Abstract
Objectives To assess the neurobiological substrate of initial cognitive decline in Parkinson's disease (PD) to inform patient management, clinical trial design, and development of treatments. Methods We longitudinally assessed, up to 3 years, 423 newly diagnosed patients with idiopathic PD, untreated at baseline, from 33 international movement disorder centers. Study outcomes were four determinations of cognitive impairment or decline, and biomarker predictors were baseline dopamine transporter (DAT) single photon emission computed tomography (SPECT) scan, structural magnetic resonance imaging (MRI; volume and thickness), diffusion tensor imaging (mean diffusivity and fractional anisotropy), cerebrospinal fluid (CSF; amyloid beta [Aβ], tau and alpha synuclein), and 11 single nucleotide polymorphisms (SNPs) previously associated with PD cognition. Additionally, longitudinal structural MRI and DAT scan data were included. Univariate analyses were run initially, with false discovery rate = 0.2, to select biomarker variables for inclusion in multivariable longitudinal mixedeffect models. Results By year 3, cognitive impairment was diagnosed in 15-38% participants depending on the criteria applied. Biomarkers, some longitudinal, predicting cognitive impairment in multivariable models were: (1) dopamine deficiency (decreased caudate and putamen DAT availability); (2) diffuse, cortical decreased brain volume or thickness (frontal, temporal, parietal, and occipital lobe regions); (3) co-morbid Alzheimer's disease Aβ amyloid pathology (lower CSF Aβ 1-42); and (4) genes (COMT val/val and BDNF val/val genotypes). Conclusions Cognitive impairment in PD increases in frequency 50-200% in the first several years of disease, 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 plaque pathology, and genetic factors.
| Original language | English (US) |
|---|---|
| Article number | e0175674 |
| Journal | PloS one |
| Volume | 12 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 2017 |
Funding
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 Siderwof: 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.
ASJC Scopus subject areas
- General