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Multiple modality biomarker prediction of cognitive impairment in prospectively followed de novo Parkinson disease

Lookup NU author(s): Dr Dag Aarsland, Professor David Burn

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This is the final published version of an article that has been published in its final definitive form by Public Library of Science, 2017.

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Abstract

© This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. 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.


Publication metadata

Author(s): Caspell-Garcia C, Simuni T, Tosun-Turgut D, Wu I-W, Zhang Y, Nalls M, Singleton A, Shaw LA, Kang J-H, Trojanowski JQ, Siderowf A, Coffey C, Lasch S, Aarsland D, Burn D, Chahine LM, Espay AJ, Foster ED, Hawkins KA, Litvan I, Richard I, Weintraub D, the Parkinson's Progression Markers Initiative (PPMI)

Publication type: Article

Publication status: Published

Journal: PLoS ONE

Year: 2017

Volume: 12

Issue: 5

Online publication date: 17/05/2017

Acceptance date: 29/03/2017

Date deposited: 20/06/2017

ISSN (electronic): 1932-6203

Publisher: Public Library of Science

URL: https://doi.org/10.1371/journal.pone.0175674

DOI: 10.1371/journal.pone.0175674


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