Ageing is a scientifically fascinating and complex biological occurrence characterised by morphological and functional changes due to accumulated molecular and cellular damage impairing tissue and organ function. Ageing is often accompanied by cognitive decline but is also the biggest known risk factor for Alzheimer's disease, the most common form of dementia. Emerging evidence suggests that sedentary and unhealthy lifestyles accelerate brain ageing, while regular physical activity, high cardiorespiratory fitness (CRF), or a combination of both, can mitigate cognitive impairment and reduce dementia risk. The purpose of this Review is to explore the neuroprotective mechanisms of endurance exercise and highlight the importance of CRF in promoting healthy brain ageing. Key findings show how CRF mediates the neuroprotective effects of exercise via mechanisms such as improved cerebral blood flow, reduced inflammation, and enhanced neuroplasticity. We summarise evidence supporting the integration of endurance exercise that enhances CRF into public health initiatives as a preventive measure against age-related cognitive decline. Additionally, we address important challenges such as lack of long-term studies with harmonised study designs across preclinical and clinical settings, employing carefully controlled and repeatable exercise protocols, and outline directions for future research.

Repetitive transcranial magnetic stimulation (rTMS) is a safe and effective therapy for treatment-resistant depression (TRD). A crucial next step in improving rTMS therapy is to identify response predictors to inform patient selection criteria. Brain-derived neurotrophic factor (BDNF) exerts influence over TRD treatment modalities. BDNF polymorphism, Val66Met, has shown altered cortical plasticity after single-session rTMS in healthy subjects and clinical response in noninvasive brain stimulation methods in major depressive disorder, stroke, Alzheimer's, and cerebral palsy. We sought to evaluate the effect of this BDNF polymorphism on clinical response in a standard course of rTMS therapy for TRD.

In this naturalistic study, 75 patients with TRD completed a standard course of rTMS with weekly clinical assessments via the Inventory of Depressive Symptomatology Self-Report (IDS-SR). BDNF polymorphisms were retrospectively compared in respect to treatment response and remission, baseline and final scores, percent change scores, and scores across the 6-week treatment course.

As expected, rTMS significantly decreased depressive symptoms as measured by IDS-SR scores. No difference was found in baseline, final, or percent change IDS-SR scores between polymorphism types. There was no difference between polymorphisms in IDS-SR scores across the treatment course. Response and remission rates did not differ between genotypes.

In contrast to previous research highlighting differential response between BDNF polymorphisms to motor plasticity and clinical rTMS outcomes, our data suggest that BDNF polymorphism status may not influence the response to a standard course of 10-Hz rTMS for major depressive disorder. Differences in TMS protocol, target, or BDNF serum levels may underlie our results.

Type 1 diabetes mellitus (T1DM) is associated with cognitive decline. In contrast, higher levels of neurotrophins, such as brain-derived neurotrophic factor (BDNF), may be associated with better brain health. Physical exercise has been associated with elevated levels of BDNF and consequently improved cognitive function, but whether this association is found in T1DM remains unresolved. The aim of this systematic review was to evaluate the acute effect of physical exercise on cognitive function and BDNF levels in patients affected by T1DM.

MEDLINE, Cochrane Library (CENTRAL database), EMBASE and SPORTDiscus were screened by 2 independent reviewers, who selected studies that analysed acute effects of physical exercise in patients with T1DM on BDNF levels or cognitive function tests before and after exercise. Studies in humans and English written were included. The quality of these studies was assessed using the respective Cochrane Risk of Bias tool.

After identifying 507 articles, 4 studies including 78 participants were analysed. Two studies were non-randomized clinical trials, the others were crossover trials. Selected studies performed different exercise intervention protocols, evaluating both high and moderate intensity training. BDNF levels were found higher after exercise in all studies. Cognitive function tests resulted also improved after the training intervention.

In subjects with T1DM, preliminary evidence suggests that exercise training might increase plasma BDNF levels and ameliorate cognitive deficits. However, scientific evidence is still very limited and there is a significant need for further research to clarify the possible positive neurocognitive effects of exercise in T1DM.

Over the past two decades, there has been a growing recognition of the physiological importance and pathological implications surrounding the surface diffusion of AMPA receptors (AMPARs) and their diffusional trapping at synapses. AMPAR surface diffusion entails the thermally powered random Brownian lateral movement of these receptors within the plasma membrane, facilitating dynamic exchanges between synaptic and extrasynaptic compartments. This process also enables the activity-dependent diffusional trapping and accumulation of AMPARs at synapses through transient binding to synaptic anchoring slots. Recent research highlights the critical role of synaptic recruitment of AMPARs via diffusional trapping in fundamental neural processes such as the development of the early phases of long-term potentiation (LTP), contextual fear memory, memory consolidation, and sensory input-induced cortical remapping. Furthermore, studies underscore that regulation of AMPAR diffusional trapping is altered across various neurological disease models, including Huntington's disease (HD), Alzheimer's disease (AD), and stress-related disorders like depression. Notably, pharmacological interventions aimed at correcting deficits in AMPAR diffusional trapping have demonstrated efficacy in restoring synapse numbers, LTP, and memory functions in these diverse disease models, despite their distinct pathogenic mechanisms. This review provides current insights into the molecular mechanisms underlying the dysregulation of AMPAR diffusional trapping, emphasizing its role as a converging point for multiple pathological signaling pathways. We propose that targeting AMPAR diffusional trapping represents a promising early therapeutic strategy to mitigate synaptic plasticity and memory deficits in a spectrum of brain disorders, encompassing but not limited to HD, AD, and stress-related conditions. This approach underscores an integrated therapeutic target amidst the complexity of these neurodegenerative and neuropsychiatric diseases.

Adverse childhood events (ACEs) have been associated with an increased risk of psychiatric disorders in young adulthood. To identify at-risk individuals and potential strategies to combat the negative impacts of ACE, this study investigated the mediating role of exercise in the relationship between psychological distress and ACEs. Further, we examined the moderating effect of the BDNF polymorphism in the mediation relationship.

Participants (N = 750, Mage = 20.1 years) completed questionnaires assessing ACEs divided into adverse environment (AE) and childhood maltreatment (CM), exercise, and psychological distress. Salivary genomic DNA was used for genotyping. The significance of the moderated mediation model was assessed using bootstrapping.

There was a significant association between ACEs and psychological distress mediated by exercise. After addition of BDNF polymorphism, we found that the effect of ACEs on psychological distress through exercise was moderated by the BDNF polymorphism (index of moderated mediation = -0.19, [-0.48, -0.04], p-value ≤0.05). Further dividing ACE into AE and CM, the moderated mediation relationship remains significant only with AE (index of moderated mediation = -0.41, [-0.99, -0.10], p-value ≤0.05).

The interaction between BDNF polymorphism and exercise may be a suitable target for interventions in ACEs-experienced individuals for the prevention or reduction of psychological distress.

Most of the fear literature on humans and animals tests healthy individuals. However, fear memories can differ between healthy individuals and those previously exposed to traumatic stress, such as a car accident, sexual abuse, military combat and personal assault. Traumatic stress can lead to post-traumatic stress disorder (PTSD) which presents alterations in fear memories, such as an impairment of fear extinction and extinction recall. PTSD-like animal models are exposed to a single highly stressful experience in the laboratory, such as stress immobilization or single-prolonged stress. Some days later, animals exposed to a PTSD-like model can be tested in fear procedures that help uncover molecular mechanisms of fear memories. In this review, there are discussed the molecular mechanisms in stress-induced fear memories of patients with PTSD and PTSD-like animal models. The focus is on the effects of estradiol and cortisol/corticosterone hormones and of different genes, such as FKBP prolyl isomerase 5 gene (FKBP5) - FK506 binding protein 51 (FKBP51), pituitary adenylate cyclase-activating peptide (PACAP) - pituitary adenylate cyclase-activating polypeptide type I receptor (PAC1R), endocannabinoid (eCB) system and the tropomyosin receptor kinase B (TrkB) - brain-derived neurotrophic factor (BDNF). The conclusion is that greater emphasis should be placed on investigating the molecular mechanisms of fear memories in PTSD, through direct testing of patients with PTSD or the use of relevant PTSD-like models.

This review explores the impact of physical exercise on brain-derived neurotrophic factor (BDNF) and its relationship with neurodegenerative diseases. The key role of BDNF in maintaining brain health is highlighted, and recent studies are analyzed that indicate an increase in BDNF levels following physical activity, particularly in young adults. Additionally, the interaction between the BDNF Val66Met genetic polymorphism and exercise on cognitive function is examined. The review emphasizes the possibility of exercise as a complementary therapy for neurodegenerative diseases, although further research is required to fully understand its effects.

Brain-derived neurotrophic factor (BDNF) concentrations may differ between BDNF genotype carriers. These changes occur in individuals with metabolic and mental disorders.

The aim of this study was to assess the associations of glucose homeostasis parameters and the frequency of food consumption with BDNF protein concentrations based on BDNF single nucleotide polymorphisms (SNPs).

Among the 439 participants, some common rs10835211 BDNF gene variants were analyzed. We evaluated BDNF concentrations, and measured glucose and insulin after fasting and during oral glucose tolerance tests. Anthropometric measurements, body composition, and body fat distribution were assessed, and a 3-day food intake diary and food frequency questionnaire were completed.

We observed significant differences in BDNF concentration between AA and AG genotype rs10835211 carriers (P = .018). The group of AA genotype holders were older, and positive correlation was found between age and BDNF in the whole study population (P = .012) and in the GG genotype carriers (P = .023). Moreover, BDNF protein correlated with fasting insulin (P = .015), HOMA-IR (P = .031), HOMA-B (P = .010), and the visceral/subcutaneous adipose tissue (VAT/SAT) ratio (P = .026) in the GG genotype individuals. Presence of the GG genotype was negatively correlated with nut and seed (P = .047) and lean pork consumption (P = .015), and the BDNF protein. Moreover, we observed correlations between the frequency of chicken (P = .028), pasta (P = .033), and sweet food intake (P = .040) with BDNF concentration in the general population. Among carriers of the AA genotype, we observed a positive correlation between the consumption of rice (P = .048) and sweet food (P = .028) and the BDNF protein level.

Peripheral BDNF may be associated with VAT content and insulin concentrations in GG genotype carriers and may vary with particular food intake, which warrants further investigation.

BDNF has increasingly gained attention as a key molecule controlling remyelination with a prominent role in neuroplasticity and neuroprotection. Still, it remains unclear how BDNF relates to clinicoradiological characteristics particularly at the early stage of the disease where precise prognosis for the further MS course is crucial.

BDNF, NfL and GFAP concentrations in serum and CSF were assessed in 106 treatment naïve patients with MS (pwMS) as well as 73 patients with other inflammatory/non-inflammatory neurological or somatoform disorders using a single molecule array HD-1 analyser. PwMS were evaluated for highly active profiles by applying the aggressive disease course criteria proposed by ECTRIMS. Serum/CSF values were logarithmically transformed and compared across groups using one-way ANOVA, while correlations were calculated using Pearson's correlations. ROC analysis and AUC comparisons for diagnostic performance of the three biomarkers were computed in an explorative analysis.

Serum BDNF (sBDNF) concentrations were higher in treatment naïve pwMS with disease onset after the age of 40 years (p = 0.029), in pwMS with ≥2 gadolinium-enhancing lesions (p = 0.009) and with motor, cerebellar, cognitive or sphincter symptoms at onset (p = 0.036). BDNF correlated positively with NfL (r = 0.198, p = 0.014) and GFAP (r = 0.253, p = 0.002) in serum, but not in CSF. Neurological patients with an acute inflammatory relapse showed significantly higher sBDNF levels (p = 0.03) compared to somatoform controls, while patients without acute relapse did not differ from somatoform controls (p = 0.4). Better diagnostic performance was found for sBDNF than sNfL and sGFAP in differentiating between patients with vs. without 2 or more gadolinium-enhancing lesions (p < 0.05) and for sBDNF as compared to sNfL for separating patients with disease onset after vs. before age of 40 years.

In pwMS, BDNF serum levels differ depending on disease-related characteristics, suggesting that not only inflammatory activity but also remyelination capacities may vary with disease severity. BDNF is increased when other biomarkers of neuroaxonal damage and neurodegeneration, such as NfL and GFAP, are elevated, possibly as a compensatory mechanism, and reflect possibly further pathophysiological aspects in MS beyond NfL and GFAP, probably including an apoptotic role for BDNF in neuroinflammation.

To investigate the correlation between BDNF gene polymorphism, BDNF levels, and susceptibility to mild cognitive impairment (MCI).

In this study, we investigated 107 elderly adults individuals from a community in Zhongshan, Guangdong Province, with an average age of 73.17 ± 7.081 years. The participants included 52 patients with Mild Cognitive Impairment due to Alzheimer's Disease and 55 cognitively normal elderly adults control subjects. The two groups were matched based on gender, age, and education level. We assessed their cognitive functions and analyzed their genotypes and serum BDNF levels. Analysis of covariance (ANCOVA) was used to evaluate the differences in serum BDNF levels between the MCI group and the control group. Multivariate linear regression was utilized to analyze the association between BDNF levels and susceptibility to MCI, as well as cognitive functions. Multivariate logistic regression was employed to investigate the association between BDNF gene polymorphisms and the risk of developing MCI, along with their interactions.

The ANCOVA analysis indicated that there was no significant difference in serum BDNF levels between the MCI group and the control group (P > 0.05). Correlation analysis revealed a negative correlation between Mini-Mental Status Examination (MMSE) total scores and MCI (r = -0.461, P = 0.001), with significant correlations observed in orientation (r = -0.420, P = 0.002). Multiple linear regression analysis showed that specific polymorphisms, including rs7103411 (CT+TT vs. CC), rs6265 (CT and CT+TT vs. CC), rs11030104 (AG and AG+GG vs. AA), and rs988748 (CG+CC vs. GG), were significantly associated with decreased serum BDNF levels (P < 0.05). Multivariate logistic regression showed that rs7103411 polymorphism was associated with susceptibility to MCI; individuals with the CT or CC genotype had a 0.370 times lower risk of developing MCI compared to those with the TT genotype (OR = 0.370, 95% CI: 0.141-0.970, P = 0.043). A significant interaction was found between rs7103411 and social activity, which influenced the risk of developing MCI. Specifically, individuals with the CT or TT genotype of rs7103411 who engaged in social activities had a significantly lower risk of developing MCI (OR = 0.32, 95% CI: 0.117-0.878, P = 0.027).

This study indicates that BDNF rs7103411、rs6265、rs11030104 and rs988748 are associated with decreased serum BDNF levels in MCI patients. Individuals carrying the TT genotype in the BDNF rs7103411 gene are associated with an increased susceptibility to MCI. Individuals with the rs7103411 CT or TT genotype who participated in social activities showed a significantly reduced risk of developing MCI, suggesting that the interaction between the BDNF rs7103411 genotype and social activity can help reduce the risk of MCI.

BDNF plays a crucial role in shaping the structure and function of neurons. BDNF signaling in the dorsolateral striatum (DLS) is part of an endogenous pathway that protects against the development of alcohol use disorder (AUD). Dysregulation of BDNF levels in the cortex or dysfunction of BDNF/TrkB signaling in the DLS results in the escalation of alcohol drinking and compulsive alcohol use. The major source of BDNF in the striatum is the prefrontal cortex. We identified a small ensemble of BDNF-positive neurons in the ventrolateral orbitofrontal cortex (vlOFC), a region involved in AUD, that extend axonal projections to the DLS. We speculated that BDNF in vlOFC-to-DLS circuit may play a role in limiting alcohol drinking and that heavy alcohol use disrupts this protective pathway. We found that BDNF expression is reduced in the vlOFC of male but not female mice after long-term cycles of binge alcohol drinking and withdrawal. We discovered that overexpression of BDNF in vlOFC-to-DLS but not in vlOFC-to-dorsomedial striatum (DMS) or M2 motor cortex-to-DLS circuit reduces alcohol but not sucrose intake and preference. The DLS plays a major role in habitual behaviors. We hypothesized that BDNF in vlOFC-to-DLS circuitry controls alcohol intake by gating habitual alcohol seeking. We found that BDNF over-expression in vlOFC-to-DLS circuit and systemic administration of BDNF receptor TrkB agonist, LM22A-4, biases habitually trained mice towards goal-directed alcohol seeking. Together, our data suggest that BDNF in a small ensemble of vlOFC-to-DLS neurons gates alcohol intake by attenuating habitual alcohol seeking.

NMDAR antagonists, such as memantine and ketamine, have shown efficacy in treating neurodegenerative diseases and major depression. The mechanism by which these drugs correct the aforementioned diseases is still unknown. Our study reveals that these antagonists significantly enhance 20S proteasome activity, crucial for degrading intrinsically disordered, oxidatively damaged, or misfolded proteins, factors pivotal in neurodegenerative diseases like Alzheimer's and Parkinson's. In our mouse model experiment, ketamine administration notably altered brain synaptic protein profiles within two hours, significantly downregulating proteins strongly associated with Alzheimer's and Parkinson's diseases. Furthermore, the altered proteins exhibited enrichment in terms related to plasticity and potentiation, including retrograde endocannabinoid signaling-a pivotal pathway in both short- and long-term plasticity that may elucidate the long-lasting effects of ketamine in major depression. Via the ubiquitin-independent 20S proteasome pathway (UIPS), these drugs maintain cellular protein homeostasis, which is crucial as proteasome activity declines with age, leading to protein aggregation and disease symptoms. Therefore, these findings hold promise for new treatment options not only for brain diseases but also for other systemic conditions associated with unfolded or misfolded proteins.

Major depressive disorder (MDD) is defined as mood disorder causing a persistent loss of interest and despair for two weeks or greater, with related symptoms. Depression can interfere with daily life and can cause those affected to not work, study, eat, sleep, and enjoy previously enjoyed hobbies and life events as they did previously. If untreated, it can become a serious health condition. Depression is multifactorial with a variety of factors influencing the condition. These factors include: (1) poor diet and exercise, (2) socioeconomic status, (3) gender, (4) biological clocks, (5) genetics and epigenetics, and (6) personal stressors. Treatment of depressive disorders is thus also multifactorial and utilizes the following therapies: (1) diet and exercise, (2) bright light therapy, (3) cognitive behavioral therapy, and (4) pharmaceutical therapy. Obesity is defined as body mass index over 30 and above, is believed to be causally linked to MDD through both psychological and molecular means. Atypical depression, a common form of MDD, is most strongly correlated with a high proclivity for obesity. Obesity and depression have a bidirectional relationship, a patient experiencing either condition singularly is more likely to develop the other due to the neural links between the two, including emotional lability, physical health of the brain, hormones, cytokine secretion, appetite, diet and feeding habits, inflammatory state. In individuals consuming a high fat diet (HFD) commonly ingested by those with obesity, the gut-microbiome is altered leading to systemic inflammation and the dysregulation of mood and the HPA axis impacting their neural health. The purpose of this paper is to examine the interplay of potential molecular, psychological, societal, and environmental causal factors of depressive disorders and how obesity perpetuates depression. A secondary aim of this paper is to examine current interventions that may help improve those affected by both conditions.

This study examined whether sex differences in verbal learning and memory (VLM) are mediated by plasma brain-derived neurotrophic factor (BDNF) expression.

In a sample of n = 201 participants (63.81 ± 6.04 years, 66.2% female, 65.7% family history of Alzheimer's disease [AD], 38% apolipoprotein E [APOE] ε4+) from the Wisconsin Registry for Alzheimer's Prevention, VLM was measured using trials 3 through 5 and delayed recall from the Rey Auditory Verbal Learning Test. Plasma BDNF was measured using a Human BDNF Quantikine Immunoassay. Mediation analysis used bootstrapping, and stratified mediation models tested the conditional dependence of APOE ε4 carriage.

BDNF partially mediated the sex-VLM relationship (β = -0.07; 95% confidence interval [CI]: -0.18, -0.01). Female APOE ε4 carriers had higher VLM scores (β = -0.53; p = 0.03), while female non-carriers had both higher BDNF levels (β = -0.68; p < 0.01) and VLM scores (β = -1.06; p < 0.01); BDNF was again a significant mediator (β = -0.18; 95% CI: -0.37, -0.05).

This study found that circulating BDNF mediates higher verbal memory scores in females-particularly in APOE ε4 non-carriers.

Sex differences in verbal learning and memory (VLM) were mediated by plasma brain-derived neurotrophic factor (BDNF) levels.Women exhibited higher VLM scores and plasma BDNF levels compared to men.The protective effect of BDNF in women was attenuated by apolipoprotein E ε4 carriage.Findings suggest sex-specific mechanisms against verbal memory decline in aging.

The present study investigated the role of endothelial brain-derived neurotrophic factor (BDNF) in cognition. Male adult mice with a selective knockout of BDNF in endothelial cells (BDNFECKO) and their wild-type (WT) littermates were subjected to tests for detection of anxiety- and depression-like behaviors and impaired recognition memory. Neuronal activity and synaptogenesis were assessed from hippocampal levels of c-fos and synaptophysin, respectively, and cerebral capillary density from forebrain levels of CD31. BDNF/TrkB (tropomyosin-related kinase type B) receptor signaling was investigated through hippocampal levels of BDNF and activated TrkB receptors coupled with their immunolabeling by neurons and endothelial cells from both cerebrovascular fractions enriched in capillaries and hippocampal arterioles. Endothelial nitric oxide (NO) production was assessed from the expression of endothelial NO synthase phosphorylated at serine 1177. BDNFECKO mice exhibited anxio-depressive phenotype, impaired memory, and reduced synaptogenesis. Neither neuronal activity, neuronal BDNF/TrkB signaling, nor capillary density differed between BDNFECKO and WT mice. However, endothelial-activated TrkB receptors as well as endothelial NO production and hippocampal BDNF levels were lower in BDNFECKO than those in WT mice. We conclude that endothelial BDNF is involved in cognition through mechanisms independent of neuronal BDNF/TrkB signaling and that endothelial NO might be a driver of the procognitive effect of endothelial BDNF.NEW & NOTEWORTHY The study provides the proof of concept that endothelial brain-derived neurotrophic factor (BDNF) plays a crucial role in postnatal synaptogenesis and development of behavior/memory. It also shows that neuronal tropomyosin-related kinase type B (TrkB) receptors are not a target of endothelium-derived BDNF.

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).

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.

This review discusses genetic variants associated with cognitive dysfunction in chronic kidney disease (CKD) patients, emphasising the limited research in this area. Four studies have explored genetic markers of cognitive dysfunction in CKD, with findings suggesting shared genetic biomarkers between Alzheimer's Disease and CKD.Because of the limited specific research on genetic markers of cognitive dysfunction and dementia in CKD, we extracted data from the current literature studies on genetic markers in the general population that may be relevant to the CKD population. These markers include Apolipoprotein E (APOE), Complement Receptor 1 (CR1), Clusterin (CLU), Sortilin-related receptor 1 (SORL1), Catechol-O-methyltransferase (COMT), and Brain-derived neurotrophic factor (BDNF), all of which are known to be associated with cognitive dysfunction and dementia in other populations. These genes play various roles in lipid metabolism, inflammation, Aβ clearance, and neuronal function, making them potential candidates for studying cognitive decline in CKD patients.CKD-specific research is needed to understand the role of these genetic markers in CKD-related cognitive dysfunction. Investigating how these genes influence cognitive decline in CKD patients could provide valuable insights into early detection, targeted interventions, and personalised treatment strategies. Overall, genetic studies to enhance our understanding and management of cognitive dysfunction in CKD represent a clinical research priority in this population.

This 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.

This 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.

Participants 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.

Our 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.

Our 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.

Major depressive disorder (MDD) is a global health concern with a complex etiology involving genetic, environmental and infectious factors. The exact cause of MDD remains unknown. The present study explored the association between genetic factors, human herpesvirus 6 (HHV-6) and MDD. The present study analyzed single nucleotide polymorphisms (SNPs) and HHV-6 viral load in oral buccal samples from patients with MDD (with and without blood relatives with MDD) and healthy controls. The study used high-resolution melt analysis to examine rs40184 (C>T) in the solute carrier family 6 member 3 (SLC6A31) gene, rs6265 (C>T) in the brain-derived neurotrophic factor (BDNF) gene and rs9383046 (G>A) in the jumonji and AT-rich interaction domain-containing 2 (JARID2) gene. HHV-6 infection and viral load was assessed using the quantitative PCR. Whole-exome sequencing was used to examine SNPs. The variant alleles of SNPs rs40184 [18/40 (45.00) vs. 29/238 (12.55%)] and rs6265 [30/54 (55.46) vs. 117/292 (40.06%)] were significantly more common in patients with MDD than in healthy controls, indicating they may be probable hereditary risk factors for MDD. HHV-6 positivity was significantly more common in carriers of the G/A genotype (12/15, 80%) than carriers of the G/G genotype (75/363, 20.7%) for rs9383046, implying that genetic variations may affect HHV-6 risk and MDD onset. Similarly, HHV-6 viral loads were significantly higher in carriers of the G/A genotype (99,990.85±118,392.64 copies/ng DNA) than carriers of the G/G genotype (48,249.30±101,216.28 copies/ng DNA) for rs9383046. Whole-exome sequencing identified two SNPs in JARID2 (rs11757092 and rs9383050) associated with MDD, highlighting its genetic complexity. The present study helps explain the complex interactions between HHV-6 infection, genetics and MDD onset, improving understanding of how SNPs in JARID2 contribute to HHV-6 infection and MDD onset; these findings may impact future approaches to diagnosing and treating MDD.

Procedural learning and automatization have widely been studied in behavioral psychology and typically involves a rapid improvement, followed by a plateau in performance throughout repeated training. More recently, brain imaging studies have implicated frontal-striatal brain circuits in skill learning. However, it is largely unknown whether frontal-striatal activation during skill learning and behavioral changes follow a similar learning curve pattern. To address this gap in knowledge, we performed a longitudinal brain imaging study using a procedural working memory (pWM) task with repeated measurements across two weeks to map the temporal dynamics of skill learning. We additionally explored the effect of the BDNF Val66Met polymorphism, a common genetic polymorphism impacting neural plasticity, to further inform the relevance of the identified neural markers. We used linear and exponential modeling to characterize procedural learning by means of learning curves on the behavioral and brain functional level. We show that repeated training led to an exponential decay in a distributed set of brain regions including fronto-striatal circuits, which paralleled the exponential improvement in task performance. In addition, we show that both behavioral and neurofunctional readouts were sensitive to the BDNF Val66Met polymorphism, suggesting less efficient learning in 66Met-allele carriers along with protracted signal decay in frontal and striatal brain regions. Our results extend existing literature by showing the temporal relationship between procedural learning and frontal-striatal brain function and suggest a role of BDNF in mediating neural plasticity for establishing automatized behavior.

There is noticeable heterogeneity in weight loss outcomes following intragastric balloon (IGB) treatment, with average weight loss ranging between 11% to 15% of total body weight. Genetic variations associated with obesity have been found to influence weight loss response, however such variations are limited. Therefore, the aim of this study is to investigate the impact of the obesity associated brain-derived neurotrophic factor (BDNF) gene polymorphism rs11030104 with weight loss outcomes following IGB treatment.

In this cross-sectional study, BDNF rs11030104 was analysed in 106 individuals who underwent intragastric balloon treatment. Weight loss metrics were evaluated at the three-month follow-up: percentage of total weight loss (%TWL), percentage of excess weight loss (%EWL), and percentage of body mass index loss (%EBMIL). The effects of additive and dominant genetic models were evaluated. Both linear and logistic regression were applied to assess associations between rs11030104 genotypes and weight loss metrics.

A total of 71 participants completed the 3-month follow-up assessment (loss to follow-up: 33%). This study found a significant association between the BDNF rs11030104 polymorphism and weight loss. A-allele carriers showed a better response to IGB treatment. Individuals carrying the AA genotype were found to have a greater %TWL than those carrying the GG genotype at 3 months post-IGB treatment (11.05% vs 5.09%, p=0.003).

Our results suggest that BDNF rs11030104 influences the response to weight loss after IGB treatment and therefore could be added to the growing list of genetic variants that predict greater weight loss response.

In military populations, gene-environment interactions can influence performance and health outcomes. Brain-derived neurotrophic factor (BDNF) is a central nervous system protein that is important for neuronal function and synaptic plasticity. A BDNF single nucleotide polymorphism, rs6265, leads to an amino acid substitution of valine (Val) with methionine (Met) at codon 66 (Val66Met), which may influence an individual's response to occupational stress, and predispose military members to psychological disorders. Telomere length (TL), a novel measure of biological aging, can be used as a biomarker of stress. Accordingly, telomere shortening may be a surrogate indicator of physiological weathering due to chronic disease and stressful life events. To increase our understanding about the potential effect of the Val66Met mutation on the human stress response, we evaluated the relationships between Val66Met, TL, and mental health symptoms in a military population. In this pilot study (N = 164), we observed an association between Val66Met and reduced TL (p = 0.048). There was no relationship between Val66Met and mental health symptoms. These results support the investigation of gene-environment interactions, and their potential influence on TL due to occupational stress such as military service.

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders with strong genetic heterogeneity and more prevalent in males than females. We and others hypothesize that diminished activity-dependent neural signaling is a common molecular pathway dysregulated in ASD caused by diverse genetic mutations. Brain-derived neurotrophic factor (BDNF) is a key growth factor mediating activity-dependent neural signaling in the brain. A common single nucleotide polymorphism (SNP) in the pro-domain of the human BDNF gene that leads to a methionine (Met) substitution for valine (Val) at codon 66 (Val66Met) significantly decreases activity-dependent BDNF release without affecting basal BDNF secretion. By using mice with genetic knock-in of this human BDNF methionine (Met) allele, our previous studies have shown differential severity of autism-like social deficits in male and female BDNF+/Met mice. Pyramidal neurons are the principal neurons in the prefrontal cortex (PFC), a key brain region for social behaviors. Here, we investigated the impact of diminished activity-dependent BDNF signaling on the intrinsic excitability of pyramidal neurons in the PFC. Surprisingly, diminished activity-dependent BDNF signaling significantly increased the intrinsic excitability of pyramidal neurons in male mice, but not in female mice. Notably, significantly decreased thresholds of action potentials were observed in male BDNF+/Met mice, but not in female BDNF+/Met mice. Voltage-clamp recordings revealed that the sodium current densities were significantly increased in the pyramidal neurons of male BDNF+/Met mice, which were mediated by increased transcriptional level of Scn2a encoding sodium channel NaV 1.2. Medium after hyperpolarization (mAHP), another important parameter to determine intrinsic neuronal excitability, is strongly associated with neuronal firing frequency. Further, the amplitudes of mAHP were significantly decreased in male BDNF+/Met mice only, which were mediated by the downregulation of Kcnn2 encoding small conductance calcium-activated potassium channel 2 (SK2). This study reveals a sexually dimorphic signature of diminished activity-dependent BDNF signaling on the intrinsic neuronal excitability of pyramidal neurons in the PFC, which provides possible cellular and molecular mechanisms underpinning the sex differences in idiopathic ASD patients and human autism victims who carry BDNF Val66Met SNP.

Irritable bowel syndrome (IBS), a disorder of gut-brain interaction, is often comorbid with somatic pain and psychological disorders. Dysregulated signaling of brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), has been implicated in somatic-psychological symptoms in individuals with IBS. We investigated the association of 10 single-nucleotide polymorphisms (SNPs) in the regulatory 3' untranslated region of neurotrophic receptor tyrosine kinase-2 (NTRK2) kinase domain-deficient truncated isoform (TrkB.T1) and BDNF Val66Met SNP with somatic and psychological symptoms and quality-of-life (QoL) in a cohort from the United States (IBS, n = 464; healthy controls, n = 156). We found that the homozygous recessive genotype (G/G) of rs2013566 in individuals with IBS is associated with worsened somatic symptoms, including headache, back pain, joint pain, muscle pain, and somatization as well as diminished sleep quality, energy level, and overall QoL. Validation using United Kingdom BioBank data confirmed the association of rs2013566 with an increased likelihood of headache. Several SNPs (rs1627784, rs1624327, and rs1147198) showed significant associations with muscle pain in our U.S. cohort. These 4 SNPs are predominantly located in H3K4Me1-enriched regions, suggesting their enhancer and/or transcription regulation potential. Our findings suggest that genetic variation within the 3' untranslated region region of the TrkB.T1 isoform may contribute to comorbid conditions in individuals with IBS, resulting in a spectrum of somatic and psychological symptoms impacting their QoL. These findings advance our understanding of the genetic interaction between BDNF/TrkB pathways and somatic-psychological symptoms in IBS, highlighting the importance of further exploring this interaction for potential clinical applications. PERSPECTIVE: This study aims to understand the genetic effects on IBS-related symptoms across somatic, psychological, and quality-of-life (QoL) domains, validated by United Kingdom BioBank data. The rs2013566 homozygous recessive genotype correlates with worsened somatic symptoms and reduced QoL, emphasizing its clinical significance.

Traumatic brain injury (TBI) is a major life-threatening event. In addition to neurological deficits, it can lead to long-term impairments in attention and memory. Deep brain stimulation (DBS) is an established therapy for movement disorders that has been recently investigated for memory improvement in various disorders. In models of TBI, stimulation delivered to different brain targets has been administered to rodents long after the injury with the objective of treating motor deficits, coordination and memory impairment.

To test the hypothesis that DBS administered soon after TBI may prevent the development of memory deficits and exert neuroprotective effects.

Male rats were implanted with DBS electrodes in the anterior nucleus of the thalamus (ANT) one week prior to lateral fluid percussion injury (FPI). Immediately after TBI, animals received active or sham stimulation for 6 h. Four days later, they were assessed in a novel object/novel location recognition test (NOR/NLR) and a Barnes maze paradigm. After the experiments, hippocampal cells were counted. Separate groups of animals were sacrificed at different timepoints after TBI to measure cytokines and brain derived neurotrophic factor (BDNF). In a second set of experiments, TBI-exposed animals receiving active or sham stimulation were injected with the tropomyosin receptor kinase B (TrkB) antagonist ANA-12, followed by behavioural testing.

Rats exposed to TBI given DBS had an improvement in several variables of the Barnes maze, but no significant improvements in NOR/NLR compared to Sham DBS TBI animals or non-implanted controls. Animals receiving stimulation had a significant increase in BDNF levels, as well as in hippocampal cell counts in the hilus, CA3 and CA1 regions. DBS failed to normalize the increased levels of TNFα and the proinflammatory cytokine IL1β in the perilesional cortex and the hippocampus of the TBI-exposed animals. Pharmacological experiments revealed that ANA-12 administered alongside DBS did not counter the memory improvement observed in ANT stimulated animals.

DBS delivered immediately after TBI mitigated memory deficits, increased the expression of BDNF and the number of hippocampal cells in rats. Mechanisms for these effects were not related to an anti-inflammatory effect or mediated via TrkB receptors.

Autism Spectrum Disorders (ASD) comprise a range of early age-onset neurodevelopment disorders with genetic heterogeneity. Most ASD related genes are involved in synaptic function, which is regulated by mature brain-derived neurotrophic factor (mBDNF) and its precursor proBDNF in a diametrically opposite manner: proBDNF inhibits while mBDNF potentiates synapses. Here we generated a knock-in mouse line (BDNFmet/leu) in which the conversion of proBDNF to mBDNF is attenuated. Biochemical experiments revealed residual mBDNF but excessive proBDNF in the brain. Similar to other ASD mouse models, the BDNFmet/leu mice showed reduced dendritic arborization, altered spines, and impaired synaptic transmission and plasticity in the hippocampus. They also exhibited ASD-like phenotypes, including stereotypical behaviors and deficits in social interaction. Moreover, the plasma proBDNF/mBDNF ratio was significantly increased in ASD patients compared to normal children in a case-control study. Thus, deficits in proBDNF to mBDNF conversion in the brain may contribute to ASD-like behaviors, and plasma proBDNF/mBDNF ratio may be a potential biomarker for ASD.

This narrative review examines the relationship between dopamine-related genetic polymorphisms, personality traits, and athletic success. Advances in sports genetics have identified specific single nucleotide polymorphisms (SNPs) in dopamine-related genes linked to personality traits crucial for athletic performance, such as motivation, cognitive function, and emotional resilience. This review clarifies how genetic variations can influence athletic predisposition through dopaminergic pathways and environmental interactions. Key findings reveal associations between specific SNPs and enhanced performance in various sports. For example, polymorphisms such as COMT Val158Met rs4680 and BDNF Val66Met rs6265 are associated with traits that could benefit performance, such as increased focus, stress resilience and conscientiousness, especially in martial arts. DRD3 rs167771 is associated with higher agreeableness, benefiting teamwork in sports like football. This synthesis underscores the multidimensional role of genetics in shaping athletic ability and advocates for integrating genetic profiling into personalized training to optimize performance and well-being. However, research gaps remain, including the need for standardized training protocols and exploring gene-environment interactions in diverse populations. Future studies should focus on how genetic and epigenetic factors can inform tailored interventions to enhance both physical and psychological aspects of athletic performance. By bridging genetics, personality psychology, and exercise science, this review paves the way for innovative training and performance optimization strategies.

The spinal muscular atrophy (SMA) phenotype strongly correlates with the SMN2 gene copy number. However, the severity and progression of the disease vary widely even among affected individuals with identical copy numbers. This study aimed to investigate the impact of genetic variability in oxidative stress, inflammatory, and neurodevelopmental pathways on SMA susceptibility and clinical progression. Genotyping for 31 genetic variants across 20 genes was conducted in 54 SMA patients and 163 healthy controls. Our results revealed associations between specific polymorphisms and SMA susceptibility, disease type, age at symptom onset, and motor and respiratory function. Notably, the TNF rs1800629 and BDNF rs6265 polymorphisms demonstrated a protective effect against SMA susceptibility, whereas the IL6 rs1800795 was associated with an increased risk. The polymorphisms CARD8 rs2043211 and BDNF rs6265 were associated with SMA type, while SOD2 rs4880, CAT rs1001179, and MIR146A rs2910164 were associated with age at onset of symptoms after adjustment for clinical parameters. In addition, GPX1 rs1050450 and HMOX1 rs2071747 were associated with motor function scores and lung function scores, while MIR146A rs2910164, NOTCH rs367398 SNPs, and GSTM1 deletion were associated with motor and upper limb function scores, and BDNF rs6265 was associated with lung function scores after adjustment. These findings emphasize the potential of genetic variability in oxidative stress, inflammatory processes, and neurodevelopmental pathways to elucidate the complex course of SMA. Further exploration of these pathways offers a promising avenue for developing personalized therapeutic strategies for SMA patients.

Assessing candidate gene sequence variations and expression helps to understand methamphetamine use disorder and inform potential treatments. We investigated single nucleotide polymorphisms (SNPs) and gene expression in four candidate genes: SLC18A1, SLC18A2, BDNF, and FAAH, between controls and people with methamphetamine use disorder.

Fifty-nine participants (29 people with methamphetamine use disorder and 30 controls) completed a clinical interview, cognitive tasks, and provided a blood sample. SLC18A1, SLC18A2, BDNF, and FAAH SNPs were genotyped, and gene expression was assessed with real-time quantitative PCR.

SLC18A1 Pro4Thr was associated with methamphetamine use disorder (OR = 6.22; p = .007). SLC18A2 variants, rs363227 and rs363387, were negatively associated with methamphetamine use severity (p = .003) and positively associated with inhibitory control performance (p = .006), respectively. BDNF Val66Met was associated with the severity of use (p = .008). SLC18A2 and FAAH mRNA levels were lower in people who use methamphetamine relative to controls (p = .021 and .010, respectively).

SLC18A1 is identified for the first time to play a potential role in methamphetamine use disorder. Lower levels of blood SLC18A2 and FAAH mRNA in people with methamphetamine use disorder suggest reduced monoamine reuptake, recycling, or release, and higher anandamide levels in this clinical group, which may be potential therapeutic targets.

Prior studies suggest that the reductions in physical activity during Covid-19-related lockdowns impacted physical and mental health. Whether reductions in physical activity that occurred during lockdowns also relate to cognitive functions such as memory and attention is less explored. Here, we investigated whether changes in physical activity (PA) that occurred during and following Covid-19-related lockdowns could predict a variety of measures of cognitive performance in 318 young adults. Participants were assessed on their engagement in PA before, during, and after lockdowns. They also completed tests of cognitive control, working memory, and short-term memory following lockdown(s). As expected, engagement in PA decreased during lockdown and returned to near baseline levels thereafter. Decreases in PA during lockdown predicted individual differences in cognitive performance following lockdown. Greater reductions in PA during lockdown were associated with lower scores on the go/no-go task, a measure of cognitive control ability, and the n-back task, a measure of working memory performance. Larger post-lockdown increases in PA were associated with higher scores on the same tasks. Individual differences in pandemic-related stress and insomnia also predicted cognitive outcomes. These findings suggest that reductions of PA can predict cognitive performance, and underscore the importance of maintaining PA for cognitive health, especially in situations such as lockdowns.

Traumatic brain injury is a common health problem affecting millions of people each year. BDNF has been investigated in the context of traumatic brain injury due to its crucial role in maintaining brain homeostasis. Val66Met is a functional single-nucleotide polymorphism that results in a valine-to-methionine amino acid substitution at codon 66 in the BDNF prodomain, which ultimately reduces secretion of BDNF. Here, we review experimental animal models as well as clinical studies investigating the role of the Val66Met single-nucleotide polymorphism in traumatic brain injury outcomes, including cognitive function, motor function, neuropsychiatric symptoms, and nociception. We also review studies investigating the role of BDNF on traumatic brain injury pathophysiology as well as circulating BDNF as a biomarker of traumatic brain injury.

Aging is associated with progressive brain atrophy and declines in learning and memory, often attributed to hippocampal or cortical deterioration. The role of brain-derived neurotrophic factor (BDNF) in modulating the structural and functional changes in the brain and visual system, particularly in relation to BDNF Val66Met polymorphism, remains underexplored. In this present cross-sectional observational study, we aimed to assess the effects of BDNF polymorphism on brain structural integrity, cognitive function, and visual pathway alterations. A total of 108 older individuals with no evidence of dementia and a mean (SD) age of 67.3 (9.1) years were recruited from the Optic Nerve Decline and Cognitive Change (ONDCC) study cohort. The BDNF Met allele carriage had a significant association with lower entorhinal cortex volume (6.7% lower compared to the Val/Val genotype, P = 0.02) and posterior cingulate volume (3.2% lower than the Val/Val group, P = 0.03), after adjusting for confounding factors including age, sex and estimated total intracranial volumes (eTIV). No significant associations were identified between the BDNF Val66Met genotype and other brain volumetric or diffusion measures, cognitive performances, or vision parameters except for temporal retinal nerve fibre layer thickness. Small but significant correlations were found between visual structural and functional, cognitive, and brain morphological metrics. Our findings suggest that carriage of BDNF Val66Met polymorphism is associated with lower entorhinal cortex and posterior cingulate volumes and may be involved in modulating the cortical morphology along the aging process.

Obsessive-compulsive disorder (OCD) has been associated with neurocognitive impairments. The present study examined the effect of treatment on neurocognitive performance in OCD and the relationship between neurocognitive change and symptom change. The present study also examined polymorphisms influencing brain derived neurotrophic factor (BDNF) as predictors of neurocognitive change.

Treatment-seeking participants with OCD (N = 125) were assigned to cognitive behavioural therapy (CBT) alone, CBT combined with regular physical exercise, exercise alone, or a waitlist control group. Measures of OCD symptom severity and a neuropsychological battery were completed pre- and post-treatment. Blood or saliva samples were used to genotype the BDNF Val66Met polymorphism.

OCD symptom severity was not cross-sectionally associated with neurocognitive performance. Several neurocognitive measures improved over treatment. The BDNF Val66Met polymorphism was significantly associated with worse performance on the Stroop test but did not significantly predict change in neurocognitive performance over time.

Limitations include lack of a healthy control group.

Improvement in neurocognitive performance corresponded to symptomatic improvement and was independent of the BDNF Val66Met genotype.

Primary cilia are hair-like solitary organelles growing on most mammalian cells that play fundamental roles in embryonic patterning and organogenesis. Defective cilia often cause a suite of inherited diseases called ciliopathies with multifaceted manifestations. Intraflagellar transport (IFT), a bidirectional protein trafficking along the cilium, actively facilitates the formation and absorption of primary cilia. IFT172 is the largest component of the IFT-B complex, and its roles in Bardet-Biedl Syndrome (BBS) have been appreciated with unclear mechanisms.

We performed a battery of behavioral tests with Ift172 haploinsufficiency (Ift172+/-) and WT littermates. We use RNA sequencing to identify the genes and signaling pathways that are differentially expressed and enriched in the hippocampus of Ift172+/- mice. Using AAV-mediated sparse labeling, electron microscopic examination, patch clamp and local field potential recording, western blot, luciferase reporter assay, chromatin immunoprecipitation, and neuropharmacological approach, we investigated the underlying mechanisms for the aberrant phenotypes presented by Ift172+/- mice.

Ift172+/- mice displayed excessive self-grooming, elevated anxiety, and impaired cognition. RNA sequencing revealed enrichment of differentially expressed genes in pathways relevant to axonogenesis and synaptic plasticity, which were further confirmed by less spine density and synaptic number. Ift172+/- mice demonstrated fewer parvalbumin-expressing neurons, decreased inhibitory synaptic transmission, augmented theta oscillation, and sharp-wave ripples in the CA1 region. Moreover, Ift172 haploinsufficiency caused less BDNF production and less activated BDNF-TrkB signaling pathway through transcription factor Gli3. Application of 7,8-Dihydroxyflavone, a potent small molecular TrkB agonist, fully restored BDNF-TrkB signaling activity and abnormal behavioral phenotypes presented by Ift172+/- mice. With luciferase and chip assays, we provided further evidence that Gli3 may physically interact with BDNF promoter I and regulate BDNF expression.

Our data suggest that Ift172 per se drives neurotrophic effects and, when defective, could cause neurodevelopmental disorders reminiscent of autism-like disorders.

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.

Brain-derived neurotrophic factor (BDNF) is vital for synaptic plasticity, cell persistence, and neuronal development in peripheral and central nervous systems (CNS). Numerous intracellular signalling pathways involving BDNF are well recognized to affect neurogenesis, synaptic function, cell viability, and cognitive function, which in turn affects pathological and physiological aspects of neurons. Stroke has a significant psycho-socioeconomic impact globally. Central post-stroke pain (CPSP), also known as a type of chronic neuropathic pain, is caused by injury to the CNS following a stroke, specifically damage to the somatosensory system. BDNF regulates a broad range of functions directly or via its biologically active isoforms, regulating multiple signalling pathways through interactions with different types of receptors. BDNF has been shown to play a major role in facilitating neuroplasticity during post-stroke recovery and a pro-nociceptive role in pain development in the nervous system. BDNF-tyrosine kinase receptors B (TrkB) pathway promotes neurite outgrowth, neurogenesis, and the prevention of apoptosis, which helps in stroke recovery. Meanwhile, BDNF overexpression plays a role in CPSP via the activation of purinergic receptors P2X4R and P2X7R. The neuronal hyperexcitability that causes CPSP is linked with BDNF-TrkB interactions, changes in ion channels and inflammatory reactions. This review provides an overview of BDNF synthesis, interactions with certain receptors, and potential functions in regulating signalling pathways associated with stroke and CPSP. The pathophysiological mechanisms underlying CPSP, the role of BDNF in CPSP, and the challenges and current treatment strategies targeting BDNF are also discussed.

Over the past century, age-related diseases, such as cancer, type-2 diabetes, obesity, and mental illness, have shown a significant increase, negatively impacting overall quality of life. Studies on aged animal models have unveiled a progressive discoordination at multiple regulatory levels, including transcriptional, translational, and post-translational processes, resulting from cellular stress and circadian derangements. The circadian clock emerges as a key regulator, sustaining physiological homeostasis and promoting healthy aging through timely molecular coordination of pivotal cellular processes, such as stem-cell function, cellular stress responses, and inter-tissue communication, which become disrupted during aging. Given the crucial role of hypothalamic circuits in regulating organismal physiology, metabolic control, sleep homeostasis, and circadian rhythms, and their dependence on these processes, strategies aimed at enhancing hypothalamic and circadian function, including pharmacological and non-pharmacological approaches, offer systemic benefits for healthy aging. Intranasal brain-directed drug administration represents a promising avenue for effectively targeting specific brain regions, like the hypothalamus, while reducing side effects associated with systemic drug delivery, thereby presenting new therapeutic possibilities for diverse age-related conditions.

Major depressive disorder (MDD) is one of the leading causes of disease burden and disability worldwide. Brain-derived neurotrophic factor (BDNF) seems to have an important role in the molecular mechanisms underlying MDD aetiology, given its implication in regulating neuronal plasticity. There is evidence that physical activity (PA) improves depressive symptoms, with a key role of BDNF in this effect. We aim to perform a systematic review examining the relationship between the BDNF Val66Met polymorphism and the BDNF protein, PA and MDD.

Both observational and experimental design original articles or systematic reviews were selected, according to the PRISMA statement.

Six studies evaluated the Val66Met polymorphism, suggesting a greater impact of physical activity on depression depending on the Val66Met genotype. More discordant findings were observed among the 13 studies assessing BDNF levels with acute or chronic exercise interventions, mainly due to the high heterogeneity found among intervention designs, limited sample size, and potential bias.

Overall, there is cumulative evidence supporting the potential role of BDNF in the interaction between PA and MDD. However, this review highlights the need for further research with more homogeneous and standardised criteria, and pinpoints important confounding factors that must be considered in future studies to provide robust conclusions.

Reduced brain derived neurotrophic factor (BDNF) concentration is reported to be associated with a cognitive decline in schizophrenia, depending on the stage of the disease. Aim of the study was to examine the possible association between plasma BDNF and cognitive decline in chronic stable schizophrenia and mild cognitive impairment (MCI). The study included 123 inpatients of both sexes with schizophrenia, 123 patients with MCI and 208 healthy control subjects. Cognitive abilities were assessed using mini mental state examination (MMSE), Clock Drawing test (CDT) and cognitive subscale of the Positive and Negative Syndrome Scale (PANSS). Plasma BDNF concentration was determined using ELISA. BDNF concentration was lower in patients with schizophrenia and MCI compared to age-matched healthy controls and was similar in carriers of different BDNF Val/66Met genotypes. The MMSE and CDT scores were lower in patients with schizophrenia compared to healthy controls and subjects with MCI. Reduced plasma BDNF was significantly associated with lower MMSE scores in all subjects. BDNF concentration in patients with schizophrenia was not affected by clinical and demographic factors. BDNF Val66Met polymorphism was not associated with the MMSE scores in all participants. Further studies should include longitudinal follow-up and other cognitive scales to confirm these results and offer cognition-improving strategies to prevent cognitive decline in chronic schizophrenia.