Original Article
A Double-Blind, Delayed-Start Trial of Rasagiline in Parkinson's Disease
N Engl J Med 2009; 361:1268-1278September 24, 2009
- Abstract
Background
A therapy that slows disease progression is the major unmet need in Parkinson's disease.
Methods
In this double-blind trial, we examined the possibility that rasagiline has disease-modifying effects in Parkinson's disease. A total of 1176 subjects with untreated Parkinson's disease were randomly assigned to receive rasagiline (at a dose of either 1 mg or 2 mg per day) for 72 weeks (the early-start group) or placebo for 36 weeks followed by rasagiline (at a dose of either 1 mg or 2 mg per day) for 36 weeks (the delayed-start group). To determine a positive result with either dose, the early-start treatment group had to meet each of three hierarchical end points of the primary analysis based on the Unified Parkinson's Disease Rating Scale (UPDRS, a 176-point scale, with higher numbers indicating more severe disease): superiority to placebo in the rate of change in the UPDRS score between weeks 12 and 36, superiority to delayed-start treatment in the change in the score between baseline and week 72, and noninferiority to delayed-start treatment in the rate of change in the score between weeks 48 and 72.
Results
Early-start treatment with rasagiline at a dose of 1 mg per day met all end points in the primary analysis: a smaller mean (±SE) increase (rate of worsening) in the UPDRS score between weeks 12 and 36 (0.09±0.02 points per week in the early-start group vs. 0.14±0.01 points per week in the placebo group, P=0.01), less worsening in the score between baseline and week 72 (2.82±0.53 points in the early-start group vs. 4.52±0.56 points in the delayed-start group, P=0.02), and noninferiority between the two groups with respect to the rate of change in the UPDRS score between weeks 48 and 72 (0.085±0.02 points per week in the early-start group vs. 0.085±0.02 points per week in the delayed-start group, P<0.001). All three end points were not met with rasagiline at a dose of 2 mg per day, since the change in the UPDRS score between baseline and week 72 was not significantly different in the two groups (3.47±0.50 points in the early-start group and 3.11±0.50 points in the delayed-start group, P=0.60).
Conclusions
Early treatment with rasagiline at a dose of 1 mg per day provided benefits that were consistent with a possible disease-modifying effect, but early treatment with rasagiline at a dose of 2 mg per day did not. Because the two doses were associated with different outcomes, the study results must be interpreted with caution. (ClinicalTrials.gov number, NCT00256204.)
Media in This Article
Figure 1
Schematic Illustration of the Three Primary End Points of the Study.Figure 2
Randomization and Treatment of the Study Subjects.Article Activity
- Article
A neuroprotective therapy that slows or stops disease progression is the major unmet medical need in Parkinson's disease.1 Although current therapies provide beneficial effects on symptoms that help control the classic motor features of the disease (i.e., tremor, rigidity, and bradykinesia), intolerable disability eventually develops in most patients.2 Numerous agents have neuroprotective effects in laboratory models, but none have been shown to have disease-modifying effects in patients with Parkinson's disease.3 A limiting factor is the requirement for a clinical end point that reliably measures disease progression and is not confounded by the study intervention's effects on symptoms.
The delayed-start design was introduced to address this problem.4,5 Delayed-start studies are conducted in two phases. In phase 1, subjects are randomly assigned to receive either active drug or placebo. Differences between groups at the end of this phase could be related to effects on symptoms, disease-modifying effects, or both. In phase 2, subjects in both groups receive the active drug. Persistent differences between the two groups at the end of phase 2 cannot be readily explained by effects on symptoms alone, since both groups are receiving the same treatment, and these differences are consistent with the possibility of a disease-modifying effect.
Rasagiline (N-propargyl-[1R]-aminoindan) (Azilect, Teva Pharmaceutical Industries) is an inhibitor of monoamine oxidase type B (MAO-B) that is approved for the symptomatic treatment of Parkinson's disease.6-8 Rasagiline also provides neuroprotective effects in laboratory models of neurodegeneration.9-12 In the present study, we used the delayed-start design to examine the potential disease-modifying effects of rasagiline in Parkinson's disease.13
Methods
Study Design
The Attenuation of Disease Progression with Azilect Given Once-daily (ADAGIO) study was an 18-month, double-blind, placebo-controlled, multicenter trial that used a delayed-start design.13 The study was performed in two phases, each lasting 36 weeks. In phase 1, subjects were randomly assigned to one of four study groups: rasagiline at a dose of either 1 mg or 2 mg per day (the early-start groups) or corresponding placebo. In phase 2, subjects in the early-start groups continued to receive their assigned treatment while subjects in the placebo groups switched to rasagiline at a dose of 1 mg or 2 mg per day (the delayed-start groups). Thus, the early-start groups received rasagiline (1 mg or 2 mg per day) for 72 weeks, and the delayed-start groups received placebo for 36 weeks followed by rasagiline (1 mg or 2 mg per day) for 36 weeks. No concomitant antiparkinsonian medication was permitted. If subjects required additional treatment during phase 1, they could proceed directly to phase 2. Subjects who required additional therapy in phase 2 were withdrawn from the study.
Subjects
Men and women between 30 and 80 years of age who were not currently receiving treatment for Parkinson's disease were eligible for the study. The diagnosis of Parkinson's disease was based on the presence of at least two of the three cardinal features of the disease (resting tremor, bradykinesia, or rigidity); if resting tremor was not present, subjects had to have unilateral onset of symptoms. Subjects who had previously received any antiparkinsonian medication for more than 3 weeks or who had received rasagiline or selegiline (at any dose) or coenzyme Q10 (at more than 300 mg per day) within the previous 120 days were not eligible. Other exclusion criteria included a disease duration of more than 18 months since diagnosis, a Hoehn and Yahr stage of 3 or higher (scores in the Hoehn and Yahr staging system for Parkinson's disease range from 1 to 5, with higher scores indicating more severe disability), and atypical or secondary parkinsonism.
Visits were performed at baseline and at weeks 4, 12, 24, 36, 42, 48, 54, 60, 66, and 72. At each visit (except week 4), subjects were evaluated with the Unified Parkinson's Disease Rating Scale (UPDRS, which ranges from 0 to 176 and includes subscales of mental function, activities of daily living, and motor function, with higher scores indicating more severe disease).14 Adverse events and vital signs were recorded at each visit. There was no restriction in dietary intake of tyramine, and certain antidepressant agents were allowed.
Teva Pharmaceutical Industries funded the study and was responsible for data collection, monitoring, and statistical analysis. The authors were responsible for the study design, interpretation of the data, the writing of the manuscript, and the decision to submit the manuscript for publication. The authors had complete access to the database, performed independent statistical analyses, and vouch for the completeness and accuracy of the data and data analysis.
Statistical Analysis
The primary analysis comprised three hierarchical end points based on the change from baseline in the total UPDRS score (Figure 1Figure 1
Schematic Illustration of the Three Primary End Points of the Study.). The first end point compared estimates of slope (the change in UPDRS points per week) between the rasagiline groups (1 mg or 2 mg per day) and placebo groups from weeks 12 through 36. This comparison determined whether there was a difference in the rate of disease progression, as reflected by the UPDRS score, between each rasagiline group and placebo after week 12, when it was assumed that the full effect of rasagiline on symptoms had been established. A disease-modifying agent would be expected to slow the rate of progression, as compared with placebo.The second end point compared the estimated change in the total UPDRS score between baseline and week 72 in the early-start and delayed-start rasagiline groups (1 mg or 2 mg per day). This comparison determined whether the benefits observed in the early-start group at the end of phase 1 were still present at the end of the study, when subjects in the early-start and delayed-start groups were receiving the same treatment. Benefits of early-start treatment would be expected to persist if the treatment had a disease-modifying effect.
The third end point tested for the noninferiority of slope estimates for the rate of change from baseline in the UPDRS score between weeks 48 and 72 in the early-start groups as compared with the delayed-start groups. A noninferiority margin of 0.15 UPDRS points per week was prespecified. This end point was designed to determine whether the difference between the groups was enduring (as would be expected with a disease-modifying effect) and not diminishing (as would be expected with an agent that had a prolonged and cumulative effect on symptoms).
For each dose, all three end points had to be met to declare the study positive. The secondary end point was the change in the total UPDRS score between baseline and the last observed value in phase 1. The sample size was based on the calculation used in the Rasagiline (TVP-1012) in Early Monotherapy for Parkinson's Disease Outpatients (TEMPO) study (ClinicalTrials.gov number, NCT00203060).15 This calculation indicated that 1100 subjects would be required to provide an 87% power to detect a difference of 1.8 UPDRS points between the early-start and delayed-start groups in the mean change in the UPDRS score from baseline to the average of the UPDRS scores from weeks 48 to 72, with an alpha level of 0.05 and a 15% dropout rate.
For the first primary end point, all subjects who underwent evaluations at baseline and week 12 or later were included in the analysis. For the second and third primary end points, all subjects who received at least 24 weeks of treatment during phase 1 and who underwent an evaluation at the week 48 visit or later were included. Safety assessments included all subjects who were randomly assigned to a study treatment.
Statistical analysis was performed with a mixed-model repeated-measures analysis of covariance that included the following fixed effects: treatment group, week in trial, week-by-treatment interaction, center, and total UPDRS score at baseline. The first end point was analyzed with the use of the combined placebo groups. For end points two and three, the model was fitted separately for each dose because heterogeneous covariate effects were observed between the two doses. To maintain a type I error of 0.05 in the overall study, the hierarchical method was used to account for multiple primary end points for each dose and the Hochberg step-up Bonferroni method was used to account for testing of two doses16; this allowed for each dose to be tested separately. Various prespecified sensitivity and supportive analyses, including multiple imputation strategies, were used to validate the results and address the issue of missing data. For the secondary end point, an analysis-of-covariance model was used to assess the adjusted mean change in the total UPDRS score between baseline and the last observed value in phase 1.
To address the possibility that an effect on symptoms might mask a disease-modifying effect in this cohort of subjects with very mild disease, a post hoc subgroup analysis was conducted in subjects with high total UPDRS scores (i.e., the highest quartile of scores) at baseline.
Results
Characteristics of the Subjects
A total of 1176 subjects were recruited from 129 centers in 14 countries, signed an informed-consent form approved by the local institutional review board, and were assigned to a treatment group according to a centralized, computer-generated randomization schedule (Figure 2Figure 2
Randomization and Treatment of the Study Subjects.). A total of 1164 subjects (99%) were included in the first primary end-point analysis, and 996 subjects (85%) were included in the second and third primary end-point analyses. Baseline demographic and clinical characteristics are shown in Table 1Table 1
Baseline Characteristics of the Subjects.. There were no significant differences among the treatment groups. The mean duration of disease from the time of diagnosis was 4.5 months, and the mean total UPDRS score was 20.4.Responses to Treatment
Results of the three end points comprising the primary analysis and the secondary end point for each dose are shown in Table 2Table 2
Results for the Primary and Secondary End Points.. For each dose, the mean change in the UPDRS score from baseline to each visit is shown in Figure 3Figure 3
Changes in Scores on the Unified Parkinson's Disease Rating Scale (UPDRS) in the Four Study Groups..Among subjects who received rasagiline at a dose of 1 mg per day, the estimates of change in the slope of UPDRS scores per week between weeks 12 and 36 showed a slower rate of worsening (i.e., increase in the UPDRS score) for rasagiline (0.09±0.02 points per week) than for placebo (0.14±0.01 points per week) (P=0.01). The early-start group had less worsening in the mean total UPDRS score between baseline and week 72 (2.82±0.53 points) than the delayed-start group (4.50±0.56 points) (P=0.02). The estimates of the change in the UPDRS scores (slope) between weeks 48 and 72 showed noninferiority of the response in the early-start group (0.085±0.02 points per week) as compared with the response in the delayed-start group (0.085±0.02 points per week) (P<0.001). Thus, rasagiline at a dose of 1 mg per day met all three end points in the primary analysis. The model for the first primary end point assumed linearity in the rate of change in UPDRS points per week; results were confirmed by means of an alternative categorical model. The results of the second primary end point were confirmed by several predefined sensitivity and confirmatory analyses (Table 1 in the Supplementary Appendix, available with the full text of this article at NEJM.org).
For the secondary end point (the change in the total UPDRS score between baseline and the last observed value in phase 1), rasagiline at a dose of 1 mg per day (1.26±0.36 points) was superior to placebo (4.27±0.26 points) (P<0.001).
Among subjects who received rasagiline at a dose of 2 mg per day, estimates of the rate of change in the UPDRS slope between weeks 12 and 36 showed less worsening in the rasagiline group (0.07±0.02 points per week) than in the placebo group (0.14±0.01 points per week) (P<0.001). However, the change in the total UPDRS score between baseline and week 72 in the early-start group (3.47±0.50 points) did not differ significantly from that in the delayed-start group (3.11±0.50 points) (P=0.60). The estimates of the rate of change in the UPDRS score between weeks 48 and 72 showed noninferiority of the response in the early-start group (0.094±0.01 points per week) as compared with the response in the delayed-start group (0.065±0.02 points per week) (P<0.001). Thus, rasagiline at a dose of 2 mg per day did not meet all three end points of the primary analysis, and the results were negative for this dose. For the secondary end point, rasagiline at a dose of 2 mg per day (1.11±0.36 points) was superior to placebo (4.27±0.26 points) (P<0.001).
Post Hoc Subgroup Analysis
To address the possibility that rasagiline at a dose of 2 mg per day had an effect on symptoms that might have masked a disease-modifying benefit in subjects with very low UPDRS scores, the primary and secondary analyses were performed for subjects with total UPDRS scores in the highest quartile (>25.5 points) at baseline. Among subjects receiving 2 mg of rasagiline per day, the difference in the change in UPDRS scores from baseline to week 72 between the early-start and delayed-start groups was significantly greater among subjects with baseline UPDRS scores in the highest quartile than among subjects with scores in the other three quartiles (P=0.03). This interaction suggests that these subgroups can be considered separately. Subjects with baseline UPDRS scores in the highest quartile who received either 1 mg or 2 mg of rasagiline per day met all three primary end points (Table 2a in the Supplementary Appendix). In the subgroup of 114 subjects with UPDRS scores in the highest quartile who received rasagiline at a dose of 2 mg per day, subjects in the early-start group had less worsening in the UPDRS score between baseline and week 72 than subjects in the delayed-start group (−3.63±1.72 points) (P=0.04). In the 105 subjects with UPDRS scores in the highest quartile at baseline who received rasagiline at a dose of 1 mg per day, subjects in the early-start group had less worsening in the total UPDRS score between baseline and week 72 than subjects in the delayed-start group (−3.40±1.66 points) (P=0.04). In the subgroup of subjects with UPDRS scores in the lower three quartiles (≤25.5 points) at baseline, neither dose met all three primary end points (Table 2b in the Supplementary Appendix).
Adverse Events
Adverse events are listed in Table 3Table 3
Adverse Events, According to Treatment Group.. One subject in the early-start group who received rasagiline at a dose of 1 mg per day had a melanoma at week 72. No subject had tyramine or serotonin reactions.Discussion
In this study, we used a delayed-start design to look for possible disease-modifying effects of rasagiline in early Parkinson's disease. Significant benefits had to be achieved in three hierarchical primary end points for results to be considered positive for either dose. There had to be less worsening in the rate of change in the UPDRS score between weeks 12 and 36 as compared with placebo, less worsening in the UPDRS score between baseline and week 72 in the early-start group than in the delayed-start group, and noninferiority with respect to the rate of change (worsening) in the UPDRS score between weeks 48 and 72 in the early-start group as compared with the delayed-start group. Rasagiline at a dose of 1 mg per day met all three predefined end points; rasagiline at a dose of 2 mg per day did not. Both doses of rasagiline had beneficial effects on symptoms, as compared with placebo, findings that are similar to those that have been reported previously.6
It is difficult to explain why the two doses (1 mg per day and 2 mg per day) did not provide similar results. There were no significant differences in baseline characteristics between the two rasagiline groups, nor was there a significant difference in dropout rates. In the laboratory, the protective effects of propargylamines are characterized by a U-shaped curve; that is, an increase or decrease in the concentration of the propargylamine can be associated with a loss of benefit.17 However, these effects are observed with logarithmic changes, and it is difficult to imagine that protective effects could be lost with a mere doubling of the dose. A marked effect of the 2-mg dose on symptoms might have masked a benefit associated with early-start treatment in this population of patients with very mild disease. Indeed, for rasagiline at a dose of 2 mg, a post hoc subgroup analysis showed that for subjects in the highest quartile of UPDRS scores at baseline, early-start rasagiline provided a significant benefit over delayed-start rasagiline with respect to the change in the UPDRS score between baseline and 72 weeks (−3.63 UPDRS points), and all primary end points were met despite the relatively small sample. Furthermore, at a dose of 2 mg per day, early-start treatment with rasagiline was superior to delayed-start rasagiline in the TEMPO study, in which subjects had relatively high UPDRS scores at baseline (mean, 25.0 points).15 Similar findings were observed in subjects in the highest quartile of UPDRS scores who received rasagiline at a dose of 1 mg per day.
These observations are consistent with the hypothesis that the effects on symptoms associated with the dose of 2 mg per day may have masked disease-modifying effects in this population of subjects with very mild disease. Since this explanation is primarily supported by a post hoc analysis, it cannot be considered to be conclusive, and we cannot rule out the possibility that the findings with rasagiline at a dose of 1 mg per day represent false positive results rather than that the findings with 2 mg per day represent false negative results. In future delayed-start studies, it might be worthwhile to include subjects with slightly more advanced disease.
Although the study results were not consistent for the two doses, they provide support for the possibility that rasagiline at a dose of 1 mg per day has a disease-modifying effect, since at this dose, early treatment is associated with less worsening in the UPDRS score than delayed treatment. This effect cannot be readily explained by an effect on symptoms alone, since both groups received the same treatment for the last 9 months of the study. It is theoretically possible that these results are due to an effect on symptoms that evolves over a prolonged period of time, but this explanation seems unlikely, given that there was no indication that the slopes in the early-start and delayed-start groups were converging after 9 months of treatment.
The possibility that rasagiline might have a neuroprotective effect is supported by laboratory studies showing that the drug, and its metabolite 1-(R)-aminoindan, have antiapoptotic effects and protect neurons from a variety of toxins in various models.9-12,18-20 Neuroprotection in these models appears to be related to a propargyl ring incorporated within the rasagiline molecule rather than to MAO-B inhibition.20,21 Other MAO-B inhibitors and propargylamines have been tested for disease-modifying effects in Parkinson's disease. Several trials have shown positive results with selegiline, but a confounding effect of the drug on symptoms could not be ruled out.22,23 Conversely, a trial of TCH346 showed negative results, but the correct dose may not have been used.24 Although neuroprotection is a plausible explanation for the results seen with rasagiline at a dose of 1 mg per day, alternative mechanisms could account for positive results in a delayed-start study. These mechanisms include preservation of a beneficial compensatory response that, once lost, cannot be restored and prevention of a maladaptive compensatory response that, once established, cannot be reversed. Indeed, it has been proposed that early introduction of any agent that affects symptoms could influence compensatory responses and provide long-term benefits as compared with later introduction of the same agent.25
There are several possible concerns with the delayed-start design26 and with this trial specifically. First, a high dropout rate during the placebo phase could confound the results by disproportionately affecting subjects in the delayed-start group. However, we were able to maintain a relatively low dropout rate, and the results were confirmed by multiple sensitivity analyses that included a variety of imputation strategies. Second, patients in this study had very early disease, and there was a risk of misdiagnosis in such a population. However, randomization should have distributed these subjects equally among the treatment groups. Third, we used the slope estimate for the change in the UPDRS score as the first hierarchical end point, although this end point has not been used before in studies of Parkinson's disease, and there is no assurance that the worsening in UPDRS scores is linear. However, the results were positive and confirmed by an alternative categorical analysis. Finally, the placebo phase could have been too short to permit a disease-modifying effect to occur. However, we did see a benefit with 1 mg of rasagiline per day, and giving placebo to subjects with Parkinson's disease for longer than 9 months would probably result in an unacceptable dropout rate. The clinical significance of a difference of 1.7 points in the UPDRS score between the early-start and delayed-start groups that received rasagiline at a dose of 1 mg per day is not known, but it does represent a 38% reduction in the degree of change from baseline. Furthermore, the UPDRS is a relatively insensitive measure in subjects with early disease and may not capture improvement in nonmotor areas.27
It is important to consider the clinical consequences of this study. From a practical point of view, the study findings suggest a possible benefit of the early use of rasagiline at a dose of 1 mg per day; however, given the negative findings for the 2-mg dose, we cannot definitively conclude that rasagiline at a dose of 1 mg per day has disease-modifying effects. It will be important to determine whether these results can be confirmed and whether benefits seen at 18 months will endure and translate into reduced cumulative disability in clinically meaningful areas such as impairment of gait and balance and cognitive dysfunction.
Dr. Olanow reports receiving consulting and lecture fees from Teva and Lundbeck and consulting fees from Boehringer Ingelheim, Novartis/Orion, Solvay, Ceregene, and Merck Serono and owning equity in Ceregene; Dr. Rascol, receiving consulting fees from Eisai, Eutherapie, GlaxoSmithKline, Osmotica, Novartis, Schering-Plough, Boehringer Ingelheim, Solvay, and Teva, lecture fees from Eutherapie, Novartis, Boehringer Ingelheim, and Lundbeck, and grant support from Eutherapie, Novartis, Boehringer Ingelheim, Pierre Fabre, GlaxoSmithKline, and Lundbeck; Dr. Hauser, receiving consulting and lecture fees from Allergan Neuroscience, Alphamedica, ApotheCom, Axis Healthcare, Bayer Schering, Boehringer Ingelheim, CNS Schering-Plough, Centopharm, Embryon, Eisai, Genzyme, GlaxoSmithKline, Impax, Ipsen, Kyowa, Merck, Novartis, Ortho-McNeil, Pfizer, Prestwick, Quintiles, Santhera, Schwarz Pharma, Schering-Plough, Solvay, Teva Neuroscience, Valeant Pharm, and Vernalis and serving as an investigator for Allergan, Solvay, Schering-Plough, Acadia, Eisai, Bayer, SkyePharma, GlaxoSmithKline, UCB Pharma, Novartis, Kyowa, Boehringer Ingelheim, INC Research, Mentor, Asubio, Valeant Pharm, Quintiles, Vernalis, i3 Research, Teva Neuroscience, and Chelsea Therapeutics; Dr. Feigin, receiving consulting fees from Teva and being an employee of Technion–Israel Institute of Technology, a subsidiary of which receives royalties from sales of Azilect; Dr. Jankovic, receiving consulting fees from Teva and grant support from Boehringer Ingelheim, Advanced Neuromodulation Systems, Ceregene, Medtronic Neurological, Kyowa, Novartis, Schwarz Biosciences (UCB Pharma), SkyePharm (GlaxoSmithKline), Chelsea Therapeutics, Solvay, Neurogen, and Eisai; Dr. Lang, receiving consulting and lecture fees from Teva; Dr. Langston, receiving consulting and lecture fees from Teva and consulting fees from Merck Serono and Newron; Dr. Melamed, receiving lecture fees from Lundbeck; Dr. Poewe, receiving consulting fees from Teva, Boehringer Ingelheim, Genzyme, Solvay, and Novartis, lecture fees from Teva, Boehringer Ingelheim, Novartis, UCB, and Orion, and grant support from Boehringer Ingelheim and AstraZeneca; Dr. Stocchi, receiving consulting and lecture fees from Lundbeck and Teva; and Dr. Tolosa, receiving consulting fees from Teva, UCB, Novartis, and Boehringer Ingelheim and lecture fees from Novartis, Lundbeck, and Boehringer Ingelheim.
No other potential conflict of interest relevant to this article was reported.
Drs. Olanow and Rascol contributed equally to this article.
This article (10.1056/NEJMoa0809335) was updated on May 11, 2011, at NEJM.org.
We thank Eli Eyal, Yoni Weiss, and particularly Cheryl Fitzer-Attas, all from Teva Pharmaceutical Industries, as well as all the study investigators for their support.
Source Information
From the Department of Neurology and Neuroscience, Mount Sinai School of Medicine, New York (C.W.O.); INSERM CIC-9302 and UMR-825, Departments of Clinical Pharmacology and Neurosciences, Centre Hospitalier Universitaire and University of Toulouse, Faculty of Medicine, Toulouse, France (O.R.); the Department of Neurology, University of South Florida, Tampa (R.H.); the Department of Industrial Engineering and Management, Technion–Israel Institute of Technology, Haifa, Israel (P.D.F.); the Department of Neurology, Baylor College of Medicine, Houston (J.J.); the Division of Neurology, University of Toronto, Toronto (A.L.); California Parkinson Institute, Sunnyvale (W.L.); the Department of Neurology, Rabin Medical Center, Beilinson Campus, Petah Tikva, and Sackler School of Medicine, Tel Aviv — both in Israel (E.M.); the Department of Neurology, Innsbruck Medical University, Innsbruck, Austria (W.P.); Institute of Neurology, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Pisana, Rome (F.S.); and the Department of Neurology, University of Barcelona, Barcelona, and Centro de Investigacíon Biomédica en Red Sobre Enfermedades Neurodegenerativas, Madrid (E.T.).
Address reprint requests to Dr. Olanow at the Department of Neuroscience, Mount Sinai School of Medicine, 1 Gustave Levy Pl., Annenberg 14-94, New York, NY 10029, or at warren.olanow@mssm.edu.
The investigators participating in the Attenuation of Disease Progression with Azilect Given Once-daily (ADAGIO) trial are listed in the Supplementary Appendix, available with the full text of this article at NEJM.org.
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- Citing Articles (136)
Citing Articles
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Xiqun Chen, Guanhui Wu, Michael A. Schwarzschild. (2012) Urate in Parkinson’s Disease: More Than a Biomarker?. Current Neurology and Neuroscience Reports
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C. Warren Olanow, José A. Obeso. (2012) The significance of defining preclinical or prodromal Parkinson's disease. Movement Disorders 27:5, 666-669
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Johannes R. Streffer, Igor D. Grachev, Cheryl Fitzer-Attas, Baltazar Gomez-Mancilla, Babak Boroojerdi, Juliana Bronzova, Susanne Ostrowitzki, Stephen J. Victor, Paulo Fontoura, Robert Alexander. (2012) Prerequisites to launch neuroprotective trials in Parkinson's disease: An industry perspective. Movement Disorders 27:5, 651-655
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Jens P Reese, Judith Dams, Yaroslav Winter, Monika Balzer-Geldsetzer, Wolfgang H Oertel, Richard Dodel. (2012) Pharmacoeconomic considerations of treating patients with advanced Parkinson's disease. Expert Opinion on Pharmacotherapy1-20
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Horst Baas. (2012) Wo stehen wir nach 100 Jahren mit L-Dopa?. DNP - Der Neurologe und Psychiater 13:3, 61-70
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B. Pasternak, H. Svanstrom, N. M. Nielsen, L. Fugger, M. Melbye, A. Hviid. (2012) Use of Calcium Channel Blockers and Parkinson's Disease. American Journal of Epidemiology
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Houbo Jiang, Yong Ren, Eunice Y. Yuen, Ping Zhong, Mahboobe Ghaedi, Zhixing Hu, Gissou Azabdaftari, Kazuhiro Nakaso, Zhen Yan, Jian Feng. (2012) Parkin controls dopamine utilization in human midbrain dopaminergic neurons derived from induced pluripotent stem cells. Nature Communications 3, 668
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Morten Ziebell, Usman Khalid, Anders B. Klein, Susana Aznar, Gerda Thomsen, Peter Jensen, Gitte M. Knudsen. (2012) Striatal dopamine transporter binding correlates with serum BDNF levels in patients with striatal dopaminergic neurodegeneration. Neurobiology of Aging 33:2, 428.e1-428.e5
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Morten Ziebell, Birgitte B. Andersen, Gerda Thomsen, Lars H. Pinborg, Merete Karlsborg, Steen G. Hasselbalch, Gitte M. Knudsen. (2012) Predictive value of dopamine transporter SPECT imaging with [123I]PE2I in patients with subtle parkinsonian symptoms. European Journal of Nuclear Medicine and Molecular Imaging 39:2, 242-250
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Ruiping Xia, Zhi-Hong Mao. (2012) Progression of motor symptoms in Parkinson’s disease. Neuroscience Bulletin 28:1, 39-48
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Robert A Hauser. (2012) IPX066: a novel carbidopa–levodopa extended-release formulation. Expert Review of Neurotherapeutics 12:2, 133-140
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Alberto J Espay, Alfonso Fasano, Francesca Morgante. (2012) The six gaps in the search of neuroprotection for Parkinson’s disease. Expert Review of Neurotherapeutics 12:2, 111-113
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Anthony H.V Schapira. (2012) TARGETING MITOCHONDRIA FOR NEUROPROTECTION IN PARKINSON’S DISEASE. Antioxidants & Redox Signaling120109144040004
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Susana Pinto, Michael Swash, Mamede de Carvalho. (2012) Respiratory exercise in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis 13:1, 33-43
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John Y. Fang, Thomas L. Davis. 2012. Parkinson’s Disease. , 459-461.
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Maarten J Postma, Cornelis Boersma. (2012) Flexibility of Markov modeling for clinical pharmacoeconomics: illustration for cost–effectiveness in early Parkinson’s disease. Expert Review of Clinical Pharmacology 5:1, 1-4
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Ariane Park, Mark Stacy. (2012) Istradefylline for the treatment of Parkinson's disease. Expert Opinion on Pharmacotherapy 13:1, 111-114
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Hélène Pouclet, Thibaud Lebouvier, Mathurin Flamant, Emmanuel Coron, Michel Neunlist, Pascal Derkinderen, Tiphaine Rouaud. (2012) Système nerveux autonome : une source de biomarqueurs dans la maladie de Parkinson. La Presse Médicale
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H P Rang, M M Dale, J M Ritter, R J Flower, G Henderson. 2012. Neurodegenerative diseases. , 476-491.
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Philip Y. Lam, Kam Ming Ko. (2012) Schisandrin B as a Hormetic Agent for Preventing Age-Related Neurodegenerative Diseases. Oxidative Medicine and Cellular Longevity 2012, 1-9
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Anthony E. Lang. 2012. Parkinsonism. , 2326-2333.
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Alexei Korchounov, Yaroslav Winter, Wolfgang Rössy. (2012) Combined Beneficial Effect of Rasagiline on Motor Function and Depression in De Novo PD. Clinical Neuropharmacology 35:3, 121-124
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Marie Therese Armentero, Annalisa Pinna, Sergi Ferré, José Luis Lanciego, Christa E. Müller, Rafael Franco. (2011) Past, present and future of A2A adenosine receptor antagonists in the therapy of Parkinson's disease. Pharmacology & Therapeutics 132:3, 280-299
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Anthony H.V. Schapira. (2011) Monoamine Oxidase B Inhibitors for the Treatment of Parkinsonʼs Disease. CNS Drugs 25:12, 1061-1071
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K. Kalinderi, L. Fidani, Z. Katsarou, S. Bostantjopoulou. (2011) Pharmacological treatment and the prospect of pharmacogenetics in Parkinson’s disease. International Journal of Clinical Practice 65:12, 1289-1294
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Claire Henchcliffe, Richard Dodel, M. Flint Beal. (2011) Biomarkers of Parkinson's disease and Dementia with Lewy bodies. Progress in Neurobiology 95:4, 601-613
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J. Eric Ahlskog. (2011) Cheaper, Simpler, and Better: Tips for Treating Seniors With Parkinson Disease. Mayo Clinic Proceedings 86:12, 1211-1216
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Keiko Inaba-Hasegawa, Yukihiro Akao, Wakako Maruyama, Makoto Naoi. (2011) Type A monoamine oxidase is associated with induction of neuroprotective Bcl-2 by rasagiline, an inhibitor of type B monoamine oxidase. Journal of Neural Transmission
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Ronald E. Wilson, Lauren C. Seeberger, Dee Silver, Alida Griffith, Jill B. Conner, Phyllis M. Salzman. (2011) Rasagiline. The Neurologist 17:6, 318-324
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Fabrizio Gardoni, Elisa Zianni, Anna Eramo, Pier Luigi Canonico, Monica Di Luca. (2011) Effect of rasagiline on the molecular composition of the excitatory postsynaptic density. European Journal of Pharmacology 670:2-3, 458-463
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Maria Trinidad Herrero, Javier Pagonabarraga, Gurutz Linazasoro. (2011) Neuroprotective Role of Dopamine Agonists. The Neurologist 17, S54-S66
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Isabel Ybot-Gorrin, Francisco Vivancos-Matellano, José Rafael Chacón-Peña, Hortensia Alonso-Navarro, Félix Javier Jiménez-Jiménez. (2011) Assessment of Parkinson Disease. The Neurologist 17, S21-S29
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Peter Jenner, J. William Langston. (2011) Explaining ADAGIO: A critical review of the biological basis for the clinical effects of rasagiline. Movement Disorders 26:13, 2316-2323
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Dan Hurley. (2011) FDA Committee: Rasagiline Rejected as ‘Disease Modifying’ for Parkinson Disease. Neurology Today 11:21, 1
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Anthony H. V. Schapira. (2011) Mitochondrial Pathology in Parkinson's Disease. Mount Sinai Journal of Medicine: A Journal of Translational and Personalized Medicine 78:6, 872-881
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Nicola Coley, Sandrine Andrieu, Mark Jaros, Michael Weiner, Jesse Cedarbaum, Bruno Vellas. (2011) Suitability of the Clinical Dementia Rating-Sum of Boxes as a single primary endpoint for Alzheimer’s disease trials. Alzheimer's and Dementia 7:6, 602-610.e2
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P.D. Charles, R.M. Dolhun, C.E. Gill, T.L. Davis, M.J. Bliton, M.G. Tramontana, R.M. Salomon, L. Wang, P. Hedera, F.T. Phibbs, J.S. Neimat, P.E. Konrad. (2011) Deep brain stimulation in early Parkinson’s disease: Enrollment experience from a pilot trial. Parkinsonism & Related Disorders
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Susan H. Fox, Regina Katzenschlager, Shen-Yang Lim, Bernard Ravina, Klaus Seppi, Miguel Coelho, Werner Poewe, Olivier Rascol, Christopher G. Goetz, Cristina Sampaio. (2011) The Movement Disorder Society Evidence-Based Medicine Review Update: Treatments for the motor symptoms of Parkinson's disease. Movement Disorders 26:S3, S2-S41
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Zsigmond Tamas Kincses, Laszlo Vecsei. (2011) Pharmacological Therapy in Parkinson's Disease: Focus on Neuroprotection. CNS Neuroscience & Therapeutics 17:5, 345-367
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Lawrence Elmer, Robert A Hauser. (2011) Strategies for Parkinson’s disease care: prevention and management of motor fluctuations. Neurodegenerative Disease Management 1:5, 415-430
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Mark F. Lew. (2011) The Evidence for Disease Modification in Parkinson's Disease. International Journal of Neuroscience 121:S2, 18-26
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Rajesh Pahwa, Kelly E. Lyons. (2011) Introduction. International Journal of Neuroscience 121:S2, 1-2
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Kelly E. Lyons, Rajesh Pahwa. (2011) Diagnosis and Initiation of Treatment in Parkinson's Disease. International Journal of Neuroscience 121:S2, 27-36
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Janusz Lipski, Robert Nistico, Nicola Berretta, Ezia Guatteo, Giorgio Bernardi, Nicola B. Mercuri. (2011) l-DOPA: A scapegoat for accelerated neurodegeneration in Parkinson's disease?. Progress in Neurobiology 94:4, 389-407
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Mélanie Bousquet, Frédéric Calon, Francesca Cicchetti. (2011) Impact of omega-3 fatty acids in Parkinson's disease. Ageing Research Reviews 10:4, 453-463
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Werner J. Geldenhuys, Moussa B.H. Youdim, Richard T. Carroll, Cornelis J. Van der Schyf. (2011) The emergence of designed multiple ligands for neurodegenerative disorders. Progress in Neurobiology 94:4, 347-359
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(2011) The Parkinson Progression Marker Initiative (PPMI). Progress in Neurobiology
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Hasmet A. Hanagasi, Hakan Gurvit, Pınar Unsalan, Hilal Horozoglu, Nese Tuncer, Aynur Feyzioglu, Dilek Ince Gunal, Gorsev G. Yener, Raif Cakmur, Huseyin A. Sahin, Murat Emre. (2011) The effects of rasagiline on cognitive deficits in Parkinson's disease patients without dementia: A randomized, double-blind, placebo-controlled, multicenter study. Movement Disorders 26:10, 1851-1858
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R. Takeuchi, A. R. Lambert, A. N.-S. Mak, K. Jacoby, R. J. Dickson, G. B. Gloor, A. M. Scharenberg, D. R. Edgell, B. L. Stoddard. (2011) Tapping natural reservoirs of homing endonucleases for targeted gene modification. Proceedings of the National Academy of Sciences 108:32, 13077-13082
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Claire Henchcliffe, W. Lawrence Severt. (2011) Disease Modification in Parkinsonʼs Disease. Drugs & Aging 28:8, 605-615
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Trung Huynh. (2011) The Parkinson's disease market. Nature Reviews Drug Discovery 10:8, 571-572
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E. Tolosa, M. B. Stern. (2011) Efficacy, safety and tolerability of rasagiline as adjunctive therapy in elderly patients with Parkinson’s disease. European Journal of Neurologyno-no
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C. Warren Olanow, Anthony E. Lang. 2011. Prospects for Neuroprotective Therapies that can Modulate Non-Dopaminergic Features in Parkinson's Disease. , 455-461.
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C. Warren Olanow, Fabrizio Stocchi, Anthony E. Lang. 2011. The Dopaminergic and Non-Dopaminergic Features of Parkinson's Disease. , 1-6.
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M. R. Sharma, W. M. Stadler, M. J. Ratain. (2011) Randomized Phase II Trials: A Long-term Investment With Promising Returns. JNCI Journal of the National Cancer Institute 103:14, 1093-1100
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Deniz Kahraman, Carsten Eggers, Harald Schicha, Lars Timmermann, Matthias Schmidt. (2011) Visual assessment of dopaminergic degeneration pattern in 123I-FP-CIT SPECT differentiates patients with atypical parkinsonian syndromes and idiopathic Parkinson's disease. Journal of Neurology
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Santiago Perez-Lloret, Olivier Rascol. (2011) Safety of rasagiline for the treatment of Parkinson's disease. Expert Opinion on Drug Safety 10:4, 633-643
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Y. Aluf, J. Vaya, S. Khatib, J.P.M. Finberg. (2011) Alterations in striatal oxidative stress level produced by pharmacological manipulation of dopamine as shown by a novel synthetic marker molecule. Neuropharmacology 61:1-2, 87-94
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Carl E. Clarke, Smitaa Patel, Natalie Ives, Caroline Rick, Keith Wheatley, Richard Gray. (2011) Should treatment for Parkinson's disease start immediately on diagnosis or delayed until functional disability develops?. Movement Disorders 26:7, 1187-1193
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Rachel Saunders-Pullman, Cuiling Wang, Kaili Stanley, Susan B. Bressman. (2011) Diagnosis and Referral Delay in Women With Parkinson's Disease. Gender Medicine 8:3, 209-217
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Angelo Antonini. (2011) The conundrum of neuroprotection in Parkinson's disease. The Lancet Neurology 10:5, 396-397
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Olivier Rascol, Cheryl J Fitzer-Attas, Robert Hauser, Joseph Jankovic, Anthony Lang, J William Langston, Eldad Melamed, Werner Poewe, Fabrizio Stocchi, Eduardo Tolosa, Eli Eyal, Yoni M Weiss, C Warren Olanow. (2011) A double-blind, delayed-start trial of rasagiline in Parkinson's disease (the ADAGIO study): prespecified and post-hoc analyses of the need for additional therapies, changes in UPDRS scores, and non-motor outcomes. The Lancet Neurology 10:5, 415-423
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Wassilios G. Meissner, Mark Frasier, Thomas Gasser, Christopher G. Goetz, Andres Lozano, Paola Piccini, José A. Obeso, Olivier Rascol, Anthony Schapira, Valerie Voon, David M. Weiner, François Tison, Erwan Bezard. (2011) Priorities in Parkinson's disease research. Nature Reviews Drug Discovery 10:5, 377-393
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C. Warren Olanow, Kathryn B. Wunderle, Karl Kieburtz. (2011) Milestones in movement disorders clinical trials: Advances and landmark studies. Movement Disorders 26:6, 1003-1014
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Olivier Rascol, Andres Lozano, Matthew Stern, Werner Poewe. (2011) Milestones in Parkinson's disease therapeutics. Movement Disorders 26:6, 1072-1082
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Candice E. Crocker, Susan Khan, Michael D. Cameron, Harold A. Robertson, George S. Robertson, Philip LoGrasso. (2011) JNK Inhibition Protects Dopamine Neurons and Provides Behavioral Improvement in a Rat 6-Hydroxydopamine Model of Parkinson’s Disease. ACS Chemical Neuroscience 2:4, 207-212
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Jeremy W. Chambers, Alok Pachori, Shannon Howard, Michelle Ganno, Donald Hansen, Ted Kamenecka, Xinyi Song, Derek Duckett, Weimin Chen, Yuan Yuan Ling, Lisa Cherry, Michael D. Cameron, Li Lin, Claudia H. Ruiz, Philip LoGrasso. (2011) Small Molecule c-jun-N-Terminal Kinase Inhibitors Protect Dopaminergic Neurons in a Model of Parkinson’s Disease. ACS Chemical Neuroscience 2:4, 198-206
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Nikoletta Szabó, Zsigmond Tamás Kincses, László Vécsei. (2011) Novel therapy in Parkinson's disease: adenosine A 2A receptor antagonists. Expert Opinion on Drug Metabolism & Toxicology 7:4, 441-455
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Y. Ren, H. Jiang, D. Ma, K. Nakaso, J. Feng. (2011) Parkin degrades estrogen-related receptors to limit the expression of monoamine oxidases. Human Molecular Genetics 20:6, 1074-1083
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David P. Breen, Andrew W. Michell, Roger A. Barker. (2011) Parkinson's disease – the continuing search for biomarkers. Clinical Chemistry and Laboratory Medicine 49:3, 393-401
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A. H. V. Schapira. (2011) Challenges to the development of disease-modifying therapies in Parkinson’s disease. European Journal of Neurology 18, 16-21
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A. H. V. Schapira. (2011) The management of Parkinson’s disease - what is new?. European Journal of Neurology 18, 1-2
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Orly Weinreb, Orit Bar-Am, Ksenia Prosolovich, Tamar Amit, Moussa B.H. Youdim. (2011) Does 1-(R)-aminoindan Possess Neuroprotective Properties Against Experimental Parkinson's Disease?. Antioxidants & Redox Signaling 14:5, 767-775
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C. Di Caudo, M.R. Luquin. (2011) Enfermedad de Parkinson. Medicine - Programa de Formación Médica Continuada Acreditado 10:73, 4944-4951
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Nick H. G. Holford, John G. Nutt. (2011) Interpreting the results of Parkinson's disease clinical trials: Time for a change. Movement Disorders 26:4, 569-577
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O. Rascol. (2011) Drugs and drug delivery in PD: optimizing control of symptoms with pramipexole prolonged-release. European Journal of Neurology 18, 3-10
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Y.J. Zhao, H.L. Wee, W.L. Au, S.H. Seah, N. Luo, S.C. Li, L.C.S. Tan. (2011) Selegiline use is associated with a slower progression in early Parkinson’s disease as evaluated by Hoehn and Yahr Stage transition times. Parkinsonism & Related Disorders 17:3, 194-197
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Livia Dézsi, László Vécsei. (2011) Parkinson’s disease: will therapy move beyond dopaminergic medication?. Clinical Investigation 1:3, 381-398
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Jonathan R Evans, Roger A Barker. (2011) Defining meaningful outcome measures in trials of disease-modifying therapies in Parkinson's disease. Expert Opinion on Pharmacotherapy1-10
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Erwin B Montgomery. (2011) Ask the Experts: What is your interpretation of the ADAGIO study and has it influenced your clinical practice?. Neurodegenerative Disease Management 1:1, 21-24
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Cornelis J. Van der Schyf, Werner J. Geldenhuys. 2011. Multimodal drugs and their future for Alzheimer's and Parkinson's disease. , 107-125.
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Orly Weinreb, Tamar Amit, Peter Riederer, Moussa B.H. Youdim, Silvia A. Mandel. 2011. Neuroprotective profile of the multitarget drug rasagiline in Parkinson's disease. , 127-149.
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Peter Riederer, Gerd Laux. (2011) MAO-inhibitors in Parkinson's Disease. Experimental Neurobiology 20:1, 1
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Orly Weinreb, Tamar Amit, Orit Bar-Am, Moussa B.H. Youdim. 2011. A novel anti-Alzheimer's disease drug, ladostigil. , 191-215.
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Mercedes Unzeta, Elisenda Sanz. 2011. Novel MAO-B inhibitors. , 217-236.
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L.M. Chahine, M.B. Stern. 2011. Rasagiline in Parkinson's Disease. , 151-168.
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Stanley Fahn, Joseph Jankovic, Mark Hallett. 2011. Medical treatment of Parkinson disease. , 119-156.
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Ailton Melo, Larissa Monteiro, Rute M. F. Lima, Diêgo M. de Oliveira, Martins D. de Cerqueira, Ramon S. El-Bachá. (2011) Oxidative Stress in Neurodegenerative Diseases: Mechanisms and Therapeutic Perspectives. Oxidative Medicine and Cellular Longevity 2011, 1-14
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Matthias Löhle, Heinz Reichmann. (2011) Controversies in Neurology: why monoamine oxidase B inhibitors could be a good choice for the initial treatment of Parkinson's disease. BMC Neurology 11:1, 112
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Elodie Angot, Jennifer A Steiner, Christian Hansen, Jia-Yi Li, Patrik Brundin. (2010) Are synucleinopathies prion-like disorders?. The Lancet Neurology 9:11, 1128-1138
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K.Y. Chau, J.M. Cooper, A.H.V. Schapira. (2010) Rasagiline protects against alpha-synuclein induced sensitivity to oxidative stress in dopaminergic cells. Neurochemistry International 57:5, 525-529
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C. E. Clarke. (2010) Has drug therapy changed the natural history of Parkinson’s disease?. Journal of Neurology 257:S2, 262-267
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Mark J. Millan. (2010) From the cell to the clinic: A comparative review of the partial D2/D3 receptor agonist and α2-adrenoceptor antagonist, piribedil, in the treatment of Parkinson's disease. Pharmacology & Therapeutics 128:2, 229-273
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Orly Weinreb, Tamar Amit, Orit Bar-Am, Moussa B.H. Youdim. (2010) Rasagiline: A novel anti-Parkinsonian monoamine oxidase-B inhibitor with neuroprotective activity. Progress in Neurobiology 92:3, 330-344
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W. H. Oertel, A. Berardelli, B. R. Bloem, U. Bonuccelli, D. Burn, G. Deuschl, E. Dietrichs, G. Fabbrini, J. J. Ferreira, A. Friedman, P. Kanovsky, V. Kostic, A. Nieuwboer, P. Odin, W. Poewe, O. Rascol, C. Sampaio, M. Schüpbach, E. Tolosa, C. Trenkwalder. 2010. Early (Uncomplicated) Parkinson's Disease. , 217-236.
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Angelo Antonini, Paolo Barone, Roberto Ceravolo, Giovanni Fabbrini, Michele Tinazzi, Giovanni Abbruzzese. (2010) Role of Pramipexole in the Management of Parkinsonʼs Disease. CNS Drugs 24:10, 829-841
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Orly Weinreb, Tamar Amit, Silvia Mandel, Lana Kupershmidt, Moussa B.H. Youdim. (2010) Neuroprotective Multifunctional Iron Chelators: From Redox-Sensitive Process to Novel Therapeutic Opportunities. Antioxidants & Redox Signaling 13:6, 919-949
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C. Warren Olanow, Karl Kieburtz. (2010) Defining disease-modifying therapies for PD-A road map for moving forward. Movement Disorders 25:12, 1774-1779
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Ruth Williams. (2010) Slowing the decline. Nature 466:7310, S13-S14
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Anthony H.V. Schapira, Stefan Albrecht, Paolo Barone, Cynthia L. Comella, Michael P. McDermott, Yoshikuni Mizuno, Werner Poewe, Olivier Rascol, Kenneth Marek. (2010) Rationale for delayed-start study of pramipexole in Parkinson's disease: The PROUD study. Movement Disorders 25:11, 1627-1632
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G.F. Hamann, M. Dieterich. (2010) Bericht vom 2. NeuroUpdate der MedUpdate-Reihe in Wiesbaden. Der Nervenarzt 81:8, 998-1002
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Thomas W. Rösler, Oscar Arias-Carrión, Günter U. Höglinger. (2010) Zonisamide: Aspects in neuroprotection. Experimental Neurology 224:2, 336-339
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Raúl de la Fuente-Fernández, Michael Schulzer, Edwin Mak, Vesna Sossi. (2010) Trials of neuroprotective therapies for Parkinson’s disease: Problems and limitations. Parkinsonism & Related Disorders 16:6, 365-369
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Spyros N. Deftereos, Christos A. Andronis. (2010) Discordant effects of rasagiline doses in Parkinson disease. Nature Reviews Neurology 6:7,
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Jose A Obeso, Maria C Rodriguez-Oroz, Christopher G Goetz, Concepcion Marin, Jeffrey H Kordower, Manuel Rodriguez, Etienne C Hirsch, Matthew Farrer, Anthony H V Schapira, Glenda Halliday. (2010) Missing pieces in the Parkinson's disease puzzle. Nature Medicine 16:6, 653-661
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Anthony H. V. Schapira, Eduardo Tolosa. (2010) Molecular and clinical prodrome of Parkinson disease: implications for treatment. Nature Reviews Neurology 6:6, 309-317
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Alessandro Prigione, Fabrizio Piazza, Laura Brighina, Barbara Begni, Alessio Galbussera, Jacopo C. DiFrancesco, Simona Andreoni, Roberto Piolti, Carlo Ferrarese. (2010) Alpha-synuclein nitration and autophagy response are induced in peripheral blood cells from patients with Parkinson disease. Neuroscience Letters 477:1, 6-10
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Ilse Sanet Pienaar, David Trevor Dexter, Pierre Roland Burkhard. (2010) Mitochondrial proteomics as a selective tool for unraveling Parkinson’s disease pathogenesis. Expert Review of Proteomics 7:2, 205-226
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Orit Bar-Am, Orly Weinreb, Tamar Amit, Moussa B. H. Youdim. (2010) The neuroprotective mechanism of 1-( R )-aminoindan, the major metabolite of the anti-parkinsonian drug rasagiline. Journal of Neurochemistry 112:5, 1131-1137
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Gianni Pezzoli, Michela Zini. (2010) Levodopa in Parkinson's disease: from the past to the future. Expert Opinion on Pharmacotherapy 11:4, 627-635
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(2010) Rasagiline in Parkinson's Disease. New England Journal of Medicine 362:7, 657-659
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Anthony HV Schapira. (2010) Movement disorders: advances in cause and treatment. The Lancet Neurology 9:1, 6-7
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Angelo Antonini, Per Odin. (2009) Pros and cons of apomorphine and l-dopa continuous infusion in advanced Parkinson's disease. Parkinsonism & Related Disorders 15, S97-S100
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(2009) Drug may put brakes on Parkinson's disease. Nature Medicine 15:11, 1250-1250
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