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Dubois B.,University Pierre and Marie Curie | Tolosa E.,University of Barcelona | Tolosa E.,French Institute of Health and Medical Research | Katzenschlager R.,Donauspital SMZ Ost | And 9 more authors.
Movement Disorders | Year: 2012

Parkinson's disease dementia (PDD) is associated with cholinergic deficits. This report presents an efficacy and safety study of the acetylcholinesterase inhibitor donepezil hydrochloride in PDD. PDD patients (n = 550) were randomized to donepezil (5 or 10 mg) or placebo for 24 weeks. Coprimary end points were the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Clinician's Interview-Based Impression of Change plus caregiver input (CIBIC+; global function). Secondary end points measured executive function, attention, activities of daily living (ADLs), and behavioral symptoms. Safety and tolerability were assessed. ADAS-cog mean changes from baseline to week 24 (end point) were not significant for donepezil in the intent-to-treat population by the predefined statistical model (difference from placebo: -1.45, P = .050, for 5 mg; -1.45, P = .076, for 10 mg). Alternative ADAS-cog analysis, removing the treatment-by-country interaction term from the model, revealed significant, dose-dependent benefit with donepezil (difference from placebo: -2.08, P = .002, for 5 mg; -3.31, P < .001, for 10 mg). The 10-mg group, but not the 5-mg group, had significantly better CIBIC+ scores compared with placebo (3.7 vs 3.9, P = .113, for 5 mg; 3.6 vs 3.9, P = .040, for 10 mg). Secondary end points-Mini-Mental State Exam; Delis-Kaplan Executive Function System; Brief Test of Attention, representing cognitive functions particularly relevant to PDD-showed significant benefit for both donepezil doses (P ≤ .007). There were no significant differences in ADLs or behavior. Adverse events were more common with donepezil but mostly mild/moderate in severity. Although the study did not achieve its predefined primary end points, it presents evidence suggesting that donepezil can improve cognition, executive function, and global status in PDD. Tolerability was consistent with the known safety profile of donepezil. © 2012 Movement Disorder Society.

Selikhova M.,University College London | Selikhova M.,Reta Lila Weston Institute of Neurological Studies | Tripoliti E.,University College London | Fedoryshyn L.,Lviv Regional Clinical Hospital | And 6 more authors.
Clinical Neurology and Neurosurgery | Year: 2016

Introduction In the last fifteen years a new cause of chronic manganese toxicity has been recognized. It follows recreational intravenous injections of Ephedrone, synthesized from a cold remedies contained pseudoephedrine. Potassium permanganate is used as an oxidant. It presents with severe parkinsonism-dystonia and a characteristic dysarthria. Objectives We performed a focus perceptual study of dysarthria in Ephedrone induced parkinsonism and compared the findings with the speech disorders seen in Parkinson's disease (PD) and Progressive Supranuclear Palsy (PSP). Methods A digital voice recording, perceptual speech analysis (Darley, 1975) [18], serial neurological assessment and Brain Magnetic Resonance (MR) imaging were performed at the Lviv regional Clinical Hospital. The results were analysed at the Institute of Neurology in London. Results Dysarthria developed after 8.5 ± 3.2 months of daily intravenous Ephedrone abuse and was an initial symptom in a third of cases. It was characterised by a robotic-flat prosody, whispering or continuous phonation, an inability to regulate pitch and volume, frozen lip articulation, a variable degree of dystonic tightness, difficulties in speech initiation and palladia, There was no nasality and swallowing was normal. In some patients speech deteriorated even after the discontinuation of Ephedrone. MR imaging, performed soon after drug cessation showed T1 signal hyperintesity in striatum and pallidum, especially in the Globus Pallidum interna. Conclusion Ephedrone induced chronic manganese toxicity can lead to a mixed hypokinetic-dystonic dysarthria with a distinct dystonic pattern. Perceptual speech analysis can be a helpful ancillary investigation in the differential diagnosis of parkinsonism, and may permit the recognition of chronic manganese toxicity. © 2016 Elsevier B.V. All rights reserved.

Evans A.H.,Royal Melbourne Hospital | Evans A.H.,University of Melbourne | Evans A.H.,Reta Lila Weston Institute of Neurological Studies | Lawrence A.D.,University of Cardiff | And 3 more authors.
Movement Disorders | Year: 2010

A few Parkinson patients develop a disabling pattern of compulsive dopaminergic drug use ("dopamine dysregulation syndrome" - DDS). DDS patients commonly identify aversive dysphoric "OFF" mood-states as a primary motivation to compulsively use their drugs. We compared motoric, affective, nonmotor symptoms and incentive arousal after overnight medication withdrawal and after levodopa in DDS and control PD patients. Twenty DDS patients were matched to 20 control PD patients for age, gender, and disease duration and underwent a standard levodopa challenge. Somatic symptomatology, positive and negative affective states, drug effects, reward responsivity, motor disability, and dyskinesias were tested in the "OFF"-state after overnight withdrawal of medications, and then after a challenge with a standard dose of levodopa, after a full "ON"-state was achieved. In the "OFF"-state, DDS patients reported lower positive affect, and more motor and non-motor disability. In the "ON"-state, DDS patients had higher expressions of drug "wanting," reward responsivity, and dyskinesias. Positive and negative affect, non-motor symptomatology, and motor disability were comparable. These findings suggest that affective, motivational, and motoric disturbances in PD are associated with the transition to compulsive drug use in individuals who inappropriately overuse their dopaminergic medication. © 2010 Movement Disorder Society.

Doherty K.M.,Reta Lila Weston Institute of Neurological Studies | Davagnanam I.,National Hospital for Neurology and Neurosurgery | Molloy S.,Spinal Deformity Unit | Silveira-Moriyama L.,Reta Lila Weston Institute of Neurological Studies | And 2 more authors.
Journal of Neurology, Neurosurgery and Psychiatry | Year: 2013

Background: Although Pisa syndrome and scoliosis are sometimes used interchangeably to describe a laterally flexed postural deviation in Parkinson's disease (PD), the imaging findings of Pisa syndrome in PD have not been previously studied in detail. Methods: Patients with PD and Pisa syndrome (lateral flexion >10° in the standing position) were examined clinically and underwent radiological assessment using standing radiograph and supine CT scan of the whole spine. Results: Fifteen patients were included in this observational study. All patients had scoliosis on standing radiographs, and 12 had scoliosis persisting in the supine position. Scoliotic curves improved by a mean of 44% when patients moved from standing to supine. Only a quarter of patients with structural scoliosis had evidence of bony fusion on the side of their lateral deviation rendering their deformity fixed. Conclusions: Pisa syndrome describes a patient who lists to the side whereas scoliosis is defined by spinal curvature and rotation and may not be associated with lateral flexion. The finding of 'structural scoliosis' in Pisa syndrome should not preclude intervening to improve posture as most patients had little or no evidence of structural bony changes even when the deformity had been present for a number of years.

Trabzuni D.,University College London | Trabzuni D.,King Faisal Specialist Hospital And Research Center | Ryten M.,University College London | Emmett W.,University College London | And 32 more authors.
PLoS ONE | Year: 2013

Association studies have identified several signals at the LRRK2 locus for Parkinson's disease (PD), Crohn's disease (CD) and leprosy. However, little is known about the molecular mechanisms mediating these effects. To further characterize this locus, we fine-mapped the risk association in 5,802 PD and 5,556 controls using a dense genotyping array (ImmunoChip). Using samples from 134 post-mortem control adult human brains (UK Human Brain Expression Consortium), where up to ten brain regions were available per individual, we studied the regional variation, splicing and regulation of LRRK2. We found convincing evidence for a common variant PD association located outside of the LRRK2 protein coding region (rs117762348, A>G, P = 2.56×10-8, case/control MAF 0.083/0.074, odds ratio 0.86 for the minor allele with 95% confidence interval [0.80-0.91]). We show that mRNA expression levels are highest in cortical regions and lowest in cerebellum. We find an exon quantitative trait locus (QTL) in brain samples that localizes to exons 32-33 and investigate the molecular basis of this eQTL using RNA-Seq data in n = 8 brain samples. The genotype underlying this eQTL is in strong linkage disequilibrium with the CD associated non-synonymous SNP rs3761863 (M2397T). We found two additional QTLs in liver and monocyte samples but none of these explained the common variant PD association at rs117762348. Our results characterize the LRRK2 locus, and highlight the importance and difficulties of fine-mapping and integration of multiple datasets to delineate pathogenic variants and thus develop an understanding of disease mechanisms. © 2013 Trabzuni et al.

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