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.

The brain exhibits highly organized patterns of spontaneous activity as measured by resting-state functional magnetic resonance imaging (fMRI) fluctuations that are being widely used to assess the brain’s functional connectivity. Some evidence suggests that spatiotemporally coherent waves are a core feature of spontaneous activity that shapes functional connectivity, although this has been difficult to establish using fMRI given the temporal constraints of the hemodynamic signal. Here, we investigated the structure of spontaneous waves in human fMRI and monkey electrocorticography. In both species, we found clear, repeatable, and directionally constrained activity waves coursed along a spatial axis approximately representing cortical hierarchical organization. These cortical propagations were closely associated with activity changes in distinct subcortical structures, particularly those related to arousal regulation, and modulated across different states of vigilance. The findings demonstrate a neural origin of spatiotemporal fMRI wave propagation at rest and link it to the principal gradient of resting-state fMRI connectivity.

Background Deposition and spreading of misfolded proteins (α‐synuclein and tau) have been linked to Parkinson's disease cognitive dysfunction. The glymphatic system may play an important role in the clearance of these toxic proteins via cerebrospinal fluid (CSF) flow through perivascular and interstitial spaces. Recent studies discovered that sleep‐dependent global brain activity is coupled to CSF flow, which may reflect glymphatic function. Objective The objective of this current study was to determine if the decoupling of brain activity–CSF flow is linked to Parkinson's disease cognitive dysfunction. Methods Functional and structural MRI data, clinical motor (Unified Parkinson's Disease Rating Scale), and cognitive (Montreal Cognitive Assessment [MoCA]) scores were collected from 60 Parkinson's disease and 58 control subjects. Parkinson's disease patients were subgrouped into those with mild cognitive impairment (MoCA < 26), n = 31, and those without mild cognitive impairment (MoCA ≥ 26), n = 29. The coupling strength between the resting‐state global blood‐oxygen‐level‐dependent signal and associated CSF flow was quantified, compared among groups, and associated with clinical and structural measurements. Results Global blood‐oxygen‐level‐dependent signal–CSF coupling decreased significantly (P < 0.006) in Parkinson's disease patients showing mild cognitive impairment, compared with those without mild cognitive impairment and controls. Reduced global blood‐oxygen‐level‐dependent signal–CSF coupling was associated with decreased MoCA scores present in Parkinson's disease patients (P = 0.005) but not in controls (P = 0.65). Weaker global blood‐oxygen‐level‐dependent signal–CSF coupling in Parkinson's disease patients also was associated with a thinner right entorhinal cortex (Spearman's correlation, −0.36; P = 0.012), an early structural change often seen in Alzheimer's disease. Conclusions The decoupling between global brain activity and associated CSF flow is related to Parkinson's disease cognitive impairment. © 2021 International Parkinson and Movement Disorder Society

Correlations of resting-state functional magnetic resonance imaging (rsfMRI) signals are being widely used for assessing the functional brain connectivity in health and disease. However, an association was recently observed between rsfMRI connectivity modulations and the head motion parameters and regarded as a causal relationship, which has raised serious concerns about the validity of many rsfMRI findings. Here, we studied the origin of this rsfMRI-motion association and its relationship to arousal modulations. By using a template-matching method to locate arousal-related fMRI changes, we showed that the effects of high motion time points on rsfMRI connectivity are largely due to their significant overlap with arousal-affected time points. The finding suggests that the association between rsfMRI connectivity and the head motion parameters arises from their comodulations at transient arousal modulations, and this information is critical not only for proper interpretation of motion-associated rsfMRI connectivity changes, but also for controlling the potential confounding effects of arousal modulation on rsfMRI metrics.

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