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Neurology. Apr 10, 2012; 78(15): 1146–1149.
PMCID: PMC3466780
Activity enhances dopaminergic long-duration response in Parkinson disease
Un Jung Kang, MDcorresponding author and Peggy Auinger, MS, On behalf of the Parkinson Study Group ELLDOPA Investigators
From the Department of Neurology (U.J.K.), The University of Chicago, Chicago, IL; and Department of Neurology (P.A.), Center for Human Experimental Therapeutics, University of Rochester, Rochester, NY.
Stanley Fahn, MD, David Oakes, PhD, Ira Shoulson, MD, Karl Kieburtz, MD, MPH, Alice Rudolph, PhD, Kenneth Marek, MD, John Seibyl, MD, Anthony Lang, MD, C. Warren Olanow, MD, Caroline Tanner, MD, PhD, Giovanni Schifitto, MD, Hongwei Zhao, ScD, Lydia Reyes, Aileen Shinaman, JD, Cynthia L. Comella, MD, Christopher Goetz, MD, Lucia M. Blasucci, RN, CCRC, Johan Samanta, MD, Mark Stacy, MD, Kelli Williamson, RN, Mary Harrigan, RN, MN, Paul Greene, MD, Blair Ford, MD, Carol Moskowitz, ANP, MS, Daniel D. Truong, MD, Mayank Pathak, MD, Joseph Jankovic, MD, William Ondo, MD, Farah Atassi, MD, MPH, Christine Hunter, RN, Carol Jacques, RN, ANP, Joseph H. Friedman, MD, Margaret Lannon, RN, MS, David S. Russell, MD, PhD, Danna Jennings, MD, Barbara Fussell, RN, David Standaert, MD, Michael A. Schwarzschild, MD, PhD, John H. Growdon, MD, Marsha Tennis, RN, Serge Gauthier, MD, Michel Panisset, MD, Jean Hall, RN, Stephen Gancher, MD, John P. Hammerstad, MD, Claudia Stone, RA, Barbara Alexander-Brown, BS, Stewart A. Factor, DO, Eric Molho, MD, Diane Brown, RN, Sharon Evans, LPN, Jeffrey Clark, DO, Bala Manyam, MD, Patricia Simpson, MHSM, RN, CCRC, Brian Wulbrecht, BA, CCRP, Jacqueline Whetteckey, Wayne Martin, MD, Ted Roberts, MD, Pamela King, BScN, RN, Robert Hauser, MD, MBA, Theresa Zesiewicz, MD, Lisa Gauger, BA, Joel Trugman, MD, G. Frederick Wooten, MD, Elke Rost-Ruffner, RN, BSN, Joel Perlmutter, MD, Brad A. Racette, MD, Oksana Suchowersky, MD, Ranjit Ranawaya, Susan Wood, RN, Carol Pantella, RN, Roger Kurlan, MD, Irene Richard, MD, Nancy Pearson, PhD, John N. Caviness, MD, Charles Adler, MD, PhD, Marlene Lind, RN, Tanya Simuni, MD, Andrew Siderowf, MD, Amy Colcher, MD, Mary Lloyd, RN, PhD, William Weiner, MD, Lisa Shulman, MD, William Koller, MD, Kelly Lyons, PhD, Robert G. Feldman, MD, Marie H. Saint-Hilaire, MD, Samuel Ellias, MD, PhD, Cathi-Ann Thomas, RN, MS, Jorge Juncos, MD, Ray Watts, MD, Anna Partlow, RN, MSN, James Tetrud, MD, Daniel M. Togasaki, MD, PhD, Tracy Stewart, RN, Margery H. Mark, MD, Jacob I. Sage, MD, Debbie Caputo, RN, MSN, Harry Gould, MD, PhD,, Jayaraman Rao, MD, Ann McKendrick, MSW, Mitchell Brin, MD, Fabio Danisi, MD, Reina Benabou, MD, Jean Hubble, MD, George W. Paulson, MD, Carson Reider, MS, Alex Birnbaum, MD, Janis Miyasaki, MD, Lisa Johnston, RN, BSCN, CNN, Julie So, RN, Rajesh Pahwa, MD, Richard M. Dubinsky, MD, Zbigniew Wszolek, MD, Ryan Uitti, MD, Margaret Turk, RN, Paul Tuite, MD, David Rottenberg, MD, Joy Hansen, RN, MSN, Serrano Ramos, MD, Cheryl Waters, MD, Mark Lew, MD, Mickie Welsh, RN, DNS, Connie Kawai, RN, BSN, CCRC, Christopher O'Brien, MD, Rajeev Kumar, MD, Lauren Seeberger, MD, Deborah Judd, RN, C. Lynn Barclay, MD, David A. Grimes, MD, Laura Sutherland, RN, Ted Dawson, MD, PhD, Stephen Reich, MD, Rebecca Dunlop, RN, Roger Albin, MD, Kirk Frey, MD, and Kristine Wernette, RN, MS
Stanley Fahn, Columbia University, New York, principal investigator;
Stanley Fahn, MD, David Oakes, PhD, Ira Shoulson, MD, Karl Kieburtz, MD, MPH, Alice Rudolph, PhD, Kenneth Marek, MD, John Seibyl, MD, Anthony Lang, MD, C. Warren Olanow, MD, Caroline Tanner, MD, PhD, Giovanni Schifitto, MD, Hongwei Zhao, ScD, Lydia Reyes, Aileen Shinaman, JD, Cynthia L. Comella, MD, Christopher Goetz, MD, Lucia M. Blasucci, RN, CCRC, Johan Samanta, MD, Mark Stacy, MD, Kelli Williamson, RN, Mary Harrigan, RN, MN, Paul Greene, MD, Blair Ford, MD, Carol Moskowitz, ANP, MS, Daniel D. Truong, MD, Mayank Pathak, MD, Joseph Jankovic, MD, William Ondo, MD, Farah Atassi, MD, MPH, Christine Hunter, RN, Carol Jacques, RN, ANP, Joseph H. Friedman, MD, Margaret Lannon, RN, MS, David S. Russell, MD, PhD, Danna Jennings, MD, Barbara Fussell, RN, David Standaert, MD, Michael A. Schwarzschild, MD, PhD, John H. Growdon, MD, Marsha Tennis, RN, Serge Gauthier, MD, Michel Panisset, MD, Jean Hall, RN, Stephen Gancher, MD, John P. Hammerstad, MD, Claudia Stone, RA, Barbara Alexander-Brown, BS, Stewart A. Factor, DO, Eric Molho, MD, Diane Brown, RN, Sharon Evans, LPN, Jeffrey Clark, DO, Bala Manyam, MD, Patricia Simpson, MHSM, RN, CCRC, Brian Wulbrecht, BA, CCRP, Jacqueline Whetteckey, Wayne Martin, MD, Ted Roberts, MD, Pamela King, BScN, RN, Robert Hauser, MD, MBA, Theresa Zesiewicz, MD, Lisa Gauger, BA, Joel Trugman, MD, G. Frederick Wooten, MD, Elke Rost-Ruffner, RN, BSN, Joel Perlmutter, MD, Brad A. Racette, MD, Oksana Suchowersky, MD, Ranjit Ranawaya, Susan Wood, RN, Carol Pantella, RN, Roger Kurlan, MD, Irene Richard, MD, Nancy Pearson, PhD, John N. Caviness, MD, Charles Adler, MD, PhD, Marlene Lind, RN, Tanya Simuni, MD, Andrew Siderowf, MD, Amy Colcher, MD, Mary Lloyd, RN, PhD, William Weiner, MD, Lisa Shulman, MD, William Koller, MD, Kelly Lyons, PhD, Robert G. Feldman, MD, Marie H. Saint-Hilaire, MD, Samuel Ellias, MD, PhD, Cathi-Ann Thomas, RN, MS, Jorge Juncos, MD, Ray Watts, MD, Anna Partlow, RN, MSN, James Tetrud, MD, Daniel M. Togasaki, MD, PhD, Tracy Stewart, RN, Margery H. Mark, MD, Jacob I. Sage, MD, Debbie Caputo, RN, MSN, Harry Gould, MD, PhD,, Jayaraman Rao, MD, Ann McKendrick, MSW, Mitchell Brin, MD, Fabio Danisi, MD, Reina Benabou, MD, Jean Hubble, MD, George W. Paulson, MD, Carson Reider, MS, Alex Birnbaum, MD, Janis Miyasaki, MD, Lisa Johnston, RN, BSCN, CNN, Julie So, RN, Rajesh Pahwa, MD, Richard M. Dubinsky, MD, Zbigniew Wszolek, MD, Ryan Uitti, MD, Margaret Turk, RN, Paul Tuite, MD, David Rottenberg, MD, Joy Hansen, RN, MSN, Serrano Ramos, MD, Cheryl Waters, MD, Mark Lew, MD, Mickie Welsh, RN, DNS, Connie Kawai, RN, BSN, CCRC, Christopher O'Brien, MD, Rajeev Kumar, MD, Lauren Seeberger, MD, Deborah Judd, RN, C. Lynn Barclay, MD, David A. Grimes, MD, Laura Sutherland, RN, Ted Dawson, MD, PhD, Stephen Reich, MD, Rebecca Dunlop, RN, Roger Albin, MD, Kirk Frey, MD, and Kristine Wernette, RN, MS
Stanley Fahn, Columbia University, New York, principal investigator;
Tilak Mendis, MD
Tilak Mendis, Ottawa Civic Hospital, Ottawa;
corresponding authorCorresponding author.
Study funding: This project was supported by Parkinson Study Group/Parkinson Disease Foundation data-mining grant (U.J.K., P.A.). U.J.K. was also supported in part by NIH R01 NS064865 and American Parkinson Disease Association Advanced Center for Research.
Correspondence & reprint requests to Dr. Kang: unkang/at/uchicago.edu
Received July 25, 2011; Accepted November 17, 2011.
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.
Long-duration response (LDR) in Parkinson disease (PD) pharmacologic therapy develops over days to weeks with chronic use of the drug, and gradually decays after the drug is stopped. LDR is distinct from short-duration response (SDR) that parallels the half-life of the drug (hours). LDR is a more beneficial and durable component of dopaminergic therapy without accompanying dyskinesia and motor fluctuations,1,2 but its underlying mechanism is poorly understood. We reported that dopamine-dependent motor learning in a mouse model of PD produces the same phenomenon as LDR.3 Learning motor tasks was dependent on both dopamine and task-training and occurred over a few days. In the absence of dopamine, task-training resulted in development of aberrant learning, leading to deterioration of performance over a few days.
Therefore, we hypothesized that LDR is facilitated by a combination of active training and dopamine to a greater magnitude than achievable by either one alone. The objective of this study was to test this hypothesis using previously published clinical trial data from the Earlier versus Later Levodopa Therapy in Parkinson's Disease (ELLDOPA) study that examined the efficacy of levodopa.4 We reasoned that the preferred activity of the dominant hand can be used as a proxy for active learning experience that is reflected in motor performance tests during a clinical trial visit.
The ELLDOPA study enrolled 361 patients with early, untreated PD who were randomized to various dosages of carbidopa/levodopa or placebo.4 Motor performance data were obtained at the baseline visit and before and 1 hour after administration of the first daily dose at the 3-, 9-, 24-, and 40-week visits and 2 weeks after stopping the study medication at the 42-week follow-up visit. Subjects performed 2-point finger-tapping using mechanical counters mounted 20 cm apart on a table and alternatively touched them over 1 minute as many times as possible. The change in predose finger-tapping counts at subsequent visits compared to baseline was used as a measure of LDR. The SDR was measured as the difference in scores between pre- vs postdoses at the same visit. Patients reported their hand dominance and more vs less affected hand since their symptoms were often asymmetric. Those who noted no hand dominance were excluded from the analysis (n = 3). Those with normal [123]β-CIT scans without evidence of dopamine deficiency (SWEDD) (21 of 142 who underwent the imaging) or deemed to have less than 90% likelihood of PD at follow-up (n = 14) were excluded from our analyses.
The effect of hand dominance and asymmetry of symptoms on LDR were analyzed by a repeated-measures mixed model with a 3-way interaction including duration of treatment. The effects of levodopa treatment, duration of treatment, and hand dominance on LDR were tested with a 3-way interaction. Paired t tests were used to compare handedness of LDR and SDR at each visit and the change from the 40-week predose to the 42-week washout visit as well as mean changes in posture, gait, postural balance, and Hoehn & Yahr stage from baseline to the week 42 washout visit. Bonferroni correction was applied to account for multiple comparisons in determining statistical significance resulting in an adjusted α of 0.0125. SAS v9.2 software was used for analyses.
The specific hypothesis tested was that LDR is greater in the dominant hand than in the nondominant hand. Since many patients also had asymmetric involvement of their symptoms, the effect of more or less affected side on LDR and its interaction with hand dominance was first tested. LDR was affected by hand dominance (p = 0.007), but not by whether the hand was more or less affected (p = 0.52) in the 600 mg group. Therefore, we analyzed data combining more and less affected sides. The mean LDR was greater in the dominant compared to nondominant hand at 9 and 40 weeks in those who were treated with 600 mg (figure 1A) and at 3, 9, and 40 weeks in the 150 mg group (figure 1C). The magnitudes of LDR were dose-dependent at 9, 24, and 40 weeks, showing a linear trend determined by including treatment assignment as a continuous variable in the linear regression models (p < 0.001). There was no significant difference between the dominant and nondominant hand in the placebo group at any visit. There was consistently greater magnitude of improvement of Unified Parkinson's Disease Rating Scale hand item scores in the dominant hand than nondominant hand as well, but the differences were not statistically significant at a preset level of p < 0.0125 since these scores were low in this early PD cohort (table e-1 on the Neurology® Web site at www.neurology.org).
Figure 1
Figure 1
Mean change in 2-point finger-tapping counts from baseline to various time points
The deterioration of finger-tapping scores during the 2-week washout phase was not significantly different in the dominant hand vs the nondominant hand, and finger-tapping scores at the end of the study remained significantly improved compared to those at the baseline in both hands (p < 0.001, figure 1). This is in contrast to measures such as posture, gait, postural instability scores, and Hoehn & Yahr stage that did not improve from the baseline to the end of the study (table e-2).
Levodopa effects on SDR were not distinguishable from placebo effect and there were no differences between dominant and nondominant hands (figure 2).
Figure 2
Figure 2
Changes in 2-point finger-tapping scores from predose to 1 hour postdose
Our analysis shows that active use of the dominant hand produces greater magnitude of improvement in motor performance compared to the relative inactivity of the nondominant hand in the presence of levodopa, consistent with our hypothesis that activity and dopamine enhances LDR synergistically. The dose dependence and the lack of difference between the dominant and nondominant hands in the absence of dopamine replacement in the placebo group provide additional evidence for synergy of activity and dopamine. The improvement occurred gradually over 9 weeks and plateaued, and higher doses showed continuing increase up to 40 weeks albeit at a slower rate. This time course of LDR is much longer than that observed in previous studies, in patients who were more advanced than this cohort and in experimental settings when medications were discontinued.5,6 Our analysis also shows that the effect of levodopa mainly manifests as LDR and SDR is not significantly different from placebo effect in this early PD cohort.
Studies to demonstrate the disease-modifying effect of various therapies have been complicated by the long-lasting benefits even after withdrawing medications that produce symptomatic effects.4,7 This observation of long-lasting benefits raised controversy as to whether they represent disease modification. Disease modification may imply slowing of the degenerative process, but such evidence is lacking. Nondopaminergic mechanism of compensation was also suggested.8 We propose a specific alternative mechanism of disease modification by dopaminergic agents in producing slow and long-lasting motor learning. Dopamine-resistant symptoms deteriorated or remained unchanged (table e-2) whereas dopamine-dependent motor scores remained significantly improved compared to baseline even after drug withdrawal, supporting the notion that dopamine-dependent motor learning is responsible for the residual benefit rather than general neuroprotection. Such plasticity has been noted in experimental studies as long-term potentiation or long-term depression, depending on the level of dopamine and other conditions of the stimulus,9 and underlies motor learning.10 The limitation of the study is that this was a data-mining study that used daily activities of hand dominance as a proxy for active training and assumed that finger-tapping scores reflect such activities. Future studies with prospective designs for specific motor tasks will address the role of motor learning and provide a stronger rationale for possible benefit of early dopaminergic treatment to enhance beneficial plasticity in PD.
Supplementary Material
Data Supplement
Coinvestigators
ACKNOWLEDGMENT
The authors thank the Parkinson Study Group scientific review committee for approving the study and their suggestions; the PSG ELLDOPA investigators for access to the study data; Drs. Jeff Beeler, Stanley Fahn, Jay Nutt, and Xiaoxi Zhuang for stimulating discussion and comments; and Michael McDermott for statistical consultation.
GLOSSARY
ELLDOPAEarlier versus Later Levodopa Therapy in Parkinson's Disease
LDRlong-duration response
PDParkinson disease
SDRshort-duration response

Footnotes
Coinvestigators are listed on the Neurology® Web site at www.neurology.org.
Supplemental data at www.neurology.org
Contributor Information
Stanley Fahn, Columbia University, New York, principal investigator.
David Oakes, University of Rochester, Rochester, N.Y., chief biostatistician.
Ira Shoulson, University of Rochester, Rochester, N.Y., co-principal investigator.
Karl Kieburtz, University of Rochester, Rochester, N.Y., director, Clinical Trials Coordination Center.
Alice Rudolph, University of Rochester, Rochester, N.Y., senior project coordinator.
Kenneth Marek, Institute for Neurodegenerative Disorders, New Haven, Conn., neuroimager.
John Seibyl, Institute for Neurodegenerative Disorders, New Haven, Conn., neuroimager.
Anthony Lang, Toronto Western Hospital, Toronto.
C. Warren Olanow, Mount Sinai School of Medicine, New York.
Caroline Tanner, The Parkinson's Institute, Sunnyvale, Calif.
Giovanni Schifitto, University of Rochester, Rochester, N.Y., medical monitor.
Hongwei Zhao, University of Rochester, Rochester, N.Y., biostatistician.
Lydia Reyes, Columbia University, New York, administrator.
Aileen Shinaman, University of Rochester, Rochester, N.Y., administrator.
Cynthia L. Comella, Rush-Presbyterian-St. Luke's Medical Center, Chicago.
Christopher Goetz, Rush-Presbyterian-St. Luke's Medical Center, Chicago.
Lucia M. Blasucci, Rush-Presbyterian-St. Luke's Medical Center, Chicago.
Johan Samanta, Barrow Neurological Institute, Phoenix, Ariz.
Mark Stacy, Barrow Neurological Institute, Phoenix, Ariz.
Kelli Williamson, Barrow Neurological Institute, Phoenix, Ariz.
Mary Harrigan, Barrow Neurological Institute, Phoenix, Ariz.
Paul Greene, Columbia University, New York.
Blair Ford, Columbia University, New York.
Carol Moskowitz, Columbia University, New York.
Daniel D. Truong, Parkinson's and Movement Disorder Institute, Fountain Valley, Calif.
Mayank Pathak, Parkinson's and Movement Disorder Institute, Fountain Valley, Calif.
Joseph Jankovic, Baylor College of Medicine, Houston.
William Ondo, Baylor College of Medicine, Houston.
Farah Atassi, Baylor College of Medicine, Houston.
Christine Hunter, Baylor College of Medicine, Houston.
Carol Jacques, Brown University, Providence, R.I.
Joseph H. Friedman, Brown University, Providence, R.I.
Margaret Lannon, Brown University, Providence, R.I.
David S. Russell, Institute for Neurodegenerative Disorders, New Haven, Conn.
Danna Jennings, Institute for Neurodegenerative Disorders, New Haven, Conn.
Barbara Fussell, Institute for Neurodegenerative Disorders, New Haven, Conn.
David Standaert, Massachusetts General Hospital, Boston.
Michael A. Schwarzschild, Massachusetts General Hospital, Boston.
John H. Growdon, Massachusetts General Hospital, Boston.
Marsha Tennis, Massachusetts General Hospital, Boston.
Serge Gauthier, McGill Centre for Studies in Aging, Verdun, Que., Canada.
Michel Panisset, McGill Centre for Studies in Aging, Verdun, Que., Canada.
Jean Hall, McGill Centre for Studies in Aging, Verdun, Que., Canada.
Stephen Gancher, Oregon Health and Science University, Portland.
John P. Hammerstad, Oregon Health and Science University, Portland.
Claudia Stone, Oregon Health and Science University, Portland.
Barbara Alexander-Brown, Oregon Health and Science University, Portland.
Stewart A. Factor, Albany Medical College, Albany, N.Y.
Eric Molho, Albany Medical College, Albany, N.Y.
Diane Brown, (deceased) Albany Medical College, Albany, N.Y.
Sharon Evans, Albany Medical College, Albany, N.Y.
Jeffrey Clark, Scott and White Hospital-Texas A&M University, Temple.
Bala Manyam, Scott and White Hospital-Texas A&M University, Temple.
Patricia Simpson, Scott and White Hospital-Texas A&M University, Temple.
Brian Wulbrecht, Scott and White Hospital-Texas A&M University, Temple.
Jacqueline Whetteckey, Scott and White Hospital-Texas A&M University, Temple.
Wayne Martin, University of Alberta, Edmonton, Canada.
Ted Roberts, University of Alberta, Edmonton, Canada.
Pamela King, University of Alberta, Edmonton, Canada.
Robert Hauser, University of South Florida.
Theresa Zesiewicz, University of South Florida.
Lisa Gauger, University of South Florida.
Joel Trugman, University of Virginia, Charlottesville.
G. Frederick Wooten, University of Virginia, Charlottesville.
Elke Rost-Ruffner, University of Virginia, Charlottesville.
Joel Perlmutter, Washington University, St. Louis.
Brad A. Racette, Washington University, St. Louis.
Oksana Suchowersky, University of Calgary, Alta., Canada.
Ranjit Ranawaya, University of Calgary, Alta., Canada.
Susan Wood, University of Calgary, Alta., Canada.
Carol Pantella, University of Calgary, Alta., Canada.
Roger Kurlan, University of Rochester, Rochester, N.Y.
Irene Richard, University of Rochester, Rochester, N.Y.
Nancy Pearson, University of Rochester, Rochester, N.Y.
John N. Caviness, Mayo Clinic, Scottsdale, Ariz.
Charles Adler, Mayo Clinic, Scottsdale, Ariz.
Marlene Lind, Mayo Clinic, Scottsdale, Ariz.
Tanya Simuni, University of Pennsylvania, Philadelphia.
Andrew Siderowf, University of Pennsylvania, Philadelphia.
Amy Colcher, University of Pennsylvania, Philadelphia.
Mary Lloyd, University of Pennsylvania, Philadelphia.
William Weiner, University of Miami, Miami.
Lisa Shulman, University of Miami, Miami.
William Koller, University of Miami, Miami.
Kelly Lyons, University of Miami, Miami.
Robert G. Feldman, (deceased) Boston University, Boston.
Marie H. Saint-Hilaire, Boston University, Boston.
Samuel Ellias, Boston University, Boston.
Cathi-Ann Thomas, Boston University, Boston.
Jorge Juncos, Emory University, Atlanta.
Ray Watts, Emory University, Atlanta.
Anna Partlow, Emory University, Atlanta.
James Tetrud, The Parkinson's Institute, Sunnyvale, Calif.
Daniel M. Togasaki, The Parkinson's Institute, Sunnyvale, Calif.
Tracy Stewart, The Parkinson's Institute, Sunnyvale, Calif.
Margery H. Mark, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson, New Brunswick.
Jacob I. Sage, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson, New Brunswick.
Debbie Caputo, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson, New Brunswick.
Harry Gould, Louisiana State University, New Orleans.
Jayaraman Rao, Louisiana State University, New Orleans.
Ann McKendrick, Louisiana State University, New Orleans.
Mitchell Brin, Mount Sinai School of Medicine, New York.
Fabio Danisi, Mount Sinai School of Medicine, New York.
Reina Benabou, Mount Sinai School of Medicine, New York.
Jean Hubble, Ohio State University, Columbus.
George W. Paulson, Ohio State University, Columbus.
Carson Reider, Ohio State University, Columbus.
Alex Birnbaum, Toronto Western Hospital, Toronto.
Janis Miyasaki, Toronto Western Hospital, Toronto.
Lisa Johnston, Toronto Western Hospital, Toronto.
Julie So, Toronto Western Hospital, Toronto.
Rajesh Pahwa, University of Kansas, Kansas City.
Richard M. Dubinsky, University of Kansas, Kansas City.
Zbigniew Wszolek, Mayo Clinic, Jacksonville, Fla.
Ryan Uitti, Mayo Clinic, Jacksonville, Fla.
Margaret Turk, Mayo Clinic, Jacksonville, Fla.
Paul Tuite, Minneapolis Veterans Affairs Hospital, Minneapolis.
David Rottenberg, Minneapolis Veterans Affairs Hospital, Minneapolis.
Joy Hansen, Minneapolis Veterans Affairs Hospital, Minneapolis.
Serrano Ramos, University of Puerto Rico, San Juan.
Cheryl Waters, University of Southern California, Los Angeles.
Mark Lew, University of Southern California, Los Angeles.
Mickie Welsh, University of Southern California, Los Angeles.
Connie Kawai, University of Southern California, Los Angeles.
Christopher O'Brien, Colorado Neurological Institute, Englewood.
Rajeev Kumar, Colorado Neurological Institute, Englewood.
Lauren Seeberger, Colorado Neurological Institute, Englewood.
Deborah Judd, Colorado Neurological Institute, Englewood.
C. Lynn Barclay, Ottawa Civic Hospital, Ottawa.
David A. Grimes, Ottawa Civic Hospital, Ottawa.
Laura Sutherland, Ottawa Civic Hospital, Ottawa.
Ted Dawson, Johns Hopkins University, Baltimore.
Stephen Reich, Johns Hopkins University, Baltimore.
Rebecca Dunlop, Johns Hopkins University, Baltimore.
Roger Albin, University of Michigan, Ann Arbor.
Kirk Frey, University of Michigan, Ann Arbor.
Kristine Wernette, University of Michigan, Ann Arbor.
Stanley Fahn, Columbia University, New York, principal investigator.
David Oakes, University of Rochester, Rochester, N.Y., chief biostatistician.
Ira Shoulson, University of Rochester, Rochester, N.Y., co-principal investigator.
Karl Kieburtz, University of Rochester, Rochester, N.Y., director, Clinical Trials Coordination Center.
Alice Rudolph, University of Rochester, Rochester, N.Y., senior project coordinator.
Kenneth Marek, Institute for Neurodegenerative Disorders, New Haven, Conn., neuroimager.
John Seibyl, Institute for Neurodegenerative Disorders, New Haven, Conn., neuroimager.
Anthony Lang, Toronto Western Hospital, Toronto.
C. Warren Olanow, Mount Sinai School of Medicine, New York.
Caroline Tanner, The Parkinson's Institute, Sunnyvale, Calif.
Giovanni Schifitto, University of Rochester, Rochester, N.Y., medical monitor.
Hongwei Zhao, University of Rochester, Rochester, N.Y., biostatistician.
Lydia Reyes, Columbia University, New York, administrator.
Aileen Shinaman, University of Rochester, Rochester, N.Y., administrator.
Cynthia L. Comella, Rush-Presbyterian-St. Luke's Medical Center, Chicago.
Christopher Goetz, Rush-Presbyterian-St. Luke's Medical Center, Chicago.
Lucia M. Blasucci, Rush-Presbyterian-St. Luke's Medical Center, Chicago.
Johan Samanta, Barrow Neurological Institute, Phoenix, Ariz.
Mark Stacy, Barrow Neurological Institute, Phoenix, Ariz.
Kelli Williamson, Barrow Neurological Institute, Phoenix, Ariz.
Mary Harrigan, Barrow Neurological Institute, Phoenix, Ariz.
Paul Greene, Columbia University, New York.
Blair Ford, Columbia University, New York.
Carol Moskowitz, Columbia University, New York.
Daniel D. Truong, Parkinson's and Movement Disorder Institute, Fountain Valley, Calif.
Mayank Pathak, Parkinson's and Movement Disorder Institute, Fountain Valley, Calif.
Joseph Jankovic, Baylor College of Medicine, Houston.
William Ondo, Baylor College of Medicine, Houston.
Farah Atassi, Baylor College of Medicine, Houston.
Christine Hunter, Baylor College of Medicine, Houston.
Carol Jacques, Brown University, Providence, R.I.
Joseph H. Friedman, Brown University, Providence, R.I.
Margaret Lannon, Brown University, Providence, R.I.
David S. Russell, Institute for Neurodegenerative Disorders, New Haven, Conn.
Danna Jennings, Institute for Neurodegenerative Disorders, New Haven, Conn.
Barbara Fussell, Institute for Neurodegenerative Disorders, New Haven, Conn.
David Standaert, Massachusetts General Hospital, Boston.
Michael A. Schwarzschild, Massachusetts General Hospital, Boston.
John H. Growdon, Massachusetts General Hospital, Boston.
Marsha Tennis, Massachusetts General Hospital, Boston.
Serge Gauthier, McGill Centre for Studies in Aging, Verdun, Que., Canada.
Michel Panisset, McGill Centre for Studies in Aging, Verdun, Que., Canada.
Jean Hall, McGill Centre for Studies in Aging, Verdun, Que., Canada.
Stephen Gancher, Oregon Health and Science University, Portland.
John P. Hammerstad, Oregon Health and Science University, Portland.
Claudia Stone, Oregon Health and Science University, Portland.
Barbara Alexander-Brown, Oregon Health and Science University, Portland.
Stewart A. Factor, Albany Medical College, Albany, N.Y.
Eric Molho, Albany Medical College, Albany, N.Y.
Diane Brown, (deceased) Albany Medical College, Albany, N.Y.
Sharon Evans, Albany Medical College, Albany, N.Y.
Jeffrey Clark, Scott and White Hospital-Texas A&M University, Temple.
Bala Manyam, Scott and White Hospital-Texas A&M University, Temple.
Patricia Simpson, Scott and White Hospital-Texas A&M University, Temple.
Brian Wulbrecht, Scott and White Hospital-Texas A&M University, Temple.
Jacqueline Whetteckey, Scott and White Hospital-Texas A&M University, Temple.
Wayne Martin, University of Alberta, Edmonton, Canada.
Ted Roberts, University of Alberta, Edmonton, Canada.
Pamela King, University of Alberta, Edmonton, Canada.
Robert Hauser, University of South Florida.
Theresa Zesiewicz, University of South Florida.
Lisa Gauger, University of South Florida.
Joel Trugman, University of Virginia, Charlottesville.
G. Frederick Wooten, University of Virginia, Charlottesville.
Elke Rost-Ruffner, University of Virginia, Charlottesville.
Joel Perlmutter, Washington University, St. Louis.
Brad A. Racette, Washington University, St. Louis.
Oksana Suchowersky, University of Calgary, Alta., Canada.
Ranjit Ranawaya, University of Calgary, Alta., Canada.
Susan Wood, University of Calgary, Alta., Canada.
Carol Pantella, University of Calgary, Alta., Canada.
Roger Kurlan, University of Rochester, Rochester, N.Y.
Irene Richard, University of Rochester, Rochester, N.Y.
Nancy Pearson, University of Rochester, Rochester, N.Y.
John N. Caviness, Mayo Clinic, Scottsdale, Ariz.
Charles Adler, Mayo Clinic, Scottsdale, Ariz.
Marlene Lind, Mayo Clinic, Scottsdale, Ariz.
Tanya Simuni, University of Pennsylvania, Philadelphia.
Andrew Siderowf, University of Pennsylvania, Philadelphia.
Amy Colcher, University of Pennsylvania, Philadelphia.
Mary Lloyd, University of Pennsylvania, Philadelphia.
William Weiner, University of Miami, Miami.
Lisa Shulman, University of Miami, Miami.
William Koller, University of Miami, Miami.
Kelly Lyons, University of Miami, Miami.
Robert G. Feldman, (deceased) Boston University, Boston.
Marie H. Saint-Hilaire, Boston University, Boston.
Samuel Ellias, Boston University, Boston.
Cathi-Ann Thomas, Boston University, Boston.
Jorge Juncos, Emory University, Atlanta.
Ray Watts, Emory University, Atlanta.
Anna Partlow, Emory University, Atlanta.
James Tetrud, The Parkinson's Institute, Sunnyvale, Calif.
Daniel M. Togasaki, The Parkinson's Institute, Sunnyvale, Calif.
Tracy Stewart, The Parkinson's Institute, Sunnyvale, Calif.
Margery H. Mark, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson, New Brunswick.
Jacob I. Sage, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson, New Brunswick.
Debbie Caputo, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson, New Brunswick.
Harry Gould, Louisiana State University, New Orleans.
Jayaraman Rao, Louisiana State University, New Orleans.
Ann McKendrick, Louisiana State University, New Orleans.
Mitchell Brin, Mount Sinai School of Medicine, New York.
Fabio Danisi, Mount Sinai School of Medicine, New York.
Reina Benabou, Mount Sinai School of Medicine, New York.
Jean Hubble, Ohio State University, Columbus.
George W. Paulson, Ohio State University, Columbus.
Carson Reider, Ohio State University, Columbus.
Alex Birnbaum, Toronto Western Hospital, Toronto.
Janis Miyasaki, Toronto Western Hospital, Toronto.
Lisa Johnston, Toronto Western Hospital, Toronto.
Julie So, Toronto Western Hospital, Toronto.
Rajesh Pahwa, University of Kansas, Kansas City.
Richard M. Dubinsky, University of Kansas, Kansas City.
Zbigniew Wszolek, Mayo Clinic, Jacksonville, Fla.
Ryan Uitti, Mayo Clinic, Jacksonville, Fla.
Margaret Turk, Mayo Clinic, Jacksonville, Fla.
Paul Tuite, Minneapolis Veterans Affairs Hospital, Minneapolis.
David Rottenberg, Minneapolis Veterans Affairs Hospital, Minneapolis.
Joy Hansen, Minneapolis Veterans Affairs Hospital, Minneapolis.
Serrano Ramos, University of Puerto Rico, San Juan.
Cheryl Waters, University of Southern California, Los Angeles.
Mark Lew, University of Southern California, Los Angeles.
Mickie Welsh, University of Southern California, Los Angeles.
Connie Kawai, University of Southern California, Los Angeles.
Christopher O'Brien, Colorado Neurological Institute, Englewood.
Rajeev Kumar, Colorado Neurological Institute, Englewood.
Lauren Seeberger, Colorado Neurological Institute, Englewood.
Deborah Judd, Colorado Neurological Institute, Englewood.
C. Lynn Barclay, Ottawa Civic Hospital, Ottawa.
David A. Grimes, Ottawa Civic Hospital, Ottawa.
Laura Sutherland, Ottawa Civic Hospital, Ottawa.
Ted Dawson, Johns Hopkins University, Baltimore.
Stephen Reich, Johns Hopkins University, Baltimore.
Rebecca Dunlop, Johns Hopkins University, Baltimore.
Roger Albin, University of Michigan, Ann Arbor.
Kirk Frey, University of Michigan, Ann Arbor.
Kristine Wernette, University of Michigan, Ann Arbor.
AUTHOR CONTRIBUTIONS
U.J.K. conceived the idea, secured funding, planned the analysis, interpreted the analysis, and drafted and revised the manuscript. P.A. assisted with planning of the analysis, performed statistical analysis of the data, and revised the manuscript. The PSG ELLDOPA Study Investigators were responsible for the original study that provided the data for this study.
DISCLOSURE
Dr. Kang served on the medical advisory board of Caremark/CVS, Inc. and receives research support from the NIH, Michael J Fox Foundation for Parkinson Research, and American Parkinson Disease Association. P. Auinger reports no disclosures.
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