Parkinson Disease: Lang A

Beal F, Lang A. · No affiliation provided · Ann Neurol. · Pubmed #16862578 No free full text.

This publication has no abstract.

Marras C, Lang A. · Toronto Western Hospital, University Health Network and University of Toronto, Ontario, Canada. · Neurology. · Pubmed #18490620 No free full text.

Abstract: Recent years have seen major changes in our understanding of Parkinson disease (PD), challenging conventional wisdom, much of which was established during the Decade of the Brain. In this article, we highlight important changes in our understanding of PD in six general categories: definition, etiology, pathology, pathogenesis, clinical features, and therapeutics.

Zadikoff C, Rochon P, Lang A. · Morton and Gloria Shulman Movement Disorders Center, Toronto Western Hospital, University of Toronto, Toronto, ON, Canada. · Can J Neurol Sci. · Pubmed #16583718 No free full text.

Abstract: OBJECTIVE: To review the risk of pergolide associated cardiac valvulopathy in patients with Parkinson's disease. DATA SOURCES: MEDLINE, Embase, and the Cochrane Library. Reference lists were reviewed and librarians were consulted to identify additional trials. STUDY SELECTION: All studies and case reports in the English literature on pergolide and cardiac valvulopathy. Data extraction: Demographics of patients, study duration, dose and duration of pergolide use, echocardiogram results, length of follow-up, and clinical outcome. RESULTS: Twenty-two published articles were identified. There were no randomized controlled trials. Follow-up time varied between a few months and four years. Three case reports and four studies (three case control and one observational) assessed 246 patients. Evidence for valvulopathy was found in all studies. Variable methods were used to assess the degree of valvular regurgitation making comparisons between studies difficult. Little clinical correlation is available for echocardiogram results. Variable improvement was shown in the few patients in whom the drug was stopped. There is insufficient data to determine whether dose and duration or other comorbities have an effect on the risk of developing cardiac valvulopathy. CONCLUSION: Pergolide therapy is associated with an increased risk of developing cardiac valvulopathy but the true incidence and importance of this remains unknown. Further prospective studies are needed with standardized assessments of echocardiograms.

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.

This publication has no abstract.

Mendis T, Suchowersky O, Lang A, Gauthier S. · University of Ottawa, Ottawa Civic Hospital, SCO Hospitals, ON. · Can J Neurol Sci. · Pubmed #10352867 No free full text.

Abstract: The management of Parkinson's disease has undergone recent changes with the advent of new therapies, both pharmacotherapy and surgery. Available interventions are discussed. Levodopa remains the mainstay of therapy. New drugs include the dopamine agonists and COMT inhibitors. New dopamine agonists which may have a levodopa "sparing effect;" it has been suggested that some of the drugs should be considered as first line treatments for newly diagnosed Parkinson's disease patients. We review roles of these drugs. The concept of neuroprotection in neurodegenerative disorders such as Parkinson's disease became popular in the mid 1980s and it is hoped that eventually therapy will be directed at slowing progression of the disease. A great deal more work needs to be done before a suitable agent is identified as being neuroprotective. Potential neuroprotective agents are reviewed. Surgical therapies for Parkinson's disease consisting of various forms of lesion surgery as well as stimulation procedures are reviewed. Complications of drug therapy include motor problems such as motor response fluctuations, as well as psychiatric complications including levodopa-induced psychosis. Atypical neuroleptic agents and ECT for psychiatric syndromes associated with Parkinson's disease are discussed. Algorithms for the management of early disease as well as the management of psychosis in Parkinson's disease are included. Treatment options for advanced disease are tabulated.

Olanow CW, Hauser RA, Jankovic J, Langston W, Lang A, Poewe W, Tolosa E, Stocchi F, Melamed E, Eyal E, Rascol O. · Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029, USA. · Mov Disord. · Pubmed #18932271 No free full text.

Abstract: A neuroprotective therapy is the single most important unmet medical need in Parkinson's disease. Several promising agents in the laboratory have been tested in the clinic, but none has been established in clinical trials to have a disease modifying effect despite positive results because of potential confounding symptomatic or pharmacologic effects. The delayed start design was developed to try to avoid a symptomatic confound when testing a putative neuroprotective therapy. In this study design, patients are randomly assigned to study drug or placebo in the first phase of the study, and both groups receive the active drug in the second phase. If benefits seen at the end of phase I persist through the end of phase II, they cannot be readily explained by a symptomatic effect (as patients in both groups are receiving the same medication) and benefits in the early start group must relate to the early initiation of the treatment. Although the precise mechanism responsible for such an effect can be debated, positive results in a delayed start study indicate that patients who receive early treatment have a better outcome than those where the treatment is delayed. We are using the delayed start design to assess the potential disease modifying effects of rasagiline in a prospective double blind controlled trial (the ADAGIO study). We here describe the rationale for the study and baseline characteristics of the 1,176 patients who have been enrolled into the trial.

Fahn S, Oakes D, Shoulson I, Kieburtz K, Rudolph A, Lang A, Olanow CW, Tanner C, Marek K, Anonymous00069. · Columbia University, New York, USA. · N Engl J Med. · Pubmed #15590952 links to  free full text

Abstract: BACKGROUND: Despite the known benefit of levodopa in reducing the symptoms of Parkinson's disease, concern has been expressed that its use might hasten neurodegeneration. This study assessed the effect of levodopa on the rate of progression of Parkinson's disease. METHODS: In this randomized, double-blind, placebo-controlled trial, we evaluated 361 patients with early Parkinson's disease who were assigned to receive carbidopa-levodopa at a daily dose of 37.5 and 150 mg, 75 and 300 mg, or 150 and 600 mg, respectively, or a matching placebo for a period of 40 weeks, and then to undergo withdrawal of treatment for 2 weeks. The primary outcome was a change in scores on the Unified Parkinson's Disease Rating Scale (UPDRS) between baseline and 42 weeks. Neuroimaging studies of 142 subjects were performed at baseline and at week 40 to assess striatal dopamine-transporter density with the use of iodine-123-labeled 2-beta-carboxymethoxy-3-beta-(4-iodophenyl)tropane ([123I]beta-CIT) uptake. RESULTS: The severity of parkinsonism increased more in the placebo group than in all the groups receiving levodopa: the mean difference between the total score on the UPDRS at baseline and at 42 weeks was 7.8 units in the placebo group, 1.9 units in the group receiving levodopa at a dose of 150 mg daily, 1.9 in those receiving 300 mg daily, and -1.4 in those receiving 600 mg daily (P<0.001). In contrast, in a substudy of 116 patients the mean percent decline in the [123I]beta-CIT uptake was significantly greater with levodopa than placebo (-6 percent among those receiving levodopa at 150 mg daily, -4 percent in those receiving it at 300 mg daily, and -7.2 percent among those receiving it at 600 mg daily, as compared with -1.4 percent among those receiving placebo; 19 patients with no dopaminergic deficits on the baseline scans were excluded from the analysis) (P=0.036). The subjects receiving the highest dose of levodopa had significantly more dyskinesia, hypertonia, infection, headache, and nausea than those receiving placebo. CONCLUSIONS: The clinical data suggest that levodopa either slows the progression of Parkinson's disease or has a prolonged effect on the symptoms of the disease. In contrast, the neuroimaging data suggest either that levodopa accelerates the loss of nigrostriatal dopamine nerve terminals or that its pharmacologic effects modify the dopamine transporter. The potential long-term effects of levodopa on Parkinson's disease remain uncertain.

Holloway RG, Shoulson I, Fahn S, Kieburtz K, Lang A, Marek K, McDermott M, Seibyl J, Weiner W, Musch B, Kamp C, Welsh M, Shinaman A, Pahwa R, Barclay L, Hubble J, LeWitt P, Miyasaki J, Suchowersky O, Stacy M, Russell DS, Ford B, Hammerstad J, Riley D, Standaert D, Wooten F, Factor S, Jankovic J, Atassi F, Kurlan R, Panisset M, Rajput A, Rodnitzky R, Shults C, Petsinger G, Waters C, Pfeiffer R, Biglan K, Borchert L, Montgomery A, Sutherland L, Weeks C, DeAngelis M, Sime E, Wood S, Pantella C, Harrigan M, Fussell B, Dillon S, Alexander-Brown B, Rainey P, Tennis M, Rost-Ruffner E, Brown D, Evans S, Berry D, Hall J, Shirley T, Dobson J, Fontaine D, Pfeiffer B, Brocht A, Bennett S, Daigneault S, Hodgeman K, O'Connell C, Ross T, Richard K, Watts A, Anonymous00163. · Department of Neurology, University of Rochester, 1351 Mt. Hope Avenue, Suite 220, Rochester, NY 14620, USA. · Arch Neurol. · Pubmed #15262734 links to  free full text

Abstract: BACKGROUND: The best way to initiate dopaminergic therapy for early Parkinson disease remains unclear. OBJECTIVE: To compare initial treatment with pramipexole vs levodopa in early Parkinson disease, followed by levodopa supplementation, with respect to the development of dopaminergic motor complications, other adverse events, and functional and quality-of-life outcomes. DESIGN: Multicenter, parallel-group, double-blind, randomized controlled trial. SETTING: Academic movement disorders clinics at 22 sites in the United States and Canada. PATIENTS: Patients with early Parkinson disease (N = 301) who required dopaminergic therapy to treat emerging disability, enrolled between October 1996 and August 1997 and observed until August 2001. INTERVENTION: Subjects were randomly assigned to receive 0.5 mg of pramipexole 3 times per day with levodopa placebo (n = 151) or 25/100 mg of carbidopa/levodopa 3 times per day with pramipexole placebo (n = 150). Dosage was escalated during the first 10 weeks for patients with ongoing disability. Thereafter, investigators were permitted to add open-label levodopa or other antiparkinsonian medications to treat ongoing or emerging disability. MAIN OUTCOME MEASURES: Time to the first occurrence of dopaminergic complications: wearing off, dyskinesias, on-off fluctuations, and freezing; changes in the Unified Parkinson's Disease Rating Scale and quality-of-life scales; and adverse events. RESULTS: Initial pramipexole treatment resulted in a significant reduction in the risk of developing dyskinesias (24.5% vs 54%; hazard ratio, 0.37; 95% confidence interval [CI], 0.25-0.56; P<.001) and wearing off (47% vs 62.7%; hazard ratio, 0.68; 95% CI, 0.49-0.63; P =.02). Initial levodopa treatment resulted in a significant reduction in the risk of freezing (25.3% vs 37.1%; hazard ratio, 1.7; 95% CI, 1.11-2.59; P =.01). By 48 months, the occurrence of disabling dyskinesias was uncommon and did not significantly differ between the 2 groups. The mean improvement in the total Unified Parkinson's Disease Rating Scale score from baseline to 48 months was greater in the levodopa group than in the pramipexole group (2 +/- 15.4 points vs -3.2 +/- 17.3 points, P =.003). Somnolence (36% vs 21%, P =.005) and edema (42% vs 15%, P<.001) were more common in pramipexole-treated subjects than in levodopa-treated subjects. Mean changes in quality-of-life scores did not differ between the groups. CONCLUSIONS: Initial treatment with pramipexole resulted in lower incidences of dyskinesias and wearing off compared with initial treatment with levodopa. Initial treatment with levodopa resulted in lower incidences of freezing, somnolence, and edema and provided for better symptomatic control, as measured by the Unified Parkinson's Disease Rating Scale, compared with initial treatment with pramipexole. Both options resulted in similar quality of life. Levodopa and pramipexole both appear to be reasonable options as initial dopaminergic therapy for Parkinson disease, but they are associated with different efficacy and adverse-effect profiles.

Marras C, Lang A, Krahn M, Tomlinson G, Naglie G, Anonymous00241. · Division of Neurology, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada. · Mov Disord. · Pubmed #14743356 No free full text.

Abstract: The impact of dyskinesias and motor fluctuations on quality of life (QOL) at various stages in the course of Parkinson's disease (PD) is not well understood. In 301 subjects with early PD enrolled in a clinical trial (CALM-PD), we quantified the impact of motor complications on QOL and investigated how this changes over time. We also compared QOL related to demographic and treatment characteristics. The presence of dyskinesias was associated with visual analogue scale (VAS) scores 3.0 of 100 points higher (better) than those without dyskinesias in years 1 to 2, even when adjusting for Unified Parkinson's Disease Rating Scale (UPDRS) motor scores. The positive association between dyskinesias and QOL scores was more marked in older patients. In years 3 to 4, dyskinesias no longer had a significant relationship with QOL. Younger subjects had higher VAS scores. Gender, motor fluctuations, and treatment regimen had no significant association with QOL, although a trend was found toward a small negative effect of motor fluctuations on QOL. We conclude that motor complications that occur within the first 4 years of treatment of PD do not have a significant negative effect on quality of life as measured by a visual analogue scale for most patients.

Shoulson I, Oakes D, Fahn S, Lang A, Langston JW, LeWitt P, Olanow CW, Penney JB, Tanner C, Kieburtz K, Rudolph A, Anonymous00097. · University of Rochester Medical Center, Rochester, NY 14620, USA. · Ann Neurol. · Pubmed #12112107 No free full text.

Abstract: Deprenyl (selegiline) delays the need for levodopa therapy in patients with early Parkinson's disease, but the long-term benefits of this treatment remain unclear. During 1987 to 1988, 800 patients with early Parkinson's disease were randomized in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism trial to receive deprenyl, tocopherol, combined treatments, or a placebo and were then placed on active deprenyl (10mg/day). A second, independent randomization was carried out in early 1993 for 368 subjects who by that time had required levodopa and who had consented to continuing the deprenyl treatment (D subjects) or changing to a matching placebo (P subjects) under double-blind conditions. The first development of wearing off, dyskinesias, or on-off motor fluctuations was the prespecified primary outcome measure. During the average 2-year follow-up, there were no differences between the treatment groups with respect to the primary outcome measure (hazard ratio, 0.87; 95% confidence interval, 0.63, 1.19; p = 0.38), withdrawal from the study, death, or adverse events. Although 34% of D subjects developed dyskinesias and only 19% of P subjects did (p = 0.006), only 16% of D subjects developed freezing of gait but 29% of P subjects did (p = 0.0003). Decline in motor performance was less in D subjects than P subjects. Levodopa-treated Parkinson's disease patients who had been treated with deprenyl for up to 7 years, compared with patients who were changed to a placebo after about 5 years, experienced slower motor decline and were more likely to develop dyskinesias but less likely to develop freezing of gait.

Shoulson I, Penney J, McDermott M, Schwid S, Kayson E, Chase T, Fahn S, Greenamyre JT, Lang A, Siderowf A, Pearson N, Harrison M, Rost E, Colcher A, Lloyd M, Matthews M, Pahwa R, McGuire D, Lew MF, Schuman S, Marek K, Broshjeit S, Factor S, Brown D, Feigin A, Mazurkiewicz J, Ford B, Jennings D, Dilllon S, Comella C, Blasucci L, Janko K, Shulman L, Wiener W, Bateman-Rodriguez D, Carrion A, Suchowersky O, Lafontaine AL, Pantella C, Siemers E, Belden J, Davies R, Lannon M, Grimes D, Gray P, Martin W, Kennedy L, Adler C, Newman S, Hammerstad J, Stone C, Lewitt P, Bardram K, Mistura K, Miyasaki J, Johnston L, Cha JH, Tennis M, Panniset M, Hall J, Tetrud J, Friedlander J, Hauser R, Gauger L, Rodnitzky R, Deleo A, Dobson J, Seeberger L, Dingmann C, Tarsy D, Ryan P, Elmer L, Ruzicka D, Stacy M, Brewer M, Locke B, Baker D, Casaceli C, Day D, Florack M, Hodgeman K, Laroia N, Nobel R, Orme C, Rexo L, Rothenburgh K, Sulimowicz K, Watts A, Wratni E, Tariot P, Cox C, Leventhal C, Alderfer V, Craun AM, Frey J, McCree L, McDermott J, Cooper J, Holdich T, Read B, Anonymous00161. · No affiliation provided · Neurology. · Pubmed #11222787 No free full text.

Abstract: BACKGROUND: Preclinical studies suggest that glutamate antagonists help ameliorate motor fluctuations in patients with PD treated with levodopa. METHODS: In a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study, the authors assessed the safety, tolerability, and efficacy of the glutamate receptor blocker remacemide hydrochloride in 279 patients with motor fluctuations treated with levodopa. The primary objective was to assess the short-term tolerability and safety of four dosage levels of remacemide during 7 weeks of treatment. Patients were also monitored with home diaries and the Unified PD Rating Scale (UPDRS) to collect preliminary data on treatment efficacy. RESULTS: Remacemide was well tolerated up to a dosage of 300 mg/d on a twice daily schedule and 600 mg/d on a four times daily schedule. The most common dosage-related adverse events were dizziness and nausea, as observed in previous studies of remacemide. The percent "on" time and motor UPDRS scores showed trends toward improvement in the patients treated with 150 and 300 mg/d remacemide compared with placebo-treated patients, although these improvements were not significant. CONCLUSION: Remacemide is a safe and tolerable adjunct to dopaminergic therapy for patients with PD and motor fluctuations. Although this study had limited power to detect therapeutic effects, the observed improvement is consistent with studies of non-human primates with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonian signs and symptoms. Additional studies are warranted to confirm these results over an extended period of observation, and to explore the potential neuroprotective effects of remacemide in slowing the progression of PD.

Zadikoff C, Duong-Hua M, Sykora K, Marras C, Lang A, Rochon P. · Morton and Gloria Shulman Movement Disorders Center, Toronto Western Hospital, Department of Neurology, Toronto, Ontario, Canada. · Can J Neurol Sci. · Pubmed #18574930 No free full text.

Abstract: INTRODUCTION: Pergolide is an ergot derived dopamine agonist that is widely used for the treatment of Parkinson's disease. Studies have found an association between pergolide and valvular heart abnormalities although there is still much to be learned about the clinical significance of the valvular changes, who is at risk, and whether there is duration of exposure effect. OBJECTIVE: To assess the long term risk of hospital admissions for valvular heart disease (VHD) or congestive heart failure (CHF, a clinically overt outcome of VHD) in new users of pergolide compared to new users of levodopa. The secondary objective was to assess whether there are any characteristics that can predict who is at higher risk of developing this outcome. DESIGN: Retrospective, population-based cohort study. Setting: Ontario, Canada. SUBJECTS: Ontario residents aged 66 and older, newly started on treatment with either pergolide or levodopa. Outcomes: Admission to hospital with the most responsible diagnosis of congestive heart failure or valvular heart disease. RESULTS: The risk for admission for valvular heart disease or congestive heart failure were higher in those with 1-4 years exposure to pergolide compared with no exposure to pergolide (VHD: hazard ratio 2.4, p = 0.04; CHF: hazard ratio 1.6, p = 0.02). No such pattern was found with exposure to levodopa. CONCLUSION: Our study demonstrates that treatment with pergolide is associated with a higher risk of hospital admission for valvular heart disease or congestive heart failure and that this risk is greater in those with 1-4 years exposure than in those with less exposure. We did not find an increased risk beyond four years.

Lincoln S, Wiley J, Lynch T, Langston JW, Chen R, Lang A, Rogaeva E, Sa DS, Munhoz RP, Harris J, Marder K, Klein C, Bisceglio G, Hussey J, West A, Hulihan M, Hardy J, Farrer M. · Neurogenetic Laboratories, Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA. · Neurology. · Pubmed #12771249 No free full text.

Abstract: OBJECTIVE: To compare and contrast clinical and genetic findings in six probands with parkinsonism with a parkin exon 3 438- to 477-bp deletion (Ex3Delta40) to search for evidence of a common founder. METHOD: Clinical review, parkin gene sequencing, dosage studies, and high-resolution genotype/haplotype analysis were performed. RESULTS: All subjects had two or more signs consistent with a diagnosis of possible or probable PD with age at onset younger than 45 years (mean +/- SD 29.3 +/- 10.2 years, range 16 to 42 years). Affected individuals were either homozygotes, compound heterozygotes, or Ex3Delta40 carriers with one normal parkin allele. Haplotype analysis revealed both Ex3Delta40 and Ex7 924 C-->T (R275W) mutations originated from common founders, the former most probably of Irish descent. Although three cases had Ex7 924 C-->T (R275W) and Ex3Delta40 mutations, their clinical presentation and mode of inheritance were variable. CONCLUSION: Parkin mutations on common parkin haplotypes provide testable hypotheses of parkin function in genetically defined parkinsonism.

Fukuda M, Mentis M, Ghilardi MF, Dhawan V, Antonini A, Hammerstad J, Lozano AM, Lang A, Lyons K, Koller W, Ghez C, Eidelberg D. · Center for Neurosciences, North Shore-Long Island Jewish Research Institute, Manhasset, New York, USA. · Ann Neurol. · Pubmed #11220735 No free full text.

Abstract: We measured regional cerebral blood flow with H2 15O and positron emission tomography (PET) scanning at rest and during a motor task to study the mechanism of motor improvement induced by deep brain stimulation of the internal globus pallidus in Parkinson's disease. Six right-handed patients with Parkinson's disease were scanned while performing a predictable paced sequence of reaching movements and while observing the same screen displays and tones. PET studies were performed ON and OFF stimulation in a medication-free state. Internal globus pallidus deep brain stimulation improved off-state United Parkinson's Disease Rating Scale motor ratings (37%, p < 0.002) and reduced timing errors (movement onset time, 55%, p < 0.01) as well as spatial errors (10%, p < 0.02). Concurrent regional cerebral blood flow recordings revealed a significant enhancement of motor activation responses in the left sensorimotor cortex (Brodmann area [BA] 4), bilaterally in the supplementary motor area (BA 6), and in the right anterior cingulate cortex (BA 24/32). Significant correlations were evident between the improvement in motor performance and the regional cerebral blood flow changes mediated by stimulation. With internal globus pallidus deep brain stimulation, improved movement initiation correlated with regional cerebral blood flow increases in the left sensorimotor cortex and ventrolateral thalamus and in the contralateral cerebellum. By contrast, improved spatial accuracy correlated with regional cerebral blood flow increases in both cerebellar hemispheres and in the left sensorimotor cortex. These results suggest that internal globus pallidus deep brain stimulation may selectively improve different aspects of motor performance. Multiple, overlapping neural pathways may be modulated by this intervention.