negativity (MMN) amplitude are reportedly linked to working memory impairments in schizophrenia. However, there is evident scarcity of research aimed at exploring the relationships among the three factors. In this secondary analysis of a randomized, controlled, double-blind trial, we investigated these relationships. The trial assessed the efficacy of transcranial direct current stimulation for enhancing working memory in clinically stable schizophrenia patients, who were randomly divided into three groups: dorsolateral prefrontal cortex stimulation, posterior parietal cortex stimulation, and sham stimulation groups. Transcranial direct current stimulation was administered concurrently with a working memory task over five days. We assessed the BDNF genotype, MMN amplitude, working memory capacity, and interference control subdomains. These assessments were conducted at baseline with 54 patients and followed up post-intervention with 48 patients. Compared to BDNF Met-carriers, Val homozygotes exhibited fewer positive and general symptoms and increased working memory capacity at baseline. A correlation between MMN amplitude and working memory capacity was noted only in BDNF Val homozygotes. The correlations were significantly different in the two BDNF genotype groups. Furthermore, in the intervention group that showed significant improvement in MMN amplitude, BDNF Val homozygotes exhibited greater enhancement in working memory capacity than Met-carriers. This study provides in vivo evidence for the interaction between MMN and BDNF Val/Met polymorphism for working memory capacity. As MMN has been considered a biomarker of N-methyl-D-aspartate receptor (NMDAR) function, these data shed light on the complex interactions between BDNF and NMDAR in terms of working memory in schizophrenia.

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.

Brain-Derived Neurotrophic Factor in Pediatric Acquired Brain Injury and Recovery.

We review emerging preclinical and clinical evidence regarding brain-derived neurotrophic factor (BDNF) protein, genotype, and DNA methylation (DNAm) as biomarkers of outcomes in three important etiologies of pediatric acquired brain injury (ABI), traumatic brain injury, global cerebral ischemia, and stroke. We also summarize evidence suggesting that BDNF is (1) involved in the biological embedding of the psychosocial environment, (2) responsive to rehabilitative therapies, and (3) potentially modifiable. BDNF's unique potential as a biomarker of neuroplasticity and neural repair that is reflective of and responsive to both pre- and post-injury environmental influences separates it from traditional protein biomarkers of structural brain injury with exciting potential to advance pediatric ABI management by increasing the accuracy of prognostic tools and informing clinical decision making through the monitoring of therapeutic effects.

Interactions between tDCS treatment and COMT Val158Met in poststroke cognitive impairment

ObjectiveThis study aimed to explore the effect of catechol-O-methyltransferase (COMT) Val158Met and brain-derived neurotrophic factor (BDNF) Val66Met to post-stroke cognitive impairment (PSCI) and the interaction with transcranial direct current stimulation (tDCS). MethodsSeventy-six patients with PSCI were randomly assigned to Group (1) (n = 38) to receive anodal tDCS of left dorsolateral prefrontal cortex or Group (2) (n = 38) to receive sham stimulation. The intensity of the tDCS was 2 mA, and the stimulations were applied over the left DLPFC for 10 sessions. The Montreal Cognitive Assessment (MoCA) and backward digit span test (BDST) were assessed before, immediately after, and one month after stimulation. ResultsAfter stimulation, patients in the tDCS group showed better improvement in both MoCA and BDST than those in the sham group. The results of GLMs also supported the main effects of tDCS on general cognitive function and working memory. Then we found that COMT genotype may have a main effect on the improvement of MoCA and BDST, and there may be an interaction between COMT genotype and tDCS in enhancing BDST. In contrast, BDNF genotype showed no significant main or interaction effects on any scales. ConclusionsThese findings demonstrate that tDCS can improve cognition after stroke. Gene polymorphisms of COMT can affect the efficacy of tDCS on PSCI, but BDNF may not. SignificanceThis study found that COMT Val158Met has an interaction on the efficacy of prefrontal tDCS in cognitive function, which provides reference for future tDCS research and clinical application.

Comparison of the effects of BDNF/TRKB signalling on metabolic biomarkers in the liver of sedentary and trained rats with normal and knockout BDNF genotypes.

Introduction: The effect of brain-derived neurotrophic factor (BDNF) on the modulation of metabolic processes in the liver is poorly understood. Therefore, the aim of this study was to investigate whether hepatic concentrations or activities of metabolic biomarkers depend on altered BDNF/TrkB content in the liver, resulting from different BDNF genotypes of rats. In addition, it was assessed whether 5-week moderate endurance training modifies the levels of BDNF/Trk-B signaling and studied hepatic markers. Methods: Experiments were performed on wild-type and heterozygous BDNF knockout (HET, SD-Bdnf) rats, which were divided into four groups: control with normal genotype (Bdnf+/+), control with BDNF knockout genotype (Bdnf+/-), trained with normal genotype (Bdnf+/+T) and trained with BDNF knockout genotype (Bdnf +/-T). BDNF/TrkB concentrations as well as selected metabolic biomarkers including lipids-total cholesterol (CHOL), low-density lipoprotein (LDL), triglycerides (TG); enzymes-alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), gamma-glutamyl transferase (GGT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP); hormones-insulin (INS) and leptin (LEPT) as well as interleukin-6 (IL-6) as regeneration indicator were measured directly in liver homogenates. Results and Discussion: The study showed that Bdnf+/- rats exhibited reduced BDNF/TrkB signaling (BDNF, p < 0.0001; Trk-B, p = 0.0005), altered lipid levels (CHOL, p < 0.0001; LDL, p < 0.0001; TG, p = 0.0006) and reduced hepatic ALAT (p = 0.0004) and GGT (p < 0.0001) activity, which may contribute to hepatic steatosis and obesity, as well as indicate impairment of specific metabolic pathways in the liver. Interestingly, endurance training did not alter hepatic BDNF and TrkB content, but improved ALAT (p = 0.0366) and ASAT (p = 0.0191) activities and increased hepatic IL-6 (p = 0.0422) levels in Bdnf +/- rats, suggesting enhanced liver regeneration in animals with BDNF allele loss.

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.

Brain-Heart Axis: Brain-Derived Neurotrophic Factor and Cardiovascular Disease-A Review of Systematic Reviews.

The brain-heart axis is an intra- and bidirectional complex that links central nervous system dysfunction and cardiac dysfunction. In recent decades, brain-derived neurotrophic factor (BDNF) has emerged as a strategic molecule involved in both brain and cardiovascular disease (CVD). This systematic review of systematic reviews aimed to (1) identify and summarize the evidence for the BDNF genotype and BDNF concentration in CVD risk assessment, (2) evaluate the evidence for the use of BDNF as a biomarker of CVD recovery, and (3) evaluate rehabilitation approaches that can restore BDNF concentration. A comprehensive search strategy was developed using PRISMA. The risk of bias was assessed via ROBIS. Seven studies were identified, most of which aimed to evaluate the role of BDNF in stroke patients. Only two systematic reviews examined the association of BDNF concentration and polymorphism in CVDs other than stroke. The overall evidence showed that BDNF plays a fundamental role in assessing the risk of CVD occurrence, because lower BDNF concentrations and rs6265 polymorphism are often associated with CVD. Nevertheless, much work remains to be carried out in current research to investigate how BDNF is modulated in different cardiovascular diseases and in different populations.

Association of BDNF risk variant and dorsolateral cortical thickness with long-term treatment response to valproate in type I bipolar disorder: An exploratory study.

Valproate is among the most prescribed drugs for bipolar disorder; however, 87% of patients do not report full long-term treatment response (LTTR) to this medication. One of valproate's suggested mechanisms of action involves the brain-derived neurotrophic factor (BDNF), expressed in the brain areas regulating emotions, such as the prefrontal cortex. Nonetheless, data about the role of BDNF in LTTR and its implications in the structure of the dorsolateral prefrontal cortex (dlPFC) is scarce. We explore the association of BDNF variants and dorsolateral cortical thickness (CT) with LTTR to valproate in bipolar disorder type I (BDI). Twenty-eight BDI patients were genotyped for BDNF polymorphisms rs1519480, rs6265, and rs7124442, and T1-weighted 3D brain scans were acquired. LTTR to valproate was evaluated with Alda's scale. A logistic regression analysis was conducted to evaluate LTTR according to BDNF genotypes and CT. We evaluated CT differences by genotypes with analysis of covariance. LTTR was associated with BDNF rs1519480 and right dlPFC thickness. Insufficient responders with the CC genotype had thicker right dlPFC than TC and TT genotypes. Full responders reported thicker right dlPFC in TC and TT genotypes. In conclusion, different patterns of CT related to BDNF genotypes were identified, suggesting a potential biomarker of LTTR to valproate in our population.

Brain-derived neurotrophic factor genetic polymorphism rs6265 and creativity.

The protein brain-derived neurotrophic factor (BDNF) promotes neural plasticity of the central nervous system and plays an important role for learning and memory. A single nucleotide polymorphism (rs6265) at position 66 in the pro-region of the human BDNF gene, resulting in a substitution of the amino acid valine (val) with methionine (met), leads to attenuated BDNF secretion and has been associated with reduced neurocognitive function. Inhomogeneous results have been found regarding the effect of the BDNF genotype on behavior. We determined the BDNF genotype and performance on the Compound Remote Associate (CRA) task as a common measure of creativity in 76 healthy university students. In our main analyses, we did not find significant differences between met-carriers (n = 30) and non-met carriers (n = 46). In a secondary analysis, we found that met-carriers had a slower solution time (medium effect size) for items of medium difficulty. Our results suggest that met-carriers and non-met-carriers do not generally differ regarding their creativity, but non-met-carriers may have a certain advantage when it comes to moderately difficult problems. The wider literature suggests that both genetic variants come with advantages and disadvantages. Future research needs to sharpen our understanding of the disadvantages and, potentially, advantages met allele carriers may have.

Brain-Derived Neurotrophic Factor rs6265 polymorphism is associated with severe cancer-related fatigue and neuropathic pain in female cancer survivors

PurposeThis study examined the relationships between a single-nucleotide polymorphism (SNP) of brain-derived neurotrophic factor (BDNF) rs6265 and psychoneurological (PN) symptoms in female cancer survivors.MethodsThis secondary analysis examined 393 study participants. In addition to demographic variables, self-reported PN symptom scores (anxiety, bodily pain, depression, fatigue, neuropathic pain, and sleep disturbance) were collected using the Patient-Reported Outcomes Measurement Information System and 36-Item Short-Form Health Survey. Buccal swab samples were collected to obtain genotypes for BDNF rs6265 (Val/Val, Val/Met, or Met/Met). The PN symptom scores were compared across genotypes, and the relationships were examined using a regression model. We also explored correlations between different symptoms within each genotype.ResultsParticipants with the Met/Met genotype reported significantly worse cancer-related fatigue and neuropathic pain, which was confirmed by rank-based regression analysis. In addition, cancer-related fatigue was correlated with other PN symptoms, particularly depression. These correlations were stronger in study participants with the Met/Met genotype than those with other genotypes.ConclusionOur study suggests that female cancer survivors with the Met/Met genotype of BDNF rs6265 are likely to experience worse cancer-related fatigue and neuropathic pain and that cancer-related fatigue is a good predictor of co-occurring PN symptoms in this population.Implications for Cancer SurvivorsOur findings advance the scientific community's understanding of cancer-related PN symptoms experienced by female cancer survivors, especially the unique role of BDNF rs6265 polymorphism in these symptoms. Our findings offer valuable insights for clinical practice that the symptom experience among female cancer survivors may vary based on BDNF genotypes.

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.

Brain‐derived neurotrophic factor genes are associated with neuropsychiatric symptom progression in dementia. The Cache county dementia progression study

AbstractBackgroundPolymorphisms in genes coding for the neurotrophin, brain‐derived neurotrophic factor (BDNF) or its receptors, have been associated with Alzheimer’s disease and related disorders (ADRD), with sex‐dependent effects. Associations with neuropsychiatric symptom (NPS) progression after dementia onset has been largely unexplored. In a population‐based cohort, we examined the relationships between BDNF gene single‐nucleotide polymorphisms (SNPs) and NPS progression after dementia onset.Method880 participants [61.3% female; mean (SD) age = 82.0 (71) years] with dementia [68.2% AD; 13.5% Vascular Dementia (VaD); 18.3% other dementia (OD)] were assessed on the Neuropsychiatric Inventory (NPI) every six‐to‐18 months. Mean(SD) baseline dementia duration was 2.9(2.7) years. The following SNPs were examined as predictors of NPI scores over time in linear mixed‐effects models: rs6265 (BDNF G196A/Val66Met), rs56164415 (BDNF C270T), rs2289656 (NTRK2 receptor TrkB), and rs2072446 (NGFR p75NTR). Covariates included age of dementia onset, education, apolipoprotein E genotype, and dementia type and duration at baseline.ResultSex‐dependent effects were found for two SNPs. Compared to those with major alleles, males with the rs56164415 minor allele exhibited a lower initial Apathy score, that increased over time (C/t*sex*time2:b = ‐0.063, SE = 0.029, p = .033); by contrast, females showed no differences by SNP alleles. Females homozygous for the rs2289656 minor allele exhibited a rapid increase in Anxiety that decreased over time (t/t*sex*time2: b = ‐0.145, SE = 0.054, p = .0073). For both sexes, presence of minor alleles for BDNF polymorphisms rs6265 (G/a*time2: b = ‐0.017, SE = 0.004, p &lt; .001; a/a*time2: b = ‐0.035, SE = 0.013, p = .006) and rs56164415 (C/t*time2: b = 0.019, SE = 0.005, p &lt; .001) was associated with increased NPI Agitation/Aggression well after baseline. Rs6265 minor allele homozygotes (a/a*time2: b = ‐0.049, SE = 0.013, p &lt; .001) and rs2072446 minor allele carriers (Ct/tt*time2: b = ‐0.012, SE = 0.005, p = .025) exhibited initial increases in Delusions, which diminished approximately 5 years thereafter.ConclusionSpecific BDNF genotypes were associated with NPS presentation after dementia onset, with some sex‐dependent effects. Future research on enhancing BDNF signaling may present possible targets for intervention.

Obesity-related parameters in carriers of some BDNF genetic variants may depend on daily dietary macronutrients intake

Some common single-nucleotide polymorphisms of the brain-derived neurotrophic factor (BDNF) gene have been associated not only with the neurodegenerative diseases but also with some eating disorders. The aim of this study was to assess the possible differences in the obesity-related and glucose metabolism parameters between some BDNF genotypes’, that may depend on the daily energy and macronutrients intake. In 484 adult participants we performed the anthropometric measurements, body composition analysis, and body fat distribution. The daily dietary intake was assessed using the 3-day food intake diaries. Blood glucose and insulin concentrations were measured at fasting and during oral glucose tolerance tests. Moreover, the visceral adipose tissue/subcutaneous adipose tissue (VAT/SAT) ratio and homeostatic model assessment of insulin resistance were calculated. We noted that participants carrying the GG genotype had lower skeletal muscle mass and fat free mass (FFM) when carbohydrate intake was > 48%, whereas they presented higher fat-free mass (FFM), and surprisingly higher total cholesterol and LDL-C concentrations when daily fiber intake was > 18 g. Moreover, in these subjects we noted higher waist circumference, BMI, and fasting glucose and insulin concentrations, when > 18% of total daily energy intake was delivered from proteins, and higher VAT content and HDL-C concentrations when > 30% of energy intake was derived from dietary fat. Our results suggest that glucose homeostasis and obesity-related parameters in carriers of some common variants of BDNF gene, especially in the GG (rs10835211) genotype carriers, may differ dependently on daily energy, dietary macronutrients and fiber intake.

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.

Human assumed central sensitization in people with acute non-specific low back pain: A cross-sectional study of the association with brain-derived neurotrophic factor, clinical, psychological and demographic factors.

Early evidence suggests human assumed central sensitization (HACS) is present in some people with acute low back pain (LBP). Factors influencing individual variation in HACS during acute LBP have not been fully explored. We aimed to examine the evidence for HACS in acute LBP and the contribution of brain-derived neurotrophic factor (BDNF), clinical, psychological and demographic factors to HACS. Participants with acute LBP (<6 weeks after pain onset, N=118) and pain-free controls (N=57) from a longitudinal trial were included. Quantitative sensory testing including pressure and heat pain thresholds and conditioned pain modulation, BDNF serum concentration and genotype and questionnaires were assessed. There were no signs of HACS during acute LBP at group level when compared with controls. Sensory measures did not differ when compared between controls and LBP participants with different BDNF genotypes. Two LBP subgroups with distinct sensory profiles were identified. Although one subgroup (N=60) demonstrated features of HACS including pressure/heat pain hypersensitivity at a remote site and deficient conditioned pain modulation, pain severity and disability did not differ between the two subgroups. Variation in sensory measures (~33%) was partially explained by BDNF genotype, sex, age and psychological factors. This study confirms that HACS is present in some people with acute LBP, but this was not associated with pain or disability. Further, no relationship was observed between BDNF and HACS in acute LBP. More research is needed to understand factors contributing to individual variation in sensory measures in LBP. Human assumed central sensitization (HACS) is present in acute low back pain (LBP) but factors contributing to individual variation are not fully explored. This study investigated the relationship between factors such as brain derived neurotrophic factor (BDNF) and HACS in acute LBP. Our findings indicate that HACS was present in specific LBP subgroups but BDNF was unrelated to HACS. Combinations of BDNF genotype, demographic and psychological factors explained a small proportion of the variation in sensory measures during acute LBP.