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PLoS One. 2017 May 17;12(5):e0175674. doi: 10.1371/journal.pone.0175674. eCollection 2017.

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

Author information

1
Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, IA, United States of America.
2
Feinberg School of Medicine, Northwestern University, Chicago, IL, United States of America.
3
University of California, San Francisco, San Francisco, CA, United States of America.
4
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, United States of America.
5
Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States of America.
6
Department of Pharmacology & Clinical Pharmacology, Inha University School of Medicine, Incheon, Republic of Korea.
7
Avid Radiopharmaceuticals, Philadelphia, PA, United States of America.
8
Institute for Neurodegenerative Disorders (IND) and Molecular NeuroImaging, LLC (MNI), New Haven CT, United States of America.
9
Department of Old Age Psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, England.
10
Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.
11
Institute for Ageing and Health, Newcastle University, Newcastle, England.
12
Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States of America.
13
Department of Neurology, University of Cincinnati Academic Health Center, Cincinnati, OH, United States of America.
14
Department of Psychiatry, Yale School of Medicine, New Haven, CT, United States of America.
15
UCSD Movement Disorder Center, Department of Neurosciences, University of California San Diego, San Diego, CA, United States of America.
16
Departments of Neurology and Psychiatry, University of Rochester School of Medicine and Dentistry, Rochester, NY, United States of America.
17
Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States of America.
18
Parkinson's Disease Research, Education and Clinical Center (PADRECC and MIRECC), Philadelphia Veterans Affairs Medical Center, Philadelphia, PA, United States of America.
19
Mental Illness Research, Education and Clinical Center (MIRECC), Philadelphia Veterans Affairs Medical Center, Philadelphia, PA, United States of America.

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 mixed-effect 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.

PMID:
28520803
PMCID:
PMC5435130
DOI:
10.1371/journal.pone.0175674
[Indexed for MEDLINE]
Free PMC Article

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