Parkinson Disease: Lees A

Horstink M, Tolosa E, Bonuccelli U, Deuschl G, Friedman A, Kanovsky P, Larsen JP, Lees A, Oertel W, Poewe W, Rascol O, Sampaio C, Anonymous00036, Anonymous00037. · Department of Neurology, Radboud University Medical Centre, Nijmegen, The Netherlands. · Eur J Neurol. · Pubmed #17038032 No free full text.

Abstract: To provide evidence-based recommendations for the management of late (complicated) Parkinson's disease (PD), based on a review of the literature. Complicated PD refers to patients suffering from the classical motor syndrome of PD along with other motor or non-motor complications, either disease-related (e.g. freezing) or treatment-related (e.g. dyskinesias or hallucinations). MEDLINE, Cochrane Library and INAHTA database literature searches were conducted. National guidelines were requested from all EFNS societies. Non-European guidelines were searched for using MEDLINE. Part II of the guidelines deals with treatment of motor and neuropsychiatric complications and autonomic disturbances. For each topic, a list of therapeutic interventions is provided, including classification of evidence. Following this, recommendations for management are given, alongside ratings of efficacy. Classifications of evidence and ratings of efficacy are made according to EFNS guidance. In cases where there is insufficient scientific evidence, a consensus statement ('good practice point') is made.

Horstink M, Tolosa E, Bonuccelli U, Deuschl G, Friedman A, Kanovsky P, Larsen JP, Lees A, Oertel W, Poewe W, Rascol O, Sampaio C, Anonymous00034, Anonymous00035. · Department of Neurology, Radboud University Medical Centre, Nijmegen, The Netherlands. · Eur J Neurol. · Pubmed #17038031 No free full text.

Abstract: The aim of the study was to provide evidence-based recommendations for the management of early (uncomplicated) Parkinson's disease (PD), based on a review of the literature. Uncomplicated PD refers to patients suffering from the classical motor syndrome of PD only, without treatment-induced motor complications and without neuropsychiatric or autonomic problems. MEDLINE, Cochrane Library and International Network of Agencies for Health Technology Assessment (INAHTA) database literature searches were conducted. National guidelines were requested from all European Federation of Neurological Societies (EFNS) societies. Non-European guidelines were searched for using MEDLINE. Part I of the guidelines deals with prevention of disease progression, symptomatic treatment of motor features (parkinsonism), and prevention of motor and neuropsychiatric complications of therapy. For each topic, a list of therapeutic interventions is provided, including classification of evidence. Following this, recommendations for management are given, alongside ratings of efficacy. Classifications of evidence and ratings of efficacy are made according to EFNS guidance. In cases where there is insufficient scientific evidence, a consensus statement (good practice point) is made.

McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M, Anonymous00346. · Institute for Ageing and Health, University of Newcastle upon Tyne, UK. · Neurology. · Pubmed #16237129 No free full text.

Abstract: The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

Dubois B, Burn D, Goetz C, Aarsland D, Brown RG, Broe GA, Dickson D, Duyckaerts C, Cummings J, Gauthier S, Korczyn A, Lees A, Levy R, Litvan I, Mizuno Y, McKeith IG, Olanow CW, Poewe W, Sampaio C, Tolosa E, Emre M. · INSERM-UPMC UMRS 610, Federation of Neurology, AP-HP, Salpêtrière Hospital; Université Paris6, Paris, France. · Mov Disord. · Pubmed #18098298 links to  free full text

Abstract: A preceding article described the clinical features of Parkinson's disease dementia (PD-D) and proposed clinical diagnostic criteria for "probable" and "possible" PD-D. The main focus of this article is to operationalize the diagnosis of PD-D and to propose practical guidelines based on a two level process depending upon the clinical scenario and the expertise of the evaluator involved in the assessment. Level I is aimed primarily at the clinician with no particular expertise in neuropsychological methods, but who requires a simple, pragmatic set of tests that are not excessively time-consuming. Level I can be used alone or in concert with Level II, which is more suitable when there is the need to specify the pattern and the severity on the dementia of PD-D for clinical monitoring, research studies or pharmacological trials. Level II tests can also be proposed when the diagnosis of PD-D remains uncertain or equivocal at the end of a Level I evaluation. Given the lack of evidence-based standards for some tests when applied in this clinical context, we have tried to make practical and unambiguous recommendations, based upon the available literature and the collective experience of the Task Force. We accept, however, that further validation of certain tests and modifications in the recommended cut off values will be required through future studies.

Emre M, Aarsland D, Brown R, Burn DJ, Duyckaerts C, Mizuno Y, Broe GA, Cummings J, Dickson DW, Gauthier S, Goldman J, Goetz C, Korczyn A, Lees A, Levy R, Litvan I, McKeith I, Olanow W, Poewe W, Quinn N, Sampaio C, Tolosa E, Dubois B. · Department of Neurology, Behavioral Neurology and Movement Disorders Unit, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey. · Mov Disord. · Pubmed #17542011 links to  free full text

Abstract: Dementia has been increasingly more recognized to be a common feature in patients with Parkinson's disease (PD), especially in old age. Specific criteria for the clinical diagnosis of dementia associated with PD (PD-D), however, have been lacking. A Task Force, organized by the Movement Disorder Study, was charged with the development of clinical diagnostic criteria for PD-D. The Task Force members were assigned to sub-committees and performed a systematic review of the literature, based on pre-defined selection criteria, in order to identify the epidemiological, clinical, auxillary, and pathological features of PD-D. Clinical diagnostic criteria were then developed based on these findings and group consensus. The incidence of dementia in PD is increased up to six times, point-prevelance is close to 30%, older age and akinetic-rigid form are associated with higher risk. PD-D is characterized by impairment in attention, memory, executive and visuo-spatial functions, behavioral symptoms such as affective changes, hallucinations, and apathy are frequent. There are no specific ancillary investigations for the diagnosis; the main pathological correlate is Lewy body-type degeneration in cerebral cortex and limbic structures. Based on the characteristic features associated with this condition, clinical diagnostic criteria for probable and possible PD-D are proposed.

Lees A. · Reta Lila Weston Institute of Neurological Sciences, University College London, London, UK. · Drugs Aging. · Pubmed #16156677 No free full text.

Abstract: Parkinson's disease (PD) is primarily a disease of elderly patients. This article reviews current knowledge and recent developments relating to drugs that can be used as alternatives to levodopa as initial treatment of PD. Synthetic orally acting dopamine agonists have found increasing favour as an option for early PD in relatively young patients. This strategy is based on evidence that this approach may delay the onset of motor fluctuations, at least during the first 5 years of treatment. Subcutaneous apomorphine infusions may attenuate motor fluctuations in late-stage disease, and transdermal rotigotine, a dopamine agonist in development, has also been shown to be efficacious. The greater proclivity for dopamine agonists to cause psychotoxicity has, however, limited their routine use in the elderly. Selective monoamine oxidase type B (MAO-B) inhibitors, used as monotherapy, delay the need for the introduction of levodopa by about 9 months. These agents appear to be less efficacious than dopamine agonists but are better tolerated. Concern has been expressed about the potential of the MAO-B inhibitor selegiline (deprenyl) to induce cardiovascular adverse effects (orthostatic hypotension), either directly or through its amphetamine catabolites. Rasagiline is a new MAO-B inhibitor that is not broken down to amphetamine derivatives and is indicated as both monotherapy in early PD and as adjunctive therapy in PD patients with motor fluctuations. Two older classes of agents have undergone a resurgence of interest in recent years. Amantadine, which enhances dopaminergic transmission and has antiglutamate activity, is occasionally used as monotherapy but has recently been widely used as an antidyskinetic agent in late-stage PD. Anticholinergic drugs, such as benztropine (benzatropine) and orphenadrine also provide control of symptoms when used as monotherapy, but their psychotoxic, cognitive and autonomic adverse events make them inappropriate for the treatment of the elderly.Effective therapy in PD should prevent disease progression and abolish motor and cognitive handicap. Currently, none of the existing drugs meets all these needs.

Katzenschlager R, Sampaio C, Costa J, Lees A. · National Hospital for Neurology and Neurosurgery, Queen Square, Box 149, London, UK, WC1 N 3BG. · Cochrane Database Syst Rev. · Pubmed #12804486 No free full text.

Abstract: BACKGROUND: Anticholinergics were the first drugs available for the symptomatic treatment of Parkinson's disease and they are still widely used today, both as monotherapy and as part of combination regimes. They are commonly believed to be associated with a less favourable side effect profile than other antiparkinsonian drugs, in particular with respect to neuropsychiatric and cognitive adverse events. They have been claimed to exert a better effect on tremor than on other parkinsonian features. OBJECTIVES: To determine the efficacy and tolerability of anticholinergics in the symptomatic treatment of Parkinson's disease compared to placebo or no treatment. SEARCH STRATEGY: The literature search included electronic searches of the Cochrane Controlled Trials Register (The Cochrane Library, Issue 4, 2001), MEDLINE (1966 to 2001), Old Medline (1960-1965), Index Medicus (1927 - 1959), as well as handsearching the neurology literature including the reference lists of identified articles, other reviews and book chapters. SELECTION CRITERIA: Randomised controlled trials of anticholinergic drugs versus placebo or no treatment in de-novo or advanced Parkinson's disease, either as monotherapy or as an add-on to other antiparkinsonian drugs were included. Trials of anticholinergic drugs that were never in general clinical use were excluded. DATA COLLECTION AND ANALYSIS: Data was abstracted independently by two authors. Differences were settled by discussion among all authors. Data collected included patient characteristics, disease duration and severity, concomitant medication, interventions including duration and dose of anticholinergic treatment, outcome measures, rates of and reasons for withdrawals, and neuropsychiatric and cognitive adverse events. MAIN RESULTS: The initial search yielded 14 potentially eligible studies, five of which were subsequently excluded. In three cases this was because they dealt with substances that had never been marketed or had not been licensed for as far as could be traced back. One trial had been published twice in different languages. One study was excluded based on the assessment of its methodological quality. The remaining nine studies were all of double-blind cross-over design and included 221 patients. Trial duration was between five and 20 weeks and drugs investigated were benzhexol (mean doses: 8 to 20 mg/d), orphenadrine (mean dose not reported), benztropine (mean dose not reported), bornaprine (8 to 8.25 mg/d), benapryzine (200 mg/d), and methixine (45 mg/d). Only one study involved two anticholinergic drugs. Outcome measures varied widely across studies and in many cases, the scales applied were the authors' own and were not defined in detail. Incomplete reporting of methodology and results was frequent. The heterogeneous study designs as well as incomplete reporting precluded combined statistical analysis. Five studies used both tremor and other parkinsonian features as outcome measures. Outcome measures in these five studies were too different for a combined analysis and results varied widely, from a significant improvement in tremor only to significant improvement in other features but not in tremor. All studies except one (dealing with methixine) found a significant improvement from baseline on the anticholinergic drug in at least one outcome measure. The difference between placebo and active drug was reported in four studies and was found to be significant in all cases. No study failed to show superiority of the anticholinergic over placebo. The occurrence of neuropsychiatric and cognitive adverse events was reported in all but three studies (in 35 patients on active drug versus 13 on placebo). The most frequently reported reason for drop-outs from studies was in patients on placebo due to withdrawal from pre-trial anticholinergic treatment. REVIEWER'S CONCLUSIONS: As monotherapy or as an adjunct to other antiparkinsonian drugs, anticholinergics are more effective than placebo in improving motor function in Parkinson's disease. Neuropsychiatric and cognitive adverse events occur more frequently on anticholinergics than on placebo and are a more common reason for withdrawal than lack of efficacy. Results regarding a potentially better effect of the anticholinergic drug on tremor than on other outcome measures are conflicting and data do not strongly support a differential clinical effect on individual parkinsonian features. Data is insufficient to allow comparisons in efficacy or tolerability between individual anticholinergic drugs.

Agid Y, Ahlskog E, Albanese A, Calne D, Chase T, De Yebenes J, Factor S, Fahn S, Gershanik O, Goetz C, Koller W, Kurth M, Lang A, Lees A, Lewitt P, Marsden D, Melamed E, Michel PP, Mizuno Y, Obeso J, Oertel W, Olanow W, Poewe W, Pollak P, Tolosa E. · INSERM U 289 & Fédération de Neurologie, Hôpital de la Salpêtrière-47, Paris, France. · Mov Disord. · Pubmed #10584663 No free full text.

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Poltawski L, Edwards H, Todd A, Watson T, Lees A, James CA. · Division of Physiotherapy, University of Hertfordshire, UK. · Mov Disord. · Pubmed #19006068 No free full text.

Abstract: Apomorphine hydrochloride is a dopamine agonist used in the treatment of advanced Parkinson's disease. Its administration by subcutaneous infusions is associated with the development of nodules that may interfere with absorption of the drug. This pilot study assessed the effectiveness of ultrasound (US) in the treatment of these nodules. Twelve participants were randomly assigned to receive a course of real or sham US on an area judged unsuitable for infusion. Following treatment, no significant change was observed in measures of tissue hardness and tenderness. However, 5 of 6 participants receiving real US rated the treated area suitable for infusion compared with the 1 of 6 receiving sham US. Sonographic appearance improved in both groups, but more substantially in the real US group. Power calculations suggest a total sample size of 30 would be required to establish statistical significance. A full-scale study of the effectiveness of therapeutic US in the treatment of apomorphine nodules is warranted.

Rascol O, Poewe W, Lees A, Aristin M, Salin L, Juhel N, Waldhauser L, Schindler T, Anonymous00429. · Laboratoire de Pharmacologie Médicale et Clinique, Pôle Neurosciences, Centre d'Investigations Cliniques, Institut National de la Santé et de la Récherche Médicale, Unité 825, University Hospital, Toulouse, France. · Arch Neurol. · Pubmed #18474731 links to  free full text

Abstract: OBJECTIVE: To assess the safety and efficacy of tesofensine, a triple monoamine reuptake inhibitor, in patients with advanced Parkinson disease (PD). DESIGN: A pilot phase 2, randomized, double-blind, placebo-controlled, parallel-group trial. The study occurred in hospital-based outpatient clinics and in clinical trial units. Patients with advanced PD and levodopa-related motor fluctuations were enrolled. Tesofensine (0.125, 0.25, 0.5, or 1 mg) or placebo tablets were administered once daily for 14 weeks. MAIN OUTCOME MEASURES: Coprimary end points were the changes from baseline in Unified Parkinson Disease Rating Scale (UPDRS) subscale II (activities of daily living) plus subscale III (motor function) total score and in percentage of waking hours spent in "off" time noted in self-scoring diaries. Secondary end points were safety, pharmacokinetics, responder analysis (> or =20% reduction in UPDRS score and in off time), and changes in percentage of waking hours spent in "on" time with and without troublesome dyskinesia. RESULTS: The adjusted mean differences (relative to placebo) were -4.7 points in UPDRS subscale II plus subscale III total score (P =.005) with tesofensine, 0.5 mg, and -7.1% in off time (-68 minutes, P =.02) with tesofensine, 0.25 mg. Other dosages did not induce statistically significant effects. The plasma concentration increased with the dosage, but no clear dose-response relationship was observed. Gastrointestinal tract and neuropsychiatric adverse events were more frequent with tesofensine than with placebo, especially at the higher dosages. CONCLUSIONS: Patients with PD in advanced stages showed modest improvements in UPDRS subscale II plus subscale III total score and in off time when treated with tesofensine, but a dose-response relationship could not be established for efficacy, while adverse drug reactions tended to be more frequent at higher dosages. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00148512.

Rascol O, Dubois B, Caldas AC, Senn S, Del Signore S, Lees A, Anonymous00514. · INSERM U455, Clinical Investigation Center and Departments of Clinical Pharmacology and Neurosciences, Faculté de Médecine, Toulouse, France. · Mov Disord. · Pubmed #17013922 No free full text.

Abstract: Piribedil is a D2 dopamine agonist, which has been shown to improve symptoms of Parkinson's disease (PD) when combined with L-dopa. The objective of this study was to compare the efficacy of piribedil monotherapy to placebo in patients with early PD over a 7-month period. Four hundred and five early PD patients were randomized (double-blind) to piribedil (150-300 mg/day) or placebo. L-dopa open-label supplementation was permitted. Unified Parkinson Disease Rating Scale part III (UPDRS III) score as the last observation on monotherapy over 7 months was the primary outcome measure. Secondary outcomes were proportion of responders (UPDRS III improvement > 30%), patients remaining on monotherapy after 7 months, UPDRS III subscores, and UPDRS II. UPDRS III improved on piribedil (-4.9 points) versus a worsening on placebo (2.6 points; estimated effect = 7.26 points; 95% CI = 5.38-9.14; P < 0.0001). The proportion of responders was significantly higher for piribedil (42%) than for placebo (14%) (OR = 4.69; 95% CI = 2.82-7.80; P < 0.001). Piribedil significantly improved several UPDRS III subscores. UPDRS II improved on piribedil by -1.2 points, while it deteriorated by 1.5 points on placebo (estimated effect = 2.71; 95% CI = 1.8-3.62; P < 0.0001). The proportion of patients remaining on monotherapy after 7 months was greater in the piribedil group (OR = 3.72; 95% CI = 2.26-6.11; P < 0.001). Safety was consistent with that reported for other dopamine agonists, gastrointestinal side effects being the most common (22% of patients in piribedil group vs. 14% on placebo). Piribedil is effective and safe as early PD therapy.

Emre M, Aarsland D, Albanese A, Byrne EJ, Deuschl G, De Deyn PP, Durif F, Kulisevsky J, van Laar T, Lees A, Poewe W, Robillard A, Rosa MM, Wolters E, Quarg P, Tekin S, Lane R. · Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey. · N Engl J Med. · Pubmed #15590953 links to  free full text

Abstract: BACKGROUND: Cholinergic deficits are prominent in patients who have dementia associated with Parkinson's disease. We investigated the effects of the dual cholinesterase inhibitor rivastigmine in such patients. METHODS: Patients in whom mild-to-moderate dementia developed at least 2 years after they received a clinical diagnosis of Parkinson's disease were randomly assigned to receive placebo or 3 to 12 mg of rivastigmine per day for 24 weeks. Primary efficacy variables were the scores for the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) and Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change (ADCS-CGIC). Secondary clinical outcomes were the scores for the Alzheimer's Disease Cooperative Study-Activities of Daily Living, the 10-item Neuropsychiatric Inventory, the Mini-Mental State Examination, Cognitive Drug Research power of attention tests, the Verbal Fluency test, and the Ten Point Clock-Drawing test. RESULTS: A total of 541 patients were enrolled, and 410 completed the study. The outcomes were better among patients treated with rivastigmine than among those who received placebo; however, the differences between these two groups were moderate and similar to those reported in trials of rivastigmine for Alzheimer's disease. Rivastigmine-treated patients had a mean improvement of 2.1 points in the score for the 70-point ADAS-cog, from a baseline score of 23.8, as compared with a 0.7-point worsening in the placebo group, from a baseline score of 24.3 (P<0.001). Clinically meaningful improvements in the scores for the ADCS-CGIC were observed in 19.8 percent of patients in the rivastigmine group and 14.5 percent of those in the placebo group, and clinically meaningful worsening was observed in 13.0 percent and 23.1 percent, respectively (mean score at 24 weeks, 3.8 and 4.3, respectively; P=0.007). Significantly better outcomes were seen with rivastigmine with respect to all secondary efficacy variables. The most frequent adverse events were nausea (affecting 29.0 percent of patients in the rivastigmine group and 11.2 percent of those in the placebo group, P<0.001), vomiting (16.6 and 1.7 percent, P<0.001), and tremor (10.2 and 3.9 percent, P=0.01). CONCLUSIONS: In this placebo-controlled study, rivastigmine was associated with moderate improvements in dementia associated with Parkinson's disease but also with higher rates of nausea, vomiting, and tremor.

Grosset K, Grosset D, Lees A, Anonymous00387. · Institute of Neurological Sciences, Southern General Hospital, Glasgow, United Kingdom. · Mov Disord. · Pubmed #15580607 No free full text.

Abstract: The effect of pergolide 25 mug twice daily on levodopa initiation was assessed in a randomized, placebo-controlled, parallel group, double-blind multicenter trial in 106 untreated early Parkinson's disease patients. The primary endpoint of mean time until levodopa was 520 days (95% confidence interval [CI], 422-618 days) for pergolide versus 434 days (95% CI, 358-609 days) for placebo. However, this increase of 86 days for pergolide was not statistically significant. The wash-in effect of pergolide was significant at 6 weeks (change in mean Unified Parkinson's Disease Rating Scale [UPDRS] 2 and 3 was -0.1 [95% CI, -1.4 to 1.3] for pergolide vs. 2.2 [95% CI, 1.1-3.3] for placebo). At termination, the change from baseline in mean UPDRS 2 and 3 score was 11.4 (95% CI, 8.8-14) for pergolide and 14.6 (95% CI, 12-17.2) for placebo (P=0.08). There was no significant change in UPDRS 2 and 3 for the 83 patients achieving the planned 4-week washout at termination (pergolide 1.2 [95% CI, -0.8 to 3.2] vs. placebo 0.0 [95% CI, -1.6 to 1.6]. Adverse events were infrequent and occurred equally for pergolide and placebo. The study shows no evidence of a neuroprotective effect but indicates a mild symptomatic benefit from pergolide at a dose normally considered subtherapeutic.

Koller W, Lees A, Doder M, Hely M, Anonymous00136. · University of Miami, Miami, Florida, USA. · Mov Disord. · Pubmed #11746615 No free full text.

Abstract: In this 12-week, randomized, open-label, blinded-rater, parallel-group trial, the efficacy, safety, and tolerability of tolcapone and pergolide were compared in parkinsonian patients with a fluctuating response to levodopa. Patients received tolcapone 100 mg three times daily (t.i.d.), with a possible increase to 200 mg t.i.d., or pergolide titrated to a maximum dose of 5 mg/day by week 9 (mean final dose 2.2 mg/day). The trial involved 203 patients. Efficacy variables that decreased from baseline to week 12 with tolcapone and pergolide included "off" time (reduced by 2-3 hours/day), daily levodopa intake, sickness impact profile scores, Parkinson's disease questionnaire (PDQ)-39 scores, and Unified Parkinson's Disease Rating Scale (UPDRS) scores. Improvements in efficacy variables were similar with tolcapone and pergolide, with the exception of improvements in quality of life, which were significantly greater with tolcapone; the relative changes in PDQ-39 score at week 12 were -8.7 and -14.2 (P < 0.05) with pergolide and tolcapone, respectively. Improvements in the investigator's global assessment (IGA) of overall efficacy were recorded in 86% of tolcapone-treated patients and in 78% of pergolide-treated patients. The proportion of patients who withdrew because of adverse events was higher in the pergolide group (15%) than in the tolcapone group (5%). Confusion, hypotension, nausea, constipation, abdominal pain, and dyspepsia occurred more frequently with pergolide, whereas diarrhea and urine discoloration occurred more frequently with tolcapone. Tolcapone was better tolerated than pergolide (P < 0.01) according to the IGA of overall tolerability. We conclude that, in this 3-month study, both tolcapone and pergolide provided improvements in motor fluctuations and allowed reductions in levodopa intake when added to levodopa therapy; intent to treat analysis and a less than maximal dose of pergolide may have biased the results in favor of tolcapone. Tolcapone provided greater improvements in quality of fife, was better tolerated, and had a more favorable adverse-event profile than pergolide.

Marks L, Turner K, O'Sullivan J, Deighton B, Lees A. · Departments of Speech and Language Therapy and Neurology, UCLH/Middlesex Hospital, Mortimer Street, London W1T 8AA. · Int J Lang Commun Disord. · Pubmed #11340797 No free full text.

Abstract: Drooling and difficulty swallowing saliva are commonly reported in people with Parkinson's disease (PD). Drooling in PD is the result of swallowing difficulties rather than excessive saliva production. Currently, there is little research into the effectiveness of treatments to reduce drooling. The aims of the study were to develop objective measures of saliva volume and drooling for PD and to assess the efficacy of two therapeutic strategies to control drooling, i.e. specific speech and language therapy (SLT) including a portable metronome brooch to cue swallowing and injections of botulinum toxin into both parotid glands to reduce the amount of saliva produced. This paper will describe the assessments used, including the measurement of saliva, swallowing and drooling. The main focus will be the strategies used in the SLT intervention. The preliminary results are presented.

Grosset D, Antonini A, Canesi M, Pezzoli G, Lees A, Shaw K, Cubo E, Martinez-Martin P, Rascol O, Negre-Pages L, Senard A, Schwarz J, Strecker K, Reichmann H, Storch A, Löhle M, Stocchi F, Grosset K. · Institute of Neurological Sciences, Southern General Hospital, Glasgow, United Kingdom. · Mov Disord. · Pubmed #19191340 No free full text.

Abstract: Two small studies reported suboptimal therapy adherence in Parkinson's disease. We conducted a larger multicenter European study to assess medicine-taking behavior. Parkinson's disease patients taking dopaminergic therapy were enrolled in 8 centers in 5 countries, and disease severity and demographics recorded. Antiparkinson drug adherence was measured for 4 weeks using electronic monitoring bottles which record the date and time of cap opening (Aardex, Switzerland). One hundred twelve patients, mean age 65 years (standard deviation (SD) 10), with Parkinson's disease for 7.7 (SD 8.2) years completed the study. Total median adherence (doses taken/doses prescribed) was 97.7% (interquartile range [IQ] 90.6-100), days adherence (correct dose days) was 86.2% (IQ 61.1-96.2) and timing adherence (doses taken at correct time intervals) was 24.4% (IQ 5.3-56.5). Fourteen patients (12.5%) took less than 80% of prescribed doses, which was defined as suboptimal adherence. Patients with satisfactory adherence took a median of 8 mg/day (IQ 0-33) less than their prescribed dose of levodopa (P = NS), while suboptimal adherence patients took a median of 481 mg/day (IQ 205-670) less than their prescribed dose (P = 0.0006). The Parkinson motor score was significantly higher in patients with suboptimal adherence at 29 (IQ 20-40), versus those with satisfactory adherence at 19 (IQ 13-26), P = 0.005. Once daily drugs had significantly better adherence when compared with drugs prescribed more frequently (P < 0.0001). Suboptimal therapy adherence is associated with significant deviation from prescribed levodopa doses, despite greater Parkinson's motor severity. Optimizing oral medication intake has a potential role in maximizing the therapy response in Parkinson's disease.

Blackinton J, Kumaran R, van der Brug MP, Ahmad R, Olson L, Galter D, Lees A, Bandopadhyay R, Cookson MR. · Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, United States. · Neurosci Lett. · Pubmed #19146923 No free full text.

Abstract: Mutations in DJ-1 lead to a monogenic form of early onset recessive parkinsonism. DJ-1 can respond to oxidative stress, which has been proposed to be involved in the pathogenesis of sporadic Parkinson disease (PD). We have recently reported that DJ-1 interacts with mRNA in an oxidation-dependent manner. Here, we confirm interaction of DJ-1 and RNA in human brain using immunoprecipitation followed by quantitative real time PCR. We confirmed previous reports that DJ-1 is more oxidized in cortex from cases of sporadic PD compared to controls. In the same samples, protein and RNA expression was measured for four DJ-1 target genes GPx4, MAPK8IP1, ND2 and ND5. While no alterations in mRNA expression were observed, an increase in protein expression was observed in PD cases for GPx4 and MAPK8IP1. In the same patients, we saw decreased mRNA and protein levels of two mitochondrial targets, ND2 and ND5. These results suggest that these proteins undergo regulation at the post-transcriptional level that may involve translational regulation by DJ-1.

Goetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P, Poewe W, Sampaio C, Stern MB, Dodel R, Dubois B, Holloway R, Jankovic J, Kulisevsky J, Lang AE, Lees A, Leurgans S, LeWitt PA, Nyenhuis D, Olanow CW, Rascol O, Schrag A, Teresi JA, van Hilten JJ, LaPelle N, Anonymous00025. · Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612, USA. · Mov Disord. · Pubmed #19025984 links to  free full text

Abstract: We present a clinimetric assessment of the Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS). The MDS-UDPRS Task Force revised and expanded the UPDRS using recommendations from a published critique. The MDS-UPDRS has four parts, namely, I: Non-motor Experiences of Daily Living; II: Motor Experiences of Daily Living; III: Motor Examination; IV: Motor Complications. Twenty questions are completed by the patient/caregiver. Item-specific instructions and an appendix of complementary additional scales are provided. Movement disorder specialists and study coordinators administered the UPDRS (55 items) and MDS-UPDRS (65 items) to 877 English speaking (78% non-Latino Caucasian) patients with Parkinson's disease from 39 sites. We compared the two scales using correlative techniques and factor analysis. The MDS-UPDRS showed high internal consistency (Cronbach's alpha = 0.79-0.93 across parts) and correlated with the original UPDRS (rho = 0.96). MDS-UPDRS across-part correlations ranged from 0.22 to 0.66. Reliable factor structures for each part were obtained (comparative fit index > 0.90 for each part), which support the use of sum scores for each part in preference to a total score of all parts. The combined clinimetric results of this study support the validity of the MDS-UPDRS for rating PD.

Blomstedt P, Hariz MI, Lees A, Silberstein P, Limousin P, Yelnik J, Agid Y. · Department of Neurosurgery, University Hospital of Northern Sweden, Umeå, Sweden. · Parkinsonism Relat Disord. · Pubmed #17561432 No free full text.

Abstract: We present a 62 years old man with Parkinson's disease (PD) who underwent bilateral stimulation in the subthalamic nucleus (STN). During the intraoperative evaluation, stimulation through the lowest contact in the right STN area, induced an acute depressive state, during which the patient was crying and expressing that he did not want to live. The patient returned to his normal state of mood within seconds after the cessation of stimulation. Repeated blinded stimulations resulted in the same response. Immediate postoperative magnetic resonance imaging (MRI) revealed that the lowest contact of the right electrode was located in the substantia nigra.

Ravina B, Marder K, Fernandez HH, Friedman JH, McDonald W, Murphy D, Aarsland D, Babcock D, Cummings J, Endicott J, Factor S, Galpern W, Lees A, Marsh L, Stacy M, Gwinn-Hardy K, Voon V, Goetz C. · Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14620, USA. · Mov Disord. · Pubmed #17266092 No free full text.

Abstract: There are no standardized diagnostic criteria for psychosis associated with Parkinson's disease (PDPsy). As part of an NIH sponsored workshop, we reviewed the existing literature on PDPsy to provide criteria that distinguish PDPsy from other causes of psychosis. Based on these data, we propose provisional criteria for PDPsy in the style of the Diagnostic and Statistical Manual of Mental Disorders IV-TR. PDPsy has a well-characterized temporal and clinical profile of hallucinations and delusions, which is different than the pattern seen in other psychotic disorders such as substance induced psychosis or schizophrenia. PDPsy is associated with a poor prognosis of chronic psychosis, nursing home placement, and death. Medications used to treat Parkinson's disease (PD) contribute to PDPsy but may not be sufficient or necessary contributors to PDPsy. PDPsy is associated with Lewy bodies pathology, imbalances of monoaminergic neurotransmitters, and visuospatial processing deficits. These findings suggest that PDPsy may result from progression of the disease process underlying PD, rather than a comorbid psychiatric disorder or drug intoxication. PDPsy is not adequately described by existing criteria for psychotic disorders. We established provisional diagnostic criteria that define a constellation of clinical features not shared by other psychotic syndromes. The criteria are inclusive and contain descriptions of the full range of characteristic symptoms, chronology of onset, duration of symptoms, exclusionary diagnoses, and associated features such as dementia. These criteria require validation and may be refined, but form a starting point for studies of the epidemiology and pathophysiology of PDPsy, and are a potential indication for therapy development.

Goetz CG, Fahn S, Martinez-Martin P, Poewe W, Sampaio C, Stebbins GT, Stern MB, Tilley BC, Dodel R, Dubois B, Holloway R, Jankovic J, Kulisevsky J, Lang AE, Lees A, Leurgans S, LeWitt PA, Nyenhuis D, Olanow CW, Rascol O, Schrag A, Teresi JA, Van Hilten JJ, LaPelle N. · Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612, USA. · Mov Disord. · Pubmed #17115387 links to  free full text

Abstract: This article presents the revision process, major innovations, and clinimetric testing program for the Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson's Disease Rating Scale (UPDRS), known as the MDS-UPDRS. The UPDRS is the most widely used scale for the clinical study of Parkinson's disease (PD). The MDS previously organized a critique of the UPDRS, which cited many strengths, but recommended revision of the scale to accommodate new advances and to resolve problematic areas. An MDS-UPDRS committee prepared the revision using the recommendations of the published critique of the scale. Subcommittees developed new material that was reviewed by the entire committee. A 1-day face-to-face committee meeting was organized to resolve areas of debate and to arrive at a working draft ready for clinimetric testing. The MDS-UPDRS retains the UPDRS structure of four parts with a total summed score, but the parts have been modified to provide a section that integrates nonmotor elements of PD: I, Nonmotor Experiences of Daily Living; II, Motor Experiences of Daily Living; III, Motor Examination; and IV, Motor Complications. All items have five response options with uniform anchors of 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. Several questions in Part I and all of Part II are written as a patient/caregiver questionnaire, so that the total rater time should remain approximately 30 minutes. Detailed instructions for testing and data acquisition accompany the MDS-UPDRS in order to increase uniform usage. Multiple language editions are planned. A three-part clinimetric program will provide testing of reliability, validity, and responsiveness to interventions. Although the MDS-UPDRS will not be published until it has successfully passed clinimetric testing, explanation of the process, key changes, and clinimetric programs allow clinicians and researchers to understand and participate in the revision process.

Abou-Sleiman PM, Muqit MM, McDonald NQ, Yang YX, Gandhi S, Healy DG, Harvey K, Harvey RJ, Deas E, Bhatia K, Quinn N, Lees A, Latchman DS, Wood NW. · Department of Molecular Neuroscience, Institute of Neurology, London, United Kingdom. · Ann Neurol. · Pubmed #16969854 No free full text.

Abstract: OBJECTIVE: To investigate the significance of PINK1 mutations in sporadic Parkinson's disease (PD). METHODS: We determined the frequency of PINK1 mutations by direct sequencing in a large series of PD patients with apparently sporadic disease (n = 768). RESULTS: Twelve heterozygous mutations were identified, nine in PD patients and three in control subjects. INTERPRETATION: Given the difficulty in interpreting the pathogenic significance of the heterozygous mutations that have already been reported in parkin and DJ-1, we first determined the frequency of heterozygous PINK1 mutations in the general population by sequencing a large number of control subjects (n = 768), then subsequently assessed their functional significance by examining their effects on stress-induced alterations to the mitochondrial membrane potential (DeltaPsim). We demonstrate an enrichment of heterozygous mutations in sporadic PD patients compared with matched control subjects (1.2% in PD vs 0.4% in control subjects). Furthermore, we show that they adversely affect DeltaPsim in a similar way to the familial G309D mutation. Although it remains difficult to conclusively demonstrate the pathogenicity of heterozygous mutations, the results of this study and the previously reported subclinical nigrostriatal dysfunction in carriers of heterozygous PINK1 mutations suggest the possibility that these heterozygous mutations are a significant risk factor in the development of later onset PD.

Greggio E, Jain S, Kingsbury A, Bandopadhyay R, Lewis P, Kaganovich A, van der Brug MP, Beilina A, Blackinton J, Thomas KJ, Ahmad R, Miller DW, Kesavapany S, Singleton A, Lees A, Harvey RJ, Harvey K, Cookson MR. · Cell Biology and Gene Expression Unit, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892-3707, USA. · Neurobiol Dis. · Pubmed #16750377 No free full text.

Abstract: Mutations in the LRRK2 gene, coding for dardarin, cause dominantly inherited Parkinson's disease (PD). Dardarin is a large protein, and mutations are found throughout the gene including the kinase domain. However, it is not clear if kinase activity is important for the damaging effects of pathogenic mutations. In this study, we noted two cellular phenotypes associated with mutant dardarin. First, pathogenic mutations increase the tendency of dardarin to form inclusion bodies. Secondly, neurons and neuronal cell lines undergo cell death after expression of mutant protein. Manipulating activity by replacing the kinase domain with a 'kinase-dead' version blocks inclusion body formation and strongly delays cell death. This predicts that kinase inhibitors will be useful therapeutic agents in patients with LRRK2 mutations and, perhaps, in sporadic PD. We also show that dardarin protein is expressed within human midbrain neurons and that C-terminal epitopes are also found in some Lewy bodies.

Findley LJ, Lees A, Apajasalo M, Pitkänen A, Turunen H. · Essex Neurosciences Unit, Oldchurch Hospital, Essex, UK. · Curr Med Res Opin. · Pubmed #16004667 No free full text.

Abstract: BACKGROUND AND METHODS: A Markov model was developed to evaluate the cost-effectiveness of levodopa/carbidopa/entacapone (LCE;Stalevo), in the treatment of patients with Parkinson's disease (PD) and end-of-dose motor fluctuations (wearing-off). LCE, with or without other antiparkinsonian medications, was compared to UK standard care, comprising traditional levodopa/ dopa-decarboxylase inhibitor (DDCI) with other antiparkinsonian medications (e.g. selegiline or dopamine agonists) added as needed. The costs and outcomes of both treatments were projected over a period of 10 years from the perspective (a) of society as a whole and (b) of the UK National Health Service (NHS). Sensitivity analyses, including second-order Monte Carlo simulations, were performed to assess the confidence level of the primary results. RESULTS: Treatment with LCE produced an average gain of +1.04 quality-adjusted life-years (QALYs) per patient (2.57 vs. 1.53) in the base-case analysis (discount rate 3.5%). This gain was accompanied by a reduction in the total 10-year direct cost of care to society of 10198 pounds per patient ( approximately E14800). From the societal perspective, therefore, LCE was dominant, producing better clinical outcomes with lower costs. This dominance was reiterated in all sensitivity analyses of society-focused analysis, including a shortening of the time-frame to 5 years.Although treatment with LCE resulted in an increase in direct costs per patient of 3239 pounds (25756 pounds versus 22517 pounds) to the NHS over the 10-year period analysed, the incremental cost-effectiveness ratio (ICER) of LCE was only 3105 pounds per QALY gained (approximately E4500). All ICERs to the NHS remained below 3800 pounds per QALY gained in univariate sensitivity analyses applying different discount rates. When a shorter, 5-year, time-horizon was analysed, the NHS-related ICER for LCE was 6526 pounds per QALY gained. All these ICERs are within the range usually considered to indicate acceptable or highly acceptable cost effectiveness (defined as < 30000 pounds per QALY gained).The results of the Monte Carlo simulations indicated that the likelihood of LCE being either 'dominant' or more effective at an 'acceptable cost' from either the societal or the NHS perspective was high, exceeding 96% in the base-case sensitivity analysis, and was 93% even when all the uncertainties associated with the model were taken into consideration simultaneously. In particular, compared to standard care, the probability that LCE would provide better outcomes at a lower cost to society as a whole was 77% in the base-case sensitivity analysis and 72% in the scenario involving the highest degree of uncertainty. CONCLUSIONS: In the UK the use of LCE to treat PD patients with wearing-off is beneficial to individual patients and likely to offer money savings to society as a whole, compared with UK standard therapy. The added cost of the medication itself is exceeded by the savings made in other direct costs of PD, mainly those relating to social care or PD-related private expenditures.

Nath U, Thomson R, Wood R, Ben-Shlomo Y, Lees A, Rooney C, Burn D. · Regional Neurosciences Centre, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne NE4 6BE, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #15774434 links to  free full text

Abstract: OBJECTIVE: To estimate the mortality of progressive supranuclear palsy (PSP) and to assess the quality of death certification in patients with PSP who died in England and Wales. METHODS: An analysis was conducted of ICD-9 (International Classification of Diseases, version 9) coded deaths obtained through the Office of National Statistics over an eight year period. RESULTS: The crude annual mortality rate was 1.77 (95% confidence interval, 1.64 to 1.90) cases per million, using the mid-1996 population estimate for England and Wales. Annual mortality increased over time, possibly as a result of increased incidence or increased awareness of the disorder. Forty nine death certificates from deceased patients previously diagnosed clinically showed that the commonest proximate cause of death was pneumonia, occurring in 45% of cases (22/49). The underlying cause of death was cited as pneumonia in 14% of cases (7/49). PSP was mentioned in only 65% of death certificates (32/49). Eight of the 49 cases (16%) underwent necropsy and results were available for five of these cases. PSP was confirmed pathologically in four; the remaining case was diagnosed as Parkinson's disease. CONCLUSIONS: Further research is needed to establish the reasons for the observed increase in mortality. Determining the population mortality rate for PSP using the ICD-9 coding system is problematic but is likely to improve following the introduction of ICD-10 updated codes and coding rules.