Association of <i>COMT</i> and <i>MAO-B</i> gene polymorphic variants with sensitivity to dopaminergic therapy in patients with Parkinson’s disease

Parkinson's disease is a degenerative nervous system disorder caused by the death of dopamine-producing cells in the substantia nigra. Dopaminergic treatment could alleviate motor symptoms for a period. One of the effective dopaminergic medications for symptomatic relief was Levodopa and dopamine agonists. Clinically, Levodopa was always combined with Dopa Decarboxylase (DDC) inhibitors, which redirected Levodopa metabolism towards the COMT pathway, increasing its bioavailability in the central nervous system. The purpose of this article was to investigate the relationship between COMT and MAO-B gene polymorphisms and Levodopa in Parkinson's disease patients, starting by gathering literature on the association between COMT and MAO-B polymorphisms and Levodopa in Parkinson's disease patients using various databases. Reviewed literature revealed that the most frequent polymorphism in the COMT gene was rs4680. Some polymorphisms significantly impacted the treatment of Parkinson's disease patients. However, despite efforts to identify genetic factors influencing the risk of side effects or treatment ineffectiveness, the role of pharmacogenetics in Parkinson's disease has not been fully explored and lacks consistent clinical recommendations. Further research was needed to tailor treatment to individual polymorphisms so that pharmacogenomic approaches could be applied more consistently

Coenzyme Q10 and creatine for Parkinson disease

Identification of individual risk factors for motor complications in Parkinson's disease (PD) can help to guide personalised medical treatment, particularly since treatment options are still limited. To determine whether common functional gene polymorphisms in the dopamine metabolism predict the onset of motor complications in PD, we performed a retrospective, observer-blinded follow-up study of 30 PD patients who underwent genotyping of dopa-decarboxylase (DDC; rs921451), monoamine oxidase B (MAOB; rs1799836), catechol-O-methyltransferase (COMT; rs4680), and dopamine transporter (DAT; variable number tandem repeat) polymorphisms. Onset of wearing-off and dyskinesias was determined by blinded clinical assessments. Predictive values of genotypes for motor complications were evaluated using Cox proportional hazard models. During a median follow-up time of 11.6 years, 23 (77%) of 30 PD patients developed wearing-off, 16 (53%) dyskinesias, and 23 (77%) any motor complication. The MAOB (rs1799836) polymorphism predicted development of dyskinesias with MAOBCC/(C)/CT genotypes (resulting in low/intermediate brain enzyme activity) being associated with lower hazard ratios (unadjusted HR [95% CI]: 0.264 [0.089–0.787]; p=0.012; adjusted HR [95% CI]: 0.142 [0.039–0.520]; p=0.003) than MAOBTT/(T) genotypes (resulting in high brain enzyme activity). DDC (rs921451), COMT (rs4680), and DAT (VNTR) polymorphisms were not predictive of motor complications. Together, the MAOB (rs1799836) polymorphism predicts the development of dyskinesias in PD patients. Our results need confirmation in larger cohorts. If confirmed, individual assessment of this polymorphism might be helpful for early risk stratification and could comprise a step towards patient-tailored therapeutic strategies to prevent or delay motor complications in the course of PD.

Genetic polymorphisms have been shown to be involved in dopaminergic neurotransmission. This may influence susceptibility to Parkinson's disease (PD). We performed a case-control study of the association between PD susceptibility and a genetic polymorphism of MAOB and COMT, both separately and in combination, in Iranians. The study enrolled 103 Iranian patients with PD and 70 healthy individuals. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) methods were used for genotyping. Our data indicated that the MAOB genotype frequencies in PD patients did not differ significantly from the control group. However, the frequency of MAOB GG genotype was significantly lower in female patients. It has been shown that the distribution of MAOB allele A was slightly higher in PD patients. No statistically significant differences were found in the COMT allele and genotype distribution in PD patients in comparison to the controls. The combined haplotype of the MAOB A, A/A and COMT LL genotype showed a slight increase in the risk of PD in female patients in this Iranian population. The data may suggest that the MAOB and COMT genetic polymorphisms do not play any role in the pathogenesis of PD in Iranians. In addition, the combined haplotype of MAOB and COMT genes did not significantly affect the susceptibility to PD. Future studies involving larger control and case populations will undoubtedly lead to a more thorough understanding of the role of the polymorphisms involved in the dopamine pathway in PD.

Familial Aggregation of Panic Disturbances in Parkinson's Disease

After more than 50 years of treating Parkinson's disease with l-DOPA, there are still no guidelines on setting the optimal dose for a given patient. The dopamine transporter type 1, now known as solute carrier family 6 (neurotransmitter transporter), member 3 (SLC6A3) is the most powerful determinant of dopamine neurotransmission and might therefore influence the treatment response. We recently demonstrated that methylphenidate (a dopamine transporter inhibitor) is effective in patients with Parkinson's disease with motor and gait disorders. The objective of the present study was to determine whether genetic variants of the dopamine transporter type 1-encoding gene (SLC6A3) are associated with differences in the response to treatment of motor symptoms and gait disorders with l-DOPA and methylphenidate (with respect to the demographic, the disease and the treatment parameters and the other genes involved in the dopaminergic neurotransmission). This analysis was part of a multicentre, parallel-group, double-blind, placebo-controlled, randomized clinical trial of methylphenidate in Parkinson's disease (Protocol ID:2008-005801-20; ClinicalTrials.gov:NCT00914095). We scored the motor Unified Parkinson's Disease Rating Scale and the Stand-Walk-Sit Test before and after a standardized acute l-DOPA challenge before randomization and then after 3 months of methylphenidate treatment. Patients were screened for variants of genes involved in dopamine metabolism: rs28363170 and rs3836790 polymorphisms in the SLC6A3 gene, rs921451 and rs3837091 in the DDC gene (encoding the aromatic L-amino acid decarboxylase involved in the synthesis of dopamine from l-DOPA), rs1799836 in the MAOB gene (coding for monoamine oxidase B) and rs4680 in the COMT gene (coding for catechol-O-methyltransferase). Investigators and patients were blinded to the genotyping data throughout the study. Eighty-one subjects were genotyped and 61 were analysed for their acute motor response to l-DOPA. The SLC6A3 variants were significantly associated with greater efficacy of l-DOPA for motor symptoms. The SLC6A3 variants were also associated with greater efficacy of methylphenidate for motor symptoms and gait disorders in the ON l-DOPA condition. The difference between motor Unified Parkinson's Disease Rating Scale scores for patients with different SLC6A3 genotypes was statistically significant in a multivariate analysis that took account of other disease-related, treatment-related and pharmacogenetic parameters. Our preliminary results suggest that variants of SLC6A3 are genetic modifiers of the treatment response to l-DOPA and methylphenidate in Parkinson's disease. Further studies are required to assess the possible value of these genotypes for (i) guiding l-DOPA dose adaptations over the long term; and (ii) establishing the risk/benefit balance associated with methylphenidate treatment for gait disorders.

Anxiety, Depression, and Quality of Life in Parkinson's Disease

Pharmacologic treatment of advanced Parkinson's disease: A meta-analysis of COMT inhibitors and MAO-B inhibitors

Entacapone: A catechol- O-methyltransferase inhibitor for the adjunctive treatment of parkinson's disease

Freezing of gait (FOG) is a common axial symptom of Parkinson disease (PD). To determine the prevalence of FOG in a large group of PD patients, assess its relationship with quality of life and clinical and pharmacological factors, and explore its changes from the off to on conditions in patients with motor fluctuations. Cross-sectional survey of 683 patients with idiopathic PD. Scores for FOG were missing in 11 patients who were not included in the analysis. Patients were recruited from referral centers and general neurology clinics in public or private institutions in France. Patients with FOG were identified as those with a score of 1 or greater on item 14 of the Unified Parkinson's Disease Rating Scale (UPDRS) in the on condition. Item 14 scores for FOG in the off condition were also collected in patients with fluctuating motor symptoms. Quality of life (measured by the 39-item Parkinson's Disease Questionnaire and 36-Item Short Form Health Survey), anxiety and depression (Hospital Anxiety and Depression Scale), clinical features (UPDRS), and drug consumption. Of 672 PD patients, 257 reported FOG during the onstate (38.2%), which was significantly related to lower quality of life scores (P < .01). Freezing of gait was also correlated with longer PD duration (odds ratio, 1.92 [95% CI, 1.28-2.86]), higher UPDRS parts II and III scores (4.67 [3.21-6.78]), the presence of apathy (UPDRS item 4) (1.94 [1.33-2.82]), a higher levodopa equivalent daily dose (1.63 [1.09-2.43]), and more frequent exposure to antimuscarinics (3.07 [1.35-6.97]) (logistic regression). The FOG score improved from the off to on states in 148 of 174 patients with motor fluctuations (85.1%) and showed no change in 13.8%. The FOG score improved by more than 50% in 43.7% of patients. Greater improvement in the on state was observed in younger patients (r = -0.25; P < .01) with lower UPDRS II and III scores (r = -0.50; P < .01) and no antimuscarinic use (r = -0.21; P < .01). Freezing of gait in PD patients correlates with poor quality of life, disease severity, apathy, and exposure to antimuscarinics. Dopaminergic therapy improved FOG in most patients with motor fluctuations, especially younger ones with less severe disease and no antimuscarinic use. This finding suggests that quality of life is impaired in PD patients with FOG and that optimizing dopaminergic therapy and avoiding antimuscarinics should be considered.

Freezing of Gait (FOG) is a prevalent and debilitating symptom in idiopathic Parkinson's disease (PD). This study evaluated spatiotemporal and kinematic gait parameters in individuals with PD with a history of FOG and explored the effects of dopaminergic therapy on FOG subtypes. One hundred and nine individuals with PD underwent clinical assessments and quantitative biomechanical measures during walking cycles before and after dopaminergic therapy. Individuals with FOG were classified into levodopa-responsive and levodopa-unresponsive groups. Individuals with FOG displayed longer disease duration and higher Unified Parkinson's Disease Rating Scale (UPDRS) II, III, IV scores, and total scores and levodopa equivalent dose, than those without FOG (all p < 0.0001). Following propensity score matching of 15 pairs based on UPDRS total score and disease duration during the off-medication state, the analysis comparing the FOG and non-FOG groups revealed no significant differences in spatiotemporal and kinematic parameters. In 39 cases of FOG, dopaminergic therapy improved gait performance in individuals with PD, enhancing spatiotemporal parameters (speed, stride length, step length, step variability) and kinematic parameters (shoulder and elbow flexion/extension range of motion (ROM), pelvic rotation, and hip abduction/adduction ROM) regardless of FOG responsiveness to dopaminergic therapy. A significant difference in trunk sway ROM (p = 0.029) remained before and after dopaminergic therapy, even after adjusting for disease duration and clinical severity. Dopaminergic therapy had varying effects on PD with FOG, improving several spatiotemporal and kinematic gait parameters but being less effective in levodopa-unresponsive cases. Quantitative biomechanical measures offer detailed insights into gait performance, aiding personalized fall risk assessment and guiding individualized rehabilitation programs.

Arterial hypertension is a very heterogeneous disease, therefore the influence of environmental factors along with genetic factors leads to various options for the development and course of arterial hypertension. The aim of the study – to find out the effect of fixed combinations of antihypertensive drugs on the features of the clinical course of arterial hypertension in patients with gene polymorphism. We examined 86 patients. The patients were divided into 2 groups: group 1 consisted of 43 people who received a fixed combination of valsartan and amlodipine, group 2 included 43 patients who received a fixed combination of olmesartan and amlodipine. In patients of group 1, a significant decrease in average daily systolic blood pressure (SBP) in carriers of the AC genotype of the AGTR1 gene was established by 7.0% (p&lt;0.01), as well as SBP and DBP (diastolic blood pressure) in carriers of the CC genotype by 11.3 % and 9.8% (p&lt;0.01) respectively. Carriers of the TT, TC, and CC genotypes of the eNOS gene had a significant decrease in SBP by 7.8%, 8.3%, and 13.6% (p&lt;0.01), respectively, and DBP was significantly different from the indicator before treatment in carriers of the CC genotype and decreased by 11.0% (p&lt;0.02). In patients of group 2, a significant decrease in SBP in carriers of the AC genotype of the AGTR1 gene was established by 8.2 % and in DBP in carriers of the CC genotype by 11.2% (p&lt;0.01). Carriers of TT, TC and CC genotypes of the eNOS gene had a probable decrease in the level of average daily SBP by 8.3%, 9.7% and 16.5%, respectively, compared to the level before treatment (p&lt;0.01). In carriers of the CC genotype of the eNOS gene, BP decreased by 13.2% (p&lt;0.01). It has been proven that the use of fixed combinations of valsartan with amlodipine and olmesartan with amlodipine in terms of its effect on the clinical course and the level of SBP and DBP in patients with arterial hypertension with a gene polymorphism is almost the same and is most pronounced in carriers of the CC genotype of the AGTR1 and eNOS genes. Keywords: valsartan, olmesartan, amlodipine.

The objective of this study was to evaluate the effects of common functional polymorphisms in genes involved in dopamine metabolism on striatal dopamine turnover in de novo Parkinson's disease (PD). This was an observer-blinded cohort study investigating effects of common functional polymorphisms in dopa decarboxylase (DDC, rs921451), monoamine oxidase B (MAOB; rs1799836), catechol-O-methyltransferase (COMT, rs4680), and dopamine transporter/solute carrier family 6 member 3 (DAT/SLC6A3, variable number tandem repeats) genes on 18 F-fluorodopa uptake and an effective distribution volume ratio (inverse of dopamine turnover) measured by 18 F-fluorodopa PET in 28 untreated PD patients. Patients carrying the MAOBCC/(C)/CT genotype (low/intermediate enzyme activity) had a lower dopamine turnover in the putamen (higher mean effective distribution volume ratio) when compared with patients with MAOBTT/(T) genotype (high enzyme activity). Striatal PET measures were not different between variants in the remaining genes. The MAOB (rs1799836) polymorphism predicts putaminal dopamine turnover in early PD with the MAOBTT allele linked to high enzyme activity leading to higher intrinsic dopamine turnover, which has been demonstrated to constitute a risk factor for motor complications. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Advanced Parkinson's disease (PD) entails complications, such as motor fluctuations. In Spain, medical attention for such cases is often provided in movement disorder units (MDU). To gain further knowledge of the diagnostic resources and therapeutic approach of MDU. A descriptive cross-sectional study was conducted. The researchers designed an on-line questionnaire, addressed to neurologists from MDUs, containing 48 questions about the resources they have available, the number of patients with PD and motor fluctuations that have been attended to, as well as the therapeutic approach, according to the Hoehn and Yahr (HY) scale. Fifty-five neurologists participated. Structural neuroimaging is available to 100% of them; 89% have access to functional neuroimaging; 89% have acute pharmacological tests available for use; 78% have access to genetic tests; and 53% have transcranial ultrasound at their disposal. There are 2.5 neurologists and 1.2 nurses per unit. Of the patients with PD that they see, 19% of them are in HY stage 1, 59% are in HY stage 2-3 and 22% are in HY stage 4-5. Treatment consists, first of all, in monoamine oxidase type B inhibitors in HY stages 1 and 2, and levodopa in HY stages 3, 4 and 5. Twenty-four per cent of the patients have motor fluctuations, with 5.5 off episodes per day, lasting 44 minutes, with a total of seven off hours per day. Fourteen per cent of the patients under 70 years of age with more than three long-term off episodes per day are receiving invasive treatment for motor fluctuations. MDUs are well equipped with diagnostic and pharmacological resources. Pharmacological treatments are tailored to each patient with a wide range of combinations. Despite this optimisation, the prevalence of motor fluctuations is still high in advanced patients, and invasive therapies may be underused.

Deep brain stimulation outcomes in the malignant end of Parkinson's disease spectrum