Glymphatic Function Research Articles

Regional glymphatic abnormality in behavioral variant frontotemporal dementia

AbstractBackgroundThe pattern of glymphatic inflow overlaps with the geographic pattern of behavioral variant frontotemporal dementia (bvFTD). The glymphatic function has not yet been explored in bvFTD. The spatial correlation between regional glymphatic function and bvFTD remain unknown.MethodA total of 60 patients with bvFTD and 61 age‐ and sex‐matched healthy controls (HCs) were selected from two independent cohorts (discovery dataset from Xuanwu Hospital and replication dataset from the Frontotemporal Lobar Degeneration Neuroimaging Initiative study). All participant underwent neuropsychological assessment. Glymphatic measures evaluated from multimodal neuroimaging data, including choroid plexus volume, diffusion along perivascular space (DTI‐ALPS) index, and coupling between blood‐oxygen‐level‐dependent signals and cerebrospinal fluid signals (BOLD‐CSF coupling), were compared between the two groups. To evaluate glymphatic regional function, DTI‐ALPS and BOLD‐CSF coupling were further divided into anterior, middle, and posterior parts. BvFTD‐related metabolic pattern was identified using spatial covariance analysis based on [l8F]‐FDG‐PET.ResultPatients with bvFTD showed higher choroid plexus volume (P < 0.001); middle DTI‐ALPS (P < 0.001); and weaker anterior BOLD‐CSF coupling (P < 0.05) than HCs after controlling for cortical gray matter volume in both datasets. In bvFTD from the discovery dataset, the anterior DTI‐ALPS was negatively associated with the expression of the bvFTD‐related metabolic pattern (r = ‐0.51, P = 0.029) and positively related with regional standardized uptake value ratios of [l8F]‐FDG‐PET in bvFTD‐related brain regions (r = 0.44–0.60, P range: 0.008–0.039). Worse glymphatic function is associated with more severe global cognition decline, disease severity, and neuropsychiatric symptoms. In addition, anterior DTI‐ALPS was higher than posterior DTI‐ALPS (P < 0.001), whereas anterior BOLD‐CSF coupling was lower than posterior BOLD‐CSF coupling (P < 0.001).ConclusionOur findings reveal abnormal glymphatic function, especially in the anterior and middle regions of brain in bvFTD. Regional glymphatic dysfunction may contribute to the pathogenesis of bvFTD.

Glymphatic function maintains sleep‐sensitive cognitive performance and predicts overnight changes in plasma amyloid β in humans

AbstractBackgroundDuring sleep, the glymphatic system facilitates rapid exchange of fluid through brain tissues, clearing solutes, including amyloid β (Aβ), tau, and α synuclein that accumulate through the course of waking activity. Glymphatic clearance is widely believed to underlie the restorative effects of sleep on cognition, and its impairment is proposed to reflect the biological basis for the corrosive effects of sleep disruption. We sought to determine if glymphatic function or sleep EEG predicted changes in cognitive performance and overnight differences in Aβ biomarker levels using a new non‐invasive investigational medical device (IMD) to measure glymphatic function by dynamic impedance spectro‐tomography.MethodEighteen healthy 50‐65 y/o participants were enrolled in a cross‐over randomized control clinical trial encompassing one night of sleep and one night of sleep deprivation. Participants were instrumented with the IMD and overnight change in brain parenchymal resistance to flow, R, was measured. Sleep EEG powerbands, slow (0.4‐1Hz), delta (1‐4Hz), beta (15‐30Hz), and time spent in N2, N3 and REM sleep were derived from the device EEG. In both sleep and sleep deprivation interventions, cognitive tests (symbol digit modality test, SDMT; psychomotor vigilance test, PVT) were administered at 7am and blood Aβ biomarkers (Aβ40; Aβ42) were taken at 10pm and 7am.ResultOvernight parenchymal resistance R predicted intraindividual paired differences (sleep – sleep deprivation) in cognitive test scores (A SDMT ρ = ‐0.65, p = 0.003; B PVT STD RT, ρ = 0.41, p = 0.095) and Aβ42 blood amyloid biomarker changes (C Aβ42 ρ = ‐0.53, p = 0.03; D Aβ40 ρ = ‐0.33, p = 0.21). Sleep EEG powerbands and time spent in N2, N3, and REM sleep were not predictive of sleep‐related changes in cognition or plasma Aβ biomarker levels.ConclusionGlymphatic function, measured continuously by dynamic impedance spectro‐tomography, predicted changes in the restorative effect of sleep on cognition and plasma Ab biomarker levels as hypothesized, but not previously demonstrated. In contrast, sleep EEG powerbands and time spent in N2, N3 and REM were not predictive. Detection of glymphatic impairment in real‐world settings may permit (i) early identification of individuals at‐risk for developing sleep‐related Alzheimer’s disease pathology, and (ii) enable precision targeted enhancement of glymphatic function to enhance glymphatic function and pathological protein clearance.

Associations between glymphatic function and BBB water exchange rate and perfusion in a Latinx cohort

AbstractBackgroundThe glymphatic system is thought to clear waste products from the brain by facilitating the exchange of interstitial fluid (ISF) with cerebrospinal fluid (CSF) through aquaporin‐4 (AQP4) water channels present in astrocyte endfeet. A recent non‐invasive MRI method, diffusion tensor image analysis along the perivascular space (DTI‐ALPS), has been proposed for evaluating brain clearance function and has shown reduced glymphatic function in various neurological disorders such as Alzheimer’s disease. However, the role of microvascular perfusion and blood‐brain barrier (BBB) permeability in the glymphatic system remains unclear. In this study, we used a novel diffusion‐prepared arterial spin labeling (DP‐ASL) MRI technique to measure BBB water exchange rate (kw) and cerebral blood flow (CBF) and studied their relationships with the DTI‐ALPS score.Method44 Latinx subjects (20 male; age = 65.6±5.6 years) were recruited from the USC MarkVCID study. Imaging parameters for DP‐ASL were: resolution = 3.5×3.5×8mm3, 10 slices, scan time 10 mins. kw was calculated from the ratio of intra‐ and extra‐vascular perfusion signals with total‐general‐variation (TGV) regularized single‐pass approximation (SPA) modeling and CBF was calculated from PLD = 1800ms data using one‐compartment Kety model. kw and CBF maps were normalized into the MNI space and regional analysis was performed in the frontal/temporal/parietal lobe, and subcortical regions. Association between ALPS score and CBF/kw values were studied by linear regressions. P<0.05 was considered as significant.ResultFig.1 shows kw and CBF maps from three representative subjects with increasing ALPS scores (top to bottom). ALPS was significantly correlated with kw in MTL (β = 1.7e‐3,P = 0.04) and a positive trend was observed between ALPS and whole brain average kw (P = 0.11). While significant correlations were found between ALPS and CBF in multiple brain regions including frontal lobe (β = 7e‐3,P = 0.009), temporal lobe (β = 7e‐3,P = 0.002), parietal lobe (β = 4e‐3,P = 0.03), MTL (β = 8e‐3,P = 0.03), ACC (β = 6e‐3,P = 0.005), PCC (β = 4e‐3,P = 0.02), precuneus (β = 4e‐3,P = 0.04) and whole brain (β = 8e‐3,P = 0.01). Fig.2 shows scatter plots of ALPS versus kw (A) and CBF in MTL and whole brain, respectively.ConclusionThis is the first study in Latinx population demonstrating positive correlations between ALPS score and both CBF and kw, suggesting a possible involvement of blood flow and BBB water exchange rate in the glymphatic system.

Comparison of IVIM MRI measures of brain fluid transport against contrast‐enhanced MRI in the setting of sleep deprivation

AbstractBackgroundGlymphatic exchange of interstitial solutes may underlie the observed clinical association between sleep, aging, and Alzheimer’s Disease (AD). Furthermore, glymphatic function is currently primarily measured by contrast‐based (CE) MRI, limiting its clinical utility. In this work we test a wearable device to assess sleep architecture and a diffusion‐based intravoxel incoherent motion (IVIM) protocol to detect sleep‐related changes in the glymphatic system at two sites.Method Site 1: We recruited 13 participants (age = 62±3 yrs. old, 4F) and assessed them prior to and following overnight sleep and sleep deprivation. Sleep efficiency, relative slow delta power, N2, N3, and REM durations were measured with the wearable device. Using CE‐MRI, delayed contrast enhancement in the subarachnoid (SASe) was measured at ∼4 hrs after contrast injection to assess brain parenchymal solute clearance during a second recovery sleep opportunity. For contrast‐free MRI, we measured slow subarachnoid CSF flow (D*) in the SAS using IVIM at night and in the morning. Cognitive assessments were conducted in the morning only. Site 2: We conducted an identical sleep/sleep deprivation study (N = 10, age = 54±5 yrs. old, 9F), but without CE MRI. We tested the correlation between SASe and D*. Next, we compared changes in D* between a night of sleep and sleep deprivation and tested associations with sleep parameters.Result A. Change in D* after sleep or awake opportunity was significantly associated with SASe (p = 0.05) Greater SAS D* was associated with lesser contrast in the SAS. B. Although not significant, D* reproducibly decreases with sleep deprivation and remains unchanged after sleep. C‐D. Differences in D* during sleep were significantly associated with slow wave spindle number (p = 0.03) and N3 duration (p = 0.04). E. D* measurement concurrent with PVT administrations showed that while greater D* after staying awake was associated with longer reaction times, greater D* after a night of sleep was associated with shorter reaction times.ConclusionWith a wearable device, remote sleep assessment was successfully performed. IVIM‐derived D* was associated with CE MRI measures in the SAS providing a non‐invasive alternative to study brain fluid transport. D* showed associations with sleep parameters as well as sleep‐associated cognition.

Diffusion tensor image analysis along the perivascular space inversely correlates with age in healthy subjects

AbstractBackgroundThe glymphatic system is a brain waste fluid clearance system. Glymphatic dysfunction of glymphatic system has been seen in normal aging in many neurological diseases. Diffusion tensor image analysis along the perivascular space (DTI‐ALPS) is a novel MRI method to assess the glymphatic function. In this study, we aim to evaluate the changes in glymphatic system by aging with DTI‐ALPS method.MethodWe investigated DTI‐ALPS indices of 49 healthy subjects underwent MRI scans. Anatomical T1w MPRAGE and multi‐shell diffusion‐weighted MRI were acquired on a 3T Siemens Prisma scanner. Diffusion MRI (dMRI) images were corrected for distortions induced by susceptibility and eddy current. To evaluate the glymphatic system activity, an index called ALPS index was calculated. Linear regression analysis was used to evaluate the correlation of age and ALPS.ResultResults showed that DTI‐ALPS index inversely correlates with age: R = ‐0.42, p<0.05, meaning glymphatic system activity inversely correlates with aging in healthy subjects.ConclusionUnderstanding the factors affecting glymphatic function might help better understanding the underlying mechanism of neurological diseases and healthy aging.

Sleep fragmentation affects glymphatic system through the different expression of AQP4 in wild type and 5xFAD mouse models

AbstractBackgroundSleep is an important physiological process, during which extracellular metabolic wastes, such as amyloid and tau protein, are cleared via paravascular pathway. Changes in the timing and structure of sleep occur across the lifespan. Increased sleep fragmentation and reductions in slow wave sleep (SWS) represent the hallmark signs of age‐related changes in sleep. The origin of sleep disturbances in AD is thought to be multifactorial. In the aging brain, the impairment of glymphatic pathway function slows the clearance of interstitial Aβ, rendering the aging brain vulnerable to neurodegenerative disease. Several authors have independently shown that glymphatic flux depends upon the expression and perivascular localization of the astroglial water channel aquaporin‐4 (AQP4).MethodIn this study, we performed and validated a mouse model of AD and chronic sleep fragmentation, a sleep disorder that mimics more correctly a real condition of intermittent and continuous awakening. We analyzed the effect of sleep fragmentation in wild type and 5xFAD mice. All the animals underwent to behavioral studies to analyze anxiety and spatial and working memory. We had validated sleep fragmentation and its effect through EEG and biomolecular analysis, by observing all the macro‐areas implied in sleep regulation.ResultWe noticed that sleep fragmentation induces a general acceleration of AD progression in 5xFAD mice, while in wild type mice it affects cognitive behaviors in particular learning and memory. Both these events may be correlated to AQP4 modulation, a crucial player of the glymphatic system activity. In particular, sleep fragmentation differentially affects AQP4 expression according to the stage of the disease, with an up‐regulation in younger animals, while such change cannot be detected in older ones. Moreover, in wild type mice sleep fragmentation affects cognitive behaviors, in particular learning and memory, by compromising the glymphatic system through the decrease of AQP4.ConclusionNevertheless, an in‐depth study is needed to better understand the mechanism by which AQP4 is modulated and whether it could be considered a risk factor for the disease development in wild type mice. If our hypotheses are going to be confirmed, AQP4 modulation may represent the convergence point between AD and sleep disorder pathogenic mechanisms

MRI study of traditional Chinese medicinal physiotherapy to promote glymphatic system function in patients with insomnia

MRI study of traditional Chinese medicinal physiotherapy to promote glymphatic system function in patients with insomnia

Cross vendor test‐retest validation of diffusion tensor analysis along the perivascular space (DTI‐ALPS) method for evaluating glymphatic system function in vascular cognitive impairment and dementia (VCID)

AbstractBackgroundGlymphatic system (GS) is a recently discovered brain‐wide perivascular fluid transport system in the cerebral nervous system (CNS)(Benveniste H et al., 2019) The impairment of glymphatic transport has been demonstrated to be associated with several neurological diseases, in particular the vascular cognitive impairment and dementia (VCID)(Tang J et al., 2022). The diffusion tensor analysis along the perivascular space (DTI‐ALPS) was proposed to non‐invasively evaluate the GS clearance dysfunction which has been used to investigate the GS in various pathologies(Taoka T et al., 2017, Hsu JL et al., 2022). However, studies on the cross‐vendor and test‐retest reliability of DTI‐ALPS method are lacking. The current study aimed to perform cross‐vendor, inter‐rater and test‐retest validations of DTI‐ALPS method by using a cohort from the MarkVCID consortium.MethodFifty participants’ DTI data from the MarkVCID consortium (consists of 7 sites) were included in this study: 15 participants were scanned on four MRI scanners; 35 participants underwent two MR scans within 14 days. The DTI data were acquired used a single shell, b = 1000s/mm2, 40‐direction with a voxel size of 2.02.02.0mm3 and six b = 0 s/mm2 on 3T MR scanners from seven sites, including two Siemens systems, one Philips system and one GE system. Two pipelines by using DSI studio and FSL software were developed for data processing and ALPS index calculation (Figure 1). The mean ALPS (mALPS) index was obtained by the average of bilateral ALPS index and was used for testing the inter‐rater, cross‐vendor and test‐retest reliability. The association between mALPS index and Montreal Cognitive assessment (MoCA) scores were evaluated using a general linear model with age and gender as covariate.ResultThe Bland‐Altman plot and scatterplot illustrated the validation results of the mALPS index analyzed using DSI studio and FSL pipelines (Figure 2). The mALPS index demonstrated favorable inter‐scanner reproducibility (ICC = 0.77 to 0.95, P< 0.001), inter‐rater reliability (ICC = 0.96 to 1, P< 0.001) and test‐retest repeatability (ICC = 0.89 to 0.95, P< 0.001). A significantly positive correlation was observed between mALPS index and MoCA scores (r = 0.502, P< 0.01) (Figure 3).ConclusionThe mALPS index offers a robust potential biomarker for evaluating GS clearance function in VCID.

Region‐Specific Associations of Human Astrocytic Endfoot Genes with Alzheimer’s Disease Neuropathology and Cognitive Decline

AbstractBackgroundWe completed a well‐powered bulk transcriptomic analysis of the astrocytic water channel aquaporin‐4 (AQP4) and related glymphatic molecules and discovered significant associations with Alzheimer’s disease (AD) neuropathological and cognitive outcomes. Genes included AQP4 and dystrophin‐associated complex components, namely DMD, DTNA, DAG1, and SNTA1, which encode proteins responsible for anchoring the AQP4 channel to the astrocytic endfoot membrane.MethodLeveraging regional brain RNA sequencing from the ROS/MAP dataset (Table 1), we determined the effects of transcript‐level variation on neuropathological outcomes at autopsy and longitudinal cognition using multiple linear regression models and mixed effects models, respectively. Discrete brain regions included: the dorsolateral prefrontal cortex (DLPFC, N = 921), caudate nucleus (CN, N = 705), and posterior cingulate cortex (PCC, N = 516). Square‐root transformed neuropathological measures of amyloid and tau burden at autopsy were quantified using immunohistochemistry. Cognitive performance was assessed longitudinally with global cognition calculated as a composite score derived from 19 neuropsychological tests. All model covariates included age at death, sex, educational attainment, and post‐mortem interval. Longitudinal models also included latency to death and the fixed and random effect of interval between current and last visit.ResultHigher AQP4 expression in the DLPFC related to higher amyloid pathology (β = 0.21, P.fdr = 0.04). Similarly, higher DTNA expression was associated with higher tau burden (βDLPFC = 0.36, P.fdrDLPFC = 0.008) and a faster rate of cognitive decline (βDLPFC = ‐0.036, P.fdrDLPFC = 0.0004; βPCC = ‐0.037, P.fdrPCC = 0.02). Higher SNTA1 in the CN related to a faster rate of cognitive decline (β = ‐0.038, P.fdr = 0.03). A summary of significant associations is presented in Table 2 and select plots are provided in Figure 2. AQP4, DTNA, and SNTA1 showed comparable associations with clinical AD in independent datasets within the AMP‐AD project (https://agora.adknowledgeportal.org/).ConclusionOur results indicate that gene expression at the AQP4‐dystrophin axis relates to both AD neuropathology and cognition, particularly in the prefrontal cortex. Future analyses will incorporate single‐nucleus measures of gene expression and cell‐type deconvolution to clarify cell‐type specific contributions in this pathway. Together, these results highlight a set of genes relevant to glymphatic function that should be prioritized for future mechanistic studies.

Effects of enlarged perivascular space in Parkinson’s disease and related cognitive decline

AbstractBackgroundThe glymphatic system plays a key role in brain toxics clearance. Many studies demonstrated that disrupted glymphatic system is responsible for insufficient clearance of Aβ and tau protein in Alzheimer’s disease. Its contribution in Parkinson’s disease (PD) and related cognitive function decline has not been fully studied. Enlarged perivascular space (PVS) may be a sign of glymphatic function decline, hence leading to PD pathology and PD‐related cognitive function decline. Our objective was to study the PVS in PD and related cognitive function decline.MethodHigh‐resolution T1‐weighted and T2‐weighted MRI data were acquired from 60 PD patients and 58 age‐ and sex‐matched controls. The PVS from the centrum semiovale of the white matter (CS), striatum (ST) and midbrain (MB) of the basal ganglia were segmented using the enhanced images from T1‐ and T2‐weighted images. Total intracranial volumes (TIV) were obtained to account for individual head sizes. Montreal Assessment of Cognition (MoCA) was used to quantify cognitive function. MDS‐UPDRS III scores were obtained for motor function deficits. ANCOVA was used to compare PVS metrics between PD patients and controls adjusted for age, sex, and TIV. Multiple regression was used to corelate PVS metrics and MoCA in PD patients with age, sex, MDS‐UPDRS III score and TIV as covariates.ResultCompared to controls, PD patients had enlarged PVS in MB (p = 0.0028), but not in CS and ST. PVS metrics were strongly associated with age (p < 0.0001 for CS, p < 0.0001 for ST, and p = 0.0092 for MB), but only PVS in MB was associated sex (p = 0.0001). In PD patients, the MoCA was associated with the PVS in CS (p = 0.0132), MB (p = 0.0275) and total PVS (p = 0.0088) but only trending with PVS in ST (p = 0.0737). There is no association between MoCA and PVS metrics in controls.ConclusionOur findings suggested that PD patients have enlarged PVS in the midbrain, and their cognitive function is associated with enlarged PVS in both CS and MB. The enlarged PVS might be an etiological factor for PD pathology and related cognitive decline.

Protoplasmic Perivascular Astrocytes Play a Crucial Role in the Development of Enlarged Perivascular Spaces in Obesity, Metabolic Syndrome, and Type 2 Diabetes Mellitus

Astrocytes (ACs) are the most abundant cells in the brain and, importantly, are the master connecting and communicating cells that provide structural and functional support for brain cells at all levels of organization. Further, they are recognized as the guardians and housekeepers of the brain. Protoplasmic perivascular astrocyte endfeet and their basal lamina form the delimiting outermost barrier (glia limitans) of the perivascular spaces in postcapillary venules and are important for the clearance of metabolic waste. They comprise the glymphatic system, which is critically dependent on proper waste removal by the pvACef polarized aquaporin-4 water channels. Also, the protoplasmic perisynaptic astrocyte endfeet (psACef) are important in cradling the neuronal synapses that serve to maintain homeostasis and serve a functional and supportive role in synaptic transmission. Enlarged perivascular spaces (EPVS) are emerging as important aberrant findings on magnetic resonance imaging (MRI), and are associated with white matter hyperintensities, lacunes, and aging, and are accepted as biomarkers for cerebral small vessel disease, increased obesity, metabolic syndrome, and type 2 diabetes. Knowledge is exponentially expanding regarding EPVS along with the glymphatic system, since EPVS are closely associated with impaired glymphatic function and waste removal from the brain to the cerebrospinal fluid and systemic circulation. This review intends to focus on how the pvACef play a crucial role in the development of EPVS.

Structural connectivity as a predictive factor for responsiveness to levetiracetam treatment in epilepsy.

To investigate whether structural connectivity or glymphatic system function is a potential predictive factor for levetiracetam (LEV) response in patients with newly diagnosed epilepsy. We enrolled patients with newly diagnosed epilepsy who were administered LEV as initial monotherapy and underwent diffusion tensor imaging (DTI) at diagnosis. We categorized the patients into drug response. We used graph theory to calculate the network measures for structural connectivity based on the DTI scans in patients with epilepsy. Additionally, we evaluated glymphatic system function by calculating the DTI analysis along the perivascular space (DTI-ALPS) index based on DTI scans. We enrolled 84 patients with epilepsy. The clinical factors and DTI-ALPS index did not differ between the groups. However, some of the structural connectivity measures significantly differ between the groups. The poor responders exhibited a higher mean clustering coefficient, global efficiency, and small-worldness index than the good responders (p = 0.003, p = 0.048, and p = 0.038, respectively). In the receiver operating characteristic curve analysis, the mean clustering coefficient exhibited the highest performance in predicting the responsiveness to LEV (area under the curve of 0.677). In the multiple logistic regression analysis, the mean clustering coefficient of the structural connectivity measures was the only significant predictor of LEV response (p = 0.014). Furthermore, in the survival analysis, the mean clustering coefficient was the only significant predictor of LEV response (p = 0.026). We demonstrated that structural connectivity is a potential predictive factor for responsiveness to LEV treatment in patients with newly diagnosed epilepsy.

MMP-9 inhibition alleviates postoperative cognitive dysfunction by improving glymphatic function via regulating AQP4 polarity

Postoperative cognitive dysfunction (POCD) is a common complication after surgery, characterized by deficits in memory, attention and cognitive flexibility. However, the underlying mechanisms of POCD remain unclear. Neuroinflammation and blood–brain barrier disruption have been implicated as potential pathological processes. This study explores the neuroprotective effects and mechanisms of the matrix metalloproteinase（MMP-9）inhibitor GM6001 against POCD. We hypothesize GM6001 may reduce neuroinflammation and preserve blood–brain barrier integrity through direct inhibition of MMP-9. Moreover, GM6001 may stabilize aquaporin-4 polarity and glymphatic clearance function by modulating MMP-9-mediated cleavage of dystroglycan, a key protein for aquaporin-4 anchoring. Our results demonstrate GM6001 alleviates postoperative cognitive deficits and neuroinflammation. GM6001 also preserves blood–brain barrier integrity and rescues aquaporin-4 mislocalization after surgery. This study reveals a novel dual role for MMP-9 inhibition in cognitive protection through direct anti-neuroinflammatory effects and regulating aquaporin-4 membrane distribution. Targeting MMP-9 may represent a promising strategy to prevent postoperative cognitive dysfunction by integrating multiple protective mechanisms.

Impairments in sleep and brain molecular clearance in people with cognitive deterioration and biological evidence of AD: a report of four cases

BackgroundRecent evidence suggests that the failure of the glymphatic system – the brain’s waste clearance system, which is active during sleep – plays a key role in the pathophysiology of Alzheimer’s Disease (AD). Glymphatic function can be investigated using serial MRIs after intrathecal gadobutrol injection. This technique can reveal the health of the glymphatic system, but has not yet been used in participants with cognitive impairment due to AD.Case reportThis report describes the sleep and gadobutrol tracer clearance patterns of four participants diagnosed with mild to moderate cognitive impairment with evidence of AD pathology (pathological levels of Ab and p-tau in cerebrospinal fluid). We performed polysomnography and MRI studies before tracer injection and MRI scans at 1.5-2 h, 5–6 h, and 48 h after injection. Despite participants reporting no sleep problems, polysomnography revealed that all participants had moderate to severe sleep disturbances, including reduced sleep efficiency during the study and obstructive sleep apnea. Severe side-effects related to tracer administration were observed, impeding the completion of the protocol in two participants. Participants who finished the protocol displayed delayed and persistent tracer enrichment in the cortex and white matter, even 48 h after injection. These outcomes have not been observed in previous studies in participants without AD.ConclusionThe findings suggest that brains with sleep impairment and AD pathology have poor glymphatic function, and therefore cannot clear the contrast tracer efficiently. This is likely to have caused the severe side effects in our participants, that have not been reported in healthy individuals. Our results may therefore represent the only available data acquired with this technique in participants with AD pathology.

Mechanisms behind changes of neurodegeneration biomarkers in plasma induced by sleep deprivation.

Acute sleep deprivation has been shown to affect cerebrospinal fluid and plasma concentrations of biomarkers associated with neurodegeneration, though the mechanistic underpinnings remain unknown. This study compared individuals who, for one night, were either subject to total sleep deprivation or free sleep, (i) examining plasma concentrations of neurodegeneration biomarkers the morning after sleep deprivation or free sleep and (ii) determining how overnight changes in biomarkers plasma concentrations correlate with indices of meningeal lymphatic and glymphatic clearance functions. Plasma concentrations of amyloid-β 40 and 42, phosphorylated tau peptide 181, glial fibrillary acid protein and neurofilament light were measured longitudinally in subjects who from Day 1 to Day 2 either underwent total sleep deprivation (n = 7) or were allowed free sleep (n = 21). The magnetic resonance imaging contrast agent gadobutrol was injected intrathecally, serving as a cerebrospinal fluid tracer. Population pharmacokinetic model parameters of gadobutrol cerebrospinal fluid-to-blood clearance were utilized as a proxy of meningeal lymphatic clearance capacity and intrathecal contrast-enhanced magnetic resonance imaging as a proxy of glymphatic function. After one night of acute sleep deprivation, the plasma concentrations of amyloid-β 40 and 42 were reduced, but not the ratio, and concentrations of the other biomarkers were unchanged. The overnight change in amyloid-β 40 and 42 plasma concentrations in the sleep group correlated significantly with indices of meningeal lymphatic clearance capacity, while this was not seen for the other neurodegeneration biomarkers. However, overnight change in plasma concentrations of amyloid-β 40 and 42 did not correlate with the glymphatic marker. On the other hand, the overnight change in plasma concentration of phosphorylated tau peptide 181 correlated significantly with the marker of glymphatic function in the sleep deprivation group but not in the sleep group. The present data add to the evidence of the role of sleep and sleep deprivation on plasma neurodegeneration concentrations; however, the various neurodegeneration biomarkers respond differently with different mechanisms behind sleep-induced alterations in amyloid-β and tau plasma concentrations. Clearance capacity of meningeal lymphatics seems more important for sleep-induced changes in amyloid-β 40 and 42 plasma concentrations, while glymphatic function seems most important for change in plasma concentration of phosphorylated tau peptide 181 during sleep deprivation. Altogether, the present data highlight diverse mechanisms behind sleep-induced effects on concentrations of plasma neurodegeneration biomarkers.

Multimodal assessment of brain fluid clearance is associated with amyloid-beta deposition in humans

PurposeThe present study investigates a multimodal imaging assessment of glymphatic function and its association with brain amyloid-beta deposition. MethodsTwo brain CSF clearance measures (vCSF and DTI-ALPS) were derived from dynamic PET and MR diffusion tensor imaging (DTI) for 50 subjects, 24/50 were Aβ positive (Aβ+). T1W, T2W, DTI, T2FLAIR, and 11C-PiB and 18F-MK-6240 PET were acquired. Multivariate linear regression models were assessed with both vCSF and DTI-ALPS as independent variables and brain Aβ as the dependent variable. Three types of models were evaluated, including the vCSF-only model, the ALPS-only model and the vCSF+ALPS combined model. Models were applied to the whole group, and Aβ subgroups. All analyses were controlled for age, gender, and intracranial volume. ResultsSample demographics (N=50) include 20 males and 30 females with a mean age of 69.30 (sd=8.55). Our results show that the combination of vCSF and ALPS associates with Aβ deposition (p < 0.05, R2 = 0.575) better than either vCSF (p < 0.05, R2 = 0.431) or ALPS (p < 0.05, R2 = 0.372) alone in the Aβ+ group. We observed similar results in whole-group analyses (combined model: p < 0.05, R2 = 0.287; vCSF model: p <0.05, R2 = 0.175; ALPS model: p < 0.05, R2 = 0.196) with less significance. Our data also showed that vCSF has higher correlation (r = -0.548) in subjects with mild Aβ deposition and DTI-ALPS has higher correlation (r=-0.451) with severe Aβ deposition subjects. ConclusionThe regression model with both vCSF and DTI-ALPS is better associated with brain Aβ deposition. These two independent brain clearance measures may better explain the variation in Aβ deposition than either term individually. Our results suggest that vCSF and DTI-ALPS reflect complementary aspects of brain clearance functions.

Mechanism of anti-AD action of OAB-14 by enhancing the function of glymphatic system

The number of patients with Alzheimer's disease is increasing year by year, but only a few medications are available. We found that OAB-14, a new small molecule, can improve cognitive deficits in various mouse AD models. The structure and mechanism of OAB-14 are distinct from anti-AD medications that have been unsuccessful in recent clinical trials. OAB-14 can effectively reduce the accumulation of Aβ in the brain, but has no inhibitory effect on Aβ production enzymes. Reportedly, Aβ can be drained into the systemic circulation to be metabolized through the glymphatic system and meningeal lymphatic vessels. Our research has shown that OAB-14 is capable of enhancing the glymphatic system function by promoting the influx and efflux of the CSF tracers to the brain and deep cervical lymph nodes, respectively. After blocking the central lymphatic drainage, the effect of OAB-14 in improving cognitive impairments disappeared. Furthermore, OAB-14 may up-regulate AQP4 expression by acting on PPARγ-P2X7r-AQP4 pathway and protect the polarity of AQP4 by upregulating the expression of SNTA1, Agrin, and Abca1, which are closely associated with the proper functioning of the glymphatic system. In summary, OAB-14 can promote the clearance of brain Aβ through the glymphatic system and improve cognitive impairment.

Sleep and perivascular disruption: An illustrative case of severe sleep apnea, an enlarged Virchow-Robin space, and contralateral asymmetric periodic limb movements

Virchow-Robin spaces (VRS) are perivascular spaces that have been associated with impaired glymphatic function, poor sleep quality and sleep disorders. These spaces are also associated with neurological impairment. We report a case of a young adult male who presented with severe untreated sleep apnea, shift-work disorder, and excessive asymmetric periodic limb movements disorder in association with a prominent radiologically-identified VRS in the contralateral basal ganglia. This case illustrates the complex “chicken and egg” association between impaired sleep, the development of VRS, and subsequent sleep disorder most likely attributable to the development of this perivascular abnormality.

Decreased DTI-ALPS and choroid plexus enlargement in fibromyalgia: a preliminary multimodal MRI study.

The glymphatic system is a fluid exchange pathway that clears waste products that is crucial for the maintenance of brain homeostasis. However, the exact role it plays in the emergence of fibromyalgia (FM) is still not fully understood. Here, we explored the changes in non-invasive MRI proxy probably related to the glymphatic function in FM patients, and explored brain-behavior relationships. A total of 40 participants, consisting of 20 individuals with FM and 20 healthy controls (HCs), were included in the study. The participants underwent structural T1-weighted MRI, diffusion tensor imaging (DTI), and clinical assessment. The data was obtained from an open access dataset. The study compared non-invasive MRI indices, including choroid plexus (CP) volume and DTI analysis along the perivascular space (ALPS), between the FM and HC groups. Furthermore, correlation analysis was conducted to determine the correlation between clinical parameters and both CP volume and DTI-ALPS index. Patients with FM had significantly higher CP volume and a lower DTI-ALPS index than HCs adjusting for age and intracranial volume. Higher CP volume was associated with lower DTI-ALPS index, and longer disease duration. Our findings demonstrate aberrant glymphatic function in FM, and that dysfunction in the brain glymphatic system may play a role in the neural mechanisms underlying FM.

Ketamine Improves the Glymphatic Pathway by Reducing the Pyroptosis of Hippocampal Astrocytes in the Chronic Unpredictable Mild Stress Model.

Ketamine as a glutamate receptor antagonist has a rapid, potent, and long-lasting antidepressant effect, but its specific mechanism is still not fully understood. Depression is associated with elevated levels of glutamate and astrocyte loss in the brain; the exploration of the relationships between ketamine's antidepressant effect and astrocytes has drawn great attention. Astrocytes and aquaporin 4 (AQP4) are essential components of the glymphatic system, which is a brain-wide perivascular pathway to help transport nutrients to the parenchyma and remove metabolic wastes. In this study, we investigated pyroptosis-associated protein Nlrp3/Caspase-1/Gsdmd-N expression in the hippocampus of mice and the toxic effect of high levels of glutamate on primary astrocytes. On this basis, the protective mechanism of ketamine is explored. A single administration of ketamine (10 mg/kg) remarkably relieved anxious and depressive behaviors in the sucrose preference test, elevated plus maze test, and forced swim test. Meanwhile, ketamine reduced the level of hippocampus Nlrp3 and the expression of its downstream molecules in chronic unpredictable mild stress (CUMS) mice model by western blot and reduced the colocalization of Gfap and Gsdmd by nearly 25% via immunofluorescent staining. Ketamine also increased the Gfap-positive cells and AQP4 expression in the hippocampus of the CUMS mice. More important, ketamine increased the distribution of the fluorescent tracer of CUMS mice. Treatment with 128 mM glutamate in cortical and hippocampus astrocytes increased the level of Nlrp3, and Gsdmd-N, and ketamine alleviated high glutamate-induced pyroptosis-associated proteins. In summary, these results suggest that high glutamate-induced astrocyte pyroptosis through the Nlrp3/Caspase-1/Gsdmd-N pathway which was inhibited by ketamineandketamine can improve the damaged glymphatic function of the CUMS mice. The present study indicates that inhibiting astrocyte pyroptosis and promoting the glymphatic circulation function are a new mechanism of ketamine's antidepressant effect, and astrocyte pyroptosis may be a new target for other antidepressant medicines.