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

Yi Fang,Luyan Gu,Xiaoli Si,Baorong Zhang,Shaobing Dai,Zhe Song,Chongyao Jin,Jiali Pu,Xinzhen Yin,Ying Chen,Yaping Yan,Ting Gao

doi:10.3389/fnagi.2021.740491

Abstract

ObjectiveAquaporin-4 (AQP4) facilitates a sleep-enhanced interstitial brain waste clearance system. This study was conducted to determine the clinical implication of AQP4 polymorphisms in Parkinson’s disease (PD).MethodsThree-hundred and eighty-two patients with PD and 180 healthy controls with a mean follow-up time of 66.1 months from the Parkinson’s Progression Marker Initiative study were analyzed. We examined whether AQP4 SNPs were associated with an altered rate of motor or cognitive decline using linear mixed model and Cox regression. We then investigated whether AQP4 SNPs were associated with Aβ burden as measured by 18F Florbetapir standard uptake values. Furthermore, we examined if AQP4 SNPs moderated the association between REM sleep behavior disorder (RBD) and CSF biomarkers.ResultsIn patients with PD, AQP4 rs162009 (AA/AG vs. GG) was associated with slower dementia conversion, better performance in letter-number sequencing and symbol digit modalities, lower Aβ deposition in the putamen, anterior cingulum, and frontotemporal areas. In the subgroup of high RBD screening questionnaire score, rs162009 AA/AG had a higher CSF Aβ42 level. rs162009 AA/AG also had better performance in semantic fluency in healthy controls. Besides, rs68006382 (GG/GA vs. AA) was associated with faster progression to mild cognitive impairment, worse performance in letter-number sequencing, semantic fluency, and symbol digit modalities in patients with PD.InterpretationGenetic variations of AQP4 and subsequent alterations of glymphatic efficacy might contribute to an altered rate of cognitive decline in PD. AQP4 rs162009 is likely a novel genetic prognostic marker of glymphatic function and cognitive decline in PD.

Highlights

Aquaporin-4 (AQP4) is a water channel that lies at the astrocytic endfeet around perivascular space in the brain (Nagelhus and Ottersen, 2013)
We studied if AQP4 Single Nucleotide Polymorphisms (SNPs) modulate the association between REM sleep behavior disorder (RBD) and cerebrospinal fluid (CSF) biomarkers
Given the previously established association between AQP4 and cognitive performance in the spectrum of Alzheimer’s disease (AD), we explored this association in a cohort of patients with Parkinson’s disease (PD)

Summary

Introduction

Aquaporin-4 (AQP4) is a water channel that lies at the astrocytic endfeet around perivascular space in the brain (Nagelhus and Ottersen, 2013). The AQP4-facilitated glymphatic system clears interstitial brain waste, AQP4 SNPs in Parkinson’s Disease including amyloid β (Aβ; Iliff et al, 2012), tau (Harrison et al, 2020), and α-synuclein (Zou et al, 2019) according to animal studies. The association between AQP4 and interstitial waste clearance was further validated by a postmortem study of aging human brains, which revealed a link between reduced perivascular localization of AQP4 and Aβ deposition (Zeppenfeld et al, 2017). Single Nucleotide Polymorphisms (SNPs) of the AQP4 gene were associated with brain Aβ uptake on PET and the rate of cognitive decline in the spectrum of Alzheimer’s disease (AD; Burfeind et al, 2017; Chandra et al, 2020). AD pathologies, including extracellular amyloid and tau aggregates, are found in PD (Robinson et al, 2018).

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