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Peripheral Blood Brain-Derived Neurotrophic Factor as a Biomarker of Alzheimer's Disease: Are There Methodological Biases?
Balietti, M, Giuli, C, Conti, F
Molecular neurobiology. 2018;(8):6661-6672
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Abstract
Mounting evidence that alterations in brain-derived neurotrophic factor (BDNF) levels and signaling may be involved in the etiopathogenesis of Alzheimer's disease (AD) has suggested that its blood levels could be used as a biomarker of the disease. However, higher, lower, or unchanged circulating BDNF levels have all been described in AD patients compared to healthy controls. Although the reasons for such different findings are unclear, methodological issues are likely to be involved. The heterogeneity of participant recruitment criteria and the lack of control of variables that influence circulating BDNF levels regardless of dementia (depressive symptoms, medications, lifestyle, lack of overlap between serum and plasma, and experimental aspects) are likely to bias result and prevent study comparability. The present work reviews a broad panel of factors, whose close control could help reduce the inconsistency of study findings, and offers practical advice on their management. Research directed at elucidating the weight of each of these variables and at standardizing analytical methodologies is urgently needed.
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Association of Brain-derived neurotrophic factor gene polymorphisms with body mass index: A systematic review and meta-analysis.
Akbarian, SA, Salehi-Abargouei, A, Pourmasoumi, M, Kelishadi, R, Nikpour, P, Heidari-Beni, M
Advances in medical sciences. 2018;(1):43-56
Abstract
BACKGROUND Many studies with inconsistent results have assessed the association of Brain-derived neurotrophic factor (BDNF) gene polymorphisms with prevalence of obesity and overweight. This review aims to provide a summary of the literature evaluating the relation between BDNF genotype and body mass index (BMI). METHODS A systematic search through PubMed, Scopus, Science direct, Ovid and Cochrane was performed. We included observational studies with cross-sectional and case-control design, which investigated relationship between all kinds of BDNF polymorphisms with BMI, as a representative index of obesity and overweight. Newcastle-Ottawa Scale was used to assess the quality of included articles. RESULTS Thirty five studies were included in quantitative synthesis. Analyses were performed separately using OR, β coefficient and mean. Significant association were documented between rs925946 and BMI (OR=1.12, 95% CI=1.08-1.17, P heterogeneity=0.317), rs10501087 and BMI (OR=1.14, 95% CI=1.04-1.24, P heterogeneity=0.861), rs6265 and BMI (OR=1.13, 95% CI=1.07-1.19, P heterogeneity=0.406), rs988712 and BMI (OR=1.29, 95% CI=1.18-1.40, P heterogeneity=0.602). According to pooled β coefficient analysis, significant result was only observed in the rs925946 polymorphism subgroup. Pooled mean analysis showed that overall effects for the association between BDNF polymorphisms and BMI were not statistically significant. CONCLUSION This meta-analysis suggests that some polymorphisms in BDNF gene including rs925946, rs10501087, rs6265 and rs988712 can be considered as genetic determinants of obesity.
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Developmental origins of adult health and disease: The metabolic role of BDNF from early life to adulthood.
Briana, DD, Malamitsi-Puchner, A
Metabolism: clinical and experimental. 2018;:45-51
Abstract
Accumulating evidence suggests that the origins of adult disease may occur during fetal life. Thus, the concept of "developmental programming" has been introduced and supported by epidemiological and experimental data. This concept supports the idea that the nutritional and hormonal status during pregnancy could interfere in metabolism control. The mechanisms responsible for this "developmental programming" remain poorly documented. Current research indicates that neurotrophins and particularly brain-derived neurotrophic factor (BDNF) may play a crucial role in this process. Although mainly expressed in the nervous system, BDNF and its receptor, tropomyosin-related kinase B (TrkB), are immunolocalized in several regions of the human placenta and have important functions during pregnancy. BDNF serves widespread roles in regulating energy homeostasis in both fetuses and adults, by controlling patterns of fetal growth, adult feeding and physical activity, and by regulating glucose metabolism in peripheral tissues. Impaired BDNF signaling may be implicated in the etiopathogenesis of the metabolic syndrome. Novel BDNF-focused interventions are being developed for obesity, diabetes and neurological disorders. The aim of this article is to provide a brief comprehensive literary review regarding the potential implications of BDNF in "developmental programming", through regulation of metabolism and energy balance from early life to adulthood.
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The role of brain-derived neurotrophic factor and its single nucleotide polymorphisms in stroke patients.
Kotlęga, D, Peda, B, Zembroń-Łacny, A, Gołąb-Janowska, M, Nowacki, P
Neurologia i neurochirurgia polska. 2017;(3):240-246
Abstract
Stroke is the main cause of motoric and neuropsychological disability in adults. Recent advances in research into the role of the brain-derived neurotrophic factor in neuroplasticity, neuroprotection and neurogenesis might provide important information for the development of new poststroke-rehabilitation strategies. It plays a role as a mediator in motor learning and rehabilitation after stroke. Concentrations of BDNF are lower in acute ischemic-stroke patients compared to controls. Lower levels of BDNF are correlated with an increased risk of stroke, worse functional outcomes and higher mortality. BDNF signalling is dependent on the genetic variation which could affect an individual's response to recovery after stroke. Several single nucleotide polymorphisms of the BDNF gene have been studied with regard to stroke patients, but most papers analyse the rs6265 which results in a change from valine to methionine in the precursor protein. Subsequently a reduction in BDNF activity is observed. There are studies indicating the role of this polymorphism in brain plasticity, functional and morphological changes in the brain. It may affect the risk of ischemic stroke, post-stroke outcomes and the efficacy of the rehabilitation process within physical exercise and transcranial magnetic stimulation. There is a consistent trend of Met alleles' being connected with worse outcomes and prognoses after stroke. However, there is no satisfactory data confirming the importance of Met allele in stroke epidemiology and the post-stroke rehabilitation process. We present the current data on the role of BDNF and polymorphisms of the BDNF gene in stroke patients, concentrating on human studies.
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The Efficacy of Non-Pharmacological Interventions on Brain-Derived Neurotrophic Factor in Schizophrenia: A Systematic Review and Meta-Analysis.
Sanada, K, Zorrilla, I, Iwata, Y, Bermúdez-Ampudia, C, Graff-Guerrero, A, Martínez-Cengotitabengoa, M, González-Pinto, A
International journal of molecular sciences. 2016;(10)
Abstract
Several studies have investigated the relationship between non-pharmacological interventions (NPIs) and peripheral brain-derived neurotrophic factor (BDNF) in schizophrenia patients. We conducted a systematic review and meta-analysis to review the efficacy of NPIs on peripheral serum and plasma BDNF in subjects with schizophrenia (including schizoaffective disorder). Meta-analyses were conducted to examine the effects of NPIs on blood BDNF levels by using the standardized mean differences (SMDs) between the intervention groups and controls. In total, six randomized controlled trials with 289 participants were included. Of them, five studies used exercise, physical training or diet products. One study used cognitive training. Overall, the BDNF levels in the NPI group increased significantly compared with the control groups (SMD = 0.95, 95% confidence interval (CI) = 0.07 to 1.83, p = 0.03). Subgroup analyses indicated beneficial effects of a non-exercise intervention on peripheral BDNF levels (SMD = 0.41, 95% CI = 0.08 to 0.74, p = 0.01). Meta-regression analyses showed that the completion rate influenced the variation in SMD (p = 0.01). Despite insufficient evidence to draw a conclusion, our results suggest that use of NPIs as adjunctive treatments, specifically non-exercise interventions, may affect positively serum or plasma BDNF in patients with schizophrenia.
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[Neurotrophic effects of lithium stimulate the reduction of ischemic and neurodegenerative brain damage].
Pronin, AV, Gogoleva, IV, Torshin, IY, Gromovа, OA
Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova. 2016;(2):99-108
Abstract
For over 60 years, high doses of lithium (hundreds of milligrams of elemental lithium) have being used to treat bipolar disorder. However, only during the past 20 years the relevant basic and clinical studies have shown that neuroprotective and neurotrophic effects of lithium are possible in much smaller doses ( hundreds of micrograms of elemental lithium). These data indicate a significant potential for the clinical applications of lithium-based drugs in modern neurology for the purposes of prevention and treatment of neurodegenerative and ischemic pathologies. Pharmacological and molecular biology studies indicated that the inhibition of glycogen synthase kinase-syntentase-3 (GSK-3) and induction of brain-derived neurotrophic factors are the main mechanisms of neurotropic actions of lithium. Also, by inhibiting the NMDA receptors, lithium regulates the calcium homeostasis and inhibits the activation of calcium-dependent apotosis. These and other molecular mechanisms of lithium action protect neurons from ischemia and neurodegeneration thus contributing to a significant reduction of neurological deficit in various models of stroke and neurodegenerative diseases.
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BDNF Val66Met polymorphism and hippocampal volume in neuropsychiatric disorders: A systematic review and meta-analysis.
Harrisberger, F, Smieskova, R, Schmidt, A, Lenz, C, Walter, A, Wittfeld, K, Grabe, HJ, Lang, UE, Fusar-Poli, P, Borgwardt, S
Neuroscience and biobehavioral reviews. 2015;:107-18
Abstract
BACKGROUND Brain-derived neurotrophic factor (BDNF) is a neurotrophin involved in neurogenesis and synaptic plasticity in the central nervous system, especially in the hippocampus, and has been implicated in the pathophysiology of several neuropsychiatric disorders. Its Val66Met polymorphism (refSNP Cluster Report: rs6265) is a functionally relevant single nucleotide polymorphism affecting the secretion of BDNF and is implicated in differences in hippocampal volumes. METHODS This is a systematic meta-analytical review of findings from imaging genetic studies on the impact of the rs6265 SNP on hippocampal volumes in neuropsychiatric patients with major depressive disorder, anxiety, bipolar disorder or schizophrenia. RESULTS The overall sample size of 18 independent clinical cohorts comprised 1695 patients. Our results indicated no significant association of left (Hedge's g=0.08, p=0.12), right (g=0.07, p=0.22) or bilateral (g=0.07, p=0.16) hippocampal volumes with BDNF rs6265 in neuropsychiatric patients. There was no evidence for a publication bias or any demographic, clinical, or methodological moderating effects. Both Val/Val homozygotes (g=0.32, p=0.004) and Met-carriers (g=0.20, p=0.004) from the patient sample had significantly smaller hippocampal volumes than the healthy control sample with the same allele. The magnitude of these effects did not differ between the two genotypes. CONCLUSION This meta-analysis suggests that there is no association between this BDNF polymorphism and hippocampal volumes. For each BDNF genotype, the hippocampal volumes were significantly lower in neuropsychiatric patients than in healthy controls.
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Meta-analysis study on the role of bone-derived neurotrophic factor Val66Met polymorphism in Parkinson's disease.
Mariani, S, Ventriglia, M, Simonelli, I, Bucossi, S, Siotto, M, R, RS
Rejuvenation research. 2015;(1):40-7
Abstract
To evaluate a possible involvement of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism in susceptibility to Parkinson's disease (PD), we performed a meta-analysis of all studies on the topic published from 2002 to 2014. This article reviews and compares the data from two previous meta-analyses, including two studies not previously considered. We selected studies referring to a genetic comparison between PD patients and healthy controls, so 15 studies involving 3754 cases and 4026 controls were included in our meta-analysis. We found no association between the Val66Met polymorphism and the risk of developing PD in our overall analysis. The ethnicity-specific meta-analysis produced no significant association either. Our data do not support a major role for the BDNF Val66Met polymorphism in the pathogenesis of PD.
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Interaction between stress and the BDNF Val66Met polymorphism in depression: a systematic review and meta-analysis.
Hosang, GM, Shiles, C, Tansey, KE, McGuffin, P, Uher, R
BMC medicine. 2014;:7
Abstract
BACKGROUND Major depression is a disabling psychiatric illness with complex origins. Life stress (childhood adversity and recent stressful events) is a robust risk factor for depression. The relationship between life stress and Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene has received much attention. The aim of the present work was to review and conduct a meta-analysis on the results from published studies examining this interaction. METHODS A literature search was conducted using PsychINFO and PubMed databases until 22 November 2013. A total of 22 studies with a pooled total of 14,233 participants met the inclusion criteria, the results of which were combined and a meta-analysis performed using the Liptak-Stouffer z-score method. RESULTS The results suggest that the Met allele of BDNF Val66Met significantly moderates the relationship between life stress and depression (P = 0.03). When the studies were stratified by type of environmental stressor, the evidence was stronger for an interaction with stressful life events (P = 0.01) and weaker for interaction of BDNF Val66Met with childhood adversity (P = 0.051). CONCLUSIONS The interaction between BDNF and life stress in depression is stronger for stressful life events rather than childhood adversity. Methodological limitations of existing studies include poor measurement of life stress.
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Association between brain-derived neurotrophic factor genetic polymorphism Val66Met and susceptibility to bipolar disorder: a meta-analysis.
Wang, Z, Li, Z, Gao, K, Fang, Y
BMC psychiatry. 2014;:366
Abstract
BACKGROUND In view of previous conflicting findings, this meta-analysis was performed to comprehensively determine the overall strength of associations between brain-derived neurotrophic factor (BDNF) genetic polymorphism Val66Met and susceptibility to bipolar disorders (BPD). METHODS Literatures published and cited in Pubmed and Wanfang Data was searched with terms of 'Val66Met', 'G196A', 'rs6265', 'BDNF', 'association', and 'bipolar disorder' up to March 2014. All original case-control association studies were meta-analyzed with a pooled OR to estimate the risk and 95% confidence interval (CI) to reflect the magnitude of variance. RESULTS Twenty-one case-control association studies met our criteria for the meta-analysis. Overall, there was no significant difference in allelic distribution of Val66Met polymorphism between patients and controls with a pooled OR = 1.03 (95% CI 0.98, 1.08) although there was a trend towards association between Val66Met polymorphism and BPD in Caucasians with an OR of 1.08 (95% CI 1.00, 1.16). However, subgroup analyses showed that there was a significant association of Val allele with decreased disease susceptibility for bipolar disorder type II with a pooled OR of 0.88 (95% CI 0.78, 0.99). CONCLUSIONS There is no compelling evidence to supportVal66Met polymorphism in BDNF gene playing an important role in the susceptibility to BPD across different ethnicities.