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1.  Activity enhances dopaminergic long-duration response in Parkinson disease 
Jung Kang, Un | Auinger, Peggy | Fahn, Stanley | Oakes, David | Shoulson, Ira | Kieburtz, Karl | Rudolph, Alice | Marek, Kenneth | Seibyl, John | Lang, Anthony | Olanow, C. Warren | Tanner, Caroline | Schifitto, Giovanni | Zhao, Hongwei | Reyes, Lydia | Shinaman, Aileen | Comella, Cynthia L. | Goetz, Christopher | Blasucci, Lucia M. | Samanta, Johan | Stacy, Mark | Williamson, Kelli | Harrigan, Mary | Greene, Paul | Ford, Blair | Moskowitz, Carol | Truong, Daniel D. | Pathak, Mayank | Jankovic, Joseph | Ondo, William | Atassi, Farah | Hunter, Christine | Jacques, Carol | Friedman, Joseph H. | Lannon, Margaret | Russell, David S. | Jennings, Danna | Fussell, Barbara | Standaert, David | Schwarzschild, Michael A. | Growdon, John H. | Tennis, Marsha | Gauthier, Serge | Panisset, Michel | Hall, Jean | Gancher, Stephen | Hammerstad, John P. | Stone, Claudia | Alexander-Brown, Barbara | Factor, Stewart A. | Molho, Eric | Brown, Diane | Evans, Sharon | Clark, Jeffrey | Manyam, Bala | Simpson, Patricia | Wulbrecht, Brian | Whetteckey, Jacqueline | Martin, Wayne | Roberts, Ted | King, Pamela | Hauser, Robert | Zesiewicz, Theresa | Gauger, Lisa | Trugman, Joel | Wooten, G. Frederick | Rost-Ruffner, Elke | Perlmutter, Joel | Racette, Brad A. | Suchowersky, Oksana | Ranawaya, Ranjit | Wood, Susan | Pantella, Carol | Kurlan, Roger | Richard, Irene | Pearson, Nancy | Caviness, John N. | Adler, Charles | Lind, Marlene | Simuni, Tanya | Siderowf, Andrew | Colcher, Amy | Lloyd, Mary | Weiner, William | Shulman, Lisa | Koller, William | Lyons, Kelly | Feldman, Robert G. | Saint-Hilaire, Marie H. | Ellias, Samuel | Thomas, Cathi-Ann | Juncos, Jorge | Watts, Ray | Partlow, Anna | Tetrud, James | Togasaki, Daniel M. | Stewart, Tracy | Mark, Margery H. | Sage, Jacob I. | Caputo, Debbie | Gould, Harry | Rao, Jayaraman | McKendrick, Ann | Brin, Mitchell | Danisi, Fabio | Benabou, Reina | Hubble, Jean | Paulson, George W. | Reider, Carson | Birnbaum, Alex | Miyasaki, Janis | Johnston, Lisa | So, Julie | Pahwa, Rajesh | Dubinsky, Richard M. | Wszolek, Zbigniew | Uitti, Ryan | Turk, Margaret | Tuite, Paul | Rottenberg, David | Hansen, Joy | Ramos, Serrano | Waters, Cheryl | Lew, Mark | Welsh, Mickie | Kawai, Connie | O'Brien, Christopher | Kumar, Rajeev | Seeberger, Lauren | Judd, Deborah | Barclay, C. Lynn | Grimes, David A. | Sutherland, Laura | Dawson, Ted | Reich, Stephen | Dunlop, Rebecca | Albin, Roger | Frey, Kirk | Wernette, Kristine | Fahn, Stanley | Oakes, David | Shoulson, Ira | Kieburtz, Karl | Rudolph, Alice | Marek, Kenneth | Seibyl, John | Lang, Anthony | Olanow, C. Warren | Tanner, Caroline | Schifitto, Giovanni | Zhao, Hongwei | Reyes, Lydia | Shinaman, Aileen | Comella, Cynthia L. | Goetz, Christopher | Blasucci, Lucia M. | Samanta, Johan | Stacy, Mark | Williamson, Kelli | Harrigan, Mary | Greene, Paul | Ford, Blair | Moskowitz, Carol | Truong, Daniel D. | Pathak, Mayank | Jankovic, Joseph | Ondo, William | Atassi, Farah | Hunter, Christine | Jacques, Carol | Friedman, Joseph H. | Lannon, Margaret | Russell, David S. | Jennings, Danna | Fussell, Barbara | Standaert, David | Schwarzschild, Michael A. | Growdon, John H. | Tennis, Marsha | Gauthier, Serge | Panisset, Michel | Hall, Jean | Gancher, Stephen | Hammerstad, John P. | Stone, Claudia | Alexander-Brown, Barbara | Factor, Stewart A. | Molho, Eric | Brown, Diane | Evans, Sharon | Clark, Jeffrey | Manyam, Bala | Simpson, Patricia | Wulbrecht, Brian | Whetteckey, Jacqueline | Martin, Wayne | Roberts, Ted | King, Pamela | Hauser, Robert | Zesiewicz, Theresa | Gauger, Lisa | Trugman, Joel | Wooten, G. Frederick | Rost-Ruffner, Elke | Perlmutter, Joel | Racette, Brad A. | Suchowersky, Oksana | Ranawaya, Ranjit | Wood, Susan | Pantella, Carol | Kurlan, Roger | Richard, Irene | Pearson, Nancy | Caviness, John N. | Adler, Charles | Lind, Marlene | Simuni, Tanya | Siderowf, Andrew | Colcher, Amy | Lloyd, Mary | Weiner, William | Shulman, Lisa | Koller, William | Lyons, Kelly | Feldman, Robert G. | Saint-Hilaire, Marie H. | Ellias, Samuel | Thomas, Cathi-Ann | Juncos, Jorge | Watts, Ray | Partlow, Anna | Tetrud, James | Togasaki, Daniel M. | Stewart, Tracy | Mark, Margery H. | Sage, Jacob I. | Caputo, Debbie | Gould, Harry | Rao, Jayaraman | McKendrick, Ann | Brin, Mitchell | Danisi, Fabio | Benabou, Reina | Hubble, Jean | Paulson, George W. | Reider, Carson | Birnbaum, Alex | Miyasaki, Janis | Johnston, Lisa | So, Julie | Pahwa, Rajesh | Dubinsky, Richard M. | Wszolek, Zbigniew | Uitti, Ryan | Turk, Margaret | Tuite, Paul | Rottenberg, David | Hansen, Joy | Ramos, Serrano | Waters, Cheryl | Lew, Mark | Welsh, Mickie | Kawai, Connie | O'Brien, Christopher | Kumar, Rajeev | Seeberger, Lauren | Judd, Deborah | Barclay, C. Lynn | Grimes, David A. | Sutherland, Laura | Dawson, Ted | Reich, Stephen | Dunlop, Rebecca | Albin, Roger | Frey, Kirk | Wernette, Kristine | Mendis, Tilak
Neurology  2012;78(15):1146-1149.
Objective:
We tested the hypothesis that dopamine-dependent motor learning mechanism underlies the long-duration response to levodopa in Parkinson disease (PD) based on our studies in a mouse model. By data-mining the motor task performance in dominant and nondominant hands of the subjects in a double-blind randomized trial of levodopa therapy, the effects of activity and dopamine therapy were examined.
Methods:
We data-mined the Earlier versus Later Levodopa Therapy in Parkinson's Disease (ELLDOPA) study published in 2005 and performed statistical analysis comparing the effects of levodopa and dominance of handedness over 42 weeks.
Results:
The mean change in finger-tapping counts from baseline before the initiation of therapy to predose at 9 weeks and 40 weeks increased more in the dominant compared to nondominant hand in levodopa-treated subjects in a dose-dependent fashion. There was no significant difference in dominant vs nondominant hands in the placebo group. The short-duration response assessed by the difference of postdose performance compared to predose performance at the same visit did not show any significant difference between dominant vs nondominant hands.
Conclusions:
Active use of the dominant hand and dopamine replacement therapy produces synergistic effect on long-lasting motor task performance during “off” medication state. Such effect was confined to dopamine-responsive symptoms and not seen in dopamine-resistant symptoms such as gait and balance. We propose that long-lasting motor learning facilitated by activity and dopamine is a form of disease modification that is often seen in trials of medications that have symptomatic effects.
doi:10.1212/WNL.0b013e31824f8056
PMCID: PMC3466780  PMID: 22459675
2.  Efficacy, safety, and tolerance of the non-ergoline dopamine agonist pramipexole in the treatment of advanced Parkinson's disease: a double blind, placebo controlled, randomised, multicentre study 
OBJECTIVES—Pramipexole, a non-ergot dopamine D2/D3 receptor agonist, was investigated as an add on drug in advanced parkinsonian patients with motor fluctuations to assess efficacy, safety, and tolerance.
METHODS—Seventy eight patients of either sex with advanced Parkinson's disease and treatment complications such as motor fluctuations were enrolled into a double blind, placebo controlled, randomised, multicentre study (phase II) and assigned to add on treatment with pramipexole (n=34) versus placebo (n=44) to a previously stabilised antiparkinsonian medication (7 week dose titration interval, 4 week maintenance period). The primary end point of efficacy was the change from baseline in the total score of the unified Parkinson's disease rating scale (UPDRS) in the on "period" (2 hours after intake of study medication). Safety and tolerability were assessed on the basis of adverse events, vital signs, laboratory measurements, and ECG recordings.
RESULTS—There was a significant improvement of the pramipexole group in UPDRS total scores, subscores part II, III (activities of daily living and motor examination), and IV (complications of therapy). Mean UPDRS total score decreased by 37.3% under pramipexole compared with 12.2% under placebo (p<0.001). Patients under pramipexole reported an overall reduction in "off" periods of 12%—resulting in 1.7 more hours "on" time a day—compared with an increase in "off" periods of 2% under placebo. There were no unexpected safety results. The adverse event profile disclosed a high tolerability. The most important adverse events under pramipexole were fatigue, dyskinesia, and vivid dreams.
CONCLUSION—Pramipexole administration is an efficacious and well tolerated add on therapy in patients with advanced Parkinson's disease with an improvement in activities of daily living, motor function, and treatment associated complications.


PMCID: PMC1736320  PMID: 10201413
3.  Catechol-O-methyltransferase inhibition with tolcapone reduces the "wearing off" phenomenon and levodopa requirements in fluctuating parkinsonian patients 
BACKGROUND—More than 50% of patients with Parkinson's disease develop motor response fluctuations (the "wearing off" phenomenon) after more than five years of levodopa therapy. Inhibition of catechol-O-methyltransferase by tolcapone has been shown to increase levodopa bioavailability and plasma elimination half life, thereby prolonging the efficacy of levodopa.
OBJECTIVES—The primary objective was to evaluate the efficacy of tolcapone in reducing "wearing off" in levodopa treated, fluctuating parkinsonian patients. Secondary objectives included assessment of reduction in levodopa requirements, improvement in patients' clinical status, duration of improvements, and tolerability of tolcapone.
METHODS—In this multicentre, randomised, double blind, placebo controlled trial, 58 patients received placebo, 60 received 100 mg tolcapone three times daily (tid), and 59 received 200 mg tolcapone tid, in addition to levodopa/benserazide.
RESULTS—After three months with 200 mg tolcapone tid, "off" time decreased by 26.2% of the baseline value, "on" time increased by 20.6% (P<0.01 v placebo), and the mean total daily levodopa dose decreased by 122 mg from the baseline dose of 676 mg (P<0.01). These responses were maintained up to nine months. With 100 mg tolcapone tid, "off" time decreased by 31.5% (P<0.05), "on" time increased by 21.3% (P<0.01), and the mean total daily levodopa dose decreased by 109 mg from the baseline dose of 668 mg (P<0.05). With 200 mg tolcapone tid, unified Parkinson's disease rating scale motor and total scores were significantly reduced, and quality of life (sickness impact profile) scores were significantly improved. Both dosages were well tolerated. Dyskinesia was the most often reported levodopa induced adverse event. Diarrhoea was the most often reported non-dopaminergic adverse event and the most frequent reason for withdrawal from the study: four patients in the 100mg tolcapone tid group and six in the 200 mg tid group withdrew because of diarrhoea.
CONCLUSION—Tolcapone prolongs "on" time in fluctuating parkinsonian patients while allowing a reduction in daily levodopa dosage, thereby improving the efficacy of long term levodopa therapy.


PMCID: PMC2169755  PMID: 9343116
4.  Entacapone prolongs levodopa response in a one month double blind study in parkinsonian patients with levodopa related fluctuations. 
OBJECTIVES--To establish, in a double blind manner, the antiparkinsonian effects of repeated dosing with entacapone, a peripheral COMT inhibitor. METHODS--A one month, cross over study was conducted. During the two four-week treatment periods, entacapone (200 mg) or placebo was given with each levodopa dose four to 10 times daily. Motor responses were repeatedly quantified using the motor part of UPDRS. Plasma levodopa and its metabolites were measured. RESULTS--Entacapone prolonged the availability of levodopa in the plasma and thus to the brain by decreasing its peripheral O-methylation and slowing its elimination rate, without affecting the maximum plasma levodopa concentration or the time to maximum concentration. Corresponding with the pharmacokinetic findings, entacapone prolonged the duration of motor response to an individual levodopa/DDC inhibitor dose by 34 minutes (24%, P = 0.001) and dyskinesiae by 39 minutes (37%, P = 0.002) compared with placebo, without affecting their magnitude or starting time. Entacapone treatment resulted in a reduction of 16% in the mean total daily levodopa dose due to dyskinesiae. Also, according to the home diaries, the mean daily "on" time increased by 2.1 hours compared with placebo, despite the lowered mean levodopa intake. CONCLUSION--The efficacy of repeated entacapone dosing as an adjuvant to levodopa/DDC inhibitor treatment for Parkinson's disease with levodopa related fluctuations is verified.
PMCID: PMC486187  PMID: 8558148
5.  The acute brain response to levodopa heralds dyskinesias in Parkinson disease 
Annals of Neurology  2014;75(6):829-836.
Objective
In Parkinson disease (PD), long‐term treatment with the dopamine precursor levodopa gradually induces involuntary “dyskinesia” movements. The neural mechanisms underlying the emergence of levodopa‐induced dyskinesias in vivo are still poorly understood. Here, we applied functional magnetic resonance imaging (fMRI) to map the emergence of peak‐of‐dose dyskinesias in patients with PD.
Methods
Thirteen PD patients with dyskinesias and 13 PD patients without dyskinesias received 200mg fast‐acting oral levodopa following prolonged withdrawal from their normal dopaminergic medication. Immediately before and after levodopa intake, we performed fMRI, while patients produced a mouse click with the right or left hand or no action (No‐Go) contingent on 3 arbitrary cues. The scan was continued for 45 minutes after levodopa intake or until dyskinesias emerged.
Results
During No‐Go trials, PD patients who would later develop dyskinesias showed an abnormal gradual increase of activity in the presupplementary motor area (preSMA) and the bilateral putamen. This hyperactivity emerged during the first 20 minutes after levodopa intake. At the individual level, the excessive No‐Go activity in the predyskinesia period predicted whether an individual patient would subsequently develop dyskinesias (p < 0.001) as well as severity of their day‐to‐day symptomatic dyskinesias (p < 0.001).
Interpretation
PD patients with dyskinesias display an immediate hypersensitivity of preSMA and putamen to levodopa, which heralds the failure of neural networks to suppress involuntary dyskinetic movements. Ann Neurol 2014;75:829–836
doi:10.1002/ana.24138
PMCID: PMC4112717  PMID: 24889498
6.  Hypokinesia without decrement distinguishes progressive supranuclear palsy from Parkinson's disease 
Brain  2012;135(4):1141-1153.
Repetitive finger tapping is commonly used to assess bradykinesia in Parkinson's disease. The Queen Square Brain Bank diagnostic criterion of Parkinson's disease defines bradykinesia as ‘slowness of initiation with progressive reduction in speed and amplitude of repetitive action’. Although progressive supranuclear palsy is considered an atypical parkinsonian syndrome, it is not known whether patients with progressive supranuclear palsy have criteria-defined bradykinesia. This study objectively assessed repetitive finger tap performance and handwriting in patients with Parkinson's disease (n = 15), progressive supranuclear palsy (n = 9) and healthy age- and gender-matched controls (n = 16). The motion of the hand and digits was recorded in 3D during 15-s repetitive index finger-to-thumb tapping trials. The main finding was hypokinesia without decrement in patients with progressive supranuclear palsy, which differed from the finger tap pattern in Parkinson's disease. Average finger separation amplitude in progressive supranuclear palsy was less than half of that in controls and Parkinson's disease (P < 0.001 in both cases). Change in tap amplitude over consecutive taps was computed by linear regression. The average amplitude slope in progressive supranuclear palsy was nearly zero (0.01°/cycle) indicating a lack of decrement, which differed from the negative slope in patients with Parkinson's disease OFF levodopa (−0.20°/cycle, P = 0.002). ‘Hypokinesia’, defined as <50% of control group's mean amplitude, combined with ‘absence of decrement’, defined as mean positive amplitude slope, were identified in 87% of finger tap trials in the progressive supranuclear palsy group and only 12% in the Parkinson's disease OFF levodopa group. In progressive supranuclear palsy, the mean amplitude was not correlated with disease duration or other clinimetric scores. In Parkinson's disease, finger tap pattern was compatible with criteria-defined bradykinesia, characterized by slowness with progressive reduction in amplitude and speed and increased variability in speed throughout the tap trial. In Parkinson's disease, smaller amplitude, slower speed and greater speed variability were all associated with a more severe Unified Parkinson's Disease Rating Scale motor score. Analyses of handwriting showed that micrographia, defined as smaller than 50% of the control group's mean script size, was present in 75% of patients with progressive supranuclear palsy and 15% of patients with Parkinson's disease (P = 0.022). Most scripts performed by patients with progressive supranuclear palsy did not exhibit decrements in script size. In conclusion, patients with progressive supranuclear palsy have a specific finger tap pattern of ‘hypokinesia without decrement’ and they do not have criteria-defined limb bradykinesia. Similarly, ‘micrographia’ and ‘lack of decrement in script size’ are also more common in progressive supranuclear palsy than in Parkinson's disease.
doi:10.1093/brain/aws038
PMCID: PMC3326257  PMID: 22396397
hypokinesia; bradykinesia; repetitive finger tap; micrographia; progressive supranuclear palsy
7.  The modern pre-levodopa era of Parkinson’s disease: insights into motor complications from sub-Saharan Africa 
Brain  2014;137(10):2731-2742.
Delaying the initiation of levodopa has been proposed to reduce the risk of motor complications in Parkinson’s disease. In a 4-year multicentre study in Ghana, Cilia et al. find that motor fluctuations and dyskinesias are predicted by disease duration and levodopa dose, but not by the duration of levodopa therapy.
During the past decade, a number of large drug trials suggested that the initiation of levodopa therapy should be delayed to reduce the risk of motor complications in patients with Parkinson’s disease. However, the relative contribution of the cumulative exposure to levodopa and of disease progression to the pathophysiology of motor fluctuations and dyskinesias is still poorly understood. In this 4-year multicentre study, we investigated a large cohort of patients with Parkinson’s disease in a sub-Saharan African country (Ghana), where access to medication is limited and the initiation of levodopa therapy often occurs many years after onset. The primary objective was to investigate whether the occurrence of motor complications is primarily related to the duration of levodopa therapy or to disease-related factors. Study design included a cross-sectional case-control analysis of data collected between December 2008 and November 2012, and a prospective study of patients followed-up for at least 6 months after the initiation of levodopa therapy. Ninety-one patients fulfilled criteria for clinical diagnosis of idiopathic Parkinson’s disease (58 males, mean age at onset 60.6 ± 11.3 years). Demographic data were compared to those of 2282 consecutive Italian patients recruited during the same period, whereas nested matched subgroups were used to compare clinical variables. Demographic features, frequency and severity of motor and non-motor symptoms were comparable between the two populations, with the only exception of more frequent tremor-dominant presentation in Ghana. At baseline, the proportion of Ghanaian patients with motor fluctuations and dyskinesias was 56% and 14%, respectively. Although levodopa therapy was introduced later in Ghana (mean disease duration 4.2 ± 2.8 versus 2.4 ± 2.1 years, P < 0.001), disease duration at the occurrence of motor fluctuations and dyskinesias was similar in the two populations. In multivariate analysis, disease duration and levodopa daily dose (mg/kg of body weight) were associated with motor complications, while the disease duration at the initiation of levodopa was not. Prospective follow-up for a mean of 2.6 ± 1.3 years of a subgroup of 21 patients who were drug-naïve at baseline [median disease duration 4.5 (interquartile range, 2.3–5) years] revealed that the median time to development of motor fluctuations and dyskinesias after initiation of levodopa therapy was 6 months. We conclude that motor fluctuations and dyskinesias are not associated with the duration of levodopa therapy, but rather with longer disease duration and higher levodopa daily dose. Hence, the practice to withhold levodopa therapy with the objective of delaying the occurrence of motor complications is not justified.
doi:10.1093/brain/awu195
PMCID: PMC4163032  PMID: 25034897
Parkinson’s disease; dyskinesias; levodopa; pathophysiology
8.  Long term treatment and disease severity change brain responses to levodopa in Parkinson's disease 
Objectives: Degeneration of nigrostriatal neurons and subsequent striatal dopamine deficiency produce many of the symptoms of Parkinson disease (PD). Initially restoration of striatal dopamine with oral levodopa provides substantial benefit, but with long term treatment and disease progression, levodopa can elicit additional clinical symptoms, reflecting altered effects of levodopa in the brain. The authors examined whether long term treatment affects the brain's response to levodopa in the absence of these altered clinical responses to levodopa.
Methods: Positron emission tomography (PET) measurements were used of brain-blood flow before and after an acute dose of levodopa in three groups: PD patients treated long term with levodopa without levodopa induced dyskinesias, levodopa naive PD patients, and controls.
Results: It was found that the PD group treated long term responded to acute levodopa differently from controls in left sensorimotor and left ventrolateral prefrontal cortex. In both regions, the treated PD group had decreased blood flow whereas the control group had increased blood flow in response to levodopa. Levodopa naive PD patients had little or no response to levodopa in these regions. Within the treated PD group, severity of parkinsonism correlated with the degree of abnormality of the sensorimotor cortex response, but not with the prefrontal response.
Conclusions: It is concluded that long term levodopa treatment and disease severity affect the physiology of dopaminergic pathways, producing altered responses to levodopa in brain regions associated with motor function.
doi:10.1136/jnnp.74.7.844
PMCID: PMC1738560  PMID: 12810765
9.  Pramipexole and its Extended Release Formulation for Parkinson’s Disease 
Pramipexole has been a widely used dopamine agonist for the last decade. Recently an extended release formulation of pramipexole has been introduced as both monotherapy for patients with early Parkinson’s disease as well as for patients with more advanced disease, as an adjunct to L-DOPA. Along with the enhanced patient compliance seen with once a day dosing, there are other potential advantages of extended release preparations of dopamine agonists. Patients initiated on pramipexole have a lower incidence of developing motor fluctuations including dyskinesia than those initiated on L-DOPA. Pramipexole requires a prolonged dose titration compared to L-DOPA, and generally does not have the efficacy of L-DOPA. The extended release form of pramipexole shows comparable mean and peak serum levels with once a day dosing as seen with three times a day dosing of the immediate release preparation. The extended release preparation has been studied in randomized multicenter clinical trial against both placebo and the immediate release preparation in the setting of early Parkinson’s disease as monotherapy and in more advanced patients with motor fluctuations on L-DOPA. In both settings the extended release preparation was superior to placebo and comparable to the immediate release form in efficacy with a similar side effect profile including nausea, sleepiness, leg edema, dyskinesias, hallucinations and impulse control disorders.
doi:10.4137/JCNSD.S5210
PMCID: PMC3663603  PMID: 23861646
dopamine agonist; dyskinesia; restless leg syndrome; impulse control disorder; pharmacokinetics
10.  Caffeine Consumption and Risk of Dyskinesia in CALM-PD 
Background
Adenosine A2A receptor antagonists reduce or prevent the development of dyskinesia in animal models of levodopa-induced dyskinesia.
Methods
We examined the association between self-reported intake of the A2A receptor antagonist caffeine and time to dyskinesia in the Comparison of the Agonist Pramipexole with Levodopa on Motor Complications of Parkinson’s Disease (CALM-PD) and CALM Cohort extension studies, using a Cox proportional hazards model adjusting for age, baseline Parkinson’s severity, site, and initial treatment with pramipexole or levodopa.
Results
For subjects who consumed > 12 ounces of coffee/day, the adjusted hazard ratio for the development of dyskinesia was 0.61 (95% confidence interval, 0.37–1.01) compared to subjects who consumed < 4 ounces/day. For subjects who consumed between 4 and 12 ounces/day, the adjusted hazard ratio was 0.73 (C.I. 0.46–1.15) (test for trend, p = 0.05).
Conclusions
These results support the possibility that caffeine may reduce the likelihood of developing dyskinesia.
doi:10.1002/mds.25319
PMCID: PMC3608707  PMID: 23339054
Caffeine; adenosine; Parkinson’s disease; PD; dyskinesia
11.  Dyskinesia and the antiparkinsonian response always temporally coincide 
Neurology  2010;74(15):1191-1197.
Objective:
To clinically characterize the temporal relationship between dyskinesia and the antiparkinsonian response when dyskinesia first emerges during long-term levodopa therapy and to determine if it is consistent with the hypothesized mechanism by which dyskinesia develops.
Methods:
Dyskinesia and the antiparkinsonian response to levodopa during 2-hour levodopa infusions were monitored at intervals through the first 4 years of long-term levodopa therapy in 20 subjects with idiopathic Parkinson disease (PD) and previously untreated with levodopa. The onset and offset of the antiparkinsonian response and dyskinesia were compared when dyskinesia first appeared during the 4 years. The findings were compared to 20 subjects with PD on long-term levodopa with dyskinesia and motor fluctuations.
Results:
The onset and offset of the antiparkinsonian response and dyskinesia generally coincided when dyskinesia first appeared during the 4 years and did not suggest any temporal dissociation of the 2 responses. Further, the latency to the onsets of dyskinesia and the antiparkinsonian response tended to shorten during long-term levodopa therapy, suggesting that both responses were sensitized by long-term levodopa.
Conclusions:
The similar onsets and offsets of the antiparkinsonian response and dyskinesia when dyskinesia first appears are not consistent with the postulated progressive decrease in threshold for dyskinesia during long-term levodopa therapy. Other mechanisms for the development of dyskinesia need to be considered.
GLOSSARY
= General Clinical Research Center;
= Oregon Health & Science University;
= Parkinson disease.
doi:10.1212/WNL.0b013e3181d90050
PMCID: PMC2865731  PMID: 20220120
12.  Reward processing abnormalities in Parkinson disease 
Background
The primary motor cortex is important for motor learning and response selection, functions that require information on the expected and actual outcomes of behavior. Therefore, it should receive signals related to reward and pathways from reward centers to motor cortex exist in primates. Previously, we showed that gamma aminobutyric acid-A(GABAA)-mediated inhibition in motor cortex, measured by paired transcranial magnetic stimulation (TMS), changes with expectation and uncertainty of money rewards generated by a slot machine simulation.
Methods
We examined the role of dopamine in this phenomenon by testing 13 mildly affected Parkinson disease patients, off and on dopaminergic medications, and 13 healthy, age-matched controls.
Results
Consistent with a dopaminergic mechanism, reward expectation or predictability modulated the response to paired TMS in controls, but not in unmedicated patients. A single dose of pramipexole restored this effect of reward, mainly by increasing the paired TMS response amplitude during low expectation. Levodopa produced no such effect. Both pramipexole and levodopa increased risk-taking behavior on the Iowa Gambling Task. However, pramipexole increased risk-taking behavior more in patients showing lower paired TMS response amplitude during low expectation.
Conclusions
These results provide evidence that modulation of motor cortex inhibition by reward is mediated by dopamine signaling and that physiological states in the motor cortex are associated with levels of risk-taking behavior in patients on pramipexole. The cortical response to reward expectation may represent an endophenotype for risk-taking behavior in patients on agonist treatment.
doi:10.1002/mds.23701
PMCID: PMC3150632  PMID: 21538525
Transcranial magnetic stimulation (TMS); dopamine; gambling; motor cortex
13.  Pramipexole in patients with early Parkinson's disease (PROUD): a randomised delayed-start trial 
Lancet Neurology  2013;12(8):747-755.
Summary
Background
In models of dopaminergic neuronal loss, the dopamine agonist pramipexole has exhibited neuroprotective properties. The Pramipexole On Underlying Disease (PROUD) study was designed to identify whether early versus delayed pramipexole initiation has clinical and neuroimaging benefits in patients with Parkinson's disease (PD).
Methods
Between May 24, 2006, and April 22, 2009, at 98 centres, we recruited patients with PD diagnosed within 2 years and aged 30–79 years. We randomly assigned eligible patients (ratio 1:1), by a centralised, computerised randomisation schedule, to receive double-blind either placebo or pramipexole (1·5 mg a day) and followed them up for 15 months. At 9 months, or as early as 6 months if considered necessary, placebo recipients were assigned to pramipexole. In a neuroimaging substudy, striatal dopamine-transporter binding was assessed by SPECT. All patients, investigators, and independent raters were masked to study treatment. The primary endpoint was the 15-month change from baseline in total score on the unified Parkinson's disease rating scale (UPDRS). This trial is registered with ClinicalTrials.gov, number NCT00321854.
Findings
Of 535 patients, 261 were randomly assigned to receive pramipexole and 274 to receive placebo. At 15 months (n=411), adjusted mean change in UPDRS total score showed no significant difference between early and delayed pramipexole (−0·4 points, 95% CI −2·2 to 1·4, p=0·65). 62 patients in the early pramipexole group and 61 patients in the delayed pramipexole group were included in the neuroimaging substudy, for which the adjusted mean 15-month change in striatal 123I-FP-CIT binding was −15·1% (SE 2·1) for early and −14·6% (2·0) for delayed pramipexole (difference −0·5 percentage points, 95% CI −5·4 to 4·4, p=0·84). Overall, 180 (81%) of patients given early pramipexole and 179 (84%) patients given delayed pramipexole reported adverse events (most frequently nausea), and 22 (10%) patients in the early pramipexole group and 17 (8%) in the delayed pramipexole group had serious events, two of which (hallucinations and orthostatic hypotension) were deemed related to study drug.
Interpretation
By clinical and neuroimaging measures, pramipexole showed little evidence differentiating 15-month usage from usage delayed for 6–9 months. The results do not support the hypothesis that pramipexole has disease-modifying effects.
Funding
Boehringer Ingelheim GmbH.
doi:10.1016/S1474-4422(13)70117-0
PMCID: PMC3714436  PMID: 23726851
14.  Safety and tolerability of putaminal AADC gene therapy for Parkinson disease 
Neurology  2009;73(20):1662-1669.
Background:
In Parkinson disease (PD), the benefit of levodopa therapy becomes less marked over time, perhaps because degeneration of nigrostrial neurons causes progressive loss of aromatic l-amino acid decarboxylase (AADC), the enzyme that converts levodopa into dopamine. In a primate model of PD, intrastriatal infusion of an adeno-associated viral type 2 vector containing the human AADC gene (AAV-hAADC) results in robust response to low-dose levodopa without the side effects associated with higher doses. These data prompted a clinical trial.
Methods:
Patients with moderately advanced PD received bilateral intraputaminal infusion of AAV-hAADC vector. Low-dose and high-dose cohorts (5 patients in each) were studied using standardized clinical rating scales at baseline and 6 months. PET scans using the AADC tracer [18F]fluoro-l-m-tyrosine (FMT) were performed as a measure of gene expression.
Results:
The gene therapy was well tolerated, but 1 symptomatic and 2 asymptomatic intracranial hemorrhages followed the operative procedure. Total and motor rating scales improved in both cohorts. Motor diaries also showed increased on-time and reduced off-time without increased “on” time dyskinesia. At 6 months, FMT PET showed a 30% increase of putaminal uptake in the low-dose cohort and a 75% increase in the high-dose cohort.
Conclusion:
This study provides class IV evidence that bilateral intrastriatal infusion of adeno-associated viral type 2 vector containing the human AADC gene improves mean scores on the Unified Parkinson’s Disease Rating Scale by approximately 30% in the on and off states, but the surgical procedure may be associated with an increased risk of intracranial hemorrhage and self-limited headache.
GLOSSARY
= l-amino acid decarboxylase;
= adeno-associated viral type 2 vector containing the human AADC gene;
= dopamine;
= [18F]fluoro-l-m-tyrosine;
= 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine;
= medium spiny neurons;
= not significant;
= Parkinson disease;
= Unified Parkinson’s Disease Rating Scale.
doi:10.1212/WNL.0b013e3181c29356
PMCID: PMC2839805  PMID: 19828868
15.  Mucuna pruriens in Parkinson's disease: a double blind clinical and pharmacological study 
Background: The seed powder of the leguminous plant, Mucuna pruriens has long been used in traditional Ayurvedic Indian medicine for diseases including parkinsonism. We have assessed the clinical effects and levodopa (L-dopa) pharmacokinetics following two different doses of mucuna preparation and compared them with standard L-dopa/carbidopa (LD/CD).
Methods: Eight Parkinson's disease patients with a short duration L-dopa response and on period dyskinesias completed a randomised, controlled, double blind crossover trial. Patients were challenged with single doses of 200/50 mg LD/CD, and 15 and 30 g of mucuna preparation in randomised order at weekly intervals. L-Dopa pharmacokinetics were determined, and Unified Parkinson's Disease Rating Scale and tapping speed were obtained at baseline and repeatedly during the 4 h following drug ingestion. Dyskinesias were assessed using modified AIMS and Goetz scales.
Results: Compared with standard LD/CD, the 30 g mucuna preparation led to a considerably faster onset of effect (34.6 v 68.5 min; p = 0.021), reflected in shorter latencies to peak L-dopa plasma concentrations. Mean on time was 21.9% (37 min) longer with 30 g mucuna than with LD/CD (p = 0.021); peak L-dopa plasma concentrations were 110% higher and the area under the plasma concentration v time curve (area under curve) was 165.3% larger (p = 0.012). No significant differences in dyskinesias or tolerability occurred.
Conclusions: The rapid onset of action and longer on time without concomitant increase in dyskinesias on mucuna seed powder formulation suggest that this natural source of L-dopa might possess advantages over conventional L-dopa preparations in the long term management of PD. Assessment of long term efficacy and tolerability in a randomised, controlled study is warranted.
doi:10.1136/jnnp.2003.028761
PMCID: PMC1738871  PMID: 15548480
16.  Parkinson's disease 
Clinical Evidence  2007;2007:1203.
Introduction
Around 1% of adults have Parkinson’s disease, with a median time of 9 years between diagnosis and death.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments in people with early-stage Parkinson’s disease? What are the effects of adding other treatments in people with Parkinson’s disease who have motor complications from levodopa? What are the effects of surgery in people with later Parkinson’s disease? What are the effects of nursing and rehabilitation treatments in people with Parkinson’s disease? We searched: Medline, Embase, The Cochrane Library and other important databases up to November 2006 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 59 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding a catechol-methyl transferase inhibitor, or dopamine agonist to levodopa; amantadine; dopamine agonists; levodopa (immediate-release, modified-release); monoamine oxidase B inhibitors; occupational therapy; pallidal deep brain stimulation; pallidotomy; Parkinson’s disease nurse specialist interventions; physiotherapy; speech and language therapy; subthalamic nucleus deep brain stimulation; subthalamotomy; swallowing therapy; thalamic deep brain stimulation; and thalamotomy.
Key Points
Around 1% of adults have Parkinson's disease, with a median time of 9 years between diagnosis and death.
Levodopa is considered effective at reducing symptoms in early Parkinson's disease, but can cause irreversible dyskinesias and motor fluctuation in the long term. We don't know whether levodopa, or any other treatment, improves survival. Modified-release levodopa seems no more effective than immediate-release levodopa at improving symptoms, and delaying motor complications.
Monoamine oxidase B inhibitors (MAOBIs) may improve symptoms, reduce motor fluctuations, and delay the need for levodopa, but can cause adverse effects.
We don't know whether amantadine is beneficial for people with early Parkinson's disease, although it is currently used to treat dyskinesia. People taking amantadine for dyskinesia in early Parkinson's may have a higher risk of psychiatric adverse effects in the later stages of the disease.
Adding a catechol-O-methyl transferase (COMT) inhibitor or dopamine agonist to levodopa, or using dopamine agonists as monotherapy, may reduce ‘off' time and improve symptoms compared with levodopa alone, but can cause adverse effects. The COMT inhibitor tolcapone can cause fatal hepatic toxicity.
Surgery may be considered in people with later Parkinson's disease, but can cause fatalities. Post-operative complications include speech problems and apraxia. Although evidence is lacking, many clinicians feel that both pallidal deep brain stimulation and subthalamic nucleus deep brain stimulation improve symptoms of advanced Parkinson's disease.Bilateral subthalamic nucleus deep brain stimulation may lead to greater improvement in motor symptoms, but more cognitive impairment, than pallidal deep brain stimulation. Pallidal deep brain stimulation is associated with severe intraoperative complications.Adding subthalamic nucleus deep brain stimulation to medical treatment may improve quality of life and motor symptoms compared with medical treatment alone or other forms of surgery. It can, however, cause neurological complications, neuropsychological adverse effects, and fatal surgical complications.Unilateral pallidotomy may improve symptoms and function more than medical treatment, but may be less effective than bilateral subthalamic stimulation.We don't know whether subthalamotomy or thalamotomy are effective.
Nurse specialist interventions, occupational therapy, physiotherapy, speech and language therapy and swallowing therapy are generally considered effective and safe in people with Parkinson's disease, although few studies have been found.
PMCID: PMC2943804  PMID: 19454106
17.  Profile of idiopathic parkinson’s disease in Moroccan patients 
Objective
To characterize clinical aspects of Idiopathic Parkinson’s disease from a movement disorders consultation in University Hospital of Rabat.
Methods
Retrospective review of medical records of 117 patients with diagnosis of Idiopathic Parkinson’s disease seen in our outpatient clinic from 2006 to 2011.
Results
Mean age was 64 ± 10 years with predominance of men (61.5%). Mean age at disease onset was 57 ± 11 years. Early onset Parkinson’s Disease was recorded in 12.8%. The median duration of disease was 5 years. Initial symptom appeared on the right side in 56.5%. Tremor presentation was the most frequent (40.2%). Symptom severity was mild to moderate in 80% of cases (UPDRS < 30). Forty four per cent of patients were receiving both Dopamine Agonists and Levodopa and in 69% of cases Levodopa was introduced within the first year following onset. The mean Levodopa Equivalent Doses (LED) was 667 ± 446 mg/day. Motor complications were found in 42% with motor fluctuations in 28.7% and 2dyskinesias in 26.7%. Non motor complications are represented mainly by autonomic disorders (44%). There were no differences in the clinical presentation related to the age at onset. Age of onset < 45 and LED > 600 mg are identified as risk factors for motor fluctuations whereas duration of Levodopa treatment is a risk factor of dyskinesias.
Conclusion
Our patients are younger compared to most series with high prevalence of early onset forms. In the majority of cases, Levodopa was introduced within the first year following onset which expose patients to dyskinesias early in the course of the disease.
doi:10.1186/1755-7682-7-10
PMCID: PMC3946767  PMID: 24602214
Parkinson’s disease; Clinical features; Treatment; Motor complications; On-motor complications
18.  Effect of Tianqi antitremor granules on behavioral manifestations and expression of G protein-coupled receptor kinase 6 and β-arrestin1 in levodopa-induced dyskinesia in a rat model of Parkinson’s disease 
Background
Recent studies have shown that expression of G protein-coupled receptor kinase 6 (GRK6) and β-arrestin1 in the striatum is closely associated with hyperactive dopamine receptors in rats with levodopa-induced dyskinesia (LID). Our research group has shown that Tianqi antitremor granules have a significant effect on the motor complications of Parkinson’s disease (PD). However, whether Tianqi antitremor granules have an effect on the behavioral manifestations and expression of GRK6 and β-arrestin1 in rats with LID is unknown.
Methods
Rats with PD received twice daily intraperitoneal injections of levodopa for 4 weeks to induce dyskinesia. Rats with LID were randomly divided into five groups: an LID-control group, an LID group, a levodopa plus Tianqi antitremor granules as traditional Chinese medicine (TCM)-low group, a levodopa plus TCM-medium group, and levodopa plus TCM-high group. Peak intensity of rotations was measured. GRK6 and β-arrestin1 expression in the striatum of the dyskinetic rats was observed by immunohistochemistry and Western blotting.
Results
Pulsatile treatment with levodopa induced abnormal involuntary movements in rats with PD similar to LID in patients with PD. We found that repeated levodopa administration increased peak rotations in dyskinetic rats. However, peak rotations were decreased in rats given levodopa plus the different doses of Tianqi antitremor granules. In accordance with changed behavior, GRK6 and β-arrestin1 expression was decreased in rats with PD and was persistently low in rats with LID, but this decrease was prevented by coadministration of levodopa and Tianqi antitremor granules.
Conclusion
Tianqi antitremor granules ameliorated levodopa-induced dyskinetic behavior, reversed the decrease in GRK6 and β-arrestin1 expression, and acted as a useful adjunctive medicine for the treatment of LID.
doi:10.2147/DDDT.S48488
PMCID: PMC3864941  PMID: 24376341
Parkinson’s disease; dyskinesia; traditional Chinese medicine; herbal granules; G protein-coupled receptor kinase 6; β-arrestin1
19.  Therapeutic interventions and adjustments in the management of Parkinson disease: role of combined carbidopa/levodopa/entacapone (Stalevo®) 
Parkinson disease (PD) is a neurodegenerative disorder characterized by 3 cardinal motor symptoms: resting tremor, rigidity, and bradykinesia. Since its introduction 40 years ago, levodopa has represented the gold standard for dopaminergic stimulation therapy in patients with PD. Levodopa is routinely combined with a dopa-decarboxylase inhibitor (DDCI) to prevent the conversion of levodopa into dopamine in peripheral circulation. However, up to 80% of patients treated with continuous levodopa manifest the onset of disabling motor complications capable of producing an adverse effect on quality of life as the disease progresses. In recent years, a new, safe, and efficacious armamentarium of treatment options has been provided by the marketing of the catechol-O-methyltransferase (COMT) inhibitor, entacapone, a peripheral blocker of dopa to 3-0-methyldopa metabolism, which increments levodopa brain availability. When administered with levodopa, entacapone conjugates the rapid onset of levodopa-induced effects with a protracted efficiency, thus providing additional benefits to classic levodopa treatment by increasing “on” time in fluctuating PD patients, and theoretically providing a more continuous and physiological-like stimulation of dopamine receptors implying a reduced risk of motor complications. In this context, the use of a single administration of combined carbidopa/ levodopa/entacapone (Stalevo®) in the treatment of PD affords clinical improvements similar to those obtained by 2 separate tablets (ie, levodopa/DDCI and entacapone), although the former produces a more positive effect on quality of life than the latter. Additionally, the STalevo Reduction In Dyskinesia Evaluation (STRIDE-PD) study was designed with the aim of demonstrating that the combination of levodopa, carbidopa, and entacapone, used as initial levodopa therapy, significantly delays the onset of dyskinesias compared with the conventional levodopa/carbidopa formulation. Unfortunately, STRIDEPD failed to prove the benefit of continuous dopaminergic stimulation with triple therapy in a clinical setting. Recently, the effect of combined COMT inhibitor with levodopa administration in reducing homocysteine synthesis has been described. To this regard, clear evidence has been presented indicating homocysteine as a risk factor for vascular diseases, cognitive impairment, and dementia. Several studies have discussed the potential of entacapone as adjunct to levodopa/ DDCI in reducing plasma homocysteine levels with contrasting results.
PMCID: PMC2938297  PMID: 20856911
Parkinson disease; carbidopa/levodopa/entacapone
20.  Carbidopa/levodopa/entacapone: the evidence for its place in the treatment of Parkinson’s disease 
Core Evidence  2010;5:1-10.
Introduction:
Parkinson’s disease (PD) is a common neurodegenerative disease. In the 1960s, it was shown that the degeneration of dopamine producing neurons in the substantia nigra (SN) caused the motor features of PD. Dopamine replacement with levodopa, a dopamine precursor, resulted in remarkable benefit. Yet, the intermittent administration of levodopa is a major cause of motor complications, such as “wearing-off” of levodopa’s benefit and involuntary movements, known as dyskinesia. Therefore, agents that prolong levodopa’s half-life were employed, such as carbidopa, an aromatic amino acid decarboxylase (AADC) inhibitor, and entacapone, a catechol-O-methyltransferase (COMT) inhibitor. The combination product carbidopa/levodopa/entacapone (CLE) was approved in 2003 for the treatment of PD patients.
Aims:
To assess the evidence for the place of CLE in the treatment of PD.
Evidence review:
CLE has a good efficacy, safety and tolerability profile, similar to that of entacapone taken separately with carbidopa/levodopa (CL). Compared to CL alone, it prolongs levodopa’s benefit, and improves the quality of life but not the motor performance in PD patients with nondebilitating “wearing-off” or dyskinesia. However, it increases the dyskinesia rate in early PD patients, and has adverse events in advanced patients with significant motor complications. There is insufficient evidence regarding cost-effectiveness.
Place in therapy:
CLE is an attractive alternative for patients with nondisabling “wearing-off” or dyskinesia taking CL with or without entacapone. It cannot be recommended for early PD patients, as it can induce more dyskinesia than CL alone, or in any patients who seem to have more adverse events.
PMCID: PMC2915499  PMID: 20694135
Parkinson’s disease; levodopa; entacapone; carbidopa; treatment
21.  Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson’s disease patients 
The Journal of Clinical Investigation  2014;124(3):1340-1349.
Levodopa-induced dyskinesias (LIDs) are the most common and disabling adverse motor effect of therapy in Parkinson’s disease (PD) patients. In this study, we investigated serotonergic mechanisms in LIDs development in PD patients using 11C-DASB PET to evaluate serotonin terminal function and 11C-raclopride PET to evaluate dopamine release. PD patients with LIDs showed relative preservation of serotonergic terminals throughout their disease. Identical levodopa doses induced markedly higher striatal synaptic dopamine concentrations in PD patients with LIDs compared with PD patients with stable responses to levodopa. Oral administration of the serotonin receptor type 1A agonist buspirone prior to levodopa reduced levodopa-evoked striatal synaptic dopamine increases and attenuated LIDs. PD patients with LIDs that exhibited greater decreases in synaptic dopamine after buspirone pretreatment had higher levels of serotonergic terminal functional integrity. Buspirone-associated modulation of dopamine levels was greater in PD patients with mild LIDs compared with those with more severe LIDs. These findings indicate that striatal serotonergic terminals contribute to LIDs pathophysiology via aberrant processing of exogenous levodopa and release of dopamine as false neurotransmitter in the denervated striatum of PD patients with LIDs. Our results also support the development of selective serotonin receptor type 1A agonists for use as antidyskinetic agents in PD.
doi:10.1172/JCI71640
PMCID: PMC3934188  PMID: 24531549
22.  Elevated Homocysteine by Levodopa Is Detrimental to Neurogenesis in Parkinsonian Model 
PLoS ONE  2012;7(11):e50496.
Background
Modulation of neurogenesis that acts as an endogenous repair mechanism would have a significant impact on future therapeutic strategies for Parkinson’s disease (PD). Several studies demonstrated dopaminergic modulation of neurogenesis in the subventricular zone (SVZ) of the adult brain. Levodopa, the gold standard therapy for PD, causes an increase in homocysteine levels that induces neuronal death via N-methyl-D-aspartate (NMDA) receptor. The present study investigated whether elevated homocysteine by levodopa treatment in a parkinsonian model would modulate neurogenesis via NMDA receptor signal cascade and compared the effect of levodopa and pramipexol (PPX) on neurogenic activity.
Methodology/Principal Findings
Neurogenesis was assessed in vitro using neural progenitor cells (NPCs) isolated from the SVZ and in vivo with the BrdU-injected animal model of PD using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Modulation of homocysteine levels was evaluated using co-cultures of NPCs and astrocytes and PD animals. Immunochemical and Western blot analyses were used to measure neurogenesis and determine the cell death signaling. Levodopa treatment increased release of homocysteine on astrocytes culture media as well as in plasma and brain of PD animals. Increased homocysteine by levodopa led to increased apoptosis of NPCs through the NMDA receptor-dependent the extracellular signal-regulated kinase (ERK) signaling pathways. The administration of a NMDA antagonist significantly attenuated apoptotic cell death in levodopa-treated NPCs and markedly increased the number of BrdU-positive cells in the SVZ of levodopa-treated PD animals. Comparative analysis revealed that PPX treatment significantly increased the number of NPCs and BrdU-positive cells in the SVZ of PD animals compared to levodopa treatment. Our present study demonstrated that increased homocysteine by levodopa has a detrimental effect on neurogenesis through NMDA receptor-mediated ERK signaling pathway.
Conclusions/Significance
Modulation of levodopa-induced elevated homocysteine by NMDA antagonist or dopamine agonist has a clinical relevance for PD treatment in terms of adult neurogenesis.
doi:10.1371/journal.pone.0050496
PMCID: PMC3509089  PMID: 23209759
23.  Neurochemical changes in the striatum of dyskinetic rats afteradministration of the cannabinoid agonist WIN55,212-2 
Neurochemistry international  2008;54(1):56-64.
Chronic use of levodopa, the most effective treatment for Parkinson’s disease, causes abnormal involuntary movements named dyskinesias, which are linked to maladaptive changes in plasticity and disturbances of dopamine and glutamate neurotransmission in the basal ganglia. Dyskinesias can be modeled in rats with unilateral 6-hydroxydopamine lesions by repeated administration of low doses of levodopa (6 mg/kg, s.c.). Previous studies from our lab showed that sub-chronic treatment with the cannabinoid agonist WIN55,212-2 attenuates levodopa-induced dyskinesias at doses that do not interfere with physiological motor function. To investigate the neurochemical changes underlying WIN55,212-2 anti-dyskinetic effects, we used in vivo microdialysis to monitor extracellular dopamine and glutamate in the dorsal striatum of the both hemisphere of freely-moving 6-hydroxydopamine-treated, SHAM-operated and intact rats receiving levodopa acutely or chronically (11 days), and studied how sub-chronic WIN55,212-2 (1 injection × 3 days, 20 min before levodopa) affected these neurochemical outputs.
Our data indicate that: 1) the 6-hydroxydopamine lesion decreases dopamine turnover in the denervated striatum; 2) levodopa injection reduces extracellular glutamate in the side ipsilateral to the lesion of dyskinetic rats; 3) sub-chronic WIN55,212-2 prevents levodopa-induced glutamate volume transmission unbalances across the two hemispheres; 4) levodopa-induced dyskinesias are inversely correlated with glutamate levels in the denervated striatum. These data indicate that the anti-dyskinetic properties of WIN55,212-2 are accompanied by changes of dopamine and glutamate outputs in the two brain hemispheres of 6-hydroxydopamine-treated rats.
doi:10.1016/j.neuint.2008.10.007
PMCID: PMC2657321  PMID: 19010365
24.  Motor response to acute dopaminergic challenge with apomorphine and levodopa in Parkinson's disease: implications for the pathogenesis of the on-off phenomenon. 
OBJECTIVES--To evaluate the contribution of postsynaptic changes to motor fluctuations, three groups of parkinsonian patients with differing responses to treatment were acutely challenged with two dopaminergic drugs-apomorphine and levodopa-having different mechanisms of action. METHODS--Forty two patients with Parkinson's disease (14 untreated, eight with a stable response to levodopa, and 20 with levodopa induced motor fluctuations) were challenged on two consecutive days with apomorphine and levodopa. The latency, duration, and magnitude of motor response was measured. RESULTS--A progressive shortening of mean latency after levodopa challenge was found passing from the untreated to the stable and fluctuating groups; the difference between untreated and fluctuating patients was statistically significant (P < 0.01). Response duration after levodopa challenge was similar in untreated and stable patients, whereas it showed a significant shortening in patients with motor fluctuations (P < 0.05 v both untreated and stable patients). When subcutaneous apomorphine was given, untreated patients had a longer response duration than those who had developed motor fluctuations (P < 0.05). Although baseline disability was significantly greater in the fluctuating patients than in the untreated and stable patients, the severity of residual parkinsonian signs after both apomorphine and levodopa challenge was similar for all three groups; as a result, the degree of improvement in parkinsonian signs after dopaminergic stimulation was substantially greater in more advanced than in early cases. Linear regression analysis also indicated that latency and duration after apomorphine challenge did not significantly correlate with those after levodopa challenge, whereas magnitude of response to apomorphine showed a strong positive correlation with that after levodopa challenge (r = 0.9, P < 0.001). CONCLUSION--The progressive shortening of motor response after both apomorphine and levodopa suggests that pharmacodynamic factors play an important part in determining the duration of motor response and argue against altered central pharmacokinetics of levodopa being principally responsible for the on-off effect. The widening response amplitude and increasing off phase disability occurring during disease progression are also critical factors in determining the appearance of motor fluctuations.
PMCID: PMC1073946  PMID: 8648329
25.  Performance of a motor task learned ON levodopa deteriorates when subsequently practiced OFF 
Background
Studies in animals and in people with Parkinson's Disease (PD) demonstrate complex effects of dopamine on learning motor tasks; its effect on retention of motor learning has received little attention. Recent animal studies demonstrate that practicing a task in the OFF state, when initially learned in the ON state, leads to progressive deterioration in performance.
Methods
We measured the acquisition and retention of 3 different motor tasks in the presence and absence of levodopa. Twenty individuals with Hoehn and Yahr Stage 1.5-3 PD practiced the tasks for two, 4-day weeks, half practicing ON levodopa the first week and OFF the second week. The other half practiced OFF levodopa both weeks. The tasks were: 1. alternate tapping of two keys, 2. moving the body toward two targets on a posturography device and 3. mirror drawing of a star.
Results
For the finger tapping and body movement tests, those who practiced ON the first week had a progressive decline in performance with practice during Week 2, while subjects OFF during Week 1 maintained or improved. In contrast, for the mirror task, subjects ON levodopa initially had much more difficulty completing the task compared to subjects who practiced OFF. Both groups improved with practice during the first week and had flat performance the second week.
Conclusions
These data suggest that performance of speed-accuracy tasks learned in the ON state may progressively worsen if practiced in the OFF state. In addition, performance, but not learning, of some tasks may be impeded by levodopa.
doi:10.1002/mds.25702
PMCID: PMC3943672  PMID: 24132873
levodopa; learning; Parkinson's

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