Dataset Information

Polymorphism of the Dopa-Decarboxylase Gene Modifies the Motor Response to Levodopa in Chinese Patients With Parkinson's Disease.

ABSTRACT: Levodopa (L-DOPA) is the most effective drug for Parkinson's disease (PD). However, the response to L-DOPA remains individually variable, which hampers the practical value of L-DOPA in the clinic. Genetic factors play a role in L-DOPA efficacy. This study explored the associations between polymorphisms and motor response to L-DOPA in Chinese patients with PD. A total of 51 Chinese PD patients were enrolled in this study. Patients underwent an acute L-DOPA challenge and were evaluated by the Unified Parkinson Disease Rating Scale (UPDRS) part III at baseline and after L-DOPA administration. Subjects were genotyped for polymorphisms: rs921451 and rs3837091 in the DDC loci, rs3836790 in the SLC6A3 locus, rs4680 in the COMT locus, and rs1799836 in the MAOB locus. We found that patients carrying the DDC CT or TT genotype exhibited a better motor response to L-DOPA than patients with the DDC CC genotype, and there was still a significant difference after adjustment for the L-DOPA dose in the acute challenge. Improvement in the UPDRS III subscores, including bradykinesia and axial symptoms, was significantly lower in patients with the DDC CC genotype than in patients with the CT or TT genotype. There were no significant associations between the motor response to L-DOPA and the rs3837091, rs3836790, rs4680, and rs1799836 variants. The DDC single nucleotide polymorphism rs921451 modulated the motor response to L-DOPA in Chinese PD patients. Our results suggested that DDC may be a modifier gene for the L-DOPA treatment response in PD.

SUBMITTER: Li L

PROVIDER: S-EPMC7673431 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Polymorphism of the Dopa-Decarboxylase Gene Modifies the Motor Response to Levodopa in Chinese Patients With Parkinson's Disease.

Li Lanting L Lin Huixia H Hua Ping P Yan Lei L Dong Hui H Li Tan T Liu Weiguo W

Frontiers in neurology 20201029

Levodopa (L-DOPA) is the most effective drug for Parkinson's disease (PD). However, the response to L-DOPA remains individually variable, which hampers the practical value of L-DOPA in the clinic. Genetic factors play a role in L-DOPA efficacy. This study explored the associations between polymorphisms and motor response to L-DOPA in Chinese patients with PD. A total of 51 Chinese PD patients were enrolled in this study. Patients underwent an acute L-DOPA challenge and were evaluated by the Unif ...[more]

PMID: 33250838

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Project description:BackgroundAs Parkinson's disease progresses, levodopa treatment loses efficacy, partly through the loss of the endogenous dopamine-synthesizing enzyme L-amino acid decarboxylase (AADC). In the phase I PD-1101 study, putaminal administration of VY-AADC01, an investigational adeno-associated virus serotype-2 vector for delivery of the AADC gene in patients with advanced Parkinson's disease, was well tolerated, improved motor function, and reduced antiparkinsonian medication requirements.ObjectivesThis substudy aimed to determine whether the timing and magnitude of motor response to intravenous levodopa changed in PD-1101 patients after VY-AADC01 administration.MethodsParticipants received 2-hour threshold (0.6 mg/kg/h) and suprathreshold (1.2 mg/kg/h) levodopa infusions on each of 2 days, both before and approximately 6 months after VY-AADC01. Infusion order was randomized and double blinded. Unified Parkinson's Disease Rating Scale motor scores, finger-tapping speeds, and dyskinesia rating scores were assessed every 30 minutes for 1 hour before and ≥3 hours after start of levodopa infusion.ResultsOf 15 PD-1101 patients, 13 participated in the substudy. Unified Parkinson's Disease Rating Scale motor score area under the curve responses to threshold and suprathreshold levodopa infusions increased by 168% and 67%, respectively, after VY-AADC01; finger-tapping speeds improved by 162% and 113%, and dyskinesia scores increased by 208% and 72%, respectively, after VY-AADC01. Adverse events (mild/moderate severity) were reported in 5 participants during levodopa infusions pre-VY-AADC01 and 2 participants post-VY-AADC01 administration.ConclusionsVY-AADC01 improved motor responses to intravenous levodopa given under controlled conditions. These data and findings from the parent study support further clinical development of AADC gene therapy for people with Parkinson's disease. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Project description: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.

Project description:The extent to which the degeneration of the substantia nigra (SN) and putamen each contribute to motor impairment in Parkinson's disease (PD) is unclear, as they are usually investigated using different imaging modalities. To examine the pathophysiological significance of the SN and putamen in both motor impairment and the levodopa response in PD using diffusion microstructure imaging (DMI). In this monocentric retrospective cross-sectional study, DMI parameters from 108 patients with PD and 35 healthy controls (HC) were analyzed using a voxel- and region-based approach. Linear models were applied to investigate the association between individual DMI parameters and Movement Disorder Society Unified Parkinson's Disease Rating Scale-Part 3 performance in ON- and OFF-states, as well as the levodopa response, controlling for age and sex. Voxel- and region-based group comparisons of DMI parameters between PD and HC revealed significant differences in the SN and putamen. In PD, a poorer MDS-UPDRS-III performance in the ON-state was associated with increased free fluid in the SN (b-weight = 65.79, p = 0.004) and putamen (b-weight = 86.00, p = 0.006), and contrariwise with the demise of cells in both structures. The levodopa response was inversely associated with free fluid both in the SN (b-weight = -83.61, p = 0.009) and putamen (b-weight = -176.56, p < 0.001). Interestingly, when the two structures were assessed together, the integrity of the putamen, but not the SN, served as a predictor for the levodopa response (b-weight = -158.03, p < 0.001). Structural alterations in the SN and putamen can be measured by diffusion microstructure imaging in PD. They are associated with poorer motor performance in the ON-state, as well as a reduced response to levodopa. While both nigral and putaminal integrity are required for good performance in the ON-state, it is putaminal integrity alone that determines the levodopa response. Therefore, the structural integrity of the putamen is crucial for the improvement of motor symptoms to dopaminergic medication, and might therefore serve as a promising biomarker for motor staging.

Project description:The natural pattern of progression of Parkinson's disease is largely unknown because patients are conventionally followed on treatment. As Parkinson's disease progresses, the true magnitude of the long-duration response to levodopa remains unknown, because it can only be estimated indirectly in treated patients. We aimed to describe the natural course of motor symptoms by assessing the natural OFF in consecutive Parkinson's disease patients never exposed to treatment (drug-naïve), and to investigate the effects of daily levodopa on the progression of motor disability in the OFF medication state over a 2-year period. In this prospective naturalistic study in sub-Saharan Africa, 30 Parkinson's disease patients (age at onset 58?±?14 years, disease duration 7?±?4 years) began levodopa monotherapy and were prospectively assessed using the Unified Parkinson's disease Rating Scale (UPDRS). Data were collected at baseline, at 1-year and 2-years follow-up. First-ever levodopa intake induced a significant improvement in motor symptoms (natural OFF versus ON state UPDRS-III 41.9?±?15.9 versus 26.8?±?15.1, respectively; P?<?0.001). At 1-year follow-up, OFF state UPDRS-III score after overnight withdrawal of levodopa was considerably lower than natural OFF (26.5?±?14.9; P?<?0 .001). This effect was not modified by disease duration. At the 2-year follow-up, motor signs after overnight OFF (30.2?±?14.2) were still 30% milder than natural OFF (P?=?0.001). The ON state UPDRS-III at the first-ever levodopa challenge was similar to the overnight OFF score at 1-year follow-up and the two conditions were correlated (r?=?0.72, P?<?0.001). Compared to the natural progression of motor disability, levodopa treatment resulted in a 31% lower annual decline in UPDRS-III scores in the OFF state (3.33 versus 2.30 points/year) with a lower model's variance explained by disease duration (67% versus 36%). Using the equation regressed on pretreatment data, we predicted the natural OFF at 1-year and 2-year follow-up visits and estimated that the magnitude of the long-duration response to levodopa ranged between 60% and 65% of total motor benefit provided by levodopa, independently of disease duration (P?=?0.13). Although levodopa therapy was associated with motor fluctuations, overnight OFF disability during levodopa was invariably less severe than the natural course of the disease, independently of disease duration. The same applies to the yearly decline in UPDRS-III scores in the OFF state. Further research is needed to clarify the mechanisms underlying the long-duration response to levodopa in Parkinson's disease. Understanding the natural course of Parkinson's disease and the long-duration response to levodopa may help to develop therapeutic strategies increasing its magnitude to improve patient quality of life and to better interpret the outcome of randomized clinical trials on disease-modifying therapies that still rely on the overnight OFF to define Parkinson's disease progression.

Project description:BACKGROUND: Dopa decarboxylase (DDC) is a pyridoxal 5-phosphate (PLP)-dependent enzyme that catalyzes the decarboxylation of L-Dopa to dopamine, and involved in complex neuroendocrine-immune regulatory network. The function for DDC in the immunomodulation remains unclear in invertebrate. METHODOLOGY: The full-length cDNA encoding DDC (designated CfDDC) was cloned from mollusc scallop Chlamys farreri. It contained an open reading frame encoding a polypeptide of 560 amino acids. The CfDDC mRNA transcripts could be detected in all the tested tissues, including the immune tissues haemocytes and hepatopancreas. After scallops were treated with LPS stimulation, the mRNA expression level of CfDDC in haemocytes increased significantly (5.5-fold, P<0.05) at 3 h and reached the peak at 12 h (9.8-fold, P<0.05), and then recovered to the baseline level. The recombinant protein of CfDDC (rCfDDC) was expressed in Escherichia coli BL21 (DE3)-Transetta, and 1 mg rCfDDC could catalyze the production of 1.651±0.22 ng dopamine within 1 h in vitro. When the haemocytes were incubated with rCfDDC-coated agarose beads, the haemocyte encapsulation to the beads was increased significantly from 70% at 6 h to 93% at 24 h in vitro in comparison with that in the control (23% at 6 h to 25% at 24 h), and the increased haemocyte encapsulation was repressed by the addition of rCfDDC antibody (which is acquired via immunization 6-week old rats with rCfDDC). After the injection of DDC inhibitor methyldopa, the ROS level in haemocytes of scallops was decreased significantly to 0.41-fold (P<0.05) of blank group at 12 h and 0.47-fold (P<0.05) at 24 h, respectively. CONCLUSIONS: These results collectively suggested that CfDDC, as a homologue of DDC in scallop, modulated the immune responses such as haemocytes encapsulation as well as the ROS level through its catalytic activity, functioning as an indispensable immunomodulating enzyme in the neuroendocrine-immune regulatory network of mollusc.

Dataset Information

Polymorphism of the Dopa-Decarboxylase Gene Modifies the Motor Response to Levodopa in Chinese Patients With Parkinson's Disease.

Publications

Polymorphism of the Dopa-Decarboxylase Gene Modifies the Motor Response to Levodopa in Chinese Patients With Parkinson's Disease.

Similar Datasets

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