Polymorphism of the dopamine transporter type 1 gene modifies the treatment response 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.

Targeting chelatable iron as a therapeutic modality in Parkinson's disease.

AIMS: The pathophysiological role of iron in Parkinson's disease (PD) was assessed by a chelation strategy aimed at reducing oxidative damage associated with regional iron deposition without affecting circulating metals. Translational cell and animal models provided concept proofs and a delayed-start (DS) treatment paradigm, the basis for preliminary clinical assessments. RESULTS: For translational studies, we assessed the effect of oxidative insults in mice systemically prechelated with deferiprone (DFP) by following motor functions, striatal dopamine (HPLC and MRI-PET), and brain iron deposition (relaxation-R2*-MRI) aided by spectroscopic measurements of neuronal labile iron (with fluorescence-sensitive iron sensors) and oxidative damage by markers of protein, lipid, and DNA modification. DFP significantly reduced labile iron and biological damage in oxidation-stressed cells and animals, improving motor functions while raising striatal dopamine. For a pilot, double-blind, placebo-controlled randomized clinical trial, early-stage Parkinson's patients on stabilized dopamine regimens enrolled in a 12-month single-center study with DFP (30 mg/kg/day). Based on a 6-month DS paradigm, early-start patients (n=19) compared to DS patients (n=18) (37/40 completed) responded significantly earlier and sustainably to treatment in both substantia nigra iron deposits (R2* MRI) and Unified Parkinson's Disease Rating Scale motor indicators of disease progression (p<0.03 and p<0.04, respectively). Apart from three rapidly resolved neutropenia cases, safety was maintained throughout the trial. INNOVATION: A moderate iron chelation regimen that avoids changes in systemic iron levels may constitute a novel therapeutic modality for PD. CONCLUSIONS: The therapeutic features of a chelation modality established in translational models and in pilot clinical trials warrant comprehensive evaluation of symptomatic and/or disease-modifying potential of chelation in PD.

Dopa-decarboxylase gene polymorphisms affect the motor response to L-dopa in Parkinson's disease.

BACKGROUND: In Parkinson's disease (PD), the response to L-dopa is highly variable and unpredictable. The major pathway for dopamine synthesis from L-dopa is decarboxylation by aromatic L-amino acid decarboxylase (AAAD, encoded by the DDC gene). OBJECTIVE: To determine the motor response to L-dopa in PD patients as a function of the DDC gene promoter polymorphisms (rs921451 T > C polymorphism (DDC(T/C)) and rs3837091 AGAG del (DDC(AGAG/-))). METHODS: Thirty-three Caucasian PD patients underwent an acute l-dopa challenge together with the peripheral AAAD inhibitor benserazide and were genotyped for rs921451 and rs3837091. The primary efficacy criterion was the motor response to L-dopa, as estimated by the area under the curve for the change in the Unified Parkinson's Disease Rating Scale part III (UPDRS) score relative to baseline (AUCΔUPDRS) in the 4 h following L-dopa administration. Secondary endpoints were pharmacokinetic parameters for plasma levels of L-dopa and dopamine. Investigators and patients were blinded to genotypes data throughout the study. RESULTS: When adjusted for the L-dopa dose, the AUCΔUPDRS was significantly lower in DDC(CC/CT) patients (n = 14) than in DDC(TT) patients (n = 19) and significantly lower in DDC(-/- or AGAG/-) patients (n = 8) than in DDC(AGAG/AGAG) patients (n = 25). There were no significant intergroup differences in plasma pharmacokinetic parameters for L-dopa and dopamine. DISCUSSION: The rs921451 and rs3837091 polymorphisms of the DDC gene promoter influence the motor response to L-dopa but do not significantly change peripheral pharmacokinetic parameters for L-dopa and dopamine. Our results suggest that DDC may be a genetic modifier of the l-dopa response in Parkinson's disease.

[Biological diagnosis of pheochromocytomas and paragangliomas]. / Diagnostic biologique des phéochromocytomes et paragangliomes.

Pheochromocytomas and/or paragangliomas are rare, heterogeneous tumors of the chromaffin cells. Thirty percent of the patients presented with these diseases in a hereditary context. The biological diagnosis relies on the identification of excessive secretion of the metanephrines which are more sensitive and specific than those of catecholamines The published recommendations give the opportunity to choose between the free metanephrines and the fractionated metanephrines in sera or urines. The concentrations of the free plasmatic metanephrines reflect the ongoing production of tumor. They are little sensitive to the renal failure. The assay of the vanillylmandelic acid should be dropped because of its inefficiency. The assay of the chromogranin A in serum should be used in association with those of metanephrines in the diagnosis but also in the follow-up. Its role still has to be precised.

An analysis of the biochemical diagnosis of 66 pheochromocytomas.

OBJECTIVES: The aims of this study were to determine the performance of each variable, to define the optimal diagnostic thresholds and to determine the relative value of assaying chromogranin A (CgA). DESIGN: Prospective study. METHODS: Two groups of patients were studied: a control group of 71 patients and a group of 63 patients with a histologically-proven pheochromocytoma (52 pheochromocytomas and 14 paragangliomas). Fourteen of the patients had a family history of the disease. Eleven variables were assayed in each patient, i.e. the plasma and urinary concentrations of amines and their derivatives, and the CgA serum concentration. RESULTS: The study of the control group showed that all the serum assays gave false positive results (from 6 to 23%), as did four of the six urinary assays (from 2.9 to 12.3%). The areas under the receiver operating characteristic curves varied from 0.689 to 0.992. The variables relating to the epinephrine pathway were significantly less expressed in the hereditary diseases than in the sporadic cases. The diagnostic thresholds of the three most efficient variables have been raised. CONCLUSIONS: Plasma determinations of metanephrines are now an easy and convenient tool for the diagnosis of pheochromocytoma. However, in our study the best specificity was obtained with the urinary tests rather than with the plasma assays while the highest sensitivities were for the normetanephrine assays. The assay of CgA was highly efficient in diagnosing pheochromocytomas in the absence of renal insufficiency. By combining it with fractionated metanephrine assays, the sensitivities of the latter were increased.