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BDNF Val66Met and spontaneous dyskinesias in non-clinical psychosis.

ABSTRACT: Evidence indicating that symptoms of non-clinical psychosis (NCP) occur in 6-8% of the general population suggests that psychosis may occur across a continuum. Although a number of studies have examined environmental contributors, to date there have been few investigations of biological/genetic factors in this integral population. A recent study observed spontaneous dyskinetic movements (reflecting an innervated striatal system) in individuals reporting NCP. The present investigation is designed to replicate this finding and determine if brain-derived neurotrophic factor (BDNF) (implicated in striatal dopamine function) is associated with dyskinesias.A total of 68 young-adult participants reporting High and Low-NCP were assessed for dyskinetic movements using a sensitive instrumental measure of force variability. Saliva from the participants was genotyped for val66met (rs6265), a common functional polymorphism of the BDNF gene (the Met allele is associated with lower activity-dependent release of BDNF).Participants in the High-NCP group showed significantly elevated levels of force variability. Met allele carriers exhibited significantly higher levels of force variability when compared with the Val homozygotes. Logistic regression indicated that the odds of membership in the High-NCP group were significantly higher given the presence of dyskinesias (OR=2.32; CI: 1.25-4.28).Findings of elevated force variability suggest that individuals with NCP exhibit subtle signs of striatal vulnerability, reflected more dramatically as jerking and hyperkinetic movements in patients with formal psychosis. The results are consistent with a larger literature implicating BDNF as a critical factor underlying abnormal movements, and suggest that specific candidate genes underlie putative markers across a psychosis continuum.

SUBMITTER: Mittal VA

PROVIDER: S-EPMC3423560 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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BDNF Val66Met and spontaneous dyskinesias in non-clinical psychosis.

Mittal Vijay A VA Smolen Andrew A Dean Derek J DJ Pelletier Andrea L AL Lunsford-Avery Jessica J Smith Ashley A

Schizophrenia research 20120704 1-3

<h4>Background</h4>Evidence indicating that symptoms of non-clinical psychosis (NCP) occur in 6-8% of the general population suggests that psychosis may occur across a continuum. Although a number of studies have examined environmental contributors, to date there have been few investigations of biological/genetic factors in this integral population. A recent study observed spontaneous dyskinetic movements (reflecting an innervated striatal system) in individuals reporting NCP. The present invest ...[more]

PMID: 22766130

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Project description:Background:Brain-derived neurotrophic factor is implicated in the pathophysiology of major depressive disorder and suicide. Both are partly caused by early life adversity, which reduces brain-derived neurotrophic factor protein levels. This study examines the association of brain-derived neurotrophic factor Val66Met polymorphism and brain brain-derived neurotrophic factor levels with depression and suicide. We hypothesized that both major depressive disorder and early life adversity would be associated with the Met allele and lower brain brain-derived neurotrophic factor levels. Such an association would be consistent with low brain-derived neurotrophic factor mediating the effect of early life adversity on adulthood suicide and major depressive disorder. Methods:Brain-derived neurotrophic factor Val66Met polymorphism was genotyped in postmortem brains of 37 suicide decedents and 53 nonsuicides. Additionally, brain-derived neurotrophic factor protein levels were determined by Western blot in dorsolateral prefrontal cortex (Brodmann area 9), anterior cingulate cortex (Brodmann area 24), caudal brainstem, and rostral brainstem. The relationships between these measures and major depressive disorder, death by suicide, and reported early life adversity were examined. Results:Subjects with the Met allele had an increased risk for depression. Depressed patients also have lower brain-derived neurotrophic factor levels in anterior cingulate cortex and caudal brainstem compared with nondepressed subjects. No effect of history of suicide death or early life adversity was observed with genotype, but lower brain-derived neurotrophic factor levels in the anterior cingulate cortex were found in subjects who had been exposed to early life adversity and/or died by suicide compared with nonsuicide decedents and no reported early life adversity. Conclusions:This study provides further evidence implicating low brain brain-derived neurotrophic factor and the brain-derived neurotrophic factor Met allele in major depression risk. Future studies should seek to determine how altered brain-derived neurotrophic factor expression contributes to depression and suicide.

Project description:The val(66)met polymorphism in brain-derived neurotrophic factor (BDNF) has been associated with poorer outcomes after stroke. The mechanism for this finding remains uncertain but might be related to the reduced motor system activation associated with this polymorphism in healthy people.The current study examined whether the presence of the BDNF val(66)met polymorphism is associated with reduced motor system activation after stroke.Forty-two patients with stroke who were enrolled in 1 of 2 studies of robot-assisted arm motor therapy participated in the study. All participants were tested for the BDNF val(66)met polymorphism followed by functional magnetic resonance imaging during affected hand movement.Participants averaged 12 months poststroke and had wide-ranging motor deficits (Fugl-Meyer scale scores=14-60). Brain activation in participants without the BDNF val(66)met polymorphism (n=26) spanned bilateral motor networks with a larger volume (total=334 cc) than that found in participants with this polymorphism (n=16) (97 cc). Regional analyses were consistent. Participants without this polymorphism showed larger ipsilesional primary sensorimotor cortex activation volume and magnitude compared with those in whom the polymorphism was present.The extent to which these findings generalize to other populations of people with stroke, such as those with stroke <7 days prior, remains uncertain.Functional magnetic resonance imaging during affected hand movement showed decreased brain activation among participants with the BDNF val(66)met polymorphism compared with those lacking this polymorphism, especially in the ipsilesional primary sensorimotor cortex contralateral to movement. These results echo findings in healthy people and suggest that genetic factors affecting the normal brain continue to be operative after stroke. The findings suggest a potential imaging-based endophenotype for the BDNF val(66)met polymorphism's effect on the motor system that may be useful in a clinical trial setting.

Project description:Purpose: The goal of this study was to compare whole heart transcriptomes of hBDNF trasngenic mice to ascertain underlying molecular mechanisms for differences in cardiac function among genotypes Methods: Total RNA extracted from whole hearts of 8-week-old mice, and RNA libraries were constructed using the Illumina TruSeq Stranded Total RNA kit. Libraries were sequenced using Illumina HiSeq 3000 on paired-end-150 flow cell runs at ~32M PF reads per sample. Raw reads (fastq files) were uploaded to the Partek Flow server and pre-alignment quality assessment was performed. Mean base-call quality scores were above Phred-like values of 36 in all positions of all samples, and no hard trimming of the reads was necessary. Sequences were aligned to the mm10 assembly of the mouse genome using STAR 2.5.3a and resulting summary of reads filtered (<80) and quantified at the gene level to Ensemble transcripts 83 using Partek’s expectation maximization (E/M) annotation model. Gene counts were normalized to total read count per sample and then log-transformed (with an offset of 0.0001). To identify differentially expressed genes, statistical analysis was performed using Partek’s Gene Specific Analysis (GSA) multimodal estimation algorithm, followed by SYBR Green qPCR validation. Results: We found female-specific cardiac alterations in both heterozygous and homozygous carriers, including reduction in the gene encoding SERCA2 (Atp2a2) in homozygous Met/Met mice but more profoundly in females compared to males. Enriched functions in females with the Met allele included cardiac hypertrophy in response to stress, with down-regulation of the gene encoding titin (Tcap) and upregulation of BNP (Nppb), in line with altered cardiac functional parameters. Homozygous male mice on the other hand exhibited an inflammatory profile characterized by interferon-γ (IFN-γ)-mediated Th1 immune responses. Conclusions: . These results provide evidence for sex-based differences in how the BDNF polymorphism modifies cardiac physiology, including female-specific alterations of cardiac-specific transcripts and male-specific activation of inflammatory targets.

Dataset Information

BDNF Val66Met and spontaneous dyskinesias in non-clinical psychosis.

Publications

BDNF Val66Met and spontaneous dyskinesias in non-clinical psychosis.

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