Aquaporin-4 Polymorphisms Are Associated With Cognitive Performance in Parkinson’s Disease

Fang, Yi; Dai, Shaobing; Jin, Chong‐Yao; Su, Xiaoli; Gu, Luyan; Song, Zhe; Gao, Ting; Chen, Ying; Yan, Yaping; Yin, Xinzhen; Pu, Jiali; Zhang, Baorong

doi:10.3389/fnagi.2021.740491

Cited by 21 publications

(29 citation statements)

References 59 publications

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“…Conversely, alpha-synuclein has been shown to cause aggressive neuroinflammatory insults and AQP4 deficiency which perpetuates glymphatic impairment, causing dopaminergic degeneration in the SN as well as in other brain regions. Although a recent genetic study has shown associations between different AQP4 polymorphisms and varying rate of cognitive decline in PD [ 104 ], further work is vital to determine if a strong link exists between glymphatic dysfunction and the pathogenesis of the human disease.…”

Section: Discussionmentioning

confidence: 99%

Glymphatic System Dysfunction and Sleep Disturbance May Contribute to the Pathogenesis and Progression of Parkinson’s Disease

Scott-Massey

Boag

Magnier

et al. 2022

IJMS

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Parkinson’s disease (PD) is a multisystem alpha-synucleinopathic neurodegenerative disease and the most prevalent neurodegenerative disorder after Alzheimer’s disease with a high incidence rate in the elderly population. PD is highly multifactorial in etiology and has complex and wide-ranging pathogenic mechanisms. Environmental exposures and genetic predisposition are prominent risk factors. However, current evidence suggests that an intimate link may exist between the risk factor of sleep disturbance and PD pathogenesis. PD is characterized by the pathological hallmarks of alpha-synuclein aggregations and dopaminergic neuron degeneration in the substantia nigra. The loss of dopamine-producing neurons results in both motor and non-motor symptoms, most commonly, bradykinesia, tremor, rigidity, psychiatric disorders, sleep disorders and gastrointestinal problems. Factors that may exacerbate alpha-synuclein accumulation and dopamine neuron loss include neuroinflammation and glymphatic system impairment. Extracellular alpha-synuclein can induce an inflammatory response which can lead to neural cell death and inhibition of neurogenesis. The glymphatic system functions most optimally to remove extracellular brain solutes during sleep and therefore sleep disruption may be a crucial progression factor as well as a risk factor. This literature review interprets and analyses data from experimental and epidemiological studies to determine the recent advances in establishing a relationship between glymphatic system dysfunction, sleep disturbance, and PD pathogenesis and progression. This review addresses current limitations surrounding the ability to affirm a causal link between improved glymphatic clearance by increased sleep quality in PD prevention and management. Furthermore, this review proposes potential therapeutic approaches that could utilize the protective mechanism of sleep, to promote glymphatic clearance that therefore may reduce disease progression as well as symptom severity in PD patients.

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Section: Discussionmentioning

confidence: 99%

Glymphatic System Dysfunction and Sleep Disturbance May Contribute to the Pathogenesis and Progression of Parkinson’s Disease

Scott-Massey

Boag

Magnier

et al. 2022

IJMS

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“…A study by Rainey-Smith et al (2018) utilized a self-reported “overall” sleep quality assessment and demonstrated that several AQP4 single nucleotide polymorphisms were associated with poorer sleep ( Rainey-Smith et al, 2018 ). Another recent study on Parkinson’s disease demonstrated that specific mutations in AQP4 were likely the cause of sleep disturbance and may act as a prognostic marker for cognitive decline ( Fang et al, 2022 ). Conversely, some studies have found that sleep disturbance results in AQP4 mislocalization; one such study found that mice who were sleep deprived showed AQP4 mislocalization away from astrocyte end-feet ( Liu et al, 2017 ).…”

Section: Glymphatic Systemmentioning

confidence: 99%

Perivascular spaces as a potential biomarker of Alzheimer’s disease

et al. 2022

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Alzheimer’s disease (AD) is a highly damaging disease that affects one’s cognition and memory and presents an increasing societal and economic burden globally. Considerable research has gone into understanding AD; however, there is still a lack of effective biomarkers that aid in early diagnosis and intervention. The recent discovery of the glymphatic system and associated Perivascular Spaces (PVS) has led to the theory that enlarged PVS (ePVS) may be an indicator of AD progression and act as an early diagnostic marker. Visible on Magnetic Resonance Imaging (MRI), PVS appear to enlarge when known biomarkers of AD, amyloid-β and tau, accumulate. The central goal of ePVS and AD research is to determine when ePVS occurs in AD progression and if ePVS are causal or epiphenomena. Furthermore, if ePVS are indeed causative, interventions promoting glymphatic clearance are an attractive target for research. However, it is necessary first to ascertain where on the pathological progression of AD ePVS occurs. This review aims to examine the knowledge gap that exists in understanding the contribution of ePVS to AD. It is essential to understand whether ePVS in the brain correlate with increased regional tau distribution and global or regional Amyloid-β distribution and to determine if these spaces increase proportionally over time as individuals experience neurodegeneration. This review demonstrates that ePVS are associated with reduced glymphatic clearance and that this reduced clearance is associated with an increase in amyloid-β. However, it is not yet understood if ePVS are the outcome or driver of protein accumulation. Further, it is not yet clear if ePVS volume and number change longitudinally. Ultimately, it is vital to determine early diagnostic criteria and early interventions for AD to ease the burden it presents to the world; ePVS may be able to fulfill this role and therefore merit further research.

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“…Regarding PD patients, Fang and collaborators have recently conducted a study to determine the clinical implication of AQP4 polymorphisms in PD [ 120 ]. They investigated whether AQP4 SNPs were associated with Aβ burden as measured by 18F Florbetapir standard uptake values and examined if AQP4 SNPs moderated the association between REM sleep behavior disorder (RBD) and CSF biomarkers [ 120 ]. They conclude that genetic variations of AQP4 and subsequent alterations of glymphatic efficacy might contribute to an altered rate of cognitive decline in PD [ 120 ].…”

Section: Aqp4 Expression and Polymorphisms In Ad And Pdmentioning

confidence: 99%

“…They investigated whether AQP4 SNPs were associated with Aβ burden as measured by 18F Florbetapir standard uptake values and examined if AQP4 SNPs moderated the association between REM sleep behavior disorder (RBD) and CSF biomarkers [ 120 ]. They conclude that genetic variations of AQP4 and subsequent alterations of glymphatic efficacy might contribute to an altered rate of cognitive decline in PD [ 120 ]. Furthermore, AQP4 rs162009 can be considered a novel genetic prognostic marker of glymphatic function and cognitive decline in PD [ 120 ].…”

Section: Aqp4 Expression and Polymorphisms In Ad And Pdmentioning

confidence: 99%

“…They conclude that genetic variations of AQP4 and subsequent alterations of glymphatic efficacy might contribute to an altered rate of cognitive decline in PD [ 120 ]. Furthermore, AQP4 rs162009 can be considered a novel genetic prognostic marker of glymphatic function and cognitive decline in PD [ 120 ].…”

Section: Aqp4 Expression and Polymorphisms In Ad And Pdmentioning

confidence: 99%

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The Role of Glymphatic System in Alzheimer’s and Parkinson’s Disease Pathogenesis

et al. 2022

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Alzheimer’s disease (AD) is the most common cause of neurodegenerative dementia, whilst Parkinson’s disease (PD) is a neurodegenerative movement disorder. These two neurodegenerative disorders share the accumulation of toxic proteins as a pathological hallmark. The lack of definitive disease-modifying treatments for these neurogenerative diseases has led to the hypothesis of new pathogenic mechanisms to target and design new potential therapeutic approaches. The recent observation that the glymphatic system is supposed to be responsible for the movement of cerebrospinal fluid into the brain and clearance of metabolic waste has led to study its involvement in the pathogenesis of these classic proteinopathies. Aquaporin-4 (AQP4), a water channel located in the endfeet of astrocyte membrane, is considered a primary driver of the glymphatic clearance system, and defective AQP4-mediated glymphatic drainage has been linked to proteinopathies. The objective of the present review is to present the recent body of knowledge that links the glymphatic system to the pathogenesis of AD and PD disease and other lifestyle factors such as sleep deprivation and exercise that may influence glymphatic system function. We will also focus on the potential neuroimaging approaches that could identify a neuroimaging marker to detect glymphatic system changes.

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Aquaporin-4 Polymorphisms Are Associated With Cognitive Performance in Parkinson’s Disease

Cited by 21 publications

References 59 publications

Glymphatic System Dysfunction and Sleep Disturbance May Contribute to the Pathogenesis and Progression of Parkinson’s Disease

Glymphatic System Dysfunction and Sleep Disturbance May Contribute to the Pathogenesis and Progression of Parkinson’s Disease

Perivascular spaces as a potential biomarker of Alzheimer’s disease

The Role of Glymphatic System in Alzheimer’s and Parkinson’s Disease Pathogenesis

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