CSF biomarkers associated with disease heterogeneity in early Parkinson’s disease: the Parkinson’s Progression Markers Initiative study
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The development of biomarkers to predict the progression of Parkinson’s disease (PD) from its earliest stage through its heterogeneous course is critical for research and therapeutic development. The Parkinson’s Progression Markers Initiative (PPMI) study is an ongoing international multicenter, prospective study to validate biomarkers in drug-naïve PD patients and matched healthy controls (HC). We quantified cerebrospinal fluid (CSF) alpha-synuclein (α-syn), amyloid-beta1-42 (Aβ1-42), total tau (t-tau), and tau phosphorylated at Thr181 (p-tau) in 660 PPMI subjects at baseline, and correlated these data with measures of the clinical features of these subjects. We found that CSF α-syn, t-tau and p-tau levels, but not Aβ1-42, were significantly lower in PD compared with HC, while the diagnostic value of the individual CSF biomarkers for PD diagnosis was limited due to large overlap. The level of α-syn, but not other biomarkers, was significantly lower in PD patients with non-tremor-dominant phenotype compared with tremor-dominant phenotype. In addition, in PD patients the lowest Aβ1-42, or highest t-tau/Aβ1-42 and t-tau/α-syn quintile in PD patients were associated with more severe non-motor dysfunction compared with the highest or lowest quintiles, respectively. In a multivariate regression model, lower α-syn was significantly associated with worse cognitive test performance. APOE ε4 genotype was associated with lower levels of Aβ1-42, but neither with PD diagnosis nor cognition. Our data suggest that the measurement of CSF biomarkers in early-stage PD patients may relate to disease heterogeneity seen in PD. Longitudinal observations in PPMI subjects are needed to define their prognostic performance.
KeywordsParkinson’s disease Cerebrospinal fluid biomarker Parkinson’s Progression Markers Initiative Aβ1-42 Tau Alpha-synuclein
The Parkinson’s Progression Markers Initiative Group includes Shirley Lasch; Emily Flagg; Werner Poewe, MD; Todd Sherer, PhD; Claire Meunier; Alice Rudolph, PhD; Cindy Casaceli, MBA; John Seibyl, MD; Susan Mendick, MPH; Norbert Schuff, PhD; Liz Uribe, MS; Jon Yankey, MS; Karen Crawford; Tatiana Foroud, PhD; Paola Casalin, MD, PhD, FRCP; Giulia Malferrari, PhD; Keith Hawkins, PsyD; David Russell, MD, PhD; Laura Leary, BS; Stewart Factor, DO; Barbara Sommerfeld, RN, MSN; Penelope Hogarth, MD; Emily Pighetti; Karen Williams; David Standaert, MD, PhD; Stephanie Guthrie, MSN; Robert Hauser, MD, MBA; Joseph Jankovic, MD; Christine Hunter, RN; Matthew Stern, MD; Abigail Darin; Jim Leverenz, MD; Marne Baca; Sam Frank, MD; Cathi-Ann Thomas, RN, MS; Irene Richard, MD; Cheryl Deeley, MSN; Linda Rees, MPH; Fabienne Sprenger, MD; Wolfgang Oertel, MD; Diana Willeke; Holly Shill, MD; Hubert Fernandez, MD; Jennifer Mule; Daniela Berg, MD; Katharina Gauss; Douglas Galasko, MD; Deborah Fontaine, BSN, MS; Zoltan Mari, MD; Arita McCoy, RN; David Brooks, MD; Bina Shah, BSc; Paolo Barone, MD, PhD; Stuart Isaacson, MD; Angela James; Alberto Espay, MD, MSc; Kristy Espay; Dominic Rowe, MD, PhD; Madelaine Ranola, BN.
The Parkinson’s Progression Markers Initiative Group Affiliations Institute for Neurodegenerative Disorders, New Haven, Connecticut (Lasch, Seibyl, Mendick, Russell, Leary); Clinical Trials Coordination Center, University of Rochester, Rochester, New York (Flagg, Casaceli); Innsbruck Medical University, Innsbruck, Austria (Poewe, Sprenger); The Michael J. Fox Foundation for Parkinson’s Research, New York, New York (Sherer, Meunier); Institute on Aging, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia (Rudolph); University of California, San Francisco (Schuff); University of Iowa, Iowa City (Uribe, Yankey); Laboratory of Neuro Imaging, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles (Crawford); Coriell Institute for Medical Research, Camden, New Jersey (Scutti); BioRep, Milan, Italy (Casalin, Malferrari); Yale University, New Haven, Connecticut (Hawkins); Emory University School of Medicine, Atlanta, Georgia (Factor, Sommerfeld); Oregon Health and Science University, Portland (Hogarth, Pighetti); Northwestern University, Chicago, Illinois (Williams); University of Alabama at Birmingham (Standaert, Guthrie); Baylor College of Medicine, Houston, Texas (Hauser, Jankovic, Hunter); University of Pennsylvania, Philadelphia (Stern, Darin); University of Washington, Seattle (Leverenz, Baca); Boston University, Boston, Massachusetts (Frank, Thomas); University of Rochester, Rochester, New York (Richard, Deeley); Parkinson’s Institute, Sunnyvale, California (Rees); Paracelsus-Elena-Klinik, Kassel, Germany (Oertel, Willeke); Cleveland Clinic, Cleveland, Ohio (Shill, Fernandez, Mule); University of Tuebingen, Tuebingen, Germany (Berg, Gauss); University of California, San Diego (Galasko, Fontaine); Johns Hopkins University, Baltimore, Maryland (Mari, McCoy); Imperial College London, London, England (Brooks, Shah); University of Salerno, Salerno, Italy (Barone); Parkinson’s Disease and Movement Disorders Center of Boca Raton, Boca Raton, Florida (Isaacson, James); University of Cincinnati, Cincinnati, Ohio (A. Espay, K. Espay); Macquarie University, Sydney, Australia (Rowe, Ranola).
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Conflict of interest
Frasier is an employee of The Michael J. Fox Foundation for Parkinson’s Research. Marek has been a consultant for Pfizer Inc, GE Healthcare, Merck and Co, Eli Lilly and Co, Bristol-Myers Squibb, Piramal, Neotope Biosciences, and Neuro Phage Pharmaceuticals and has equity interest in Molecular NeuroImaging. Kieburtz has been a consultant for the National Institute of Neurological Disorders and Stroke, National Institutes of Health, US Food and Drug Administration, Veterans Affairs, Abbott, Acorda, Aptiv, Astra-Zeneca, Auspex, BiogenIdec, Biotie, Biovail, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Ceregene, CHDI, Civitas, Clintrex, Cynapsus, Eli Lilly and Co, Endo, Impax, Intec, Ipsen, Isis, Knopp, Lundbeck, LZ Therapeutics, Medivation, Merck and Co, Merz, Neotope/Elan, Novartis, Orion, Otsuka, Pharma2B, Phytopharm, Roche, Siena Biotech, Sofinnova, Synagile, Synosia, Teva, UCB Pharma, Upsher-Smith, US World Meds, Vaccinex, Vectura, and Xenoport; and has performed legal consulting for Thompson Hine. Tanner has served on the scientific advisory boards of The Michael J. Fox Foundation for Parkinson’s Research and the National Spasmodic Dystonia Association; has been a consultant for Impax Pharmaceuticals and Adamas Pharmaceuticals; and is an employee of the Parkinson’s Institute and Clinical Center. Chowdhury is an employee of The Michael J. Fox Foundation for Parkinson’s Research. Shaw was previously a consultant for Fujirebio and collaborates on quality assessment activities as part of the Parkinson’s Progression Markers Initiative and as part of the Alzheimer’s Disease Neuroimaging Initiative. Leverenz has received compensation for consultation from Bayer Pharmaceuticals, Navidea Biopharmaceuticals, and Piramal Healthcare. Galasko serves as editor of Alzheimer’s Disease Research and Treatment; serves on data safety monitoring boards for Elan, Janssen, and Balance Pharmaceuticals; and is a consultant for Elan Pharmaceuticals; No other disclosures were reported.
This work was supported by The Michael J. Fox Foundation for Parkinson’s Research, Abbott, Avid Radiopharmaceuticals, BiogenIdec, Covance, Elan, Eli Lilly and Co, F. Hoffman–LaRoche Ltd, GE Healthcare, Genentech, Glaxo Smith Kline, Merck and Co, Pfizer Inc, and UCB Pharma SA. Trojanowski and Chen-Plotkin were supported by core grant P50NS053488-05 from the Morris K. Udall Center of Excellence for Parkinson’s Disease Research. Irwin was supported by Training in Age-Related Neurodegenerative Diseases grant T32-AG000255 from the National Institute on Aging, National Institutes of Health. Singleton was supported by Grant Z01AG000949-06 from the Intramural Research Program, National Institute on Aging, National Institutes of Health. Ju-Hee was supported by Grant MRC 2014009392 from the National Research Foundation of Korea, Ministry of Science, ICT and Future Planning. Kieburtz has received grants and/or research support from the National Eye Institute, National Institute of Neurological Disorders and Stroke, National Institute on Aging, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Neurosearch, and Medication. Tanner has received grants and/or research support from Brin Foundation, James and Sharron Clark, Parkinson’s Institute and Clinical Center, Parkinson’s Disease Foundation, US Army Medical Research Acquisition Activity (Telemedicine and Advanced Technology Research Center—managed Neurotoxin Exposure Treatment Research Program), National Institute of Neurological Disorders and Stroke, Agency for Healthcare and Research Quality, and National Institute of Environmental Health Sciences. Galasko receives research support from the National Institutes of Health, and the Alzheimer’s Drug Discovery Foundation.
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