Reduced coupling between cerebrospinal fluid flow and global brain activity is linked to Alzheimer disease–related pathology

Feng Han,Yameng Gu,Orfeu M Buxton,Xiao Liu,Jing Chen,Aaron Belkin-Rosen,Liying Luo,Maiken Nedergaard

doi:10.1371/journal.pbio.3001233

Abstract

The glymphatic system plays an important role in clearing the amyloid-β (Aβ) and tau proteins that are closely linked to Alzheimer disease (AD) pathology. Glymphatic clearance, as well as Aβ accumulation, is highly dependent on sleep, but the sleep-dependent driving forces behind cerebrospinal fluid (CSF) movements essential to the glymphatic flux remain largely unclear. Recent studies have reported that widespread, high-amplitude spontaneous brain activations in the drowsy state and during sleep, which are shown as large global signal peaks in resting-state functional magnetic resonance imaging (rsfMRI), are coupled with CSF movements, suggesting their potential link to glymphatic flux and metabolite clearance. By analyzing multimodal data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) project, here we showed that the coupling between the global fMRI signal and CSF influx is correlated with AD-related pathology, including various risk factors for AD, the severity of AD-related diseases, the cortical Aβ level, and cognitive decline over a 2-year follow-up. These results provide critical initial evidence for involvement of sleep-dependent global brain activity, as well as the associated physiological modulations, in the clearance of AD-related brain waste.

Highlights

The pathogenesis of Alzheimer disease (AD) is widely believed to be driven by the aggregation of toxic proteins, e.g., the amyloid-β (Aβ) and tau, which cannot be adequately cleared from the brain [1,2,3]
The primary goal of Alzheimer’s Disease Neuroimaging Initiative (ADNI) has been to test whether serial magnetic resonance imaging (MRI), positron emission tomography (PET), other biological markers, and clinical and neuropsychological assessment can be combined to measure the progression of mild cognitive impairment (MCI) and early Alzheimer’s disease (AD)
We investigated whether the blood oxygen level–dependent (BOLD)–cerebrospinal fluid (CSF) coupling is related to the AD-related pathology, including AD risk factors, disease condition, and neurobiological and neuropsychological markers

Summary

Introduction

The pathogenesis of Alzheimer disease (AD) is widely believed to be driven by the aggregation of toxic proteins, e.g., the amyloid-β (Aβ) and tau, which cannot be adequately cleared from the brain [1,2,3]. The “glymphatic system” plays an important role in the clearance of the toxic proteins in the extracellular interstitial space [4,5,6,7,8]. In this clearance pathway, the movement of the cerebrospinal fluid (CSF) from the periarterial space into the interstitial space, which is facilitated by astroglial aquaporin-4 (AQP4) channels, drives convective interstitial fluid (ISF) flux and interstitial solutes, including Aβ and tau, into the perivenous space surrounding. Neuroimaging marker of glymphatic process and AD pathology http://adni.loni.usc.edu/data-samples/access-data/.

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Conclusion