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1. A randomized clinical trial of coenzyme Q10 and GPI-1485 in early Parkinson disease

Author

Margaret Marie Cox, Stephanie Sendek, Margaret F. Turk, Julie H. Carter, Susan C. Fagan, Lorelei Derwent, Oksana Suchowersky, Jay S. Schneider, Linda Paul, Gwyn Vernon, Stephen Gollomp, Karl Kieburtz, Debbie Baker, I. Van Bodis-Wollner, Germaine McInnes, Marian A. Perez, G. Webster Ross, Katharine Pabst, Jorge L. Juncos, Chad W. Christine, Jessie Roth, Joseph M. Savitt, Peter A LeWitt, Hubert H. Fernandez, Matthew Brodsky, Mark F. Lew, Jay M. Gorell, Natividad R. Stover, Paulo Guimaraes, Andrew Feigin, Anita Blenke, Martha Nance, Elizabeth Hayes, Andrew Siderowf, W.R. Wayne Martin, Tammie Kelsey, Susan Bennett, Sharon McCarthy, Charles H. Adler, Beverly Olsen, Pauline LeBlanc, Richard B. Dewey, Rodger J. Elble, Richard S. Burns, Carlos Singer, Amy Parsons, John W. Taylor, Tracy Stewart, Maryan DeAngelis, Barbara C. Tilley, William J. Weiner, Brad A. Racette, Wendy R. Galpern, Michael J. Aminoff, Kapil D. Sethi, Jayaraman Rao, Robert A. Hauser, Debbie Fraser, Connie Kawai, David Coffey, Kelly E. Lyons, Kristine Wernette, Becky Dunlop, Holly Delgado, Marlene Lind, Rajesh Pahwa, Chris Weaver, Ray L. Watts, Patricia Deppen, Ryan J. Uitti, Marwan N. Sabbagh, Lynn Marlor, Joann Belden, Burton L. Scott, Theresa McClain, Roger L. Albin, John Y. Fang, Zoran Obradov, Yuko Y. Palesch, Maureen Cook, Pamela Andrews, Jeana Jaglin, Joanne Wojcieszek, Mary Louise Musante Weeks, Susan Peterson, James H. Bower, Maureen A. Leehey, Joanne Field, Lisa M. Shulman, Caroline M. Tanner, Jacob I. Sage, Jordan J. Elm, Joseph Jankovic, Patrick D. Mauldin, Aileen Shinaman, Peng Huang, G. Frederick Wooten, Alicia Brocht, Gordon H. Brown, Peggy Roberge, Dorothy Shearon, Buff Dill, Margaret F. Keller, Charlene Young, Christine Hunter, Janis M. Miyasaki, Susan Torgrimson, Cornelia Kamp, Brigid Hayward, Christopher G. Goetz, Emily Kosa, Marilyn Flewellen, David Simon, Rebecca McMurray, Sue Reichwein, Jacci Bainbridge, Robert W. Hamill, Stephanie Terashita, Kathleen M. Shannon, Frederick Wooten, Danna Jennings, Shana Krstevska, and Bernard Ravina

Subjects
Male, medicine.medical_specialty, Future studies, Neurology, Ubiquinone, Coenzymes, Disease, Placebo, Tacrolimus, law.invention, chemistry.chemical_compound, Double-Blind Method, Randomized controlled trial, law, Rating scale, Internal medicine, Humans, Medicine, Aged, Coenzyme Q10, business.industry, Headache, Nausea, Parkinson Disease, Middle Aged, Clinical trial, chemistry, Physical therapy, Female, Neurology (clinical), business
Abstract

Objective: To determine if future studies of coenzyme Q10 and GPI-1485 in Parkinson disease (PD) may be warranted. Methods: We conducted a randomized, double-blind, calibrated futility clinical trial of coenzyme Q10 and GPI-1485 in early untreated PD using placebo data from the DATATOP study to establish the futility threshold. Results: The primary outcome measure (change in total Unified Parkinson's Disease Rating Scale scores over 1 year) did not meet the prespecified criteria for futility for either agent. Secondary analyses using calibration controls and other more recent placebo data question the appropriateness of the predetermined definition of futility, and suggest that a more restrictive threshold may be needed. Conclusions: Coenzyme Q10 and GPI-1485 may warrant further study in Parkinson disease, although the data are inconsistent. Additional factors (cost, availability of other agents, more recent data on placebo outcomes, other ongoing trials) should also be considered in the selection of agents for Phase III studies. NEUROLOGY 2007;68:20-28

Published
2007
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2. R1514Q substitution in Lrrk2 is not a pathogenic Parkinson's disease mutation

Author

Karen Williams, Carolyn Peterson, S. Narayan, Margaret F. Turk, Julie H. Carter, C. Schell, Carlos Singer, Chad W. Christine, Paul J. Tuite, Robyn Schacherer, J. Whetteckey, S. Phipps, Diane K. Marek, William C. Nichols, John M. Bertoni, A. H. Rajput, Kenneth Marek, An Tran, P. Ryan, J. Hevezi, Joan Werner, Kelvin L. Chou, S. Chouinard, James Sutton, Margaret C. Lannon, T. Ajax, Joan Young, Deborah Judd, L. Zelaya, David Grimes, Magali Fernandez, Theresa A. Zesiewicz, Mark Stacy, Peggy Gray, Debra Berry, Michael J. Aminoff, C. Horn, C. Costan-Toth, J. Mannetter, Patricia Simpson, Susan Rolandelli, Tatiana Foroud, T. Tra, S. Wilson, Judith Dobson, Nestor Galvez-Jimenez, Donna Schwieterman, Shirley Uy, K. Price, J. Wojcieszek, Anette Nieves, Paul Atchison, Susan Bennett, L. Klassen, A. Podichetty, Vincent Calabrese, Becky Dunlop, D. Kamp, Holly Delgado, Sandra Roque, Maureen A. Leehey, Richard Camicioli, Julie So, Jayaraman Rao, Kelly E. Lyons, Kapil D. Sethi, A. Wang, Lynn Marlor, David Oakes, S. Culver, Juan Sanchez-Ramos, L. Woodward, J. Danielson, Jeannine Petit, Joann Belden, E. Licari, M. Meacham, Deborah Fontaine, Sharon Evans, C. Stone, S. Morehouse, Christopher F. O'Brien, G. Podskalny, J. Fraser, Anthony E. Lang, W.R. Wayne Martin, Carmen Serrano, H. Poiffaut, Stewart A. Factor, Joanne Wojcieszek, S. Belber, L. Davis, C. Allen, J. Hall, Judy Richman, Joseph Jankovic, Carson Reider, Stephen G. Reich, Stephanie Thomas, Kathy Davis, Richard B. Dewey, Karen Marder, T. Demarcaida, A. Kaczmarek, Lauren Seeberger, C. Halter, Mary Lou Klimek, Donald S. Higgins, Miodrag Velickovic, Joanna Hamann, Eric Siemers, E. Ohmann, C. Dingmann, Galit Kleiner-Fisman, Shari Niswonger, Theresa Derian, Maryan DeAngelis, Aileen Shinaman, Tilak Mendis, M. Rundle, Susan Mendick, L. Giffin, Karen Blindauer, Paul Gordon, Andrew Feigin, L. Shulman, Maureen Cook, Brian Wulbrecht, Rajesh Pahwa, T. Foroud, Un Jung Kang, Arthur Watts, Oksana Suchowersky, C. Joubert, J. Vo, Mandar Jog, M. Panisset, Roberta Winnick, Ronald F. Pfeiffer, Barbara Shannon, Jean P. Hubble, Clifford W. Shults, T. Gales, Tanya Simuni, M. Wolff, Hubert H. Fernandez, Pam Andrews, Karyn Boyar, Brad A. Racette, Vicki Hunt, Christine Hunter, Daniel D. Truong, L. Good, Robert L. Rodnitzky, P. Rodriguez, Sandra K. Kostyk, T. Shirley, Cheryl Halter, Peter A LeWitt, W. Weiner, Ryan J. Uitti, Lisa Scollins, Marc L. Gordon, J. Carpenter, Alice Rudolph, Lewis Sudarsky, Robert A. Hauser, Cliff Shults, Bala V. Manyam, Francis O. Walker, Juliette Harris, Marguerite Wieler, K. Dustin, Kelli Williamson, Brenda Pfeiffer, William C. Koller, Frederick J. Marshall, V. Hagen, A. Campbell, B. Hutchinson, L. Elmer, Anja Rudolph, K. Haas, Tori Ross, Rachel Saunders-Pullman, Nathan Pankratz, E. Aiken, Mariann DiMinno, Peggy Roberge, Arif Dalvi, B. Hayward, Mayank Pathak, David Simon, Michael W. Pauciulo, Holly A. Shill, M. Marotta-Kollarus, K. Ligon, Alok Sahay, Joseph H. Friedman, Neal Hermanowicz, E. Julian-Baros, Irenita Gardiner, N. Luong, Danna Jennings, R. Kurlan, and P. M. Conneally

Subjects
Adult, Male, Parkinson's disease, Adolescent, Genotype, Arginine, Guanine, Protein Serine-Threonine Kinases, Biology, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, medicine.disease_cause, Diagnosis, Differential, chemistry.chemical_compound, Degenerative disease, medicine, Humans, Point Mutation, Aged, Aged, 80 and over, Genetics, Mutation, Substitution (logic), Adenine Nucleotide Translocator 1, Genetic Variation, Parkinson Disease, Middle Aged, medicine.disease, LRRK2, nervous system diseases, Amino Acid Substitution, Neurology, chemistry, Female, Neurology (clinical), Carrier Proteins
Abstract

Mutations in LRRK2 were first reported as causing Parkinson's disease (PD) in late 2004. Since then, approximately a dozen LRRK2 substitutions have been identified that are believed to be pathogenic mutations. The substitution of adenine for guanine at nucleotide 4541 (4541G>A) in LRRK2 was recently reported. This substitution resulted in the replacement of an arginine at position 1514 with a glutamine (R1514Q). Although this substitution was not found in a large cohort of controls, its pathogenicity could not be verified. We have now genotyped the R1514Q substitution in a sample of 954 PD patients from 429 multiplex PD families. This substitution was identified in 1.8% of the PD patients; however, the majority of the PD sibships segregating this substitution were discordant for this putative mutation. In addition, the R1514Q substitution was detected in 1.4% of neurologically evaluated, control individuals. These data suggest that the R1514Q variant is not a pathogenic LRRK2 mutation. We believe it is imperative that the causative nature of any newly identified genetic variant be determined before it is included in any panel for diagnostic testing.

Published
2007
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3. The Parkinson Progression Marker Initiative (PPMI)

Author

Kenneth Marek, Danna Jennings, Shirley Lasch, Andrew Siderowf, Caroline Tanner, Tanya Simuni, Chris Coffey, Karl Kieburtz, Emily Flagg, Sohini Chowdhury, Werner Poewe, Brit Mollenhauer, Paracelsus-Elena Klinik, Todd Sherer, Mark Frasier, Claire Meunier, Alice Rudolph, Cindy Casaceli, John Seibyl, Susan Mendick, Norbert Schuff, Ying Zhang, Arthur Toga, Karen Crawford, Alison Ansbach, Pasquale De Blasio, Michele Piovella, John Trojanowski, Les Shaw, Andrew Singleton, Keith Hawkins, Jamie Eberling, Deborah Brooks, David Russell, Laura Leary, Stewart Factor, Barbara Sommerfeld, Penelope Hogarth, Emily Pighetti, Karen Williams, David Standaert, Stephanie Guthrie, Robert Hauser, Holly Delgado, Joseph Jankovic, Christine Hunter, Matthew Stern, Baochan Tran, Jim Leverenz, Marne Baca, Sam Frank, Cathi-Ann Thomas, Irene Richard, Cheryl Deeley, Linda Rees, Fabienne Sprenger, Elisabeth Lang, Holly Shill, Sanja Obradov, Hubert Fernandez, Adrienna Winters, Daniela Berg, Katharina Gauss, Douglas Galasko, Deborah Fontaine, Zoltan Mari, Melissa Gerstenhaber, David Brooks, Sophie Malloy, Paolo Barone, Katia Longo, Tom Comery, Bernard Ravina, Igor Grachev, Kim Gallagher, Michelle Collins, Katherine L. Widnell, Suzanne Ostrowizki, Paulo Fontoura, Tony Ho, Johan Luthman, Marcel van der Brug, Alastair D. Reith, and Peggy Taylor

Subjects
Diagnostic Imaging, Male, medicine.medical_specialty, International Cooperation, Disease, Bioinformatics, Article, Cohort Studies, Dopamine transporter imaging, Humans, Multicenter Studies as Topic, Medicine, Alpha synuclein, Medical physics, Web site, business.industry, General Neuroscience, Healthy subjects, Parkinson Disease, Biomarker, Therapeutic trial, Disease etiology, Cerebrospinal fluid, Diffusion tensor imaging, Disease Progression, Biomarker (medicine), Female, Observational study, business, Neuroscience, Biomarkers
Abstract

The Parkinson Progression Marker Initiative (PPMI) is a comprehensive observational, international, multi-center study designed to identify PD progression biomarkers both to improve understanding of disease etiology and course and to provide crucial tools to enhance the likelihood of success of PD modifying therapeutic trials. The PPMI cohort will comprise 400 recently diagnosed PD and 200 healthy subjects followed longitudinally for clinical, imaging and biospecimen biomarker assessment using standardized data acquisition protocols at twenty-one clinical sites. All study data will be integrated in the PPMI study database and will be rapidly and publically available through the PPMI web site- www.ppmi-info.org. Biological samples including longitudinal collection of blood, cerebrospinal fluid (CSF) and urine will be available to scientists by application to an independent PPMI biospecimen review committee also through the PPMI web site. PPMI will rely on a partnership of government, PD foundations, industry and academics working cooperatively. This approach is crucial to enhance the potential for success of this ambitious strategy to develop PD progression biomarkers that will accelerate research in disease modifying therapeutics.

Published
2011
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4. Presence of an APOE4 allele results in significantly earlier onset of Parkinson's disease and a higher risk with dementia

Author

Karen Blindauer, Lauren Seeberger, Brian Wulbrecht, Joan Young, Victoria Hunt, Judith Dobson, Lisa Byder, Clifford W. Shults, Deborah Fontaine, William C. Nichols, P. Michael Conneally, Carolyn Peterson, Julie H. Carter, Hubert H. Fernandez, Margaret C. Lannon, William C. Koller, Joanne Wojcieszek, Lawrence Elmer, Jayaraman Rao, Mark Stacy, Jo Belden, Bala V. Manyam, Julie So, Theresa Shirley, Stephen G. Reich, Stephanie Thomas, John M. Bertoni, Peggy Gray, Marguerite Wieler, Anette Nieves, Rachel Saunders Pullman, Mayank Pathak, Kenneth Marek, Debra Berry, Holly Delgado, Christopher F. O'Brien, Anthony E. Lang, Karen Marder, Ali H. Rajput, Eric Siemers, Cheryl Halter, Michel Panisset, Galit Kleimer-Fisman, Kelly E. Lyons, Robyn Schacherer, Richard Camicioli, Tatiana Foroud, Alex Rajput, Carson Reider, Kathy Davis, Robert A. Hauser, Theresa A. Zesiewicz, Deborah Judd, Susan Mendick, Maryan De Angelis, Sandra Roque, Alice Rudolph, Becky Dunlop, An Tran, Maureen Cook, Christine Hunter, Daniel D. Truong, Stewart A. Factor, Michael J. Aminoff, David Oakes, Sharon Evans, Paul J. Tuite, Jean Hall, David Grimes, W.R. Wayne Martin, Magali Fernandez, Joanna Hamman, Francis O. Walker, Pam Andrews, Karyn Boyar, Juliette Harris, Tilak Mendis, Nathan Pankratz, Mariann DiMinno, Robert L. Rodnitzky, Rajesh Pahwa, Peter A. LeWitt, Jeannine Petit, William J. Weiner, Un Jung Kang, Joseph Jankovic, Ronald F. Pfeiffer, Aileen Shinaman, Jean P. Hubble, Mark Forrest Gordon, Danna Jennings, Joseph H. Friedman, Carmen Serrano Ramos, Roger Kurlan, Kelli Williamson, Brenda Pfeiffer, and Frederick J. Marshall

Subjects
Apolipoprotein E, Adult, Lewy Body Disease, Male, Risk, medicine.medical_specialty, Pathology, Parkinson's disease, Adolescent, Genotype, Apolipoprotein E4, Statistics as Topic, Disease, Neuropsychological Tests, Apolipoproteins E, Alzheimer Disease, Internal medicine, mental disorders, medicine, Dementia, Humans, Allele, Risk factor, Alleles, Aged, Aged, 80 and over, Neurologic Examination, business.industry, Genetic Carrier Screening, Homozygote, Parkinson Disease, Middle Aged, medicine.disease, Survival Analysis, Neurology, lipids (amino acids, peptides, and proteins), Female, Neurology (clinical), Alzheimer's disease, Age of onset, business, Mental Status Schedule
Abstract

The epsilon4 allele of the apolipoprotein E gene (APOE4) has been consistently associated with a greater risk of Alzheimer's disease (AD) as well as an earlier onset of AD. It is possible that APOE4 may also play a role in the etiology of other neurodegenerative disorders, such as Parkinson's disease (PD). APOE genotype, age of onset, disease duration, smoking history, and dementia status were collected for families with PD, yielding 324 Caucasian families with complete information. Logistic regression employing one individual per family and including age of onset and disease duration as covariates demonstrated a significantly increased risk of dementia for those individuals having inherited at least one epsilon4 allele (OR=3.37; P=0.002). Survival analyses also demonstrated a significantly earlier age of onset for those subjects with at least one epsilon4 allele (59.7 years) as compared with those homozygous for the more common epsilon3 allele (62.4 years; P=0.009). Thus, consistent with previous studies, we find evidence that the presence of an epsilon4 allele results in significantly earlier onset of PD and a greater likelihood of dementia. It appears the similarities between PD and AD may be due to an overlap in the diseases' genetic etiology.

Published
2005

5. Significant Linkage of Parkinson Disease to Chromosome 2q36-37

Author

Juan Sanchez-Ramos, Paul J. Tuite, Stewart A. Factor, Mark Forrest Gordon, Sharon Evans, W.R. Wayne Martin, Michel Panisset, Patricia Simpson, Joann Belden, Deborah Fontaine, Joanne Wojcieszek, William C. Nichols, P. Michael Conneally, Margaret C. Lannon, Rachel Saunders Pullman, Anhoa Tran, Mark Stacy, Debra Berry, Un Jung Kang, Hubert H. Fernandez, Peggy Gray, Anette Nieves, Joanna Hamann, Ali H. Rajput, Tatiana Foroud, Shirley Uy, Ronald F. Pfeiffer, Jean P. Hubble, Maryan DeAngelis, Mayank Pathak, Sandra Roque, David Simon, Danna Jennings, William J. Weiner, Karyn Boyar, Holly Delgado, Lawrence I. Golbe, Alice Rudolph, Kelly E. Lyons, Tilak Mendis, Joseph H. Friedman, Joseph Jankovic, Carmen Serrano Ramos, Robert L. Rodnitzky, Rajesh Pahwa, Aileen Shinaman, Susan Mendick, Jean Hall, Paul Gordon, Judith Dobson, Nathan Pankratz, Becky Dunlop, Mariann DiMinno, Cliff Shults, Pamela Andrews, Robert A. Hauser, Peter A. LeWitt, Julie So, David Oakes, Theresa Shirley, Carson Reider, Bala V. Manyam, Kathy Davis, Francis O. Walker, Jeannine Petit, Marguerite Wieler, Juliette Harris, Stephen G. Reich, Stephanie Thomas, Christine Hunter, Daniel D. Truong, Eric Siemers, William C. Koller, Julie H. Carter, Theresa A. Zesiewicz, Michael J. Aminoff, David Grimes, Magali Fernandez, Richard Camicioli, Robyn Schacherer, Joan Werner, Christopher F. O'Brien, Karen Marder, Lawrence Elmer, Victoria Hunt, Sean K. Uniacke, Cheryl Halter, Roger Kurlan, Kelli Williamson, Alex Rajput, Brenda Pfeiffer, Lisa Scollins, John M. Bertoni, Kenneth Marek, Karen Blindauer, Lauren Seeberger, Carolyn Peterson, Frederick J. Marshall, and Deborah Judd

Subjects
Genetic Markers, Male, Ubiquitin-Protein Ligases, Pedigree chart, Biology, Genetic determinism, Ligases, 03 medical and health sciences, 0302 clinical medicine, Degenerative disease, Report, medicine, Genetics, Humans, Family, Genetics(clinical), Family history, Genetics (clinical), 030304 developmental biology, Linkage (software), 0303 health sciences, Chromosome, Chromosome Mapping, Parkinson Disease, medicine.disease, Genetic marker, Chromosomes, Human, Pair 2, Female, Alzheimer's disease, Lod Score, 030217 neurology & neurosurgery
Abstract

Parkinson disease (PD) is the second most common neurodegenerative disorder, surpassed in frequency only by Alzheimer disease. Elsewhere we have reported linkage to chromosome 2q in a sample of sibling pairs with PD. We have now expanded our sample to include 150 families meeting our strictest diagnostic definition of verified PD. To further delineate the chromosome 2q linkage, we have performed analyses using only those pedigrees with the strongest family history of PD. Linkage analyses in this subset of 65 pedigrees generated a LOD score of 5.1, which was obtained using an autosomal dominant model of disease transmission. This result strongly suggests that variation in a gene on chromosome 2q36-37 contributes to PD susceptibility.

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