François Tison

Epidemiology of restless legs syndrome in French adults A nationwide survey: The INSTANT Study

Objective: To evaluate the prevalence, characteristics, and treatment of restless legs syndrome (RLS) in France. Methods: In this population-based survey, face-to-face home interviews were conducted among a random sample of 10,263 French adults. A French translation of the four features defined by the International RLS Study Group in 1995 was used to assess the prevalence of symptoms consistent with a diagnosis of RLS. Data on severity of symptoms and their management were also collected. Results: The 12-month prevalence of RLS symptoms in the French adult population was estimated to be 8.5% (95% CI 8.0%, 9.0%), with a higher prevalence (p < 0.001) observed in women (10.8%) than in men (5.8%). Prevalence increases with age until 64 years and decreases thereafter in both sexes. Half of the identified subjects reported symptoms once a week at least. Symptoms were more severe in subjects reporting symptoms once a week at least compared to subjects with less frequent symptoms. In this group, half of the subjects reported a family history, the age at onset was earlier, and severity of symptoms higher. RLS had been previously diagnosed in only 5.3% of the subjects who reported previous medical diagnosis, and recommended RLS drug treatment was received by 3.4% of the 28.7% currently treated subjects. Conclusions: Restless legs syndrome (RLS) occurred in 10% of women and 5% of men. RLS prevalence decreases after the age of 64. RLS is often underdiagnosed and few subjects receive recommended RLS drug treatment.

Priorities in Parkinson's disease research

The loss of dopaminergic neurons in the substantia nigra pars compacta leads to the characteristic motor symptoms of Parkinsons disease: bradykinesia, rigidity and resting tremors. Although these symptoms can be improved using currently available dopamine replacement strategies, there is still a need to improve current strategies of treating these symptoms, together with a need to alleviate non-motor symptoms of the disease. Moreover, treatments that provide neuroprotection and/or disease-modifying effects remain an urgent unmet clinical need. This Review describes the most promising biological targets and therapeutic agents that are currently being assessed to address these treatment goals. Progress will rely on understanding genetic mutations or susceptibility factors that lead to Parkinsons disease, better translation between preclinical animal models and clinical research, and improving the design of future clinical trials.>

The natural history of multiple system atrophy: a prospective European cohort study

Summary Background Multiple system atrophy (MSA) is a fatal and still poorly understood degenerative movement disorder that is characterised by autonomic failure, cerebellar ataxia, and parkinsonism in various combinations. Here we present the final analysis of a prospective multicentre study by the European MSA Study Group to investigate the natural history of MSA. Methods Patients with a clinical diagnosis of MSA were recruited and followed up clinically for 2 years. Vital status was ascertained 2 years after study completion. Disease progression was assessed using the unified MSA rating scale (UMSARS), a disease-specific questionnaire that enables the semiquantitative rating of autonomic and motor impairment in patients with MSA. Additional rating methods were applied to grade global disease severity, autonomic symptoms, and quality of life. Survival was calculated using a Kaplan-Meier analysis and predictors were identified in a Cox regression model. Group differences were analysed by parametric tests and non-parametric tests as appropriate. Sample size estimates were calculated using a paired two-group t test. Findings 141 patients with moderately severe disease fulfilled the consensus criteria for MSA. Mean age at symptom onset was 56·2 (SD 8·4) years. Median survival from symptom onset as determined by Kaplan-Meier analysis was 9·8 years (95% CI 8·1–11·4). The parkinsonian variant of MSA (hazard ratio [HR] 2·08, 95% CI 1·09–3·97; p=0·026) and incomplete bladder emptying (HR 2·10, 1·02–4·30; p=0·044) predicted shorter survival. 24-month progression rates of UMSARS activities of daily living, motor examination, and total scores were 49% (9·4 [SD 5·9]), 74% (12·9 [8·5]), and 57% (21·9 [11·9]), respectively, relative to baseline scores. Autonomic symptom scores progressed throughout the follow-up. Shorter symptom duration at baseline (OR 0·68, 0·5–0·9; p=0·006) and absent levodopa response (OR 3·4, 1·1–10·2; p=0·03) predicted rapid UMSARS progression. Sample size estimation showed that an interventional trial with 258 patients (129 per group) would be able to detect a 30% effect size in 1-year UMSARS motor examination decline rates at 80% power. Interpretation Our prospective dataset provides new insights into the evolution of MSA based on a follow-up period that exceeds that of previous studies. It also represents a useful resource for patient counselling and planning of multicentre trials. Funding Fifth Framework Programme of the European Union, the Oesterreichische Nationalbank, and the Austrian Science Fund.

Clozapine in drug induced psychosis in Parkinson’s disease: a randomised, placebo controlled study with open follow up

Objective: To compare the efficacy and safety of clozapine in drug induced psychosis in Parkinson’s disease (PD). Methods: A four week, randomised, double blind, parallel comparison of clozapine and placebo, followed by a 12 week clozapine open period, plus a one month period after drug discontinuation, in 60 patients with PD. The primary efficacy outcome was the “clinical global impression scale” (CGI); the positive subscore of the “positive and negative syndrome scale” (PANSS) was used as the secondary efficacy parameter and the “unified Parkinson’s disease rating scale” (UPDRS) and the “mini mental test examination” (MMSE) as safety outcomes. Results: The mean (SD) dosage of clozapine was 35.8 (12.5–50) mg at the end of the double blind period. The mean (SD) scores on the CGI improved by 1.8 (1.5) for the clozapine group compared with 0.6 (1.1) for the placebo group (p  =  0.001). The mean (SD) positive subscore of PANSS improved by 5.6 (3.9) for the clozapine group (0.8 (2.8) for the placebo group; p < 0.0001). At the end of the open period, 25 patients had completely recovered from delusions and hallucinations, and 19 experienced a relapse within one month after the clozapine washout period. The UPDRS motor and MMSE mean scores did not change significantly in either group. Somnolence was more frequent with clozapine than with placebo. Conclusions: Clozapine at a mean dose lower than 50 mg/day improves drug induced psychosis in PD without significant worsening of motor function, and the effect wears off once the treatment stops.

G2019S LRRK2 mutation in French and North African families with Parkinson's disease

Mutations in LRRK2 were recently identified in autosomal dominant Parkinsons disease (PD), including the G2019S mutation. To evaluate its frequency, we analyzed 198 probands with autosomal dominant PD, mostly from France and North Africa. Surprisingly, the frequency in North African families (7/17, 41%) was greater than those from Europe (5/174, 2.9%). The clinical features in 21 patients, including 1 with a homozygous mutation, were those of typical PD, with lower Mini‐Mental State Examination scores. There were also 15 unaffected mutation carriers, aged 32 to 74 years. LRRK2 mutations appear to be a common cause of autosomal dominant PD, particularly in North Africa. Ann Neurol 2005;58:784–787

McLeod neuroacanthocytosis: Genotype and phenotype†

McLeod syndrome is caused by mutations of XK, an X‐chromosomal gene of unknown function. Originally defined as a peculiar Kell blood group variant, the disease affects multiple organs, including the nervous system, but is certainly underdiagnosed. We analyzed the mutations and clinical findings of 22 affected men, aged 27 to 72 years. Fifteen different XK mutations were found, nine of which were novel, including the one of the eponymous case McLeod. Their common result is predicted absence or truncation of the XK protein. All patients showed elevated levels of muscle creatine phosphokinase, but clinical myopathy was less common. A peripheral neuropathy with areflexia was found in all but 2 patients. The central nervous system was affected in 15 patients, as obvious from the occurrence of seizures, cognitive impairment, psychopathology, and choreatic movements. Neuroimaging emphasized the particular involvement of the basal ganglia, which was also detected in 1 asymptomatic young patient. Most features develop with age, mainly after the fourth decade. The resemblance of McLeod syndrome with Huntingtons disease and with autosomal recessive chorea‐acanthocytosis suggests that the corresponding proteins—XK, huntingtin, and chorein—might belong to a common pathway, the dysfunction of which causes degeneration of the basal ganglia.

Pathophysiology of L-dopa-induced motor and non-motor complications in Parkinson's disease.

Involuntary movements, or dyskinesia, represent a debilitating complication of levodopa (L-dopa) therapy for Parkinsons disease (PD). L-dopa-induced dyskinesia (LID) are ultimately experienced by the vast majority of patients. In addition, psychiatric conditions often manifested as compulsive behaviours, are emerging as a serious problem in the management of L-dopa therapy. The present review attempts to provide an overview of our current understanding of dyskinesia and other L-dopa-induced dysfunctions, a field that dramatically evolved in the past twenty years. In view of the extensive literature on LID, there appeared a critical need to re-frame the concepts, to highlight the most suitable models, to review the central nervous system (CNS) circuitry that may be involved, and to propose a pathophysiological framework was timely and necessary. An updated review to clarify our understanding of LID and other L-dopa-related side effects was therefore timely and necessary. This review should help in the development of novel therapeutic strategies aimed at preventing the generation of dyskinetic symptoms.

A simple method to measure stride length as an index of nigrostriatal dysfunction in mice.

Reduced stride length characterizes Parkinsonian gait. We aimed to demonstrate that it could be measured simply and reliably in mice by pawprints and used as an index of basal ganglia dysfunction. In C57BL/6 mice, stride length measurements proved to be consistent across measurements and experimenters. It was slightly lower in the hindlimbs and was correlated to femur size and animal velocity. Dopamine depletion by reserpine and striatal dopamine receptor blockade by haloperidol resulted in reduced mean stride length in four limbs. Significant forelimb/hindlimb difference was also observed both in mice with 3-nitropropionic acid (3-NP) induced striatal lesions and in those with MPTP-induced nigral cell loss. Reduction of hindlimb stride length was correlated significantly with the magnitude of cell loss, either in the substantia nigra or in the lateral mid-striatum. Stride length is, therefore, a simple method to obtain an index of motor disorders due to basal ganglia dysfunction in mice.

Deleterious effects of minocycline in animal models of Parkinson's disease and Huntington's disease.

Minocycline has been shown to exert anti‐inflammatory effects underlying its putative neuroprotective properties in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) mouse model of Parkinsons disease and in the R6/2 mouse model of Huntingtons disease (HD). However, contradictory results have recently been reported. We report deleterious effects of minocycline in two phenotypic (toxic) models of Parkinsons disease and HD in monkey and mouse. Of seven MPTP‐intoxicated female cynomolgus monkeys (0.2 mg/kg, i.v. until day 15), three received minocycline (200 mg b.i.d.). While placebo‐MPTP‐treated animals displayed mild parkinsonism at day 15, the minocycline/MPTP‐treated animals tended to be more affected (P = 0.057) and showed a greater loss of putaminal dopaminergic nerve endings (P < 0.0001). In the 3‐nitropropionic acid (3‐NP) mouse model of HD, minocycline (45 mg/kg i.p.) was administered 30 min before each i.p. injection of 3‐NP (b.i.d., cumulated dose, 360 mg/kg in 5 days). Mice receiving minocycline exhibited a worsening of the mean motor score with a slower recovery slope, more impaired general activity and significantly deteriorated performances on the rotarod, pole test and beam‐traversing tasks. The histopathological outcome demonstrated that minocycline‐treated mice presented significantly more severe neuronal cell loss in the dorsal striatum. The effect of minocycline vs. 3‐NP was also investigated on hippocampal and cortical cell cultures. minocycline blocked 3‐NP‐induced neurotoxicity at certain doses (1 mm cortical neurons) but not at higher doses (10 mm). Thus, minocycline may have variable and even deleterious effects in different species and models according to the mode of administration and dose.

Genome-wide association study confirms BST1 and suggests a locus on 12q24 as the risk loci for Parkinson's disease in the European population

We performed a three-stage genome-wide association study (GWAS) to identify common Parkinsons disease (PD) risk variants in the European population. The initial genome-wide scan was conducted in a French sample of 1039 cases and 1984 controls, using almost 500 000 single nucleotide polymorphisms (SNPs). Two SNPs at SNCA were found to be associated with PD at the genome-wide significance level (P < 3 × 10(-8)). An additional set of promising and new association signals was identified and submitted for immediate replication in two independent case-control studies of subjects of European descent. We first carried out an in silico replication study using GWAS data from the WTCCC2 PD study sample (1705 cases, 5200 WTCCC controls). Nominally replicated SNPs were further genotyped in a third sample of 1527 cases and 1864 controls from France and Australia. We found converging evidence of association with PD on 12q24 (rs4964469, combined P = 2.4 × 10(-7)) and confirmed the association on 4p15/BST1 (rs4698412, combined P = 1.8 × 10(-6)), previously reported in Japanese data. The 12q24 locus includes RFX4, an isoform of which, named RFX4_v3, encodes brain-specific transcription factors that regulate many genes involved in brain morphogenesis and intracellular calcium homeostasis.