Cognitive impairment in Parkinson's disease is associated with Default Mode Network subsystem connectivity and cerebrospinal fluid Aβ

Pardis Zarifkar; Jeehyun Kim; Christian La; Kai Zhang; Sophie YorkWilliams; Taylor F Levine; Lu Tian; Per Borghammer; Kathleen L Poston

doi:10.1016/j.parkreldis.2021.01.002

Cognitive impairment in Parkinson's disease is associated with Default Mode Network subsystem connectivity and cerebrospinal fluid Aβ

Parkinsonism Relat Disord. 2021 Feb:83:71-78. doi: 10.1016/j.parkreldis.2021.01.002. Epub 2021 Jan 12.

Authors

Pardis Zarifkar¹, Jeehyun Kim², Christian La³, Kai Zhang⁴, Sophie YorkWilliams⁵, Taylor F Levine⁶, Lu Tian⁷, Per Borghammer⁸, Kathleen L Poston⁹

Affiliations

¹ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA; Department of Nuclear Medicine and PET, Aarhus University Hospital, Denmark. Electronic address: pardis.zarifkar@regionh.dk.
² Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA. Electronic address: jehn92@gmail.com.
³ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA. Electronic address: christian.la013@gmail.com.
⁴ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA. Electronic address: kyezhang@gmail.com.
⁵ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA; Department of Psychology and Neuroscience, University of Colorado, Boulder, CO, 80309, USA. Electronic address: sophie.yorkwilliams@gmail.com.
⁶ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA; Department of Psychological & Brain Sciences, Washington University, 1 Brookings Drive, St. Louis, MO, 63130, USA. Electronic address: trhendershott@wustl.edu.
⁷ Department of Biomedical Data Science, Stanford University School of Medicine, 150 Governor's Lane, Stanford, CA, 94305, USA. Electronic address: lutian@stanford.edu.
⁸ Department of Nuclear Medicine and PET, Aarhus University Hospital, Denmark. Electronic address: borghammer@clin.au.dk.
⁹ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA; Department of Neurosurgery, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA. Electronic address: klposton@stanford.edu.

Abstract

Introduction: To identify clinically implementable biomarkers of cognitive impairment in Parkinson's Disease (PD) derived from resting state-functional MRI (rs-fMRI) and CSF protein analysis.

Methods: In this single-center longitudinal cohort study, we analyzed rs-fMRI and CSF biomarkers from 50 PD patients (23 cognitively normal, 18 mild cognitive impairment, 9 dementia) and 19 controls, who completed comprehensive neuropsychological testing. A subgroup of participants returned for follow-up cognitive assessments three years later. From rs-fMRI, we studied the connectivity within two distinct Default Mode Network subsystems: left-to-right hippocampus (LHC-RHC) and medial prefrontal cortex-to-posterior cingulate cortex (mPFC-PCC). We used regression analyses to determine whether imaging (LHC-RHC, mPFC-PCC), clinical (CSF Aβ-42:40, disease duration), and demographic (age, sex, education) variables were associated with global and domain-specific cognitive impairments.

Results: LHC-RHC (F_3,67 = 3.41,p=0.023) and CSF Aβ-42:40 (χ²(3) = 8.77,p = 0.033) were reduced across more cognitively impaired PD groups. Notably, LHC-RHC connectivity was significantly associated with all global and domain-specific cognitive impairments (attention/executive, episodic memory, visuospatial, and language) at the baseline visit. In an exploratory longitudinal analysis, mPFC-PCC was associated with future global and episodic memory impairment.

Conclusion: We used biomarker techniques that are readily available in clinical and research facilities to shed light on the pathophysiologic basis of cognitive impairment in PD. Our findings suggest that there is a functionally distinct role of the hippocampal subsystem within the DMN resting state network, and that intrinsic connectivity between the hippocampi is critically related to a broad range of cognitive functions in PD.

Keywords: Biomarkers; CSF; Default mode network; Dementia; Mild cognitive impairment; Parkinson's disease/Parkinsonism; rs-fMRI.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Amyloid beta-Peptides / cerebrospinal fluid*
Biomarkers / cerebrospinal fluid
Cognitive Dysfunction* / cerebrospinal fluid
Cognitive Dysfunction* / diagnosis
Cognitive Dysfunction* / etiology
Cognitive Dysfunction* / physiopathology
Connectome*
Default Mode Network / diagnostic imaging
Default Mode Network / physiopathology*
Female
Gyrus Cinguli / diagnostic imaging
Gyrus Cinguli / physiopathology*
Hippocampus / diagnostic imaging
Hippocampus / physiopathology*
Humans
Magnetic Resonance Imaging
Male
Middle Aged
Parkinson Disease* / cerebrospinal fluid
Parkinson Disease* / complications
Parkinson Disease* / diagnosis
Parkinson Disease* / physiopathology
Prefrontal Cortex / diagnostic imaging
Prefrontal Cortex / physiopathology*

Substances

Amyloid beta-Peptides
Biomarkers

Abstract

Publication types

MeSH terms

Substances

Grants and funding