MAO-B and COMT Genetic Variations Associated With Levodopa Treatment Response in Patients With Parkinson's Disease

9siThe most commonly used Parkinson’s disease (PD) treatment is the replacement of dopamine by its levodopa precursor (L-dopa).Monoamine oxidase- B (MAO-B) and catechol-o-methyl transferase (COMT) are enzymes involved in the metabolism and regulation of dopamine availability. In our study we investigated the possible relation among selected single-nucleotide polymorphisms (SNPs) in the MAO-B (rs1799836) and COMT (rs4680) genes and the therapeutic response to levodopa (L-dopa).A total of 162 Brazilian patients from the Pro-Parkinson service of Clinics Hospital of Pernambuco diagnosed with sporadic PD and treated with levodopa were enrolled. PD patients were stratified into 2 groups according to the daily levodopa dose. MAO-B and COMT SNP genotyping was conducted by polymerase chain reaction–restriction fragment length polymorphism. After multivariate analysis,we observed a significant difference between PD groups for the following variables: sex (P = .02), longer duration of disease (P = .02), longer levodopa therapy duration (P = .01), younger onset of PD (P = .01), and use of COMT inhibitor (P = .02).We observed that patients carrying MAO-B (rs1799836) A and AA genotypes and COMT (rs4680) LL genotype suffered more frequently from levodopa-induced-dyskinesia. In addition,we found an increased risk of 2.84-fold for male individuals carrying the MAO-B G allele to be treated with higher doses of levodopa (P = .04).We concluded that before beginning PD pharmacological treatment, it is important to consider the genetic variants of the MAO-B and COMT genes and the sex, reinforcing the evidence that sexual dimorphism in the genes related to dopamine metabolism might affect PD treatment.partially_openopenSampaio, Tiago Furtado; dos Santos, Erinaldo Ubirajara Damasceno; de Lima, Gessica Dayane Cordeiro; dos Anjos, Rute Salgues Gueiros; da Silva, Ronaldo Celerino; Asano, Amdore Guescel C.; Asano, Nadja Maria Jorge; Crovella, Sergio; de Souza, Paulo Roberto EleutérioSampaio, Tiago Furtado; dos Santos, Erinaldo Ubirajara Damasceno; de Lima, Gessica Dayane Cordeiro; dos Anjos, Rute Salgues Gueiros; da Silva, Ronaldo Celerino; Asano, Amdore Guescel C.; Asano, Nadja Maria Jorge; Crovella, Sergio; de Souza, Paulo Roberto Eleutéri

Navigating the garden of forking paths for data exclusions in fear conditioning research

In this report, we illustrate the considerable impact of researcher degrees of freedom with respect to exclusion of participants in paradimgs with a learning element. We illustrate this empirically through case examples from human fear conditioning research where the exclusion of ‘non-learners’ and ‘non-responders’ is common-despite a lack of consensus on how to define these groups. We illustrate the substantial heterogeneity in exclusion criteria based on a systematic literature search and highlight potential problems and pitfalls of different definitions through case examples based on re-analyses of existing data sets. Based on this, we propose a consensus on evidence-based rather than idiosyncratic criteria including clear guidelines on reporting details. Taken together, we illustrate how flexibility in data collection and analysis can be avoided, which will benefit the robustness and replicability of research findings and can be expected to be applicable to other fields of research that involve a learning element

Platelet monoamine oxidase activity predicts alcohol sensitivity and voluntary alcohol intake in rhesus monkeys

Platelet monoamine oxidase B (MAO-B) has been proposed to be a biological marker for the properties of monoamine systems, with low activity being associated with vulnerability for high scores on personality traits such as sensation seeking, monotony avoidance, and impulsiveness, as well as for vulnerability for alcoholism. In the present study, platelet MAO-B activity was analysed in 78 rhesus macaques, and its relation to voluntary alcohol intake and behaviours after intravenous alcohol administration was observed

Serotonin transporter gene polymorphisms and brain function during emotional distraction from cognitive processing in posttraumatic stress disorder

BACKGROUND: Serotonergic system dysfunction has been implicated in posttraumatic stress disorder (PTSD). Genetic polymorphisms associated with serotonin signaling may predict differences in brain circuitry involved in emotion processing and deficits associated with PTSD. In healthy individuals, common functional polymorphisms in the serotonin transporter gene (SLC6A4) have been shown to modulate amygdala and prefrontal cortex (PFC) activity in response to salient emotional stimuli. Similar patterns of differential neural responses to emotional stimuli have been demonstrated in PTSD but genetic factors influencing these activations have yet to be examined. METHODS: We investigated whether SLC6A4 promoter polymorphisms (5-HTTLPR, rs25531) and several downstream single nucleotide polymorphisms (SNPs) modulated activity of brain regions involved in the cognitive control of emotion in post-9/11 veterans with PTSD. We used functional MRI to examine neural activity in a PTSD group (n = 22) and a trauma-exposed control group (n = 20) in response to trauma-related images presented as task-irrelevant distractors during the active maintenance period of a delayed-response working memory task. Regions of interest were derived by contrasting activation for the most distracting and least distracting conditions across participants. RESULTS: In patients with PTSD, when compared to trauma-exposed controls, rs16965628 (associated with serotonin transporter gene expression) modulated task-related ventrolateral PFC activation and 5-HTTLPR tended to modulate left amygdala activation. Subsequent to combat-related trauma, these SLC6A4 polymorphisms may bias serotonin signaling and the neural circuitry mediating cognitive control of emotion in patients with PTSD. CONCLUSIONS: The SLC6A4 SNP rs16965628 and 5-HTTLPR are associated with a bias in neural responses to traumatic reminders and cognitive control of emotions in patients with PTSD. Functional MRI may help identify intermediate phenotypes and dimensions of PTSD that clarify the functional link between genes and disease phenotype, and also highlight features of PTSD that show more proximal influence of susceptibility genes compared to current clinical categorizations

A review on experimental and clinical genetic associations studies on fear conditioning, extinction and cognitive-behavioral treatment

Fear conditioning and extinction represent basic forms of associative learning with considerable clinical relevance and have been implicated in the pathogenesis of anxiety disorders. There is considerable inter-individual variation in the ability to acquire and extinguish conditioned fear reactions and the study of genetic variants has recently become a focus of research. In this review, we give an overview of the existing genetic association studies on human fear conditioning and extinction in healthy individuals and of related studies on cognitive-behavioral treatment (CBT) and exposure, as well as pathology development after trauma. Variation in the serotonin transporter (5HTT) and the catechol-o-methyltransferase (COMT) genes has consistently been associated with effects in pre-clinical and clinical studies. Interesting new findings, which however require further replication, have been reported for genetic variation in the dopamine transporter (DAT1) and the pituitary adenylate cyclase 1 receptor (ADCYAP1R1) genes, whereas the current picture is inconsistent for variation in the brain-derived neurotrophic factor (BDNF) gene. We end with a discussion of the findings and their limitations, as well as future directions that we hope will aid the field to develop further