Impact of the Dopamine System on Long-Term Cognitive Impairment in Parkinson Disease: An Exploratory Study

the Parkinson’s Progression Markers Initiative

doi:10.1002/mdc3.13751

Impact of the Dopamine System on Long-Term Cognitive Impairment in Parkinson Disease: An Exploratory Study

the Parkinson’s Progression Markers Initiative

Neurology

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Background: Little is known about the impact of the dopamine system on development of cognitive impairment (CI) in Parkinson disease (PD). Objectives: We used data from a multi-site, international, prospective cohort study to explore the impact of dopamine system-related biomarkers on CI in PD. Methods: PD participants were assessed annually from disease onset out to 7 years, and CI determined by applying cut-offs to four measures: (1) Montreal Cognitive Assessment; (2) detailed neuropsychological test battery; (3) Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) cognition score; and (4) site investigator diagnosis of CI (mild cognitive impairment or dementia). The dopamine system was assessed by serial Iodine-123 Ioflupane dopamine transporter (DAT) imaging, genotyping, and levodopa equivalent daily dose (LEDD) recorded at each assessment. Multivariate longitudinal analyses, with adjustment for multiple comparisons, determined the association between dopamine system-related biomarkers and CI, including persistent impairment. Results: Demographic and clinical variables associated with CI were higher age, male sex, lower education, non-White race, higher depression and anxiety scores and higher MDS-UPDRS motor score. For the dopamine system, lower baseline mean striatum dopamine transporter values (P range 0.003–0.005) and higher LEDD over time (P range <0.001–0.01) were significantly associated with increased risk for CI. Conclusions: Our results provide preliminary evidence that alterations in the dopamine system predict development of clinically-relevant, cognitive impairment in Parkinson's disease. If replicated and determined to be causative, they demonstrate that the dopamine system is instrumental to cognitive health status throughout the disease course. TRIAL REGISTRATION: Parkinson's Progression Markers Initiative is registered with ClinicalTrials.gov (NCT01141023).

Original language	English (US)
Pages (from-to)	943-955
Number of pages	13
Journal	Movement Disorders Clinical Practice
Volume	10
Issue number	6
DOIs	https://doi.org/10.1002/mdc3.13751
State	Published - Jun 2023

Funding

This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, part of the Department of Health and Human Services; project ZO1 AG000949 (CB and AS) and the Michael J. Fox Foundation for Parkinson's Research (MP). Data used in the preparation of this article were obtained from the Parkinson's Progression Markers Initiative (PPMI) database (www.ppmi-info.org/access-data-specimens/download-data). For up-to-date information on the study, visit ppmi-info.org. This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, part of the Department of Health and Human Services; project ZO1 AG000949 (CB and AS) and the Michael J. Fox Foundation for Parkinson's Research (MP). Data used in the preparation of this article were obtained from the Parkinson's Progression Markers Initiative (PPMI) database ( www.ppmi-info.org/access-data-specimens/download-data ). For up‐to‐date information on the study, visit ppmi-info.org . In the past year Dr. Weintraub has received research funding or support from Michael J. Fox Foundation for Parkinson's Research, Alzheimer's Therapeutic Research Initiative (ATRI), Alzheimer's Disease Cooperative Study (ADCS), International Parkinson and Movement Disorder Society (IPMDS), National Institute on Health (NIH), Parkinson's Foundation; U.S. Department of Veterans Affairs and Acadia Pharmaceuticals; honoraria for consultancy from Acadia Pharmaceuticals, Alkahest, Aptinyx, Cerevel Therapeutics, CHDI Foundation, Clintrex LLC (Otsuka), EcoR1 Capital, Eisai, Ferring, Gray Matter Technologies, Great Lake Neurotechnologies, Intra‐Cellular Therapies, Janssen, Merck, Sage, Scion and Signant Health; and license fee payments from the University of Pennsylvania for the QUIP and QUIP‐RS. No other authors have a financial relationship related to content of manuscript, and will provide full disclosures on request. The authors report no conflicts of interest in the previous 12 months. Financial Disclosures for the Previous 12 Months:

Keywords

Parkinson's disease
cognition
dopamine

ASJC Scopus subject areas

Neurology
Clinical Neurology

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10.1002/mdc3.13751

Cite this

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title = "Impact of the Dopamine System on Long-Term Cognitive Impairment in Parkinson Disease: An Exploratory Study",

abstract = "Background: Little is known about the impact of the dopamine system on development of cognitive impairment (CI) in Parkinson disease (PD). Objectives: We used data from a multi-site, international, prospective cohort study to explore the impact of dopamine system-related biomarkers on CI in PD. Methods: PD participants were assessed annually from disease onset out to 7 years, and CI determined by applying cut-offs to four measures: (1) Montreal Cognitive Assessment; (2) detailed neuropsychological test battery; (3) Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) cognition score; and (4) site investigator diagnosis of CI (mild cognitive impairment or dementia). The dopamine system was assessed by serial Iodine-123 Ioflupane dopamine transporter (DAT) imaging, genotyping, and levodopa equivalent daily dose (LEDD) recorded at each assessment. Multivariate longitudinal analyses, with adjustment for multiple comparisons, determined the association between dopamine system-related biomarkers and CI, including persistent impairment. Results: Demographic and clinical variables associated with CI were higher age, male sex, lower education, non-White race, higher depression and anxiety scores and higher MDS-UPDRS motor score. For the dopamine system, lower baseline mean striatum dopamine transporter values (P range 0.003–0.005) and higher LEDD over time (P range <0.001–0.01) were significantly associated with increased risk for CI. Conclusions: Our results provide preliminary evidence that alterations in the dopamine system predict development of clinically-relevant, cognitive impairment in Parkinson's disease. If replicated and determined to be causative, they demonstrate that the dopamine system is instrumental to cognitive health status throughout the disease course. TRIAL REGISTRATION: Parkinson's Progression Markers Initiative is registered with ClinicalTrials.gov (NCT01141023).",

keywords = "Parkinson's disease, cognition, dopamine",

author = "{the Parkinson{\textquoteright}s Progression Markers Initiative} and Daniel Weintraub and Marina Picillo and Cho, {Hyunkeun Ryan} and Chelsea Caspell-Garcia and Cornelis Blauwendraat and Brown, {Ethan G.} and Chahine, {Lana M.} and Coffey, {Christopher S.} and Dobkin, {Roseanne D.} and Tatiana Foroud and Doug Galasko and Karl Kieburtz and Kenneth Marek and Kalpana Merchant and Brit Mollenhauer and Poston, {Kathleen L.} and Tanya Simuni and Andrew Siderowf and Andrew Singleton and John Seibyl and Tanner, {Caroline M.}",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.",

year = "2023",

month = jun,

doi = "10.1002/mdc3.13751",

language = "English (US)",

volume = "10",

pages = "943--955",

journal = "Movement Disorders Clinical Practice",

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T1 - Impact of the Dopamine System on Long-Term Cognitive Impairment in Parkinson Disease

T2 - An Exploratory Study

AU - the Parkinson’s Progression Markers Initiative

AU - Weintraub, Daniel

AU - Picillo, Marina

AU - Cho, Hyunkeun Ryan

AU - Caspell-Garcia, Chelsea

AU - Blauwendraat, Cornelis

AU - Brown, Ethan G.

AU - Chahine, Lana M.

AU - Coffey, Christopher S.

AU - Dobkin, Roseanne D.

AU - Foroud, Tatiana

AU - Galasko, Doug

AU - Kieburtz, Karl

AU - Marek, Kenneth

AU - Merchant, Kalpana

AU - Mollenhauer, Brit

AU - Poston, Kathleen L.

AU - Simuni, Tanya

AU - Siderowf, Andrew

AU - Singleton, Andrew

AU - Seibyl, John

AU - Tanner, Caroline M.

PY - 2023/6

Y1 - 2023/6

N2 - Background: Little is known about the impact of the dopamine system on development of cognitive impairment (CI) in Parkinson disease (PD). Objectives: We used data from a multi-site, international, prospective cohort study to explore the impact of dopamine system-related biomarkers on CI in PD. Methods: PD participants were assessed annually from disease onset out to 7 years, and CI determined by applying cut-offs to four measures: (1) Montreal Cognitive Assessment; (2) detailed neuropsychological test battery; (3) Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) cognition score; and (4) site investigator diagnosis of CI (mild cognitive impairment or dementia). The dopamine system was assessed by serial Iodine-123 Ioflupane dopamine transporter (DAT) imaging, genotyping, and levodopa equivalent daily dose (LEDD) recorded at each assessment. Multivariate longitudinal analyses, with adjustment for multiple comparisons, determined the association between dopamine system-related biomarkers and CI, including persistent impairment. Results: Demographic and clinical variables associated with CI were higher age, male sex, lower education, non-White race, higher depression and anxiety scores and higher MDS-UPDRS motor score. For the dopamine system, lower baseline mean striatum dopamine transporter values (P range 0.003–0.005) and higher LEDD over time (P range <0.001–0.01) were significantly associated with increased risk for CI. Conclusions: Our results provide preliminary evidence that alterations in the dopamine system predict development of clinically-relevant, cognitive impairment in Parkinson's disease. If replicated and determined to be causative, they demonstrate that the dopamine system is instrumental to cognitive health status throughout the disease course. TRIAL REGISTRATION: Parkinson's Progression Markers Initiative is registered with ClinicalTrials.gov (NCT01141023).

AB - Background: Little is known about the impact of the dopamine system on development of cognitive impairment (CI) in Parkinson disease (PD). Objectives: We used data from a multi-site, international, prospective cohort study to explore the impact of dopamine system-related biomarkers on CI in PD. Methods: PD participants were assessed annually from disease onset out to 7 years, and CI determined by applying cut-offs to four measures: (1) Montreal Cognitive Assessment; (2) detailed neuropsychological test battery; (3) Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) cognition score; and (4) site investigator diagnosis of CI (mild cognitive impairment or dementia). The dopamine system was assessed by serial Iodine-123 Ioflupane dopamine transporter (DAT) imaging, genotyping, and levodopa equivalent daily dose (LEDD) recorded at each assessment. Multivariate longitudinal analyses, with adjustment for multiple comparisons, determined the association between dopamine system-related biomarkers and CI, including persistent impairment. Results: Demographic and clinical variables associated with CI were higher age, male sex, lower education, non-White race, higher depression and anxiety scores and higher MDS-UPDRS motor score. For the dopamine system, lower baseline mean striatum dopamine transporter values (P range 0.003–0.005) and higher LEDD over time (P range <0.001–0.01) were significantly associated with increased risk for CI. Conclusions: Our results provide preliminary evidence that alterations in the dopamine system predict development of clinically-relevant, cognitive impairment in Parkinson's disease. If replicated and determined to be causative, they demonstrate that the dopamine system is instrumental to cognitive health status throughout the disease course. TRIAL REGISTRATION: Parkinson's Progression Markers Initiative is registered with ClinicalTrials.gov (NCT01141023).

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Impact of the Dopamine System on Long-Term Cognitive Impairment in Parkinson Disease: An Exploratory Study

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