A. Destée

Genomic triplication of the α-synuclein gene (SNCA) has been reported to cause hereditary early-onset parkinsonism with dementia. These findings prompted us to screen for multiplication of the SNCA locus in nine families in whom parkinsonism segregates as an autosomal dominant trait. One kindred was identified with SNCA duplication by semiquantitative PCR and confirmed by fluorescent in-situ hybridisation analysis in peripheral leucocytes. By contrast with SNCA triplication families, the clinical phenotype of SNCA duplication closely resembles idiopathic Parkinson's disease, which has a late age-of-onset, progresses slowly, and in which neither cognitive decline nor dementia are prominent. These findings suggest a direct relation between SNCA gene dosage and disease progression.

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.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.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.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.

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. Antioxid. Redox Signal. 21, 195–210.

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.

Background Previous studies have suggested that patients with Lewy-body-related dementias might benefit from treatment with the N-methyl D-aspartate receptor antagonist memantine, but further data are needed. Therefore, the efficacy and safety of memantine were investigated in patients with mild to moderate Parkinson's disease dementia (PDD) or dementia with Lewy bodies (DLB). Methods Patients (≥50 years of age) with mild to moderate PDD or DLB were recruited from 30 specialist centres in Austria, France, Germany, the UK, Greece, Italy, Spain, and Turkey. They were randomly assigned to placebo or memantine (20 mg per day) according to a computer-generated list. Patients and all physicians who had contact with them were masked to treatment assignment. No primary endpoint was defined. Safety analyses were done for all patients who took at least one dose of memantine or placebo, and efficacy analyses were done for all patients who had at least one valid postbaseline assessment. This trial is registered with ClinicalTrials.gov, number NCT00855686. Findings Of the 199 patients randomly assigned to treatment, 34 with DLB and 62 with PDD were given memantine, and 41 with DLB and 58 with PDD were given placebo. 159 (80%) patients completed the study: 80 in the memantine group and 79 in the placebo group. 93 patients treated with memantine and 97 patients treated with placebo were included in the efficacy analysis. At week 24, patients with DLB who received memantine showed greater improvement according to Alzheimer's disease cooperative study (ADCS)-clinical global impression of change scores than did those who received placebo (mean change from baseline 3·3 vs 3·9, respectively, difference −0·6 [95% CI −1·2 to −0·1]; p=0·023). No significant differences were noted between the two treatments in patients with PDD (3·6 with memantine vs 3·8 with placebo, −0·1 [−0·6 to 0·3]; p=0·576) or in the total population (3·5 with memantine vs 3·8 with placebo, −0·3 [−0·7 to 0·1]; p=0·120). Neuropsychiatric-inventory scores showed significantly greater improvement in the memantine group than in the placebo group (−4·3 vs 1·7, respectively, −5·9 [−11·6 to −0·2]; p=0·041) in patients with DLB, but not in those with PDD (−1·6 vs −0·1, respectively, −1·4 [−5·9 to 3·0]; p=0·522) or in the total patient population (−2·6 vs 0·4, respectively, −2·9 [−6·3 to 0·5]; p=0·092). In most of the cognitive test scores, ADCS-activities of daily living, and Zarit caregiver burden scores, there were no significant differences between the two treatment groups in any of the study populations. The incidence of adverse events and number of discontinuations due to adverse events were similar in the two groups. The most common serious adverse events were stroke (n=3 in memantine group), falls (n=2 in memantine group; n=1 in placebo group), and worsening of dementia (n=2 in memantine group). Interpretation Memantine seems to improve global clinical status and behavioural symptoms of patients with mild to moderate DLB, and might be an option for treatment of these patients. Funding Lundbeck.

Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C). VPS13C mutations are associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease. In cell models, VPS13C partly localized to the outer membrane of mitochondria. Silencing of VPS13C was associated with lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, exacerbated PINK1/Parkin-dependent mitophagy, and transcriptional upregulation of PARK2 in response to mitochondrial damage. This work suggests that loss of function of VPS13C is a cause of autosomal-recessive early-onset parkinsonism with a distinctive phenotype of rapid and severe progression.

<b>Background: </b> Severe gait disturbances and freezing episodes (frequently resistant to optimal dopaminergic treatment) often appear in advanced Parkinson disease (PD). Even several years after initiation, high-frequency subthalamic nucleus deep brain stimulation (STN-DBS) is still very effective for controlling segmental symptoms. However, there are no long-term data on the management of gait disorders and freezing in STN-DBS. <b>Objectives: </b> To compare the effects of various STN-DBS parameters on freezing of gait and to determine whether such effects are more related to stimulation energy (usual voltages vs high voltages at 130 Hz) or frequency (130 Hz vs approximately half this frequency: 60 Hz). <b>Methods: </b> We blindly assessed STN-DBS parameters in 13 PD patients reporting severe gait disorders. We compared the effects on gait of two different voltages (the patient’s usual voltage [median 3 volts] and a high voltage [median 3.7 volts]) and two different frequencies (60 and 130 Hz, while maintaining the same total energy delivered) vs “off-stimulation” conditions. <b>Results: </b> The number of freezing episodes was significantly lower at the 60-Hz “high voltage/equivalent energy” and higher at the 130-Hz/high voltage than for “off stimulation.” The slight improvement in the Unified Parkinson’s Disease Rating Scale motor score observed (at 130 Hz) did not achieve statistical significance. <b>Conclusions: </b> Our results prompt consideration of a new strategy for two-stage subthalamic nucleus deep brain stimulation (STN-DBS) frequency optimization, with stimulation at 130 Hz and the usual voltage during the initial years of STN-DBS and then at 60 Hz at a high voltage in Parkinson disease patients who develop severe gait disorders.

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.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.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]).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.National PHRC; Cerebral Palsy Foundation: Fondation Motrice/APETREIMC; French INSERM Dystonia National Network; Medtronic.

Genome-wide analysis of a multi-incident family with autosomal-dominant parkinsonism has implicated a locus on chromosomal region 3q26-q28. Linkage and disease segregation is explained by a missense mutation c.3614G>A (p.Arg1205His) in eukaryotic translation initiation factor 4-gamma (EIF4G1). Subsequent sequence and genotype analysis identified EIF4G1 c.1505C>T (p.Ala502Val), c.2056G>T (p.Gly686Cys), c.3490A>C (p.Ser1164Arg), c.3589C>T (p.Arg1197Trp) and c.3614G>A (p.Arg1205His) substitutions in affected subjects with familial parkinsonism and idiopathic Lewy body disease but not in control subjects. Despite different countries of origin, persons with EIF4G1 c.1505C>T (p.Ala502Val) or c.3614G>A (p.Arg1205His) mutations appear to share haplotypes consistent with ancestral founders. eIF4G1 p.Ala502Val and p.Arg1205His disrupt eIF4E or eIF3e binding, although the wild-type protein does not, and render mutant cells more vulnerable to reactive oxidative species. EIF4G1 mutations implicate mRNA translation initiation in familial parkinsonism and highlight a convergent pathway for monogenic, toxin and perhaps virally-induced Parkinson disease.

Abstract Depression is one of the most common psychiatric disturbances in Parkinson's disease (PD). Recent reviews have highlighted the lack of controlled trials and the ensuing difficulty in formulating recommendations for antidepressant use in PD. We sought to establish whether antidepressants provide real benefits and whether tricyclic and selective serotonin reuptake inhibitor (SSRI) antidepressants differ in their short‐term efficacy, because the time to onset of therapeutic benefit remains an important criterion in depression. The short‐term efficacy (after 14 and 30 days) of two antidepressants (desipramine, a predominantly noradrenergic reuptake inhibitor tricyclic and citalopram, a SSRI) was assessed in a double‐blind, randomized, placebo‐ controlled study of 48 nondemented PD patients suffering from major depression. After 14 days, desipramine prompted an improvement in the Montgomery Asberg Depression Rating Scale (MADRS) score, compared with citalopram and placebo. Both antidepressants produced significant improvements in the MADRS score after 30 days. Mild adverse events were twice as frequent in the desipramine group as in the other groups. A predominantly noradrenergic tricyclic antidepressant induced a more intense short‐term effect on parkinsonian depression than did an SSRI. However, desipramine's lower tolerability may outweigh its slight short‐term clinical advantage. © 2008 Movement Disorder Society

Freezing of gait (FOG) is a common axial symptom of Parkinson disease (PD).To determine the prevalence of FOG in a large group of PD patients, assess its relationship with quality of life and clinical and pharmacological factors, and explore its changes from the off to on conditions in patients with motor fluctuations.Cross-sectional survey of 683 patients with idiopathic PD. Scores for FOG were missing in 11 patients who were not included in the analysis. Patients were recruited from referral centers and general neurology clinics in public or private institutions in France.Patients with FOG were identified as those with a score of 1 or greater on item 14 of the Unified Parkinson's Disease Rating Scale (UPDRS) in the on condition. Item 14 scores for FOG in the off condition were also collected in patients with fluctuating motor symptoms.Quality of life (measured by the 39-item Parkinson's Disease Questionnaire and 36-Item Short Form Health Survey), anxiety and depression (Hospital Anxiety and Depression Scale), clinical features (UPDRS), and drug consumption.Of 672 PD patients, 257 reported FOG during the onstate (38.2%), which was significantly related to lower quality of life scores (P < .01). Freezing of gait was also correlated with longer PD duration (odds ratio, 1.92 [95% CI, 1.28-2.86]), higher UPDRS parts II and III scores (4.67 [3.21-6.78]), the presence of apathy (UPDRS item 4) (1.94 [1.33-2.82]), a higher levodopa equivalent daily dose (1.63 [1.09-2.43]), and more frequent exposure to antimuscarinics (3.07 [1.35-6.97]) (logistic regression). The FOG score improved from the off to on states in 148 of 174 patients with motor fluctuations (85.1%) and showed no change in 13.8%. The FOG score improved by more than 50% in 43.7% of patients. Greater improvement in the on state was observed in younger patients (r = -0.25; P < .01) with lower UPDRS II and III scores (r = -0.50; P < .01) and no antimuscarinic use (r = -0.21; P < .01).Freezing of gait in PD patients correlates with poor quality of life, disease severity, apathy, and exposure to antimuscarinics. Dopaminergic therapy improved FOG in most patients with motor fluctuations, especially younger ones with less severe disease and no antimuscarinic use. This finding suggests that quality of life is impaired in PD patients with FOG and that optimizing dopaminergic therapy and avoiding antimuscarinics should be considered.

Abstract To establish phenotype–genotype correlations in early‐onset parkinsonism, we have compared the phenotype of a large series of 146 patients with and 250 patients without parkin mutations. Although no single sign distinguished the groups, patients with mutations had significantly earlier and more symmetrical onset, dystonia more often at onset and hyperreflexia, slower progression of the disease, and a tendency toward a greater response to levodopa despite lower doses. After forward stepwise multiple logistic regression analysis, dystonia at onset and brisk reflexes were not longer significantly different but were correlated with age at onset rather than the presence of the parkin mutation. Age at onset in carriers of parkin mutations varied as did the rate of progression of the disease: the younger the age at onset the slower the evolution. The genotype influenced the phenotype: carriers of at least one missense mutation had a higher United Parkinson's Disease Rating Scale motor score than those carrying two truncating mutations. The localization of the mutations was also important because missense mutations in functional domains of parkin resulted in earlier onset. Patients with a single heterozygous mutation had significantly later and more asymmetrical onset and more frequent levodopa‐induced fluctuations and dystonia than patients with two mutations. Ann Neurol 2003

Apathy is usually defined as a lack of motivation. It may occur as part of another disorder (notably depression and dementia) or as an isolated syndrome. In Parkinson's disease (PD), apathy is common and several studies have reported an association between this condition and more severe cognitive symptoms, such as executive dysfunction. However, this association has not been thoroughly investigated. The aim of this study (in nondepressed, nondemented PD patients) was to examine whether or not cognitive decline and/or dementia occurred more frequently in apathetic subjects than in nonapathetic subjects. Forty consecutive PD patients participated in the study (20 with apathy and 20 without). None of the subjects were either demented or depressed at the time of study entry. The patients' cognitive functions were extensively assessed twice: at study entry and after an 18-month follow-up period. At study entry, the apathetic PD patients had significantly lower global cognitive status and executive function scores than the nonapathetic subjects. After a median period of 18 months, the rate of conversion to dementia was found to be significantly higher in the apathetic group than in the nonapathetic group (8 of 20 and 1 of 20, respectively). Even in nondemented patients, the decrease over time in cognitive performance (mainly executive function but also memory impairment) was significantly greater in apathetic subjects than in nonapathetic subjects. These findings suggest that in nondemented, nondepressed PD patients, apathy may be a predictive factor for dementia and cognitive decline over time.

The main aetiologies of acute myelopathy (AM) are: multiple sclerosis, systemic disease (SD), spinal cord infarct (SCI), parainfectious myelopathy (PIM) and delayed radiation myelopathy (DRM). Although a large amount of data have been published for each individual aetiology, comparison studies are scarce. The aim of this study was to assess the various aetiological and outcome profiles of AM. We studied 79 cases: 34 (43%) in multiple sclerosis; 13 (16.5%) in SD; 11 (14%) in SCI; five (6%) in PIM; and three (4%) in DRM. Myelopathies were of unknown origin in 13 (16.5%) patients. We evaluated clinical, spinal cord and brain MRI, CSF and evoked potentials data at admission, MRI outcome at 6 months and clinical outcome at 12 months. A statistical comparison of clinical, laboratory and outcome data was only performed between multiple sclerosis, SD and SCI patients due to the small number of cases in the other groups. A motor deficit was more frequent in SD and SCI than in multiple sclerosis where initial symptoms were predominantly sensory (P < 0.001). Spinal cord MRI showed lateral or posterior lesions of less than two vertebral levels in multiple sclerosis, in contrast to SD and SCI, where lesions involved more vertebral levels and were centromedullar (P < 0.001). Brain MRI was most frequently abnormal in multiple sclerosis (68%), but was also abnormal in 31% of SD patients (P < 0.05). Oligoclonal bands in CSF were more frequent in multiple sclerosis than in SD (P < 0.001) and were never found in SCI. Clinical outcome at 12 months was good in 88% of multiple sclerosis cases, and poor or fair in 91% of SCI and 77% of SD. Aetiologies of AM may be differentiated on the basis of clinical, spinal cord and brain MRI, CSF and outcome data, and allow a probable diagnosis to be made in previously undetermined cases. These findings may have therapeutic implications for cases with a questionable diagnosis.

The objective of this study was to use the Lille Apathy Rating Scale to assess apathy in a large population of Parkinson's disease (PD) patients and identify several different apathy profiles. One hundred fifty-nine patients with probable PD and 58 healthy controls participated in the study. Apathy was assessed using the Lille Apathy Rating Scale. Motor, cognitive, and depressive symptoms were rated on standardized scales. Data were analyzed using linear regression and multivariate analyses of variance. Thirty-two percent of the PD patients were classified as apathetic. Apathy was more frequent in patients with dementia. The four apathy dimensions contributed differently to the overall severity of the apathetic condition. Action initiation and intellectual curiosity had a marked influence. Linear regression analysis revealed that the apathy level was mainly determined by cognitive impairment, not associated with the severity of motor symptoms, and only associated with the apathy subcomponent of the Montgomery and Asberg Depression Rating Scale. Apathy is highly prevalent in PD patients. Apathy profiles vary according to the clinical presentation of PD. The high prevalence of apathy in PD suggests the involvement of frontal-subcortical circuits. Although the neurochemical substrate of apathy remains poorly characterized, the strong link between apathy and cognitive impairment observed in several studies suggests the participation of nondopaminergic circuits.

To explore changes in melatonin secretion patterns and biologic rhythms in Parkinson's disease patients with or without levodopa-related motor complications (LDRMCs), the authors investigated, in an observational study, circadian rhythms of central temperature, motor activity, plasma cortisol, and melatonin in three groups: de novo untreated patients (group I), patients treated with levodopa + dopamine agonist and without LDRMCs (group II), and patients treated with levodopa + dopamine agonist and with LDRMCs (group III). There were no differences among the three groups for the rhythm of temperature, motor activity, or plasma cortisol. There was a significant (p < 0.05) phase advance in plasma melatonin secretion in patients receiving a dopaminergic treatment compared with untreated patients. The daytime area under the curve (AUC) was increased significantly in group III, and the nighttime AUC-to-daytime AUC ratio of melatonin secretion decreased significantly in group III, suggesting that the nychthemeral pattern of melatonin secretion was changed in patients with LDRMCs. Comparison of the three groups suggests a slight but insignificant phase advance and amplitude decrease of circadian melatonin secretion related to both evolution and treatment of Parkinson's disease. Despite the lack of a global desynchronization in other circadian biologic rhythms, the circadian secretion pattern of melatonin is modified in patients with LDRMCs.

We performed a three-stage genome-wide association study (GWAS) to identify common Parkinson's 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.

Despite optimum medical management, many patients with Parkinson's disease are incapacitated by gait disorders including freezing of gait. We aimed to assess whether methylphenidate--through its combined action on dopamine and noradrenaline reuptake--would improve gait disorders and freezing of gate in patients with advanced Parkinson's disease without dementia who also received subthalamic nucleus stimulation.This multicentre, parallel, double-blind, placebo-controlled, randomised trial was done in 13 movement disorders departments in France between October, 2009, and December, 2011. Eligible patients were younger than 80 years and had Parkinson's disease, severe gait disorders, and freezing of gate despite optimised treatment of motor fluctuations with dopaminergic drugs and subthalamic stimulation. We randomly assigned patients (1:1 with a computer random-number generator in blocks of four) to receive methylphenidate (1 mg/kg per day) or placebo capsules for 90 days. Patients, their carers, study staff, investigators, and data analysts were masked to treatment allocation. To control for confounding effects of levodopa we assessed patients under standardised conditions with an acute levodopa challenge. Our primary outcome was a change in the number of steps during the stand-walk-sit (SWS) test without levodopa. We compared the respective mean numbers of steps at day 90 in the methylphenidate and placebo groups in a covariance analysis and adjusted for baseline differences. This trial is registered with ClinicalTrials.gov, number NCT00914095.We screened 81 patients and randomly assigned 35 to receive methylphenidate and 34 to receive placebo. 33 patients in the methylphenidate group and 32 patients in the placebo group completed the study. Efficacy outcomes were assessed in the patients who completed the study. Compared with patients in the placebo group (median 33 steps [IQR 26-45]), the patients in the methylphenidate group made fewer steps at 90 days (31 [26-42], F((1, 62))=6·1, p=0·017, adjusted size effect 0·61). Adverse events were analysed in all randomly assigned patients. There were significantly more adverse events in the methylphenidate group compared with placebo. Patients on methylphenidate had a significant increase in heart rate (mean 3·6 [SD 7·2] beats per min) and decrease in weight (mean 2·2 [SD 1·8] kg) compared with the placebo group.Methylphenidate improved gait hypokinesia and freezing in patients with advanced Parkinson's disease receiving subthalamic nucleus stimulation. Methylphenidate represents a therapeutic option in the treatment of gait disorders at the advanced stage of Parkinson's disease. The long term risk-benefit balance should be further studied.French Ministry of Health and Novartis Pharma.

<h3>Background</h3> Even with optimal dopaminergic treatments, many patients with Parkinson9s disease (PD) are frequently incapacitated by apathy prior to the development of dementia. We sought to establish whether rivastigmine9s ability to inhibit acetyl- and butyrylcholinesterases could relieve the symptoms of apathy in dementia-free, non-depressed patients with advanced PD. <h3>Methods</h3> We performed a multicentre, parallel, double-blind, placebo-controlled, randomised clinical trial (Protocol ID: 2008-002578-36; clinicaltrials.gov reference: NCT00767091) in patients with PD with moderate to severe apathy (despite optimised dopaminergic treatment) and without dementia. Patients from five French university hospitals were randomly assigned 1:1 to rivastigmine (transdermal patch of 9.5 mg/day) or placebo for 6 months. The primary efficacy criterion was the change over time in the Lille Apathy Rating Scale (LARS) score. <h3>Finding</h3> 101 consecutive patients were screened, 31 were eligible and 16 and 14 participants were randomised into the rivastigmine and placebo groups, respectively. Compared with placebo, rivastigmine improved the LARS score (from −11.5 (−15/−7) at baseline to −20 (−25/−12) after treatment; F_{(1, 25)}=5.2; p=0.031; adjusted size effect: −0.9). Rivastigmine also improved the caregiver burden and instrumental activities of daily living but failed to improve quality of life. No severe adverse events occurred in the rivastigmine group. <h3>Interpretation</h3> Rivastigmine may represent a new therapeutic option for moderate to severe apathy in advanced PD patients with optimised dopaminergic treatment and without depression dementia. These findings require confirmation in a larger clinical trial. Our results also confirmed that the presence of apathy can herald a pre-dementia state in PD. <h3>Registration</h3> Clinicaltrials.gov reference: NCT00767091.

Mutations in the spastic paraplegia 7 (SPG7) gene encoding paraplegin are responsible for autosomal recessive hereditary spasticity. We screened 135 unrelated index cases, selected in five different settings: SPG7-positive patients detected during SPG31 analysis using SPG31/SPG7 multiplex ligation-dependent probe amplification (n = 7); previously reported ambiguous SPG7 cases (n = 5); patients carefully selected on the basis of their phenotype (spasticity of the lower limbs with cerebellar signs and/or cerebellar atrophy on magnetic resonance imaging/computer tomography scan and/or optic neuropathy and without other signs) (n = 24); patients with hereditary spastic paraparesis referred consecutively from attending neurologists and the national reference centre in a diagnostic setting (n = 98); and the index case of a four-generation family with autosomal dominant optic neuropathy but no spasticity linked to the SPG7 locus. We identified two SPG7 mutations in 23/134 spastic patients, 21% of the patients selected according to phenotype but only 8% of those referred directly. Our results confirm the pathogenicity of Ala510Val, which was the most frequent mutation in our series (65%) and segregated at the homozygous state with spastic paraparesis in a large family with autosomal recessive inheritance. All SPG7-positive patients tested had optic neuropathy or abnormalities revealed by optical coherence tomography, indicating that abnormalities in optical coherence tomography could be a clinical biomarker for SPG7 testing. In addition, the presence of late-onset very slowly progressive spastic gait (median age 39 years, range 18-52 years) associated with cerebellar ataxia (39%) or cerebellar atrophy (47%) constitute, with abnormal optical coherence tomography, key features pointing towards SPG7-testing. Interestingly, three relatives of patients with heterozygote SPG7 mutations had cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs, suggesting that SPG7 mutations at the heterozygous state might predispose to late-onset neurodegenerative disorders, mimicking autosomal dominant inheritance. Finally, a novel missense SPG7 mutation at the heterozygous state (Asp411Ala) was identified as the cause of autosomal dominant optic neuropathy in a large family, indicating that some SPG7 mutations can occasionally be dominantly inherited and be an uncommon cause of isolated optic neuropathy. Altogether, these results emphasize the clinical variability associated with SPG7 mutations, ranging from optic neuropathy to spastic paraplegia, and support the view that SPG7 screening should be carried out in both conditions.

Autosomal dominant parkinsonism (ADP) is caused in a large percentage of familial and sporadic cases by mutations in the LRRK2 gene, particularly G2019S. It is also caused by mutations in genes associated with autosomal dominant cerebellar ataxia (ADCA), notably CAG/CAA repeat expansions in SCA2.We screened 164 families with ADP for expansions in the SCA2, 3, and 17 genes and for the G2019S mutation in LRRK2. The SCA2 CAG/CAA repeat expansion was sequenced to determine its structure. The phenotypes of patients with ADP caused by the SCA2, LRRK2, and unknown mutations were compared, as well as those of SCA2 patients with interrupted or uninterrupted expansions of the same size.Three French ADP families had SCA2 mutations. The expansions ranged from 37 to 39 repeats and were interrupted and stable upon transmission. All patients (n = 9) had levodopa-responsive parkinsonism without cerebellar signs. They had significantly more symmetric signs and less rigidity than ADP caused by the G2019S mutation in LRRK2 or by unknown mutations. Interestingly, two sisters carrying both the SCA2 and the G2019S LRRK2 mutations had markedly earlier onset than their mother with only SCA2. In contrast, similar-sized but uninterrupted repeats were associated with ADCA in which cerebellar ataxia was constant and associated only rarely with one or more mild parkinsonian signs.These results suggest that the configuration of the SCA2 CAG/CAA repeat expansions plays an important role in phenotype variability. Uninterrupted SCA2 repeat expansions found in families with autosomal dominant cerebellar ataxia result in somatic mosaicism and produce large hairpin RNAs, which may interact with double-stranded RNA-binding proteins. These characteristics are modified by interruption of the SCA2 repeat expansion as found in families with autosomal dominant parkinsonism.

Genomic multiplications of the alpha-synuclein gene (SNCA) cause autosomal dominant Parkinson disease (ADPD). The aim of this study was to assess the frequency and phenotype of SNCA rearrangements in a large series of families with typical or atypical AD parkinsonism.Patients were screened by the exon dosage of the SNCA gene. The genotype of patients and relatives carrying SNCA rearrangements, the size of the multiplied regions, and the centromeric and telomeric breakpoints were determined by microsatellite dosage and 250K Affymetrix Single Polymorphism Nucleotide microarrays (Affymetrix, Santa Clara, California).Index cases and, whenever appropriate, relatives of 286 mainly European families with ADPD were screened.Four of 264 families (1.5%) with typical ADPD carried duplications and 1 of 22 families (4.5%) with atypical AD parkinsonism carried a triplication of SNCA. Genotyping and dosage analyses showed that the multiplied regions were variable in size (0.42-5.29 megabase pairs), suggesting that SNCA multiplications occurred independently. Phenotype analyses showed that the severity of the disease correlated with the SNCA copy number, but not with the minimal number of multiplied genes (1 to 33). Haplotype analysis of polymorphic markers suggested that multiplication of the SNCA gene occurred by both interchromosomal and intrachromosomal rearrangement.Our results suggest that SNCA rearrangements may be more frequent than point mutations in ADPD. Furthermore, our results indicate that the phenotype associated with SNCA multiplications correlates with the number of copies of the gene and provides the first insight into the mechanisms underlying SNCA multiplication.

<h3>Objective:</h3> Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown. <h3>Methods:</h3> Investigators from the Genetic Epidemiology of Parkinson9s Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry. <h3>Results:</h3> In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78–0.87 (<i>LAMP3</i>, <i>BST1</i>, and <i>MAPT</i>) and susceptibility per-allele odds ratios of 1.14–1.43 (<i>STK39</i>, <i>GAK</i>, <i>SNCA</i>, <i>LRRK2</i>, <i>SYT11</i>, and <i>HIP1R</i>). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (<i>I</i>² estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the <i>BST1</i> (rs11724635) in Asian vs Caucasian populations and similar effects for <i>SNCA</i>, <i>LRRK2</i>, <i>LAMP3</i>, <i>HIP1R</i>, and <i>STK39</i> in Asian and Caucasian populations, while <i>MAPT</i> rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD. <h3>Conclusion:</h3> Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity. <i>Neurology</i>® 2012;79:659–667

AFQ056 is a novel, selective metabotropic glutamate receptor 5 antagonist. This was a 13-week, double-blind, placebo-controlled study. Patients with Parkinson's disease and moderate-to-severe levodopa (l-dopa)-induced dyskinesia who were receiving stable l-dopa/anti-parkinsonian treatment and were not currently receiving amantadine were randomized to receive either AFQ056 (at doses of 20, 50, 100, 150, or 200 mg daily) or placebo (1:1:1:1:2:3 ratio) for 12 weeks. The primary outcome was the modified Abnormal Involuntary Movements Scale. Secondary outcomes included the 26-item Parkinson's Disease Dyskinesia Scale, the Patient's/Clinician's Global Impression of Change, and the Unified Parkinson's Disease Rating Scale parts III (motor evaluation) and IV (severity of motor complications). Safety was assessed. In total, 98 of 133 (73.7%) AFQ056-treated patients and 47 of 64 (73.4%) patients in the placebo group completed the study. Baseline characteristics were comparable. Patients randomized to AFQ056 200 mg daily administered in 2 doses demonstrated significant improvements at Week 12 on the modified Abnormal Involuntary Movements Scale compared with placebo (difference, -2.8; 95% confidence interval [CI], -5.2, -0.4; P = 0.007). Based on final actual doses, there was a dose-response relationship on the modified Abnormal Involuntary Movements Scale, with 200 mg daily demonstrating the most robust effect (difference, -3.6; 95% CI, -7.0, -0.3; P = 0.012). Improvements in dyskinesia were supported by change on Unified Parkinson's Disease Rating Scale part IV item 32 (50 mg daily: difference, -0.7; 95% CI, -1.1, -0.2; P = 0.003; 200 mg daily: difference, -0.5; 95% CI, -0.8, -0.1; P = 0.005). No significant changes were observed on the 26-item Parkinson's Disease Dyskinesia Scale, the Unified Parkinson's Disease Rating Scale part IV item 33 or items 32 and 33, or the Patient's/Clinician's Global Impression of Change. Unified Parkinson's Disease Rating Scale part III scores were not significantly changed, indicating no worsening of motor symptoms. The most common adverse events (with incidence greater with AFQ056 than with placebo) were dizziness, hallucination, fatigue, nasopharyngitis, diarrhea, and insomnia. AFQ056 demonstrated anti-dyskinetic efficacy in this population without worsening underlying motor symptoms. These results will guide dose selection for future clinical trials.

<h3>Objective:</h3> The AMANDYSK trial was designed to assess long-term efficacy of chronic treatment with amantadine in patients with Parkinson disease (PD) and levodopa-induced dyskinesia (LID). <h3>Methods:</h3> This was a 3-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group, wash-out study conducted in 57 amantadine-treated (≥200 mg/d for ≥6 months) dyskinetic patients with PD. The primary outcome measure was the change from baseline in a Unified Parkinson’s Disease Rating Scale (UPDRS) dyskinesia subscore (items 32 [duration] + 33 [severity]). Secondary outcomes included other LID measurements (“responders” analysis, premature dropout for LID, Abnormal Involuntary Movement Scale). Exploratory outcomes included time with troublesome dyskinesia as measured by diaries, UPDRS Motor Examination (part III) for motor symptoms of PD, and fatigue and apathy scores for nonmotor symptoms. <h3>Results:</h3> UPDRS items 32 + 33 deteriorated more in patients switched to placebo (“discontinuing” group) (+1.7 ± 2.0 units; 95% confidence interval 0.9, 2.4) as compared with those maintained on amantadine (“continuing” group) (+0.2 ± 1.5 units; 95% confidence interval −0.4, 0.8; <i>p</i> = 0.003). Secondary outcomes confirmed this difference because there were significantly more responders, more dropouts for LID, greater increase in “ON” time with troublesome dyskinesia, and greater worsening of Abnormal Involuntary Movement Scale score in the discontinuing group. There were no between-group differences in the UPDRS Motor Examination, whereas apathy (as measured by caregivers) and fatigue scores tended to worsen more in patients randomized to placebo. <h3>Conclusion:</h3> Wash-out of amantadine in dyskinetic patients with PD significantly worsened LID. No significant effect was observed on motor parkinsonian symptoms, while exploratory outcomes suggested that amantadine might improve apathy and fatigue in such patients. <h3>Classification of evidence:</h3> This article provides Class II evidence that in patients with PD, withdrawing amantadine significantly aggravates LID in a median time of 7 days.

Parkinson's disease (PD) is a progressive movement neurodegenerative disease associated with a loss of dopaminergic neurons in the substantia nigra of the brain. Oxidative stress, a condition that occurs due to imbalance in oxidant and antioxidant status, is thought to play an important role in dopaminergic neurotoxicity. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases are multi-subunit enzymatic complexes that generate reactive oxygen species as their primary function. Increased immunoreactivities for the NADPH oxidases catalytic subunits Nox1, Nox2 and Nox4 have been reported in the brain of PD patients. Furthermore, knockout or genetic inactivation of NADPH oxidases exert a neuroprotective effect and reduce detrimental aspects of pathology in experimental models of the disease. However, the connections between NADPH oxidases and the biological processes believed to contribute to neuronal death are not well known. This review provides a comprehensive summary of our current understanding about expression and physiological function of NADPH oxidases in neurons, microglia and astrocytes and their pathophysiological roles in PD. It summarizes the findings supporting the role of both microglial and neuronal NADPH oxidases in cellular disturbances associated with PD such as neuroinflammation, alpha-synuclein accumulation, mitochondrial and synaptic dysfunction or disruption of the autophagy-lysosome system. Furthermore, this review highlights different steps that are essential for NADPH oxidases enzymatic activity and pinpoints major obstacles to overcome for the development of effective NADPH oxidases inhibitors for PD.

Therapeutic management of gait disorders in patients with advanced Parkinson's disease (PD) can sometimes be disappointing, since dopaminergic drug treatments and subthalamic nucleus (STN) stimulation are more effective for limb-related parkinsonian signs than for gait disorders. Gait disorders could also be partly related to norepinephrine system impairment, and the pharmacological modulation of both dopamine and norepinephrine pathways could potentially improve the symptomatology.To assess the clinical value of chronic, high doses of methylphenidate (MPD) in patients with PD having gait disorders, despite their use of optimal dopaminergic doses and STN stimulation parameters.Efficacy was blindly assessed on video for 17 patients in the absence of L-dopa and again after acute administration of the drug, both before and after a 3-month course of MPD, using a Stand-Walk-Sit (SWS) Test, the Tinetti Scale, the Unified Parkinson's Disease Rating Scale (UPDRS) part III score and the Dyskinesia Rating Scale.An improvement was observed in the number of steps and time in the SWS Test, the number of freezing episodes, the Tinetti Scale score and the UPDRS part III score in the absence of L-dopa after 3 months of taking MPD. The L-dopa-induced improvement in these various scores was also stronger after the 3-month course of MPD than before. The Epworth Sleepiness Scale score fell dramatically in all patients. No significant induction of adverse effects was found.Chronic, high doses of MPD improved gait and motor symptoms in the absence of L-dopa and increased the intensity of response of these symptoms to L-dopa in a population with advanced PD.

Abnormal levels of interleukin (IL)-6 were described in patients with ALS, related to an inflammatory process. The authors compared IL-6 and tumor necrosis factor α (TNF-α) levels in CSF and sera from 10 hypoxemics and 10 normoxemics patients with ALS to those of 10 hypoxemics and 10 normoxemics neurologic controls. The same pattern exists in patients with ALS and controls: the highest levels are found in hypoxic conditions and undetectable levels are found in normoxemic conditions. Elevated IL-6 levels in ALS could correspond to a normal response to hypoxemia.

Event-related desynchronization (ERD) of alpha components was studied in young and elderly subjects during planning of voluntary movement. ERD was quantified from 11 source derivations covering regions of the scalp corresponding to the supplementary motor area, the left and right primary sensorimotor areas, the vertex, and the medial posterior parietal cortex. Spatio-temporal display of ERD showed a very different pattern in elderly subjects, with mainly a spatial diffusion of ERD over the parietal and frontal regions. On the contrary, ERD in young subjects was limited to the central regions. ERD was also more lasting in elderly subjects. Changes of the ERD pattern in elderly subjects could indicate a change of cortical activation during voluntary movement. The data also confirm that ERD study is a useful electrophysiological exploration to observe the changes of cortical activation during cerebral aging.

Background: Camptocormia, characterised by extreme forward flexion of the thoracolumbar spine and severe stooping in the supine position, seems to be prevalent in Parkinson's disease.Objective: The aim of this study was to identify features of parkinsonian camptocormia and to describe the main clinical characteristics of patients with Parkinson's disease who develop the condition.Methods: An extensive range of clinical, biochemical and imaging data were gathered for 23 patients with Parkinson's disease with camptocormia, notably including magnetic resonance imaging (MRI) of the brain and spine, electromyographic recordings of the paravertebral muscles and muscle biopsies.Results: Camptocormia occurred in severe Parkinson's disease with axial predominance, motor fluctuations and dysautonomic symptoms.The condition was often associated with spondyloarthritic changes and pain.MRI showed paraspinal muscle signal abnormalities in five patients and fatty involution in seven patients.The seven patients had motor unit reductions on the spinal erector electromyogram.The MRI results for the girdle muscles were normal.Cranial MRI showed signal abnormalities for the basal ganglia in three patients.Discussion: Various mechanisms may contribute to the development of parkinsonian camptocormia: dopaminergic depletion in Parkinson's disease induces functional changes in the organisation of the corticospinal and reticulospinal tracts, where dysfunction could contribute to axial rigidity.Furthermore, rigidity of the spinal flexion muscles could lead to under-use of the spinal extension muscles, which become progressively atrophic.Rigidity may also induce spinal deformations, leading to a neurogenic syndrome via compression of the spinal nerves.Conclusion: The screening and early management of camptocormia in Parkinson's disease is likely to be important for preventing axial disorders and spinal deformations.

Deletion of the hypoxia-response element in the vascular endothelial growth factor (VEGF) promoter causes motor neuron degeneration in a mouse model. "At-risk" haplotypes with low circulating VEGF levels have been demonstrated in humans. Here the authors report low VEGF levels in the CSF of ALS patients during their first year of the disease, independently of VEGF promoter polymorphism. This finding early in ALS patients suggests a possible role for VEGF gene regulation in the pathogenesis of ALS.

Abstract In Parkinson's disease (PD), festination corresponds to a tendency to speed up when performing repetitive movements. First described in gait (and then in handwriting and speech), festination is one of the most disabling axial symptoms. To establish the phenomenology of oral festination (OF) and the condition's potential links with other axial disorders, we submitted a simple, rhythmic, repetitive, vocal motor task to 40 PD patients and 20 controls. Forty‐five percent of the 40 patients presented OF, which was strongly associated with gait festination but not with the severity of freezing of gait (FOG) or dysarthria. With respect to the two pathophysiological hypotheses that have been put forward, a possible link with tremor (as previously suggested in tapping) was not confirmed in this study and so, in view of the significant increase in variability observed, we conclude that OF shares the same pathophysiology as gait disorders. © 2007 Movement Disorder Society

To assess the effects of bilateral pallidal deep brain stimulation (DBS) on mood and cognitive performance in patients with dystonia before surgery (at baseline, while patients received their usual treatment) and 12 months postoperatively (while patients received neurostimulation and their medications) in a multicenter prospective study.Twenty-two patients with primary generalized dystonia were evaluated with tests focused on executive functions. The authors considered the patients' severe disability and selected the following tests: Raven Progressive Matrices 38, Similarities and Arithmetic subtests of the Wechsler Adult Intelligence Scale-R, Grober and Buschke, Wisconsin Card Sorting Test (WCST), verbal fluency, Trail Making Test, and the Beck Depression Inventory. Median age at surgery was 30 years (range = 14 to 54 years), median duration of disease was 18.5 years (range = 4 to 37 years).Before surgery, no patients showed cognitive decline or depression. The surgical procedure appeared to be benign cognitively. One year after surgery, free recall improved. There was a significant reduction in the number of errors in the WCST. No behavioral or mood changes were found.Bilateral pallidal stimulation has a good benefit-to-risk ratio as it did not negatively affect cognitive performance and mood in primary dystonia, while a significant motor improvement was obtained. Moreover, a significant mild improvement in executive functions was observed, which may have been related either to the surgical treatment or to the marked decrease in anticholinergic drugs.

Abstract Objective: We studied the independent and joint effects of the genes encoding alpha‐synuclein ( SNCA ) and microtubule‐associated protein tau ( MAPT ) in Parkinson disease (PD) as part of a large meta‐analysis of individual data from case–control studies participating in the Genetic Epidemiology of Parkinson's Disease (GEO‐PD) consortium. Methods: Participants of Caucasian ancestry were genotyped for a total of 4 SNCA (rs2583988, rs181489, rs356219, rs11931074) and 2 MAPT (rs1052553, rs242557) single nucleotide polymorphism (SNPs). Individual and joint effects of SNCA and MAPT SNPs were investigated using fixed‐ and random‐effects logistic regression models. Interactions were studied on both a multiplicative and an additive scale, and using a case–control and case‐only approach. Results: Fifteen GEO‐PD sites contributed a total of 5,302 cases and 4,161 controls. All 4 SNCA SNPs and the MAPT H1‐haplotype–defining SNP (rs1052553) displayed a highly significant marginal association with PD at the significance level adjusted for multiple comparisons. For SNCA , the strongest associations were observed for SNPs located at the 3′ end of the gene. There was no evidence of statistical interaction between any of the 4 SNCA SNPs and rs1052553 or rs242557, neither on the multiplicative nor on the additive scale. Interpretation: This study confirms the association between PD and both SNCA SNPs and the H1 MAPT haplotype. It shows, based on a variety of approaches, that the joint action of variants in these 2 loci is consistent with independent effects of the genes without additional interacting effects. ANN NEUROL 2011

Introduction: Abnormal oro‐buccal functions including dysarthria, sialorrhea and dysphagia commonly affect patients with Parkinson’s disease (PD). Objectives: To estimate the prevalence of such oro‐buccal symptoms at baseline in the first 419 patients with PD included in the COPARK cohort and to analyze their correlations with patients’ demographics, clinical characteristics, and drugs consumption. Methods: Patients were assessed using the Unified PD Rating Scale, the Hospital Anxiety and Depression Scale, and the PDQ‐39. Dysarthria, sialorrhea, and dysphagia were defined as UPDRS items 5, 6, or 7 ≥ 1. Results: Dysarthria, sialorrhea, or dysphagia were present in 51%, 37%, or 18% out of the 419 patients, respectively. At least one of these symptom was present in 267/419 patients (65%), whilst a combination of symptoms was present in 136/419 (33%). Logistic regression showed that the presence of each of the three oro‐buccal symptoms was significantly correlated with that of the two others. Other correlations included male gender, hallucinations, disease severity, levodopa use and lack of opiates consumption for dysarthria; disease severity, orthostatic hypotension and absence of antidepressants consumption for sialorrhea; female gender, motor fluctuations, and depressive symptoms for dysphagia. None of the three oro‐buccal symptoms were associated with a reduced PDQ‐39 score. Conclusion: Oro‐buccal symptoms were present in two of three patients with moderate PD, the presence of each symptoms being significantly correlated with that of the two others.

Abstract Background: Parkinsonian dysarthria (as typically characterized by hypophonia, monotony of pitch, and rhythm abnormalities) is often accompanied by gait disturbances. The long‐term effect of subthalamic nucleus deep brain stimulation (STN DBS) on dysarthria remains unclear. Methods: Given STN DBS's known improvement of gait disorders, we analyzed speech intelligibility and aerodynamic and acoustic parameters in 11 advanced PD patients in three double‐blind, randomized conditions: “defined Off,” 60 Hz STN DBS and 130 Hz STN DBS. Results: An improvement in aerodynamic speech parameters during 60 Hz STN DBS was accompanied by significant clinical benefit. Conclusions: Chronic treatment with low‐frequency STN DBS may have a beneficial impact on dysarthropneumophonia, even in advanced PD patients. © 2011 Movement Disorder Society

To gain insight into systemic molecular events associated with an age-related neurodegenerative disorder, we compared gene expression patterns in peripheral blood mononuclear cells (PBMCs) sampled from elderly, healthy controls and from Parkinson's disease (PD) patients carrying the most frequently found mutation of the LRRK2 gene (G2019S). A transcriptomic approach enabled us to detect differentially expressed genes and revealed perturbations of pathways known to be involved in PD-related neurodegeneration: the ubiquitin–proteasome system, the mitochondrial oxidation system, inflammation, axonal guidance, calcium signalling and apoptosis. Moreover, alterations of the MAP kinase pathway, the actin cytoskeleton, the ephrin receptor system and vesicular transport – all recently associated with the LRRK2 G2019S mutation pathogenesis – were noted. Furthermore, we acquired new evidences of dysregulation in leukocyte extravasation signalling and immune system pathways in PD. These data show that the G2019S mutation affects the entire body and highlight some of the molecular events observed in the brain. This PBMC transcriptomic approach could be used to better understand neurodegeneration in PD and decipher new pathogenetic mechanisms, even at early stages of the disease.

Most available pattern recognition methods in neuroimaging address binary classification problems. Here, we used relevance vector machine (RVM) in combination with booststrap resampling (‘bagging’) for non-hierarchical multiclass classification. The method was tested on 120 cerebral 18fluorodeoxyglucose (FDG) positron emission tomography (PET) scans performed in patients who exhibited parkinsonian clinical features for 3.5 years on average but that were outside the prevailing perception for Parkinson's disease (PD). A radiological diagnosis of PD was suggested for 30 patients at the time of PET imaging. However, at follow-up several years after PET imaging, 42 of them finally received a clinical diagnosis of PD. The remaining 78 APS patients were diagnosed with multiple system atrophy (MSA, N = 31), progressive supranuclear palsy (PSP, N = 26) and corticobasal syndrome (CBS, N = 21), respectively. With respect to this standard of truth, classification sensitivity, specificity, positive and negative predictive values for PD were 93% 83% 75% and 96%, respectively using binary RVM (PD vs. APS) and 90%, 87%, 79% and 94%, respectively, using multiclass RVM (PD vs. MSA vs. PSP vs. CBS). Multiclass RVM achieved 45%, 55% and 62% classification accuracy for, MSA, PSP and CBS, respectively. Finally, a majority confidence ratio was computed for each scan on the basis of class pairs that were the most frequently assigned by RVM. Altogether, the results suggest that automatic multiclass RVM classification of FDG PET scans achieves adequate performance for the early differentiation between PD and APS on the basis of cerebral FDG uptake patterns when the clinical diagnosis is felt uncertain. This approach cannot be recommended yet as an aid for distinction between the three APS classes under consideration.

Neurite outgrowth inhibitor A (Nogo-A) is thought to have a role in the pathophysiology of amyotrophic lateral sclerosis (ALS). A monoclonal antibody against Nogo-A showed a positive effect in the SOD1G93A mouse model of ALS, and a humanised form of this antibody (ozanezumab) was well tolerated in a first-in-human trial. Therefore, we aimed to assess the safety and efficacy of ozanezumab in patients with ALS.This randomised, double-blind, placebo-controlled, phase 2 trial was done in 34 centres in 11 countries. Patients aged 18-80 years with a diagnosis of familial or sporadic ALS were randomly assigned (1:1), centrally according to a computer-generated allocation schedule, to receive ozanezumab (15 mg/kg) or placebo as intravenous infusions over 1 h every 2 weeks for 46 weeks, followed by assessments at week 48 and week 60. Patients and study personnel were masked to treatment assignment. The primary outcome was a joint-rank analysis of function (ALS Functional Rating Scale-Revised) and overall survival, analysed at 48 weeks in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01753076, and with GSK-ClinicalStudyRegister.com, NOG112264, and is completed.Between Dec 20, 2012, and Nov 1, 2013, we recruited 307 patients, of whom 303 were randomly assigned to receive placebo (n=151) or ozanezumab (n=152). The adjusted mean of the joint-rank score was -14·9 (SE 13·5) for the ozanezumab group and 15·0 (13·6) for the placebo group, with a least squares mean difference of -30·0 (95% CI -67·9 to 7·9; p=0·12). Overall, reported adverse events, serious adverse events, and adverse events leading to permanent discontinuation of study drug or withdrawal from study were similar between the treatment groups, except for dyspepsia (ten [7%] in the ozanezumab group vs four [3%] in the placebo group), depression (11 [7%] vs five [3%]), and diarrhoea (25 [16%] vs 12 [8%]). Respiratory failure was the most common serious adverse event (12 [8%] vs seven [5%]). At week 60, the number of deaths was higher in the ozanezumab group (20 [13%]) than in the placebo group (16 [11%]), mainly as a result of respiratory failure (ten [7%] vs five [3%]). Two deaths were considered related to the study drug (bladder transitional cell carcinoma in the ozanezumab group and cerebrovascular accident in the placebo group).Ozanezumab did not show efficacy compared with placebo in patients with ALS. Therefore, Nogo-A does not seem to be an effective therapeutic target in ALS.GlaxoSmithKline.

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.

Expression or phosphorylation levels of leucine-rich repeat kinase 2 (LRRK2) and its Rab substrates have strong potential as disease or pharmacodynamic biomarkers. The main objective of this study is therefore to assess the LRRK2-Rab pathway for use as biomarkers in human, non-human primate (NHP) and rat urine. With urine collected from human subjects and animals, we applied an ultracentrifugation based fractionation protocol to isolate small urinary extracellular vesicles (uEVs). We used western blot with antibodies directed against total and phosphorylated LRRK2, Rab8, and Rab10 to measure these LRRK2 and Rab epitopes in uEVs. We confirm the presence of LRRK2 and Rab8/10 in human and NHP uEVs, including total LRRK2 as well as phospho-LRRK2, phospho-Rab8 and phospho-Rab10. We also confirm LRRK2 and Rab expression in rodent uEVs. We quantified LRRK2 and Rab epitopes in human cohorts and found in a first cohort that pS1292-LRRK2 levels were elevated in individuals carrying the LRRK2 G2019S mutation, without significant differences between healthy and PD groups, whether for LRRK2 G2019S carriers or not. In a second cohort, we found that PD was associated to increased Rab8 levels and decreased pS910-LRRK2 and pS935-LRRK2. In animals, acute treatment with LRRK2 kinase inhibitors led to decreased pT73-Rab10. The identification of changes in Rab8 and LRRK2 phosphorylation at S910 and S935 heterologous phosphosites in uEVs of PD patients and pT73-Rab10 in inhibitor-dosed animals further reinforces the potential of the LRRK2-Rab pathway as a source of PD and pharmacodynamic biomarkers in uEVs.

The authors evaluated the long-term clinical outcome of neurosarcoidosis and determined predictive factors of disease course. Twenty-seven patients with neurosarcoidosis were followed for at least 5 years from the onset of neurologic symptoms. Patients with CNS involvement during the course of the disease had a higher Modified Oxford Handicap Scale score than those with peripheral nervous system involvement (p < 0.02). CNS involvement may be a predictive factor for a less favorable disease course. Early and intensive treatment should be considered in such cases.

Gait analysis studies involve continuous curves of data measured over a gait cycle. Curve analysis and interpretation require adequate statistical methods. Three principal problems may be encountered in clinical practice: (i) the reliability of gait curves for a given patient, (ii) classifying a new subject as belonging to a given population or not and (iii) comparison of two populations (independent or paired). This paper presents three statistical tools for solving these problems: (i) intra-class correlation coefficients, (ii) confidence bands for a population (iii) a combination of analysis of variance and confidence bands for the difference between the means and shows how they can be used in clinical practice.

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.

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.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.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%.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.

Abnormal low- and high-frequency oscillatory activities have been linked to abnormal movement control in Parkinson’s disease. We aimed to study how low- and high-frequency oscillatory activities are modulated by movement in the contralateral and ipsilateral subcorticocortical loops. We studied mu, beta and gamma rhythm event-related desynchronisation (ERD) and synchronisation (ERS) recorded from electrode contacts in the subthalamic nucleus (STN) areas and over the primary sensorimotor (PSM) cortex. Mu and beta ERD/ERS patterns were very similar when comparing PSM cortex and STN areas and very different when comparing contralateral and ipsilateral structures. Beta rhythm ERS was more predominant over contralateral structures than over ipsilateral ones. Gamma rhythm ERS was only recorded from the contralateral STN area (particularly following administration of L-Dopa). For all patients, the best bipolar derivations – as defined by the earliest mu and beta ERD and the strongest beta and gamma ERS – always included the STN electrode contacts that produced the best clinical results. Movement-related activity is involved in the movement preparation in the contralateral subthalamo-cortical loop and in the movement execution in the bilateral subthalamo-cortical loops. Contralateral beta rhythm ERD seemed to be related to bradykinesia of the limb performing the movement.

We tested the ability of simvastatin, atorvastatin, fenofibrate and bezafibrate (two synthetic peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonists) to prevent dopaminergic cell death in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Tyrosine hydroxylase (TH) immunochemistry was performed 8 days after acute MPTP intoxication. When orally administered for the week prior to intoxication and a week thereafter, fenofibrate prevented the MPTP-induced dopaminergic cell loss in the substantia nigra pars compacta (SNpc) and attenuated the loss of tyrosine hydroxylase immunoreactivity in the striatum. The dosage of 1-methyl-4-phenyl pyridinium (MPP+) in the striatum by high-performance liquid chromatography indicated that fenofibrate did not affect MPTP metabolism. Bezafibrate had no effect and, strikingly, simvastatin and atorvastatin had a negative effect. We also demonstrated the presence of PPAR-alpha in the dopaminergic neurons of the murine substantia nigra. Our data suggest that PPAR-alpha activation by fenofibrate could have a neuroprotective effect in PD through inhibition of inflammation, oxidative stress and/or apoptosis.

Le régime cétogène est employé dans le traitement des épilepsies pharmacorésistantes de l’enfant depuis 1921, bien que son mode d’action soit mal connu. Nous rapportons le cas d’un homme de 54 ans présentant un état de mal épileptique partiel, prolongé, résistant aux antiépileptiques usuels et d’évolution favorable sept jours après introduction d’un régime cétogène en association aux traitements antiépileptiques. Très peu de travaux dans la littérature sont disponibles concernant l’intérêt du régime cétogène dans le traitement des épilepsies de l’adulte ou des états de mal épileptique. C’est un traitement bien toléré qui a montré son efficacité chez l’enfant. Il existe toutefois des contraintes d’observance et la nécessité d’une collaboration multidisciplinaire étroite lors de son instauration. Le régime cétogène pourrait constituer une alternative pour le traitement des épilepsies pharmacorésistantes de l’adulte et dans le traitement des états de mal résistants, comme chez l’enfant. Des études complémentaires permettront de préciser son possible effet prolongé et son impact dans la réduction des traitements antiépileptiques. Ketogenic diets have been employed for the treatment of intractable epilepsiy in children since 1921, although underlying mechanism remains unknown. We report the case of a 54-year-old man with partial refractory status epilepticus who exhibited a favourable outcome about seven days after introduction of a ketogenic diet in association with antiepileptic drugs. Although its efficiency was largely demonstrated in children, little is known about the impact of a ketogenic diet in adults with refractory epilepsy. Introduction of a ketogenic diet requires a multidisciplinary approach. Its usefulness in adult intractable epilepsy and/or refractory status epilepticus merits further study into its efficacy in reducing the frequency of seizures and a possible prolonged effect.

Since Next Generation DNA Sequencing (NGS) was first used to study Miller syndrome,[1][1] exome capture and sequencing have uncovered novel causative mutations in an increasing number of genetic disorders, including neurodegenerative diseases.[2][2],[–][3],[4][4] Two independent groups recently

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.

Given that memantine is thought to decrease N-methyl-D-aspartic-acid-related (NMDA) glutamatergic hyperactivity and improve locomotion in rats, we sought to assess the drug's impact on axial symptoms in advanced Parkinson's disease (PD).We performed a 90-day, randomised, double-blind, study with two parallel arms: 20 mg/day memantine versus placebo (ClinicalTrials.gov:NCT01108029). The main inclusion criterion was the presence of a severe gait disorder and an abnormal, forward-leaning stance. The following parameters were analysed under standardised conditions before and after acute administration of L-dopa: gait (stride length as primary criterion), the United-Parkinson's-Disease-Rating-Scale (UPDRS) motor score and its axial subscore, the hypertonia and strength of the axial extensors and flexors (isokinetic dynamometer), the Dyskinesia Rating Scale score (DRS) and its axial subscore.Twenty-five patients were included. The memantine and placebo group did not differ significantly in terms of stride length. However, in the memantine group, we observed significantly better results (vs placebo) for the overall UPDRS score (F(1,21)=4.9; p=0.039(-1)) and its axial subscore (F(1,21)=7.2; p=0.014(-1.1)), axial hypertonia, the axial and overall DRS and axial strength.Memantine treatment was associated with lower axial motor symptom and dyskinesia scores but did not improve gait. These benefits must be confirmed in a broader population of patients.

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.

Autosomal dominant cerebellar ataxia corresponds to a clinically and genetically heterogeneous group of neurodegenerative disorders that primarily affect the cerebellum. Here, we report the identification of the causative gene in spinocerebellar ataxia 21, an autosomal-dominant disorder previously mapped to chromosome 7p21.3-p15.1. This ataxia was firstly characterized in a large French family with slowly progressive cerebellar ataxia, accompanied by severe cognitive impairment and mental retardation in two young children. Following the recruitment of 12 additional young family members, linkage analysis enabled us to definitively map the disease locus to chromosome 1p36.33-p36.32. The causative mutation, (c.509C>T/p.P170L) in the transmembrane protein gene TMEM240, was identified by whole exome sequencing and then was confirmed by Sanger sequencing and co-segregation analyses. Index cases from 368 French families with autosomal-dominant cerebellar ataxia were also screened for mutations. In seven cases, we identified a range of missense mutations (c.509C>T/p.P170L, c.239C>T/p.T80M, c.346C>T/p.R116C, c.445G>A/p.E149K, c.511C>T/p.R171W), and a stop mutation (c.489C>G/p.Y163*) in the same gene. TMEM240 is a small, strongly conserved transmembrane protein of unknown function present in cerebellum and brain. Spinocerebellar ataxia 21 may be a particular early-onset disease associated with severe cognitive impairment.

Background and purpose Studies assessing the correlations between L‐ DOPA ‐induced dyskinesias ( LID s) and motor fluctuations with health‐related quality of life ( HRQ oL) in Parkinson's disease ( PD ) have yielded conflicting results. This study aimed to assess the relationship between LID s and motor fluctuations with HRQ oL in patients with PD , and to assess the relative contribution of their severity and duration in a large sample of patients with PD . Methods A total of 683 patients with PD from the COPARK survey were evaluated. HRQ oL was assessed using the 39‐Item Parkinson's Disease Questionnaire (PDQ‐39) (primary outcome) and 36‐Item Short Form Survey (SF‐36). The daily duration and severity of LID s were obtained from Unified Parkinson's Disease Rating Scale ( UPDRS) IV items 32 and 33, respectively. The daily duration of motor fluctuations was obtained from UPDRS IV item 36 and severity was estimated as the difference between the UPDRS 2 (Activities of Daily Living) score in ‘ OFF’ versus ‘ ON ’ condition. Results A total of 235 patients with PD (35%) experienced motor fluctuations and 182 (27%) experienced LID s. The PDQ ‐39 total and SF ‐36 physical scores were significantly worse in patients with LID s, after adjusting for the presence of motor fluctuations. The PDQ ‐39 total score and SF ‐36 physical and mental score were significantly worse in patients with motor fluctuations, after adjusting for the presence of LID s. The severity of LID s and the duration of motor fluctuations significantly and independently affected PDQ ‐39 scores. The SF ‐36 physical score was affected only by the severity of motor fluctuations, whereas the mental score was not affected by any of the aforementioned variables. Conclusion Our findings suggest that LID s (mainly their severity) and motor fluctuations (mainly their duration) correlate independently with HRQ oL in patients with PD .

<h2>Abstract</h2><h3>Background</h3> Subthalamic nucleus deep brain stimulation (STN-DBS) has demonstrated its efficacy on motor complications in advanced Parkinson's disease (PD) but does not modify disease progression. Genetic forms of PD have been associated with different cognitive progression profiles. <h3>Objective</h3> To assess the effect of PD-related genetic mutations on cognitive outcome after STN-DBS. <h3>Methods</h3> Patients with STN-DBS were screened for <i>LRRK2</i>, <i>GBA</i>, and <i>PRKN</i> mutations at the Pitié-Salpêtrière Hospital between 1997 and 2009. Patients with known monogenetic forms of PD from six other centers were also included. The Mattis Dementia Rating Scale (MDRS) was used to evaluate cognition at baseline and one-year post-surgery. The standardized Unified PD Rating Scale (UPDRS) evaluation On and Off medication/DBS was also administered. A generalized linear model adjusted for sex, ethnicity, age at onset, and disease duration was used to evaluate the effect of genetic factors on MDRS changes. <h3>Results</h3> We analyzed 208 patients (131 males, 77 females, 54.3 ± 8.8 years) including 25 GBA, 18 <i>LRRK2</i>, 22 <i>PRKN</i>, and 143 PD patients without mutations. <i>PRKN</i> patients were younger and had a longer disease duration at baseline. A <i>GBA</i> mutation was the only significant genetic factor associated with MDRS change (β = −2.51, p = 0.009). <i>GBA</i> mutation carriers had a more pronounced post-operative MDRS decline (3.2 ± 5.1) than patients with <i>LRRK2</i> (0.9 ± 4.8), <i>PRKN</i> (0.5 ± 2.7) or controls (1.4 ± 4.4). The motor response to DBS was similar between groups. <h3>Conclusion</h3> <i>GBA</i> mutations are associated with early cognitive decline following STN-DBS. Neuropsychological assessment and discussions on the benefit/risk ratio of DBS are particularly important for this population.

Parkinson´s disease (PD) is a common neurodegenerative movement disorder and leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for disease intervention. However, the ability to stratify patients who will benefit from such treatment modalities based on shared etiology is critical for the success of disease-modifying therapies. Ciliary and centrosomal alterations are commonly associated with pathogenic LRRK2 kinase activity and can be detected in many cell types. We previously found centrosomal deficits in immortalized lymphocytes from G2019S-LRRK2 PD patients. Here, to investigate whether such deficits may serve as a potential blood biomarker for PD which is susceptible to LRKK2 inhibitor treatment, we characterized patient-derived cells from distinct PD cohorts. We report centrosomal alterations in peripheral cells from a subset of early-stage idiopathic PD patients which is mitigated by LRRK2 kinase inhibition, supporting a role for aberrant LRRK2 activity in idiopathic PD. Centrosomal defects are detected in R1441G-LRRK2 and G2019S-LRRK2 PD patients and in non-manifesting LRRK2 mutation carriers, indicating that they accumulate prior to a clinical PD diagnosis. They are present in immortalized cells as well as in primary lymphocytes from peripheral blood. These findings indicate that analysis of centrosomal defects as a blood-based patient stratification biomarker may help nominate idiopathic PD patients who will benefit from LRRK2-related therapeutics.

To establish the pathophysiological mechanisms of striatopallidal and thalamic dystonia.Five patients from among 26 who presented (between March 1987 and July 1996) with focal dystonia, segmental dystonia, or hemidystonia caused by a single localised vascular lesion, were selected. Patients with lesions with indefinite boundaries, and diffuse, or multiple, or large brain lesions were excluded. Three dimensional T1 weighted MRI (1.5 tesla) was performed to determine the topography of the lesions. The atlas of Hassler allowed the stereotactic localisation of the lesions to be specified exactly.Three patients had dystonic spasms associated with striatopallidal lesions and one with a thalamic and striatopallidal lesion. One other patient presented with a myoclonic dystonia related to a thalamic lesion. The striatopallidal lesions were located in the sensorimotor area with a somatotopical distribution. The pure thalamic lesion involved the centromedian nucleus, the sensory nuclei, and the pulvinar whereas the thalamic and striatopallidal lesion was located in the pallidonigral thalamic territory, which receives pallidonigral inputs.The striatopallidal dystonia might be the consequence of the interruption of the cortico-striato-pallido-thalamo-cortical loop induced by lesions located within the sensorimotor part of the striatopallidal complex. By contrast, it is suggested that thalamic dystonia might be caused by lesions located in the centro-median or the ventral intermediate nuclei, outside the pallidonigral territory, but leading also to a dysfunction of the cortico-striato-pallido-thalamo-cortical loop.

Background: The autosomal dominant cerebellar ataxias (ADCA) are a clinically heterogeneous group of disorders. The mutations for SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, and SCA-12 are identified and caused by an expansion of a CAG or a CTG repeat sequence of these genes. Six additional loci for SCA4, SCA5, SCA-10, SCA-11, SCA-13, and SCA-14 are mapped. The growing heterogeneity of the autosomal dominant forms of these diseases shows that the genetic etiologies of at least 20% of ADCA have yet to be elucidated.Methods: The authors ascertained and clinically characterized a four-generation pedigree segregating an autosomal dominant phenotype for SCA. Direct mutation analysis, repeat expansion detection analysis, and linkage analysis for all known SCA loci were performed.Results: Direct mutational analysis excluded SCA1, 2, 3, 6, 7, 8, and 12; genetic linkage analysis excluded SCA4, 5,10, 11, 13, and 14, giving significant negative lod scores. Examination of the family showed that all affected members had gait ataxia and akinesia with variable features of dysarthria, hyporeflexia, and mild intellectual impairment. Eye movements were normal. Head MRI showed atrophy of the cerebellum without involvement of the brainstem. In 10 parent–child pairs, median onset occurred 10.5 years earlier in offspring than in their parents, suggesting anticipation.Conclusion: This family is distinct from other families with SCA and is characterized by cerebellar ataxia and extrapyramidal signs.

In five generations of the French M-E kindred, 11 members are now known to be or have been affected by a form of spongiform encephalopathy previously recorded as Gerstmann-Sträussler-Scheinker disease. Mean age at onset was 28 years (range 21-34 years). In six instances, these patients were hospitalized in psychiatric institutions with various diagnoses, the most frequent being mania or mania-like symptoms. Dementia occurred progressively after a lengthy course. Histological studies showed atrophy of the cerebellar molecular layer, which contained kuru and multicentric plaques labelled with anti-prion protein antibodies. Spongiosis was not prominent and remained largely limited to the periphery of plaques; it was more marked in the thalamus, where plaques were scarce. A 192 base pair (bp) insert (eight extra repeats of 24 bp) in the octapeptide coding region of the prion protein gene (PRNP) within a codon-129 methionine allele was found in four symptomatic subjects. Early age at onset, the prominence of psychiatric symptoms and the long course of the disease are noticeable clinical features in this family with an inherited prion disease due to a new insertional mutation in PRNP.

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.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.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).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.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.

Abstract We investigated a French family with a new type of autosomal dominant spinocerebellar ataxia that was excluded from all previously identified genes and loci. The patients exhibited a slowly progressive gait and limb ataxia variably associated with akinesia, rigidity, tremor, and hyporeflexia. A mild cognitive impairment also was observed in some cases. We performed a genomewide search and found significant evidence for linkage to chromosome 7p21.3‐p15.1. Analysis of key recombinants and haplotype reconstruction traced this novel spinocerebellar ataxia locus to a 24cM interval flanked by D7S2464 and D7S516.

Abstract Benign hereditary chorea is a rare autosomal dominant disorder presenting with a childhood‐onset and slowly progressive chorea. The objective of this study was to describe the clinical and genetic features of 3 patients who developed childhood‐onset chorea. Three affected patients from three generations of a family with benign hereditary chorea associated with a multisystemic disorder of the basal ganglia, thyroid, lungs, salivary glands, bowels, and teeth. The TITF‐1 gene was screened by microsatellite analysis, gene sequencing, and fluorescence in situ hybridization. Genetic analysis revealed a novel 0.9‐Mb deletion on chromosome 14, which includes the TITF‐1 and PAX9 genes. We have identified a novel deletion responsible for a new syndrome of benign hereditary chorea, including symptoms of brain–thyroid–lung syndrome associated with bowels, salivary glands, and teeth disorders. Associated signs, sometimes of slight expression, remain of high interest for the clinical and genetic diagnosis of benign hereditary chorea. © 2006 Movement Disorder Society

To assess the prevalence of vigilance disorders in Parkinson's disease patients, relate the observed phenomena to potential causes and confirm these troubles with polysomnographic analysis.A questionnaire was used to gather information on demographic data, previous and current treatments, disease characteristics, sleep and vigilance troubles. Somnolence was measured using the Epworth Sleepiness Scale (ESS). Nocturnal polysomnography (PSG) and multiple sleep latency tests (MSLT) were performed for a sample of parkinsonian patients.Two hundred twenty-two parkinsonian patients completed the questionnaire, and 36 patients had objective analyses. Of the patients, 43.2% had an ESS score >10, and 28.4% reported somnolence in the hour after taking dopaminergic drugs, whereas 6.8% reported unintended sleep episodes. In view of questionnaire data, these vigilance disorders may be partly explained not only by the impact of nocturnal sleep disorders (e.g. sleep apnea syndromes) but also by dopaminergic therapy (especially with dopaminergic agonists). With PSG and MSLT results, we have shown a significant correlation between mean sleep latency and ESS score. Patients with unintended sleep episodes have severe sleepiness in MSLT compared with others patients.Vigilance disorders are frequently observed in Parkinson's disease. We recommend informing patients of the risk of occurrence of such conditions, notably for patients with unintended sleep episodes and with sleepiness in the hour after taking dopaminergic drugs.

Bilateral subthalamic nucleus (STN) stimulation is recognised as a treatment for parkinsonian patients with severe levodopa related motor complications. Although adverse effects are infrequent, some behavioural disturbances have been reported.To investigate the consequences of STN stimulation on emotional information processing in Parkinson's disease by assessing the performance of an emotional facial expression (EFE) decoding task in a group of patients before and after surgery.12 non-demented patients with Parkinson's disease were studied. They were assessed one month before surgery and three months after. Their ability to decode EFEs was assessed using a standardised quantitative task. Overall cognitive function, executive function, visuospatial perception, depression, and anxiety were also measured. Twelve healthy controls were matched for age, sex, and duration of education.Before surgery, the patients showed no impairment in EFE decoding compared with the controls. Their overall cognitive status was preserved but they had a moderate dysexecutive syndrome. Three months after surgery, they had significant impairment of EFE decoding. This was not related to their overall cognitive status or to depression/anxiety scores. Visuospatial perception was not impaired. There was no change in the extent of the dysexecutive syndrome except for a reduction in phonemic word fluency.Bilateral STN stimulation disturbs negative emotional information processing in Parkinson's disease. The impairment appears specific and unrelated to certain secondary variables. This behavioural complication of STN may have implications for the patient's social life.

Idiopathic hypertrophic cranial pachymeningitis (IHCP) is a rare clinical entity, characterized by a chronic inflammation causing thickening of the dura. Adequate therapeutic management is still a matter of debate. We present a patient with an IHCP, non-responsive to corticotherapy. Oral methotrexate was introduced (12.5 mg weekly) and total remission was observed after 6 weeks, both clinically and after neuro-imaging. We conclude that methotrexate can be effective and a therapeutical option in patients with IHCP who are resistant to corticotherapy or present major side-effects of chronic corticosteroids use.

Sir, In 2007, we described the clinical features and natural history of neuroferritinopathy in 41 patients defined at the molecular genetic level by the presence of Eco N1 restriction digestion site in exon 4 of FTL (also referred to as FTL1 ), the gene coding for the ferritin light polypeptide (Chinnery et al. , 2007). Three French patients in our paper (Cases 13, 36 and 39 in Table 1) had an identical restriction enzyme banding pattern to the original Cumbrian neuroferritinopathy family (Curtis et al. , 2001). Their early clinical course (Caparros-Lefebvre et al. , 1997) and molecular genetic analysis (Chinnery et al. , 2003) had been previously described. We recently received a DNA sample to confirm the diagnosis in a new member of the same French family. Given the recent description of three new FTL mutations (Vidal et al. , 2004; Maciel et al. , 2005; Mancuso et al. , 2005; Ohta et al. , 2008), we now sequence exon 4 of FTL to provide a more comprehensive molecular diagnostic approach. This showed that the new French patient had a different mutation, 458dupA, which segregated with the phenotype in the French family and was not found in 300 European controls. This mutation creates the same Eco N1 restriction site as 460dupA described in the original neuroferritinopathy family (Curtis et al. , 2001), and given that both the French and English pedigrees shared a …

Abstract Apathy is reported in 16.5% to 70% of Parkinson's disease (PD) patients. Our recently developed Lille Apathy Rating Scale (LARS) has been specifically validated for patient‐based assessment of apathy in PD. The aim of the present study was to validate a caregiver‐based version of the LARS. Sixty consecutive PD patients and their respective caregivers participated in the study. An informant‐based version of the LARS (LARS‐i) was developed to rate apathy via a caregiver‐based structured interview. Apathy was also assessed in a patient‐based interview using the LARS and the informant‐ and clinician‐rated versions of the Apathy Evaluation Scale (AES). Cronbach's alpha and standardized alpha coefficients were 0.872 and 0.877, respectively, and the split‐half reliability was 0.901 (revealing good internal consistency). The test‐retest and inter‐rater reliability values were 0.960 and 0.996, respectively. Criterion‐related validity (according to an independent, expert diagnosis) was good. Scores on the LARS and the LARS‐i were highly correlated. However, apathy was rated significantly more severely by the caregiver than by the patient. This difference was significantly higher for demented than nondemented PD patients. The LARS‐i was seen to have excellent psychometric properties and appears to be valid for use in PD with respect to the patient‐based LARS and the informant‐ and clinician‐rated versions of the AES. © 2008 Movement Disorder Society

Freezing of gait (FOG) in Parkinson's disease (PD) is defined as a sudden inability to maintain effective stepping movements. However, its pathophysiology remains unclear. The objectives are: (1) To assess the contribution of both spatial (walking speed, stride length) and temporal parameters (cadence, stride time) and their coefficients of variation to the genesis of FOG in PD. (2) To evaluate whether and how externally imposed modifications of self-determined gait would elicit FOG. We included ten patients with advanced PD, and with daily off drug FOG episodes. We focused on walking in an open runway. For each subject, we manipulated gait by externally imposing four changes in walking speed and four changes in cadence. FOG episodes, often with a long duration of more than 5-s, were observed mostly under conditions with a high imposed cadence. The steps that immediately preceded these episodes were mainly characterized by an increase in cadence and an increase in stride length variability. The results also underscore that FOG can be elicited in a laboratory setting when patients are placed under considerable strain, at least in advanced stages of PD. Patients were unable to adequately negotiate the extreme imposed cadence condition, and this resulted in frequent FOG episodes, even while walking in an open runway. Placing advanced PD patients into extreme imposed conditions leads to a motor wise and mental collapse response, culminating in FOG. Future work should establish the relevance of these findings for the more common forms of FOG, including brief episodes during turning or gait initiation.

Recently, mutations in DCTN1 were found to cause Perry syndrome, a parkinsonian disorder with TDP-43-positive pathology. Previously, mutations in DCTN1 were identified in a family with lower motor neuron disease, in amyotrophic lateral sclerosis (ALS), and in a family with ALS/frontotemporal dementia (FTD), suggesting a central role for DCTN1 in neurodegeneration.In this study we sequenced all DCTN1 exons and exon-intron boundaries in 286 samples diagnosed with Parkinson disease (PD), frontotemporal lobar degeneration (FTLD), or ALS.This analysis revealed 36 novel variants (9 missense, 5 silent, and 22 noncoding). Segregation analysis in families and association studies in PD, FTLD, and ALS case-control series did not identify any variants segregating with disease or associated with increased disease risk.This study suggests that pathogenic mutations in DCTN1 are rare and do not play a common role in the development of Parkinson disease, frontotemporal lobar degeneration, or amyotrophic lateral sclerosis.

Abstract Patients with Huntington's disease (HD) suffer from cognitive deficits with impaired executive functions, including limited attentional resources. We sought to use a dual‐task paradigm to evaluate attentional demands and the ability of patients with HD to concentrate on two tasks simultaneously. We analyzed the interference effects of cognitive and motor tasks on walking in HD and the contribution of clinical symptoms to gait disturbances. Patients and controls were asked to perform either a motor task (carrying a tray with four glasses), a cognitive task (counting backwards), or no task at all while walking at their preferred speed. Kinematic spatial parameters, temporal parameters, and angular parameters related to gait were recorded in 15 patients and 15 controls by means of a videomotion analysis system. Gait instability was assessed using the stride‐to‐stride variability of the various gait parameters. For patients with HD, performing a concurrent cognitive task resulted in a lower gait speed (compared with free walking), with decreased cadence and stride length. However, this effect was not observed in controls. Performing a motor task did not change any kinematic gait parameters in either HD or control subjects. We found correlations between gait speed in the dual cognitive/walking task on one hand and the motor UHDRS score, cognitive status and executive function on the other. Patients with HD had greater difficulty walking while performing a concurrent cognitive task; the drain on attentional resources deteriorated walking performance. © 2007 Movement Disorder Society

Mutations in the leucine-rich-repeat kinase 2 (LRRK2) gene have been identified in families with autosomal dominant Parkinson's disease (ADPD), the most common of which is the p.G2019S substitution that has been found at varying frequencies worldwide. Because of the size of the LRRK2 gene, few studies have analysed the entire gene in large series of ADPD families.We performed extensive mutation analyses of all 51 coding exons of the LRRK2 gene in index cases from 226 Parkinson's disease families compatible with autosomal dominant inheritance, mostly from France (n = 182) and North Africa (n = 14).We found 79 sequence variants, 29 of which were novel. Eight potentially or proven pathogenic mutations were found in 22 probands (9.7%). There were four novel amino acid substitutions that are potentially pathogenic (p.S52F, p.N363S, p.I810V, p.R1325Q) and two novel variants, p.H1216R and p.T1410M, that are probably not causative. The common p.G2019S mutation was identified in 13 probands (5.8%) including six from North Africa (43%). The known heterozygous p.R1441H and p.I1371V mutations were found in two probands each, and the p.E334K variant was identified in one single patient. Most potentially or proven pathogenic mutations were located in the functional domains of the Lrrk2 protein.This study leads us to conclude that LRRK2 mutations are a common cause of autosomal dominant Parkinson's disease in Europe and North Africa.

Mutations in the leucine-rich-repeat kinase 2 (LRRK2) gene have been identified in families with autosomal dominant Parkinson's disease (PD) and in sporadic cases; the G2019S mutation is the single most frequent. Intriguingly, the frequency of this mutation in PD patients varies greatly among ethnic groups and geographic origins: it is present at <0.1% in East Asia, approximately 2% in European-descent patients and can reach frequencies of up to 15-40% in PD Ashkenazi Jews and North African Arabs. To ascertain the evolutionary dynamics of the G2019S mutation in different populations, we genotyped 74 markers spanning a 16 Mb genomic region around G2019S, in 191 individuals carrying the mutation from 126 families of different origins. Sixty-seven families were of North-African Arab origin, 18 were of North/Western European descent, 37 were of Jewish origin, mostly from Eastern Europe, one was from Japan, one from Turkey and two were of mixed origins. We found the G2019S mutation on three different haplotypes. Network analyses of the three carrier haplotypes showed that G2019S arose independently at least twice in humans. In addition, the population distribution of the intra-allelic diversity of the most widespread carrier haplotype, together with estimations of the age of G2019S determined by two different methods, suggests that one of the founding G2019S mutational events occurred in the Near East at least 4000 years ago.

Twenty-seven to 80% of patients with Parkinson's Disease (PD) complain of subjective sleep dysfunction and insomnia symptoms. Our aim is to describe the prevalence and features of subjective sleep dysfunction and insomnia symptoms in patients with PD compared to other patients.Cross-sectional analysis of 636 adult PD patients compared to 143 age and sex-matched non-PD control patients consulting their general practitioners. Insomnia symptoms and other sleep features were assessed by the Pittsburgh Sleep Quality Index (PSQI), a global score > 5 defining impaired sleep. The Chi-square test or the Student's t-test were used to assess the potential clinical and demographic differences between groups and between PD patients with vs. without sleep dysfunction. Logistic regression analysis was employed to test multivariate effects.Sleep dysfunction and insomnia symptoms were more frequent in PD patients compared to control patients (63 vs. 45%, p = 0.001). Female gender, PD duration, presence of depression and anxiety were associated with the presence of insomnia in PD. Subjective sleep efficiency, habitual sleep quality, sleep disturbance and daytime dysfunction, but not sleep latency, were reduced in PD patients compared to controls.The prevalence of sleep dysfunction is higher in PD than in other general medical conditions. Insomnia in PD seems to affect sleep maintenance and consolidation, but not sleep onset.

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.

To investigate the neural and cognitive bases of upper limb apraxia in corticobasal degeneration (CBD).Eighteen patients with CBD underwent a cognitive neuropsychological assessment of apraxia and resting [(18)F]-fluorodeoxyglucose PET scanning. Two complementary measures of apraxia were computed for each modality of gesture production. First, a performance score measured error frequency during gesture execution. Second, as a more stringent test of the integrity of the praxis system, the correction score measured the patient's ability to correct his or her errors on a second attempt. For each measure type, a cut-off score for the presence of apraxia was defined with regard to healthy controls. Using each cut-off score, the regional cerebral glucose metabolism of patients with CBD with apraxia (i.e., performing below cut-off score) was compared with that of patients with CBD without apraxia.Mean performance scores were below normal values in all modalities. Anterior cingulate hypometabolism predominated in patients with CBD who performed below the cut-off performance score. At variance, mean correction scores were below normal values for gesture imitation only. Hypometabolism in superior parietal lobule and supplementary motor area characterized patients with CBD who were unable to correct their errors at the same rate as control subjects did.Distinct neural networks underlie distinct aspects of the upper limb apraxic deficits in CBD. Extending previous findings of gesture production deficits in CBD, the use of complementary measures of apraxic behavior discloses a visuoimitative upper limb apraxia in CBD, underlain by a metabolic decrease in a parietofrontal neural network.

To study planning of movement in Parkinson's disease.The spatiotemporal pattern of movement related desynchronisation (MRD) preceding a self paced voluntary wrist flexion was compared between two groups of 10 untreated right and left hemiparkinsonian patients receiving no treatment and 10 control subjects. The MRD was computed in the 9 to 11 Hz frequency band from 11 source derivations covering the frontocentral, central, and parietocentral areas, during two successive left and right experimental conditions.In the two patient groups the desynchronisation appeared over the primary sensorimotor area contralateral to the affected side with a shorter latency (750 ms before movement onset for the right hemiparkinsonian group and 875 ms for the left hemiparkinsonian group) than in the control group (1750 ms), only when the movements were performed with the akinetic hand. For the non-affected hand, the same latency as in the control group was noted (1750 ms).The delay of appearance of MRD in Parkinson's disease confirmed that the programming of movement is affected, thus partially explaining akinesia.

We compared autonomic function in patients with multiple system atrophy (MSA) or with idiopathic Parkinson's disease (IPD) by measuring sympathetic skin response (SSR) and R-R interval variability (RRIV). SSR was investigated in 26 patients (13 with MSA and 13 patients with IPD). RRIV during deep breathing, Valsalva maneuver, and on standing was investigated in 20 patients (nine with MSA and 11 with IPD). MSA and IPD patients had similar age, illness duration, and therapy. Abnormal SSR was more frequent in MSA (69%) than in IPD (7.7%; x2, 10.4; p < 0.002). RRIV during deep breathing and the Valsalva maneuver was lower in MSA than in IPD (p = 0.02). RRIV during standing up was not significantly different in IPD and MSA. These differences between MSA and IPD may be due to more severe and widespread autonomic disturbance in MSA, related to more severe neuropathologic involvement of the autonomic nervous system. SSR and RRIV may aid in the differential diagnosis of parkinsonism and help to exclude from clinical trials MSA patients clinically misdiagnosed as having IPD.

Abstract Sleep disturbances and vigilance disorders are frequently observed in Parkinson's disease. Despite the fact that the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) mouse is one of the best‐known animal models of Parkinson's disease, sleep analysis has never previously been performed in this system. In the present study, we explored sleep–wakefulness cycles in MPTP‐treated mice and compared the results to data from untreated mice. MPTP (25 mg/kg) was injected daily for 5 days. After recovery, polysomnography was recorded over 48 h. Dopaminergic lesions of the substantia nigra and striata were evaluated using immunohistochemical markers. Immunohistochemical analysis showed a loss of dopaminergic neurons in MPTP mice. Compared with controls, MPTP‐treated mice presented changes in sleep architecture throughout the nycthemeral period, with longer wakefulness and paradoxical sleep episodes and an increase in the amount of paradoxical sleep. We observed changes in sleep architecture in MPTP‐treated mice, compared with saline‐treated mice. MPTP mice show more consolidated vigilance states with higher amount of paradoxical sleep than controls. Although the MPTP‐treated mouse is not a good model of sleep disturbances in PD, our results suggest that it could be a good pharmacological model for studying the effects of dopaminergic treatments on animal sleep–wakefulness cycles.

Visual hallucinations are a core feature of dementia with Lewy bodies. Their pathophysiology is not well understood, because neither clinical nor histological data have shown their basic mechanisms. Here, we report the presence of pale inclusions in the outer plexiform layer of the retina in a patient with dementia with Lewy bodies. These inclusions are related to cytoskeletal disorganization of the cones at ultrastructural level and modifications of the immunohistochemical pattern of distribution of synucleins in the retina. These modifications may participate in the visual impairment in dementia with Lewy bodies.

Akinesia in basal ganglia disorders is essentially defined by delayed movement initiation; the reaction time increases and it becomes difficult (or even impossible) for the subject to initiate movement. A biomechanical study of gait initiation would help evaluate the role of akinesia in early stage Huntington's disease (HD) patients. We recorded kinematic, spatiotemporal and angular parameters (using video motion analysis, a force platform and an optoelectronic system) for the first two steps taken by 15 HD patients and 15 gender- and age-matched controls. In order to evaluate the influence of an external cue on gait initiation parameters, we studied two movement paradigms: self-triggered initiation and initiation triggered (cued) by a “beep” sound. We analyzed kinematic, spatiotemporal (the speed, length and duration of the two first steps) and angular parameters (range of joint angles) as well as kinetic data (the trajectory of the centre of pressure (COP); the speed and trajectory of the centre of mass (COM)). HD patients presented akinesia in both externally triggered and self-triggered conditions. Patients had more difficulties with self-triggered gait than with triggered gait. In HD, anticipatory postural adjustments (APAs) were more impaired in self-triggered gait initiation than in cued initiation. Indeed, an alteration in the kinetic parameters revealed a reduction in first step speed in both conditions. Hypokinesia (as assessed by a reduction in the range of angle joints) played an important role in this reduction. Akinesia is a major feature of impaired gait initiation in HD. The deficiencies in self-triggered initiation in HD seen here fit with a hypothesis whereby deficient internal cueing can be replaced by an external trigger.

The authors used flash electroretinography to demonstrate dysfunction of the photopic and scotopic retina in patients with dementia with Lewy bodies and visual hallucinations (VHs) compared with patients with Parkinson disease, patients without VHs, and controls. The retinal dysfunction may be related to slight alteration of the photoreceptors and numerous pale inclusions in the outer plexiform layer found at the post mortem examination, suggesting a specific retinopathy.

Seven patients with subdural empyema were initially treated by antibiotics without surgery.Six have recovered without sequelae.One required delayed surgery and has recovered with epilepsy.The authors emphasise the use of CT for the diagnosis and follow-up of subdural empy- ema, the principles and modalities of non-surgical treatment, and the good results, especially for late morbidity.From the medical literature, it is evident that, even when antibiotics became available, most authors have agreed there is need for surgery in all intracranial subdural empyemas.'However, this treatment has not prevented serious mortality'4 and sequelaes.'s Since the use of CT for the diagnosis of various central nervous system suppurations,6 7 some authors have treated brain abscesses,6 8 -10 extradural/intracranial abscesses" and even spinal epidural abscesses7 with- out surgery.We report here the results obtained with 7 patients with subdural empyema treated without surgery. Case reportsThe first three patients have been the subject of a previous report in a review about clinical and radiological findings in subdural empyemas.The second patient's history is reported in detail, and the six others are summarised in the table.Each patient's CT scan, before and after treatment, is shown in the figs 1-5.Patient 2This 19-year-old woman had a 1 week history of fever and bifrontal headache and received each day amoxicilline (1 g orally) for 4 days.She was admitted to the neurological department on 13 April 1982 with fever (38°5), headache and vomiting.She was lethargic, with a left hemiplegia and a palsy of both external recti.Her neck was stiff.Generalized seizures occurred.CSF contained 900 white cells/mm3 (100% polymorphonuclear), protein 0-6mg/l and glucose 0-6 g/l.ESR was 120 mm/h and WBC count was 15000 (80% polymorphonuclear).CT (fig 2a) revealed an interhemispheric area of low density with an enhanced thin

Fibrates and statins activate the Peroxisome Proliferator-Activated Receptor alpha (PPAR-alpha). This nuclear receptor regulates genes governing inflammation, apoptosis and oxidative stress, three important mechanisms of neuronal death in Parkinson's disease (PD). We retrospectively studied the effect of statins and fibrates in a cohort of 419 patients with PD. In PD patients receiving either a statin or a fibrate, the mean age of disease onset was delayed by nearly 9 years, when compared with (control) PD patients not taking a lipid-lowering treatment. According to a mixed linear model, the increase in the levodopa-equivalent daily dose over 2 years was significantly smaller in the group taking a statin (+24 mg) than in the matched control group (+212 mg) (p=0.004), whereas the Unified Parkinson's Disease Rating Scale motor score progression was similar. The course of the disease in patients taking a fibrate did not differ from the controls. These data suggest that lipid-lowering drugs may have a disease modifier effect, with a stronger action for statins than for fibrates.

Abstract In Huntington's disease (HD) patients, gait is characterized by a timing disorder with marked intraindividual variability in temporal gait parameters (caused by the presence of both hyperkinetic and hypokinetic features). We sought to determine the influence of use of a metronome on gait parameters in patients simultaneously performing motor or cognitive tasks that required attentional resources. The objective is to evaluate the influence of rhythmic cues on gait interference during self‐regulated walking and a dual task paradigm in HD. Fifteen HD patients and 15 paired controls were asked to walk and simultaneously perform another motor task (carrying a tray with four full glasses) or a cognitive task (counting backwards). We evaluated the effect of a metronome (set at 100% and 120% of the subject's self‐determined cadence) in three different task conditions (gait alone, gait + motor task, gait + cognitive task). The use of auditory cues during free gait and dual tasks did not improve kinematic parameters in HD patients, in contrast to the situation for control subjects (improvement in gait speed and cadence but not stride length when the metronome was set at 120% in all conditions). HD patients have difficulty in synchronizing their footsteps with a metronome, mainly due to attentional deficits. © 2008 Movement Disorder Society

Positron emission tomography with O-15-labeled water was used to study at rest the neurophysiological effects of bilateral external globus pallidus (GPe) deep brain stimulation in patients with Huntington's disease (HD). Five patients were compared with a control group in the on and off states of the stimulator. External globus pallidus stimulation decreased neuronal activity and modulated cerebral connectivity within the basal ganglia-thalamocortical circuitry, the sensorimotor, and the default-mode networks. These data indicate that GPe stimulation modulates functional integration in HD patients in accordance with the basal ganglia-thalamocortical circuit model.

Neurodegeneration with brain iron accumulation (NBIA) describes a group of progressive extrapyramidal disorders involving brain iron overload with diverse characteristics including pantothenate kinase-associated neurodegeneration (PKAN), neuroferritinopathy, infantile neuroaxonal dystrophy and aceruloplasminaemia.

Human MutationVolume 32, Issue 4 p. E2079-E2090 Mutation in BriefFree Access SNCA locus duplication carriers: from genetics to Parkinson disease phenotypes† Eugénie Mutez, Eugénie Mutez UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France Univ Lille Nord de France, Lille, France Movement Disorders Unit, Lille University Hospital, Lille, France These authors contributed equally to the studySearch for more papers by this authorFrédéric Leprêtre, Frédéric Leprêtre UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France Univ Lille Nord de France, Lille, France Functional Genomic Platform, UDSL, IRCL, Lille, France These authors contributed equally to the studySearch for more papers by this authorEmilie Le Rhun, Emilie Le Rhun Movement Disorders Unit, Lille University Hospital, Lille, France These authors contributed equally to the studySearch for more papers by this authorLydie Larvor, Lydie Larvor UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France Univ Lille Nord de France, Lille, France These authors contributed equally to the studySearch for more papers by this authorAurélie Duflot, Aurélie Duflot UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France Univ Lille Nord de France, Lille, FranceSearch for more papers by this authorVincent Mouroux, Vincent Mouroux UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France Univ Lille Nord de France, Lille, FranceSearch for more papers by this authorJean-Pierre Kerckaert, Jean-Pierre Kerckaert Univ Lille Nord de France, Lille, France Functional Genomic Platform, UDSL, IRCL, Lille, FranceSearch for more papers by this authorMartin Figeac, Martin Figeac Univ Lille Nord de France, Lille, France Functional Genomic Platform, UDSL, IRCL, Lille, FranceSearch for more papers by this authorKathy Dujardin, Kathy Dujardin Univ Lille Nord de France, Lille, France Movement Disorders Unit, Lille University Hospital, Lille, FranceSearch for more papers by this authorAlain Destée, Alain Destée UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France Univ Lille Nord de France, Lille, France Movement Disorders Unit, Lille University Hospital, Lille, FranceSearch for more papers by this authorMarie-Christine Chartier-Harlin, Corresponding Author Marie-Christine Chartier-Harlin [email protected] UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France Univ Lille Nord de France, Lille, FranceUMR 837 INSERM, Team 6, JParc, IRCL, Place de Verdun, 59045 Lille Cedex, FranceSearch for more papers by this author Eugénie Mutez, Eugénie Mutez UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France Univ Lille Nord de France, Lille, France Movement Disorders Unit, Lille University Hospital, Lille, France These authors contributed equally to the studySearch for more papers by this authorFrédéric Leprêtre, Frédéric Leprêtre UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France Univ Lille Nord de France, Lille, France Functional Genomic Platform, UDSL, IRCL, Lille, France These authors contributed equally to the studySearch for more papers by this authorEmilie Le Rhun, Emilie Le Rhun Movement Disorders Unit, Lille University Hospital, Lille, France These authors contributed equally to the studySearch for more papers by this authorLydie Larvor, Lydie Larvor UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France Univ Lille Nord de France, Lille, France These authors contributed equally to the studySearch for more papers by this authorAurélie Duflot, Aurélie Duflot UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France Univ Lille Nord de France, Lille, FranceSearch for more papers by this authorVincent Mouroux, Vincent Mouroux UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France Univ Lille Nord de France, Lille, FranceSearch for more papers by this authorJean-Pierre Kerckaert, Jean-Pierre Kerckaert Univ Lille Nord de France, Lille, France Functional Genomic Platform, UDSL, IRCL, Lille, FranceSearch for more papers by this authorMartin Figeac, Martin Figeac Univ Lille Nord de France, Lille, France Functional Genomic Platform, UDSL, IRCL, Lille, FranceSearch for more papers by this authorKathy Dujardin, Kathy Dujardin Univ Lille Nord de France, Lille, France Movement Disorders Unit, Lille University Hospital, Lille, FranceSearch for more papers by this authorAlain Destée, Alain Destée UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France Univ Lille Nord de France, Lille, France Movement Disorders Unit, Lille University Hospital, Lille, FranceSearch for more papers by this authorMarie-Christine Chartier-Harlin, Corresponding Author Marie-Christine Chartier-Harlin [email protected] UMR 837 INSERM, Team 6, JParc, IRCL, Lille, France Univ Lille Nord de France, Lille, FranceUMR 837 INSERM, Team 6, JParc, IRCL, Place de Verdun, 59045 Lille Cedex, FranceSearch for more papers by this author First published: 08 February 2011 https://doi.org/10.1002/humu.21459Citations: 29 † Communicated by Christine Van Broeckhoven AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract Genomic multiplication of the alpha-synuclein gene (SNCA) locus is one cause of familial Parkinson disease (PD). We performed detailed genomic, SNCA expression level, clinical, neuropsychological and functional imaging analyses of a parkinsonian kindred with a known duplication of the SNCA locus. We demonstrated that the duplication spanned 4.928 Mb (encompassing 31 known and putative genes) and was the largest to have been described at this locus. The presence of several repetitive long interspersed nuclear elements (LINEs) flanking the potential break area suggested that the duplication resulted from a genomic recombination between LINEs. We sequenced the break junction and confirmed the involvement of L1PA2 and L1PA4 in a non-allelic, homologous recombination. An analysis of mRNA levels in immortalized lymphoblastoid cells and peripheral blood mononuclear cells showed SNCA overexpression in subjects with the duplication, as well as overexpression of 13 other genes highlighting the usefulness of such cell models to study this duplication. Interestingly, abnormal tracer uptake in DaTSCAN® imaging correlated with the severity of the clinical symptoms. Our detailed genomic analysis and clinical exploration enabled us to specify the genotype-phenotype relationship, identify a case of presymptomatic PD and gain insight into the role of LINEs in SNCA locus duplication. © 2011 Wiley-Liss, Inc. Citing Literature Volume32, Issue4April 2011Pages E2079-E2090 RelatedInformation

Background In view of freezing of gait's circumstances of occurrence in Parkinson's disease, attentional resources appear to be involved in step initiation failure. Anticipatory postural adjustments (APAs) are essential because they allow unloading of the stepping leg and so create the conditions required for progression. Our main objective was to establish whether or not a change in attentional load during step initiation modulates APAs differently in patients with vs. without freezing of gait. Methods Three groups of 15 subjects were recruited: elderly people and parkinsonian patients with or without freezing of gait. Attention was modulated before step execution by means of an auditory oddball discrimination task with event-related potential recording. The primary endpoint was the occurrence of inappropriate APAs following the attentional task, i.e. APAs not followed by a step after an intercurrent auditory stimulus. Results In parkinsonian patients with freezing of gait, inappropriate APAs were recorded in 63% of the trials and were observed more frequently than in patients without freezing of gait (51%) and elderly controls (48%). Furthermore, inappropriate APAs in freezers were longer and more ample than in parkinsonian non-freezers and controls. Lastly, postural preparation was impaired in the parkinsonian patients. Conclusion Our results indicate that allocation of attentional resources during step preparation influences the release of APAs differently in freezers and non-freezers. Modulating attentional load is partly responsible for triggering an inappropriate motor program. This difficulty in focusing attention or resisting interference may contribute (at least in part) to the gait initiation failure observed in parkinsonian freezers.

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.

The best validated susceptibility variants for Parkinson's disease are located in the α-synuclein (SNCA) and microtubule-associated protein tau (MAPT) genes. Recently, a protective p.N551K-R1398H-K1423K haplotype in the leucine-rich repeat kinase 2 (LRRK2) gene was identified, with p.R1398H appearing to be the most likely functional variant. To date, the consistency of the protective effect of LRRK2 p.R1398H across MAPT and SNCA variant genotypes has not been assessed. To address this, we examined 4 SNCA variants (rs181489, rs356219, rs11931074, and rs2583988), the MAPT H1-haplotype–defining variant rs1052553, and LRRK2 p.R1398H (rs7133914) in Caucasian (n = 10,322) and Asian (n = 2289) series. There was no evidence of an interaction of LRRK2 p.R1398H with MAPT or SNCA variants (all p ≥ 0.10); the protective effect of p.R1398H was observed at similar magnitude across MAPT and SNCA genotypes, and the risk effects of MAPT and SNCA variants were observed consistently for LRRK2 p.R1398H genotypes. Our results indicate that the association of LRRK2 p.R1398H with Parkinson's disease is independent of SNCA and MAPT variants, and vice versa, in Caucasian and Asian populations.

In treatment for severe Parkinson's disease (PD), a recent procedure was developed which consists of implanting electrodes in the internal Globus Pallidus (GPi) for chronic electrical stimulation. The consequences on cognitive function of such an intervention are quite variable. Although most group studies observed no significant post-operative change, individual cases of post-operative cognitive impairment were reported. The present study reports the case of a PD patient who underwent bilateral implantation of deep brain stimulation electrodes in the GPi and who, after surgery, suffered from a severe dysexecutive syndrome. An extensive neuropsychological examination showed a selective negative effect of pallidal stimulation on tests assessing executive function. When the stimulation was turned off, the impairment was partly reversible. This observation emphasizes the role of the GPi in executive function.