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.

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

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.

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.

Resting-state functional magnetic resonance imaging (rsfMRI) is being widely used for charting brain connectivity and dynamics in healthy and diseased brains. However, the resting state paradigm allows an unconstrained fluctuation of brain arousal, which may have profound effects on resting-state fMRI signals and associated connectivity/dynamic metrics. Here, we review current understandings of the relationship between resting-state fMRI and brain arousal, in particular the effect of a recently discovered event of arousal modulation on resting-state fMRI. We further discuss potential implications of arousal-related fMRI modulation with a focus on its potential role in mediating spurious correlations between resting-state connectivity/dynamics with physiology and behavior. Multiple hypotheses are formulated based on existing evidence and remain to be tested by future studies.

Importance: The specific pattern/trajectory of β-amyloid (Aβ) pathology spreading in Alzheimer's disease (AD), from default mode network (DMN) regions to sensory-motor areas, is well known, but poorly understood. Objective: To determine if resting-state global brain activity is linked to early Aβ deposition in the DMN. Design: This is a retrospect analysis of multi-modal and longitudinal data from the Alzheimer's disease Neuroimaging Initiative (ADNI) cohort. Setting: The ADNI was a multicenter project involving 63 research centers. Participants: The study included 144 participants (72.6 ± 7.5 years; 73 females) of whom 28 were controls, 21 had significant memory concerns, 72 had cognitive impairment (N=72), and 23 had AD. There were both baseline and 2-year follow-up data for Aβ-PET for 112 of the subjects. They were classified into following stages based on the CSF Aβ42 (CSF+: <192 ng/L) and cortical Aβ (PET+: >0.872 SUVR) levels: non-Aβ-accumulators (CSF-/PET-); early-Aβ-accumulators (CSF+/PET-); and late-Aβ-accumulators (CSF+/PET+). Exposure: Resting-state brain activity was assessed by functional magnetic resonance imaging (rsfMRI), whereas glymphatic function was estimated by the coupling between fMRI blood-oxygen-level-dependent (BOLD) signals and CSF movements. Main Outcomes and Measures: Cortical Aβ accumulation measured by 18F-AV45 amyloid-positron emission tomography (PET), CSF Aβ42, and total and phosphorylated tau protein levels in all participants. Results: Glymphatic function assessed by fMRI was strongly (ρ > 0.43, P < 0.042) associated with various markers of protein aggregation in early Aβ accumulators in whom Aβ just begins to accumulate cortically in the DMN. Among these early accumulators, the preferential Aβ accumulation in the DMN regions in the subsequent two years was correlated with lower gBOLD signal (ρ = 0.51, P = 0.027) and lower local glymphatic function (ρ = 0.48, P = 0.041) in the same regions at baseline. Conclusions and Relevance: Resting-state global brain activity and related glymphatic function are linked to Aβ pathology, particularly its preferential deposition in the DMN at the earliest AD stages. This suggests potential novel early therapeutic directions that might provide disease modification.

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The brain exhibits highly organized patterns of spontaneous activity as measured by resting-state fMRI fluctuations that are being widely used to assess the brain functional connectivity. Some evidence suggests that spatiotemporally coherent waves are a core feature of spontaneous activity that shapes functional connectivity, though 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.