Centrosomal cohesion deficits as cellular biomarker in lymphoblastoid cell lines from LRRK2 Parkinson's disease patients.

Leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for the treatment of Parkinson's disease (PD), and orally bioavailable, brain penetrant and highly potent LRRK2 kinase inhibitors are in early stages of clinical testing. Detection of LRRK2 phosphorylation, as well as phosphorylation of Rab10, a LRRK2 kinase substrate, have been proposed as target engagement biomarkers for LRRK2 inhibitor clinical trials. However, these readouts do not seem able to stratify patients based on enhanced LRRK2 kinase activity. Here, we describe a robust cell biological assay based on centrosomal cohesion alterations which were observed in peripheral blood mononuclear cell-derived lymphoblastoid cell lines (LCLs) from patients with G2019S LRRK2 mutations as compared with healthy controls, and could also be detected in a subset of sporadic PD patient samples. We suggest that LCLs may be a valuable resource for LRRK2 research, and that determination of centrosomal cohesion deficits may assist in the stratification of a subset of sporadic PD patients.

Is there a role for ghrelin in central dopaminergic systems? Focus on nigrostriatal and mesocorticolimbic pathways.

The gastro-intestinal peptide ghrelin has been assigned many functions. These include appetite regulation, energy metabolism, glucose homeostasis, intestinal motility, anxiety, memory or neuroprotection. In the last decade, this pleiotropic peptide has been proposed as a therapeutic agent in gastroparesis for diabetes and in cachexia for cancer. Ghrelin and its receptor, which is expressed throughout the brain, play an important role in motivation and reward. Ghrelin finely modulates the mesencephalic dopaminergic signaling and is thus currently studied in pathological conditions including dopamine-related disorders. Dopamine regulates motivated behaviors, modulating reward processes, emotions and motor functions to enable the survival of individuals and species. Numerous dopamine-related disorders including Parkinson's disease or eating disorders like anorexia nervosa involve altered ghrelin levels. However, despite the growing interest for ghrelin in these pathological conditions, global integrative studies investigating its role in brain dopaminergic structures are still lacking. In this review, we discuss the role of ghrelin on dopaminergic neurons and its relevance in the search for new therapeutics for Parkinson's disease- and anorexia nervosa-related dopamine deficits.

Predictive factors for improvement of gait by low-frequency stimulation in Parkinson's disease.

BACKGROUND: After several years duration of Parkinson's disease, with or without deep brain stimulation, axial signs (such as postural instability, freezing of gait) may worsen. High-voltage, low-frequency stimulation has been shown to improve severe gait disorders in some patients. OBJECTIVE: To identify predictive factors for the efficacy of low-frequency stimulation. METHODS: We assessed the respective effects of low- and high-frequency stimulation using an acute stand-walk- sit test, and on motor performance in 22 patients with longstanding, bilateral sub-thalamic nucleus stimulation. We calculated the difference in the number of steps (delta steps) between high and low -frequency stimulation during the stand-walk-sit test. Our aim was to establish a profile for low-frequency responders, which was defined by a positive value for delta steps. RESULTS: Low frequency responders presented higher age, a severe axial phenotype five years after surgery and a lower L-dopa responsiveness of (i) the Unified Parkinson's Disease Rating Scale part III score and its akinesia subscore before surgery and (ii) the axial subscore one year after surgery. CONCLUSION: Here we defined a specific and severe axial profile of minority of patients who could benefit from low frequency stimulation parameters. Our findings challenge the conventional treatment approach (i.e. high-frequency stimulation) in patients who develop gait disorders after several years of stimulation.

Involvement of the immune system, endocytosis and EIF2 signaling in both genetically determined and sporadic forms of Parkinson's disease.

The leucine-rich repeat kinase 2 (LRRK2) G2019S mutation is a common genetic cause of Parkinson's disease (PD). Although patients with sporadic PD and individuals with LRRK2-linked PD display the classical PD phenotype, it is not known whether or not the same biological pathways are deregulated in each context. By using transcriptome profiling, we investigated the deregulation of various biological pathways in a total of 47 peripheral blood mononuclear cell (PBMC) samples from patients with sporadic PD, patients heterozygous for the LRRK2 G2019S mutation compared to healthy controls. We found that the deregulation patterns were indeed similar in PBMCs obtained from patients with sporadic PD and from LRRK2 G2019S carriers, with dysfunctions in mitochondrial pathways, cell survival signaling, cancerization, endocytosis signaling and iron metabolism. Analysis of our PBMC data and other publicly available transcriptome datasets (for whole blood samples) showed that deregulation of the immune system, endocytosis and eukaryotic initiation factor 2 (EIF2) signaling are the main features of transcriptome profiles in PD (since they are also present in the transcriptome of dopaminergic neurons from patients). Transcriptome analysis of PBMCs is thus valuable for (i) characterizing the pathophysiological pathways shared by genetic and sporadic forms of PD and (ii) identifying potential biomarkers and therapeutic targets. This minimally invasive approach opens up tremendous perspectives for better diagnosis and therapy of neurodegenerative diseases because it can be applied from the earliest stages of the disease onwards.

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.

Association between caffeine intake and age at onset in Huntington's disease.

Habitual consumption of caffeine, a non-selective adenosine receptor (AR) antagonist, has been suggested to be beneficial in Parkinson's and Alzheimer's diseases. Experimental evidence support that ARs play a role in Huntington's disease (HD) raising the hypothesis that caffeine may be a life-style modifier in HD. To determine a possible relationship between caffeine consumption and age at onset (AAO) in HD, we retrospectively assessed caffeine consumption in 80 HD patients using a dietary survey and determined relationship with AAO. Following adjustment for gender, smoking status and CAG repeat length, caffeine consumption greater than 190mg/day was significantly associated with an earlier AAO. These data support an association between habitual caffeine intake and AAO in HD patients, but further studies are warranted to understand the link between these variables.

Modifying effect of arterial hypertension on amyotrophic lateral sclerosis.

Given the high oxygen consumption of motor neurons, we sought to assess the frequency and prognostic value of arterial hypertension (affecting brain's oxygen supply) in amyotrophic lateral sclerosis (ALS). We consecutively and prospectively included all ALS patients with regular medical follow-up and documented blood pressure measurements and monitored them until death. Vascular factors diagnosed prior to the onset of motor signs in ALS patients were compared with those in a stratified, age- and gender-matched case-control population. The severity of leukoaraiosis on magnetic resonance imaging (MRI) was blindly assessed. Post mortem examinations were performed when authorized. Compared with controls (n = 408), the 102 ALS patients were significantly more likely to display hypertension (41-57%) and current smoking (15-26%). The number of years of hypertension was associated with survival (HR = 1.04 (1.01-1.07)). In a multivariate analysis, leukoaraiosis severity (HR = 1.214 (1.096-1.344)), current smoking (HR = 1.766 (1.085-2.872)) and low vital capacity (HR = 2.422 (1.266-4.633)) remained independent predictors of survival. Post mortem examinations revealed a greater frequency of leukoaraiosis in ALS patients (p = 0.02). In conclusion, the effect of chronic hypertension on survival might be exerted through abnormal neural perfusion. The higher frequency of recent hypertension in ALS patients may be due to a compensatory increase in blood pressure in response to a lower oxygen supply.

Bilateral pallidal deep brain stimulation for the treatment of patients with dystonia-choreoathetosis cerebral palsy: a prospective pilot study.

BACKGROUND: Cerebral palsy (CP) with dystonia-choreoathetosis is a common cause of disability in children and in adults, and responds poorly to medical treatment. Bilateral pallidal deep brain stimulation (BP-DBS) of the globus pallidus internus (GPi) is an effective treatment for primary dystonia, but the effect of this reversible surgical procedure on dystonia-choreoathetosis CP, which is a subtype of secondary dystonia, is unknown. Our aim was to test the effectiveness of BP-DBS in adults with dystonia-choreoathetosis CP. METHODS: We did a multicentre prospective pilot study of BP-DBS in 13 adults with dystonia-choreoathetosis CP who had no cognitive impairment, little spasticity, and only slight abnormalities of the basal ganglia on MRI. The primary endpoint was change in the severity of dystonia-choreoathetosis after 1 year of neurostimulation, as assessed with the Burke-Fahn-Marsden dystonia rating scale. The accuracy of surgical targeting to the GPi was assessed masked to the results of neurostimulation. Analysis was by intention to treat. FINDINGS: The mean Burke-Fahn-Marsden dystonia rating scale movement score improved from 44.2 (SD 21.1) before surgery to 34.7 (21.9) at 1 year post-operatively (p=0.009; mean improvement 24.4 [21.1]%, 95% CI 11.6-37.1). Functional disability, pain, and mental health-related quality of life were significantly improved. There was no worsening of cognition or mood. Adverse events were related to stimulation (arrest of the stimulator in one patient, and an adjustment to the current intensity in four patients). The optimum therapeutic target was the posterolateroventral region of the GPi. Little improvement was seen when the neurostimulation diffused to adjacent structures (mainly to the globus pallidus externus [GPe]). INTERPRETATION: Bilateral pallidal neurostimulation could be an effective treatment option for patients with dystonia-choreoathetosis CP. However, given the heterogeneity of motor outcomes and the small sample size, results should be interpreted with caution. The optimum placement of the leads seemed to be a crucial, but not exclusive, factor that could affect a good outcome. FUNDING: National PHRC; Cerebral Palsy Foundation: Fondation Motrice/APETREIMC; French INSERM Dystonia National Network; Medtronic.

CSF profiles of angiogenic and inflammatory factors depend on the respiratory status of ALS patients.

Our objective was to assess the regulation of the hypoxia response of angiogenic and inflammatory factors from 76 cerebrospinal fluids (CSF) of sporadic amyotrophic lateral sclerosis (ALS) patients with different respiratory status. We first analysed the hypoxia response capacity by measuring CSF levels of angiogenin (ANG), VEGF, angiopoietin-2 (ANG-2) and PGE-2 in 40 ALS patients according to their hypoxaemia level and compared it with 40 neurological controls. We then compared the ANG, VEGF, EPO and ANG-2 CSF levels of 36 other ALS patients, divided into three groups with either 1) normoxaemia, 2) intermittent desaturation in the absence of hypoxaemia, or 3) chronic hypoxaemia with or without desaturation. We demonstrated a lack of up-regulation of both ANG and VEGF during hypoxaemia in ALS, compared with hypoxaemic controls. In contrast, PGE-2 and ANG-2 levels were increased in both hypoxaemic ALS patients and controls. ANG and VEGF levels did not increase in patients with long disease durations and with intermittent or chronic hypoxaemia. ANG-2 and EPO levels were up-regulated early in intermittent hypoxaemia and late in chronic hypoxaemia, respectively. Our results suggest alteration of the HIF-1alpha-mediated response to hypoxia during sporadic ALS, whereas the NFK-B pathway seems early activated.

Exhaustive, one-year follow-up of subthalamic nucleus deep brain stimulation in a large, single-center cohort of parkinsonian patients.

OBJECTIVE: To prospectively assess the impact of subthalamic nucleus (STN) deep brain stimulation (DBS) at 12 months after surgery in a series of 100 consecutive patients treated in a single center. The primary objective was to describe the clinical outcome in terms of efficacy and tolerance in STN-DBS patients. A secondary objective was to discuss presurgery clinical characteristics a posteriori as a function of outcome. METHODS: One hundred and three consecutive patients with severe Parkinson's disease received bilateral STN-DBS in our clinic between May 1998 and March 2003. Clinical assessment was performed before and 12 months after surgery and was based on the Unified Parkinson's Disease Rating Scale, Parts II, III, and IV A; the Schwab and England Scale; and cognitive evaluation. Patient-rated overall improvement was also evaluated. RESULTS: Twelve months after surgery, the Unified Parkinson's Disease Rating Scale Part III score decreased by 43%, the Unified Parkinson's Disease Rating Scale Part II score (activities of daily living) fell by 34%, and the severity of dyskinesia-related disability decreased by 61%. The main surgical complications after STN-DBS were as follows: infection (n = 7), intracerebral hematoma (n = 5), electrode fracture (n = 4), and incorrect lead placement (n = 8). We observed cognitive decline and depression in 7.7 and 18% of the patients, respectively. The mean patient-rated overall improvement score was 70.7%. CONCLUSION: The efficacy and safety of STN-DBS in our center's large cohort of Parkinsonian patients are generally similar to the results obtained by other groups, albeit at the lower limit of the range of reported values. In contrast to efficacy, the occurrence of adverse events cannot be predicted. Younger patients with Parkinson's disease (i.e., those younger than 60 yr) often show an excellent response to levodopa. However, in view of our data on overall patient satisfaction and the occurrence of adverse events, we suggest that older patients (but not those older than 70 yr) and less dopa-sensitive patients (but not those with a response <50%) should still be offered the option of STN-DBS.

Effects of pulse width variations in pallidal stimulation for primary generalized dystonia.

BACKGROUND: Various pulse widths (from 60-450 mus) have been used for bilateral pallidal stimulation in generalized dystonia but, to date, no comparison of this parameter's effects is available. OBJECTIVE: To provide an analysis of the differential effects of bilateral short, medium and long stimulus pulse width (PW) on clinical improvement in primary generalized dystonia. METHODS: The most effective therapeutic stimulation parameters were recorded in 22 patients using bilateral pallidal stimulation. Six months after surgery, the effects of bilateral pallidal short (60-90 micros), medium (120-150 micros) and long (450 micros) PWs were studied in 20 of those patients. The effect of the stimulation was assessed by reviewing videotaped sessions by an observer blinded to treatment status (Burke-Fahn-Marsden movement score). Patients were tested on separate days, in random order, for the stimulation conditions (acute effect with the stimulation condition lasting 10 hours). The same contact was used for each stimulation condition. All the electrodes were set at 130 Hz (monopolar stimulation) and the intensity was set individually 10% below the side effect threshold. RESULTS: Median PWs of 60 (short), 120 (medium) and 450 micros (long) were compared,with a mean intensity of 4.46, 3.45 and 2.47 V, respectively. This study failed to demonstrate any significant difference in the movement scale dystonia mean scores depending on PW. CONCLUSION: According to our findings, short duration stimulus PWs are as effective as longer ones during a 10 hour period of observation. Confirmation of this finding for chronic use could be of importance in saving stimulator energy. Moreover, the use of smaller stimulus pulse widths are said to reduce charge injection and increase the therapeutic window between therapeutic effects and side effects.

Neurodegeneration with brain iron accumulation: clinical, radiographic and genetic heterogeneity and corresponding therapeutic options.

BACKGROUND: Neurodegeneration with brain iron accumulation (NBIA), formerly known as Hallervorden-Spatz syndrome, is a heterogeneous group of disorders with different treatment options. CASE REPORTS: In the first case, progressively generalizing dystonic symptoms appeared during childhood. A mutation in the gene encoding pantothenate kinase 2 (PANK2) was found. Brain MRI showed bilateral hypersignals within the globus pallidi on T2-weighted images. The patient was successfully treated by pallidal deep brain stimulation (DBS). In the second case an adult onset with parkinsonism was observed, for which no PANK2 mutation was found. T2-weighted brain MR images revealed multiple significant hyposignals (suggestive of iron deposits) localised in the cerebellar dentate nuclei and in the globi pallidi, the red nuclei and the substantia nigra. An antiparkinsonian treatment was proposed. CONCLUSION: The clinical, radiographic and genetic heterogeneity of NBIA has to be underlined.

Bilateral, pallidal, deep-brain stimulation in primary generalised dystonia: a prospective 3 year follow-up study.

BACKGROUND: We have previously reported the efficacy and safety of bilateral pallidal stimulation for primary generalised dystonia in a prospective, controlled, multicentre study with 1 year of follow-up. Although long-term results have been reported by other groups, no controlled assessment of motor and non-motor results is available. In this prospective multicentre 3 year follow-up study, involving the same patients as those enrolled in the 1 year follow-up study, we assessed the effect of bilateral pallidal stimulation on motor impairment, disability, quality of life, cognitive performance, and mood. METHODS: We studied 22 patients with primary generalised dystonia after 3 years of bilateral pallidal stimulation. We compared outcome at 3 years with their status preoperatively and after 1 year of treatment. Standardised video recordings were scored by an independent expert. Data were analysed on an intention-to-treat basis. FINDINGS: Motor improvement observed at 1 year (51%) was maintained at 3 years (58%). The improvement in quality of life (SF-36 questionnaire) was similar to that observed at 1 year. Relative to baseline and to the 1 year assessment, cognition and mood were unchanged 3 years after surgery, but slight improvements were noted in concept formation, reasoning, and executive functions. Pallidal stimulation was stopped bilaterally in three patients because of lack of improvement, technical dysfunction, and infection, and unilaterally in two patients because of electrode breakage and stimulation-induced contracture. No permanent adverse effects were observed. INTERPRETATION: Bilateral pallidal stimulation provides sustained motor benefit after 3 years. Mild long-term improvements in quality of life and attention were also observed.

Ictal movement disorders and hypothalamic hamartoma.

We report the case of a woman presenting with unusual, symptomatic epilepsy related to a hypothalamic hamartoma, in the absence of mental retardation or precocious puberty. The seizures manifested themselves clinically as characteristic, paroxysmal movement disorders, such as choreic/ballistic movement. This type of phenomenon is rarely of epileptic origin: we thus suggest that the movement disorder observed here could be due to functional disorganization of the basal ganglia network by the epileptic discharge, causing loss of the inhibition of thalamic activity and thus allowing the occurrence of abnormal movements.

Bilateral deep-brain stimulation of the globus pallidus in primary generalized dystonia.

BACKGROUND: Severe forms of dystonia respond poorly to medical treatment. Deep-brain stimulation is a reversible neurosurgical procedure that has been used for the treatment of dystonia, but assessment of its efficacy has been limited to open studies. METHODS: We performed a prospective, controlled, multicenter study assessing the efficacy and safety of bilateral pallidal stimulation in 22 patients with primary generalized dystonia. The severity of dystonia was evaluated before surgery and 3, 6, and 12 months postoperatively during neurostimulation, with the use of the movement and disability subscores of the Burke-Fahn-Marsden Dystonia Scale (range, 0 to 120 and 0 to 30, respectively, with higher scores indicating greater impairment). Movement scores were assessed by a review of videotaped sessions performed by an observer who was unaware of treatment status. At three months, patients underwent a double-blind evaluation in the presence and absence of neurostimulation. We also assessed the patients' quality of life, cognition, and mood at baseline and 12 months. RESULTS: The dystonia movement score improved from a mean (+/-SD) of 46.3+/-21.3 before surgery to 21.0+/-14.1 at 12 months (P<0.001). The disability score improved from 11.6+/-5.5 before surgery to 6.5+/-4.9 at 12 months (P<0.001). General health and physical functioning were significantly improved at month 12; there were no significant changes in measures of mood and cognition. At the three-month evaluation, dystonia movement scores were significantly better with neurostimulation than without neurostimulation (24.6+/-17.7 vs. 34.6+/-12.3, P<0.001). There were five adverse events (in three patients); all resolved without permanent sequelae. CONCLUSIONS: These findings support the efficacy and safety of the use of bilateral stimulation of the internal globus pallidus in selected patients with primary generalized dystonia.

Comparison of secondary vascular prevention in practice after cerebral ischemia and coronary heart disease.

BACKGROUND: Secondary prevention measures in patients with cerebral ischemia or coronary heart disease (CHD) consist of vascular risk factors management and antithrombotic therapy. The aim of this study was to compare how secondary prevention measures are applied in practice between patients with a history of CHD or cerebral ischemia. METHOD: We compared vascular risk factors management and antithrombotic therapy between patients with a history of CHD and patients with a history of cerebral ischemia that occurred 2 months to 6 years earlier. Whether patients were properly treated or not was determined by a comparison between their current treatments and European guidelines for stroke and CHD management. RESULTS: We included 107 consecutive patients with a history of cerebral ischemia and 85 consecutive patients with a history of CHD. We found that: (i). most patients did not receive an appropriate secondary prevention in both groups: 76 of 107 patients with previous cerebral ischemia (71 %) and 73 of 85 patients with CHD (85.9 %); (ii). identification of risk factors, such as hypercholesterolemia, diabetes mellitus and smoking, did not differ between both groups, but arterial hypertension was more frequent in CHD patients; (iii). an inappropriate management of risk factors was more frequent in patients with TIA vs. ischemic stroke, and angina pectoris vs. myocardial infarction; (iv). arterial hypertension and hypercholesterolemia were the 2 more frequent risk factors that were not properly treated; (v). more than half diabetic patients had hyperglycemia > or= 126 mg/dl in both groups; (vi). patients with previous CHD had twice more frequently stopped smoking than those with cerebral ischemia. CONCLUSION: Many patients were not properly treated in both groups, and differences between practice and guidelines were more frequent in the CHD group, where guidelines are more strict.

Effects of subthalamic nucleus stimulation on parkinsonian dysarthria and speech intelligibility.

Subthalamic stimulation is known to improve tremor, akinesia and rigidity in Parkinson's disease. However, other signs such as hypophonia and swallowing disorders can be relatively resistant to this technique. The effect on dysarthria remains unclear. The aim of this study was to investigate the effects of implantation of electrode and stimulation of the subthalamic nucleus (STN) on parkinsonian dysarthria. Seven patients were prospectively included. Electrodes (Medtronic) were implanted in both STN. The electrode contacts and stimulation parameters were adjusted to provide best relief of symptoms with fewest side effects. Assessment used global scales (Unified Parkinson Disease Rating Scale, UPDRS II and III), dyskinesia scale, exhaustive dysarthria assessment (bucco-facial movements, voice, articulation, intelligibility) and the 'dysarthria' item from the UPDRS III. Evaluations were performed in six conditions: before and three months after surgery (pre-op, post-op) stimulation turned off or on (off-stim, onstim), and without or with a suprathreshold levodopa dose (offdrug, on-drug). Performance level on the UPDRS III significantly improved following electrode implantation and stimulation. For dysarthria, modest beneficial effects were observed on several motor parameters, especially lip movements. Voice mildly improved, especially for the modulation in loudness and pitch. Articulation was not affected. Furthermore, intelligibility was slightly reduced in the on-stimulation condition, especially when patients received levodopa. At an individual level, negative effects on intelligibility were observed in two patients, and this was associated with a discrete increase in facial and trunk dyskinesias, but not with the electrode position or stimulation parameters. In conclusion, surgery had weak effects on dysarthria. Intelligibility can be worsened, especially in the on-drug condition. Thus, adaptation of the stimulation parameters can be difficult.

Effects of subthalamic nucleus stimulation and levodopa treatment on gait abnormalities in Parkinson disease.

BACKGROUND: Stimulation of the subthalamic nucleus is proposed for the treatment of patients presenting with severe Parkinson disease. The effect on gait is not clearly established. OBJECTIVES: To evaluate objectively the influence of bilateral subthalamic nucleus stimulation on gait in Parkinson disease and to compare it with the effects of levodopa treatment. METHODS: Ten patients underwent bilateral subthalamic nucleus stimulation. The preoperative and postoperative (3 months after surgery) clinical gait disturbances, as well as spatial and temporal gait parameters, were analyzed in off and on-drug conditions. The gait analysis was performed using a video motion analysis system (optoelectronic VICON system; Oxford Metrics, Oxford, England). RESULTS: In the off condition, there was an improvement after surgery for the total motor score and the gait subscore. In the on-drug condition, there was an improvement in levodopa-induced dyskinesias and the motor score, whereas the gait subscore was unchanged. For the gait parameters measured by the video motion analysis system system, there was also an improvement in the off condition and to a lesser extent in the on-drug condition. CONCLUSIONS: Our method allowed exact quantification of the benefit of surgery on gait parameters. Compared with the levodopa treatment, the effect of stimulation on gait kinematic parameters seems to be qualitatively similar but quantitatively different with a lower benefit on gait velocity and stride length. Concerning the pathophysiology of gait troubles in Parkinson disease, the deficit in control of stride length would be the fundamental deficit. The study underlines the possible role of the subthalamic nucleus on the stride length regulation.

Mutation analysis and association studies of the ubiquitin carboxy-terminal hydrolase L1 gene in Huntington's disease.

Huntington's disease (HD) is attributed to a triplet CAG repeat mutation, and about 70% of the variance in age-at-onset can be explained by the size of the repeat expansion. Among potential candidates as modifier genes, we investigated the role of ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) gene. We examined the association of HD with the I93M mutation and S18Y polymorphism in 138 HD patients and 136 control subjects, but we did not identify the I93M mutation. The S18Y polymorphism was present in 17% of HD patients. Of the variance in the age-at-onset that was not accounted for by the CAG repeat, 13% could be attributed to S18Y polymorphism. We sequenced the entire coding region of the UCH-L1 gene in seven HD patients with unexplained older or younger onset age. The S18Y polymorphism was found in three out of the four patients presenting with a later age-at-onset. We conclude that the UCH-L1 gene may be a genetic factor that influences the variability in age-at-onset of HD.