Biomarkers may help predict which Parkinson's disease patients will suffer significant cognitive deficits within the first 3 years of their diagnosis, according to a study published May 17, 2017, in the open-access journal PLOS ONE by Daniel Weintraub from the University of Pennsylvania, United States, and colleagues.
The researchers conducted an international, prospective study of 423 newly diagnosed and untreated Parkinson's disease patients who showed no signs of cognitive impairment at the time of their enrollment in 2010. Three years later, between 15% and 38% of these participants had developed cognitive impairment. The authors conducted brain scans, genetic tests and analyses of cerebrospinal fluid (CSF) and found that this cognitive decline correlated with biomarkers. Brain scans identified dopamine deficiency and decreased brain volume or thickness as biomarkers. The researchers also found an association with the presence in CSF of beta-amyloid protein, a marker of Alzheimer's disease, and with single nucleotide polymorphisms in the genes COMT and BDNF that had previously been associated with cognitive impairment.
The study's participants were mostly male, white and highly educated, limiting the application of these findings to other groups. Nonetheless, future validation of these biomarkers could help with clinical trial design for early therapies that may improve cognitive outcomes. Longer follow up of this cohort will also reveal whether genetic risks are important in later-onset or more advanced cognitive dysfunction in Parkinson's disease.
Dr. Weintraub summarizes: "Cognitive impairment in de novo Parkinson's disease increases in frequency 50-200% in the first several years of disease depending on the definition used, and is independently predicted by biomarker changes related to nigrostriatal or cortical dopaminergic deficits, global atrophy due to possible widespread effects of neurodegenerative disease, co-morbid Alzheimer's disease amyloid plaque pathology, and a mix of genetic factors."
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Citation: Caspell-Garcia C, Simuni T, Tosun-Turgut D, Wu I-W, Zhang Y, Nalls M, et al. (2017) Multiple modality biomarker prediction of cognitive impairment in prospectively followed de novo Parkinson disease. PLoS ONE 12(5): e0175674. https:/
Funding: Michael J Fox Foundation for Parkinson's Research (michaeljfox.org) -- study design, data collection, decision to publish, preparation of manuscript. PPMI - a public-private partnership - is funded by the Michael J. Fox Foundation for Parkinson's Research and funding partners, including Abbvie, Avid Radiopharmaceuticals, Biogen, Bristol-Myers Squibb, Covance, GE Healthcare, Genentech, GlaxoSmithKline, Lilly, Lundbeck, Merck, Meso Scale Discovery, Pfizer, Piramal, Roche, Servier, and UCB. Dr. Andrew Siderowf is an employee of Avid Radiopharmaceuticals. Avid Radiopharmaceuticals provided support in the form of salary for Dr. Siderowf, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Dr. Siderowf's specific role is articulated in the 'author contributions' section. Also supported by NINDS P50 NS053488 (Trojanowski JQ-PI). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: Alberto J. Espay: Dr. Espay has received grant support from NIH, Great Lakes Neurotechnologies and the Michael J Fox Foundation; personal compensation as a consultant/scientific advisory board member for Abbvie, TEVA, Impax, Merz, Acadia, Cynapsus, Lundbeck, and USWorldMeds; publishing royalties from Lippincott Williams & Wilkins, Cambridge University Press, and Springer; and honoraria from Abbvie, UCB, USWorldMeds, Lundbeck, Acadia, the American Academy of Neurology, and the Movement Disorders Society. He serves as Associate Editor of the Journal of Clinical Movement Disorders and on the editorial board of Parkinsonism and Related Disorders. Andrew Siderowf: Dr. Siderowf is a full-time employee of Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly and Company. Dag Aarsland, MS: Dr. Aarsland has received research support and/or honoraria from Astra-Zeneca, H. Lundbeck, Novartis Pharmaceuticals and GE Health, and serves as paid consultant for H. Lundbeck and Axovant. Irene Litvan: Dr. Litvan has been a member of the Cynapsus, Lundbeck, Biogen and Bristol-Myers Squibb Advisory Boards. She is a member of the Biotie/Parkinson Study Group Medical Advisory Board. She is an investigator in NIH Grants: 5P50 AG005131-31, 5T35HL007491, 1U01NS086659 and 1U54NS092089-01; Parkinson Study Group, Michael J Fox Foundation, AVID Pharmaceuticals, C2N Diagnostics and Bristol-Myers Squibb. She receives her salary from the University of California San Diego. John G. Trojanowski: Dr. Trojanowski may accrue revenue in the future on patents submitted by the University of Pennsylvania wherein he is co-Inventor and he received revenue from the sale of Avid to Eli Lily as co-inventor on imaging related patents submitted by the University of Pennsylvania. Mike Nalls, PhD: Dr. Nalls is supported by a consulting contact between Kelly Services and the National Institute of Aging, NIH, Bethesda, MD, USA> Tanya Simuni, MD: Dr. Simuni has served as a consultant received consulting fees from Acadia, Abbvie, Allergan, Anavex, Avid, GE Medical, Eli Lilly and Company, Harbor, Ibsen, IMPAX, Lundbeck, Merz, Inc., the National Parkinson Foundation, Navidea, Pfizer, TEVA Pharmaceuticals, UCB Pharma, Voyager, US World Meds, and the Michael J. Fox Foundation for Parkinson's Research; Dr. Simuni has served as a speaker and received an honorarium from Acadia, IMPAX, Lundbeck, TEVA Pharmaceuticals, and UCB Pharma; Dr Simuni is on the Scientific advisory board for Anavex, Sanofi, MJFF. Dr. Simuni sits on the Advisory Board for IMPAX; Dr. Simuni has received research funding from the NINDS, MJFF, NPF, TEVA Pharmaceuticals, Auspex, Biotie, Civitas, Acorda, Lundbeck, Neuroderm, NINDS, National Institutes of Health, Northwestern Foundation, and the Michael J. Fox Foundation for Parkinson's Research; Dr. Simuni received funding support for educational programs from GE Medical, TEVA, and Lundbeck. Dr. Siderowf is an employee of Avid Radiopharmaceuticals. Avid Radiopharmaceuticals provided support in the form of salary for Dr. Siderowf, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Mike A. Nalls' participation is supported by a consulting contract between dataconsult.io LLC and the National Institute on Aging, NIH, Bethesda, MD, USA. As a possible conflict of interest, Dr. Nalls also consults for Illumina Inc, the Michael J. Fox Foundation and University of California Healthcare. These do not alter our adherence to PLOS ONE policies on sharing data and materials.