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      Associations among Cognitive Functions, Plasma DNA, and Diffusion Tensor Image along the Perivascular Space (DTI-ALPS) in Patients with Parkinson's Disease

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          Abstract

          Background

          Parkinson's disease (PD) is a common neurodegenerative disease associated with accumulation of misfolding proteins and increased neuroinflammation, which may further impair the glymphatic system. The purpose of this study was to utilize diffusion tensor image analysis along the perivascular space (DTI-ALPS) to evaluate glymphatic system activity and its relationship with systemic oxidative stress status in PD patients.

          Methods

          Magnetic resonance imaging and neuropsychological tests were conducted on 25 PD patients with normal cognition (PDN), 25 PD patients with mild cognitive impairment (PD-MCI), 38 PD patients with dementia (PDD), and 47 normal controls (NC). Oxidative stress status was assessed by plasma DNA level. Differences in ALPS-index among the subgroups were assessed and further correlated with cognitive functions and plasma DNA levels.

          Results

          The PD-MCI and PDD groups showed significantly lower ALPS-index compared to normal controls. The ALPS-index was inversely correlated with plasma nuclear DNA, mitochondrial DNA levels, and cognitive scores.

          Conclusions

          Lower diffusivity along the perivascular space, represented by lower ALPS-index, indicates impairment of the glymphatic system in PD patients. The correlation between elevated plasma nuclear DNA levels and lower ALPS-index supports the notion that PD patients may exhibit increased oxidative stress associated with glymphatic system microstructural alterations.

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          Most cited references30

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          A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β.

          Because it lacks a lymphatic circulation, the brain must clear extracellular proteins by an alternative mechanism. The cerebrospinal fluid (CSF) functions as a sink for brain extracellular solutes, but it is not clear how solutes from the brain interstitium move from the parenchyma to the CSF. We demonstrate that a substantial portion of subarachnoid CSF cycles through the brain interstitial space. On the basis of in vivo two-photon imaging of small fluorescent tracers, we showed that CSF enters the parenchyma along paravascular spaces that surround penetrating arteries and that brain interstitial fluid is cleared along paravenous drainage pathways. Animals lacking the water channel aquaporin-4 (AQP4) in astrocytes exhibit slowed CSF influx through this system and a ~70% reduction in interstitial solute clearance, suggesting that the bulk fluid flow between these anatomical influx and efflux routes is supported by astrocytic water transport. Fluorescent-tagged amyloid β, a peptide thought to be pathogenic in Alzheimer's disease, was transported along this route, and deletion of the Aqp4 gene suppressed the clearance of soluble amyloid β, suggesting that this pathway may remove amyloid β from the central nervous system. Clearance through paravenous flow may also regulate extracellular levels of proteins involved with neurodegenerative conditions, its impairment perhaps contributing to the mis-accumulation of soluble proteins.
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            Sleep drives metabolite clearance from the adult brain.

            The conservation of sleep across all animal species suggests that sleep serves a vital function. We here report that sleep has a critical function in ensuring metabolic homeostasis. Using real-time assessments of tetramethylammonium diffusion and two-photon imaging in live mice, we show that natural sleep or anesthesia are associated with a 60% increase in the interstitial space, resulting in a striking increase in convective exchange of cerebrospinal fluid with interstitial fluid. In turn, convective fluxes of interstitial fluid increased the rate of β-amyloid clearance during sleep. Thus, the restorative function of sleep may be a consequence of the enhanced removal of potentially neurotoxic waste products that accumulate in the awake central nervous system.
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              Diagnostic criteria for mild cognitive impairment in Parkinson's disease: Movement Disorder Society Task Force guidelines.

              Mild cognitive impairment is common in nondemented Parkinson's disease (PD) patients and may be a harbinger of dementia. In view of its importance, the Movement Disorder Society commissioned a task force to delineate diagnostic criteria for mild cognitive impairment in PD. The proposed diagnostic criteria are based on a literature review and expert consensus. This article provides guidelines to characterize the clinical syndrome and methods for its diagnosis. The criteria will require validation, and possibly refinement, as additional research improves our understanding of the epidemiology, presentation, neurobiology, assessment, and long-term course of this clinical syndrome. These diagnostic criteria will support future research efforts to identify at the earliest stage those PD patients at increased risk of progressive cognitive decline and dementia who may benefit from clinical interventions at a predementia stage. Copyright © 2012 Movement Disorder Society.
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                Author and article information

                Contributors
                Journal
                Oxid Med Cell Longev
                Oxid Med Cell Longev
                OMCL
                Oxidative Medicine and Cellular Longevity
                Hindawi
                1942-0900
                1942-0994
                2021
                16 February 2021
                : 2021
                : 4034509
                Affiliations
                1Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
                2Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
                3Brain Research Center, National Yang-Ming University, Taipei, Taiwan
                4Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan
                5Department of Radiology, Nagoya University Graduate School of Medicine, Japan
                Author notes

                Academic Editor: Ana Lloret

                Author information
                https://orcid.org/0000-0001-9227-0240
                https://orcid.org/0000-0002-1326-0587
                Article
                10.1155/2021/4034509
                7904342
                33680283
                103b5a99-4c15-44e2-88ed-4236b7f9368e
                Copyright © 2021 Hsiu-Ling Chen et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 27 June 2020
                : 30 January 2021
                Funding
                Funded by: National Science Council
                Award ID: NMRPG8J6021 MOST 108-2314-B-182A-014-MY3
                Award ID: NMRPG8G6141-2 MOST106-2314-B-182A-031-MY2
                Categories
                Research Article

                Molecular medicine
                Molecular medicine

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