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

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          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.

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          The MoCA: well-suited screen for cognitive impairment in Parkinson disease.

          J. Dalrymple-Alford, M. R. MacAskill, C. T. Nakas … (2010)
          To establish the diagnostic accuracy of the Montreal Cognitive Assessment (MoCA) when screening externally validated cognition in Parkinson disease (PD), by comparison with a PD-focused test (Scales for Outcomes in Parkinson disease-Cognition [SCOPA-COG]) and the standardized Mini-Mental State Examination (S-MMSE) as benchmarks. A convenience sample of 114 patients with idiopathic PD and 47 healthy controls was examined in a movement disorders center. The 21 patients with dementia (PD-D) were diagnosed using Movement Disorders Society criteria, externally validated by detailed independent functional and neuropsychological tests. The 21 patients with mild cognitive impairment (PD-MCI) scored 1.5 SD or more below normative data in at least 2 measures in 1 of 4 cognitive domains. Other patients had normal cognition (PD-N). Primary outcomes using receiver operating characteristic (ROC) curve analyses showed that all 3 mental status tests produced excellent discrimination of PD-D from patients without dementia (area under the curve [AUC], 87%-91%) and PD-MCI from PD-N patients (AUC, 78%-90%), but the MoCA was generally better suited across both assessments. The optimal MoCA screening cutoffs were <21/30 for PD-D (sensitivity 81%; specificity 95%; negative predictive value [NPV] 92%) and <26/30 for PD-MCI (sensitivity 90%; specificity 75%; NPV 95%). Further support that the MoCA is at least equivalent to the SCOPA-COG, and superior to the S-MMSE, came from the simultaneous classification of the 3 PD patient groups (volumes under a 3-dimensional ROC surface, chance = 17%: MoCA 79%, confidence interval [CI] 70%-89%; SCOPA-COG 74%, CI 62%-86%; MMSE-Sevens item 56%, CI 44%-68%; MMSE-World item 62%, CI 50%-73%). The MoCA is a suitably accurate, brief test when screening all levels of cognition in PD.
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            The distinct cognitive syndromes of Parkinson's disease: 5 year follow-up of the CamPaIGN cohort.

            Caroline Williams-Gray, Jonathan Evans, An Goris … (2009)
            Cognitive abnormalities are common in Parkinson's disease, with important social and economic implications. Factors influencing their evolution remain unclear but are crucial to the development of targeted therapeutic strategies. We have investigated the development of cognitive impairment and dementia in Parkinson's disease using a longitudinal approach in a population-representative incident cohort (CamPaIGN study, n = 126) and here present the 5-year follow-up data from this study. Our previous work has implicated two genetic factors in the development of cognitive dysfunction in Parkinson's disease, namely the genes for catechol-O-methyltransferase (COMT Val(158)Met) and microtubule-associated protein tau (MAPT) H1/H2. Here, we have explored the influence of these genes in our incident cohort and an additional cross-sectional prevalent cohort (n = 386), and investigated the effect of MAPT H1/H2 haplotypes on tau transcription in post-mortem brain samples from patients with Lewy body disease and controls. Seventeen percent of incident patients developed dementia over 5 years [incidence 38.7 (23.9-59.3) per 1000 person-years]. We have demonstrated that three baseline measures, namely, age >or=72 years, semantic fluency less than 20 words in 90 s and inability to copy an intersecting pentagons figure, are significant predictors of dementia risk, thus validating our previous findings. In combination, these factors had an odds ratio of 88 for dementia within the first 5 years from diagnosis and may reflect the syndrome of mild cognitive impairment of Parkinson's disease. Phonemic fluency and other frontally based tasks were not associated with dementia risk. MAPT H1/H1 genotype was an independent predictor of dementia risk (odds ratio = 12.1) and the H1 versus H2 haplotype was associated with a 20% increase in transcription of 4-repeat tau in Lewy body disease brains. In contrast, COMT genotype had no effect on dementia, but a significant impact on Tower of London performance, a frontostriatally based executive task, which was dynamic, such that the ability to solve this task changed with disease progression. Hence, we have identified three highly informative predictors of dementia in Parkinson's disease, which can be easily translated into the clinic, and established that MAPT H1/H1 genotype is an important risk factor with functional effects on tau transcription. Our work suggests that the dementing process in Parkinson's disease is predictable and related to tau while frontal-executive dysfunction evolves independently with a more dopaminergic basis and better prognosis.
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              Evolution of cognitive dysfunction in an incident Parkinson's disease cohort.

              C. Williams-Gray, T. Foltynie, C. Brayne … (2007)
              We have previously performed detailed clinical and neuropsychological assessments in a community-based cohort of patients with newly diagnosed parkinsonism, and through analysis of a subcohort with idiopathic Parkinson's disease (PD), we have demonstrated that cognitive dysfunction occurs even at the time of PD diagnosis and is heterogeneous. Longitudinal follow-up of the cohort has now been performed to examine the evolution of cognitive dysfunction within the early years of the disease. One hundred and eighty (79%) eligible patients from the original cohort with parkinsonism were available for re-assessment at between 3 and 5 years from their initial baseline assessments. PD diagnoses were re-validated with repeated application of the UKPDS Brain Bank criteria in order to maximize sensitivity and specificity, following which a diagnosis of idiopathic PD was confirmed in 126 patients. Thirteen out of 126 (10%) had developed dementia at a mean (SD) of 3.5 (0.7) years from diagnosis, corresponding to an annual dementia incidence of 30.0 (16.4-52.9) per 1000 person-years. A further 57% of PD patients showed evidence of cognitive impairment, with frontostriatal deficits being most common amongst the non-demented group. However, the most important clinical predictors of global cognitive decline following correction for age were neuropsychological tasks with a more posterior cortical basis, including semantic fluency and ability to copy an intersecting pentagons figure, as well as a non-tremor dominant motor phenotype at the baseline assessment. This work clarifies the profile of cognitive dysfunction in early PD and demonstrates that the dementing process in this illness is heralded by both postural and gait dysfunction and cognitive deficits with a posterior cortical basis, reflecting probable non-dopaminergic cortical Lewy body pathology. Furthermore, given that these predictors of dementia are readily measurable within just a few minutes in a clinical setting, our work may ultimately have practical implications in terms of guiding prognosis in individual patients.
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                Author and article information

                Contributors
                Stephen D. Ginsberg: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 17 May 2017
                Publication date Collection: 2017
                Volume: 12
                Issue: 5
                Electronic Location Identifier: e0175674
                Affiliations
                [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
                Nathan S Kline Institute, UNITED STATES
                Author notes

                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 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.

                • Data curation: LAS.

                • Formal analysis: EDF J-HK A. Singleton MN YZ I-WW DT-T CC-G.

                • Methodology: TS CC DB LAS.

                • Project administration: DW SL CC JQT A. Singleton DT-T TS.

                • Supervision: SL.

                • Writing – original draft: CC-G TS DT-T I-WW YZ MN A. Singleton J-HK JQT A. Siderowf CC SL DA DB LMC AJE EDF KAH IL IR DW LAS.

                • Writing – review & editing: CC-G TS DT-T I-WW YZ MN A. Singleton J-HK JQT A. Siderowf CC SL DA DB LMC AJE EDF KAH IL IR DW.

                ¶ Complete membership of the author group can be found in the acknowledgments section.

                Article
                Publisher ID: PONE-D-16-51302
                DOI: 10.1371/journal.pone.0175674
                PMC ID: 5435130
                PubMed ID: 28520803
                SO-VID: b31e699a-618a-4b2c-9fc7-64e3997c9118
                License:

                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.

                History
                Date received : 28 December 2016
                Date accepted : 29 March 2017
                Page count
                Figures: 0, Tables: 5, Pages: 18
                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.
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
                Subject: Neuroscience
                Subject: Cognitive Science
                Subject: Cognitive Neuroscience
                Subject: Cognitive Neurology
                Subject: Cognitive Impairment
                Subject: Biology and Life Sciences
                Subject: Neuroscience
                Subject: Cognitive Neuroscience
                Subject: Cognitive Neurology
                Subject: Cognitive Impairment
                Subject: Medicine and Health Sciences
                Subject: Neurology
                Subject: Cognitive Neurology
                Subject: Cognitive Impairment
                Subject: Medicine and Health Sciences
                Subject: Diagnostic Medicine
                Subject: Diagnostic Radiology
                Subject: Magnetic Resonance Imaging
                Subject: Research and Analysis Methods
                Subject: Imaging Techniques
                Subject: Diagnostic Radiology
                Subject: Magnetic Resonance Imaging
                Subject: Medicine and Health Sciences
                Subject: Radiology and Imaging
                Subject: Diagnostic Radiology
                Subject: Magnetic Resonance Imaging
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Biomarkers
                Subject: Medicine and Health Sciences
                Subject: Neurology
                Subject: Neurodegenerative Diseases
                Subject: Movement Disorders
                Subject: Parkinson Disease
                Subject: Biology and Life Sciences
                Subject: Neuroscience
                Subject: Brain Mapping
                Subject: Brain Morphometry
                Subject: Diffusion Tensor Imaging
                Subject: Medicine and Health Sciences
                Subject: Diagnostic Medicine
                Subject: Diagnostic Radiology
                Subject: Magnetic Resonance Imaging
                Subject: Brain Morphometry
                Subject: Diffusion Tensor Imaging
                Subject: Research and Analysis Methods
                Subject: Imaging Techniques
                Subject: Diagnostic Radiology
                Subject: Magnetic Resonance Imaging
                Subject: Brain Morphometry
                Subject: Diffusion Tensor Imaging
                Subject: Medicine and Health Sciences
                Subject: Radiology and Imaging
                Subject: Diagnostic Radiology
                Subject: Magnetic Resonance Imaging
                Subject: Brain Morphometry
                Subject: Diffusion Tensor Imaging
                Subject: Research and Analysis Methods
                Subject: Imaging Techniques
                Subject: Neuroimaging
                Subject: Brain Morphometry
                Subject: Diffusion Tensor Imaging
                Subject: Biology and Life Sciences
                Subject: Neuroscience
                Subject: Neuroimaging
                Subject: Brain Morphometry
                Subject: Diffusion Tensor Imaging
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Body Fluids
                Subject: Cerebrospinal Fluid
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Body Fluids
                Subject: Cerebrospinal Fluid
                Subject: Biology and Life Sciences
                Subject: Physiology
                Subject: Body Fluids
                Subject: Cerebrospinal Fluid
                Subject: Medicine and Health Sciences
                Subject: Physiology
                Subject: Body Fluids
                Subject: Cerebrospinal Fluid
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Nervous System
                Subject: Cerebrospinal Fluid
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Nervous System
                Subject: Cerebrospinal Fluid
                Subject: Biology and Life Sciences
                Subject: Neuroscience
                Subject: Cognitive Science
                Subject: Cognition
                Subject: Medicine and Health Sciences
                Subject: Mental Health and Psychiatry
                Subject: Dementia
                Subject: Alzheimer Disease
                Subject: Medicine and Health Sciences
                Subject: Neurology
                Subject: Dementia
                Subject: Alzheimer Disease
                Subject: Medicine and Health Sciences
                Subject: Neurology
                Subject: Neurodegenerative Diseases
                Subject: Alzheimer Disease
                Custom metadata
                Data Availability The data underlying this study are third party data. Interested researchers may apply for access to these data at the following link: http://www.ppmi-info.org/access-data-specimens/download-data/. The authors confirm that they do not have special access privileges to these data and that interested researchers may apply to access these data in the manner described.

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