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Introduction Freezing of gait (FOG) and falls are the most disabling motor symptoms in Parkinson's disease (PD) patients. The effects of subthalamic deep-brain-stimulation (STN-DBS) on FOG and falls are still a matter of controversy, and factors contributing to their outcome have yet to be defined. Methods We examined the relationship between FOG and falls after STN-DBS and preoperative clinical features, MRI voxel-based-morphometry (VBM) analysis and statistical mapping of electrode locations. Results 331 patients (age at surgery = 57.7 ± 8.4 years; disease duration = 12.5 ± 5 years) were included in the final analysis, with VBM analysis in 151 patients. After surgery, FOG was aggravated in 93 patients and falls in 75 patients. After surgery, FOG severity was related to its level before surgery without dopaminergic treatment, the dopaminergic treatment dosage and severity of motor fluctuations after surgery; and falls severity to lower postoperative cognitive performance. VBM analyses revealed that, relative to other patient groups, patients with FOG worsening had putamen grey matter density decrease, and fallers patients a left postcentral gyrus atrophy. The best effects of STN-DBS on FOG and falls were associated with the location of contacts within the STN, but no specific location related to aggravation. Conclusions FOG and falls are reduced after STN-DBS in about 1/3 of patients, with the best effects obtained for electrodes located within the STN. Clinicians should be aware that, after STN-DBS, FOG severity is related to preoperative FOG severity whatever its dopa-sensitivity; and falls to lower postoperative cognitive performance; and atrophy of cortico-subcortical brain areas.

International audience; Background : Catecholamine-O-methyl-tranferase (COMT) initiates dopamine degradation. Its activity is mainly determined by a single nucleotide polymorphism in the COMT gene (Val158Met, rs4680) separating high (Val/Val, COMTHH), intermediate (Val/Met, COMTHL) and low metabolizers (Met/Met, COMTLL). We investigated dopaminergic denervation in the striatum in PD patients according to COMT rs4680 genotype.Methods : Patients with idiopathic PD were assessed for motor severity (UPDRS-III rating scale in OFF-state), dopaminergic denervation using [123I]-FP-CIT SPECT imaging, and genotyped for the COMT rs4680 enzyme. [123I]-FP-CIT binding potential (BP) for each voxel was defined by the ratio of tracer-binding in the region of interest (striatum, caudate nucleus and putamen) to that in a region of non-specific activity. Genotyping was performed using TaqMan® SNP genotyping assay. We used a regression model to evaluate the effect of COMT genotype on the BP in the striatum and its sub-regions.Results : Genotype distribution was: 11 (27.5%) COMTHH, 26 (65%) COMTHL and 3 (7.5%) COMTLL. There were no significant differences in disease severity, treatments, or motor scores between genotypes. When adjusted to clinical severity, gender and age, low and intermediate metabolizers showed significantly higher rates of striatal denervation (COMTHL+LL BP=1.32 +/- 0.04) than high metabolizers (COMTHH, BP=1.6 +/- 0.08; F(1.34)=9.0, p=0.005). Striatal sub-regions showed similar results. BP and UPDRS-III motor scores (r=0.44, p=0.04) (p

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 (DDCT/C) and rs3837091 AGAG del (DDCAGAG/−)). 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 DDCCC/CT patients (n = 14) than in DDCTT patients (n = 19) and significantly lower in DDC−/− or AGAG/− patients (n = 8) than in DDCAGAG/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.