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•PVS burden increases nonlinearly with age over the course of the lifespan.•PVS morphological trajectories differ in the white matter and basal ganglia.•Regions with low PVS burden in childhood undergo more rapid alterations in aging.•PVS volumetric expansion is fastest in temporal and occipital white matter.•Age-related variance in PVS volume is explained by sex and body mass index. Enlarged perivascular spaces (PVS) are considered a biomarker for vascular pathology and are observed in normal aging and neurological conditions; however, research on the role of PVS in health and disease are hindered by the lack of knowledge regarding the normative time course of PVS alterations with age. To this end, we characterized the influence of age, sex and cognitive performance on PVS anatomical characteristics in a large cross-sectional cohort (∼1400) of healthy subjects between 8 and 90 years of age using multimodal structural MRI data. Our results show age is associated with wider and more numerous MRI-visible PVS over the course of the lifetime with spatially-varying patterns of PVS enlargement trajectories. In particular, regions with low PVS volume fraction in childhood are associated with rapid age-related PVS enlargement (e.g., temporal regions), while regions with high PVS volume fraction in childhood are associated with minimal age-related PVS alterations (e.g., limbic regions). PVS burden was significantly elevated in males compared to females with differing morphological time courses with age. Together, these findings contribute to our understanding of perivascular physiology across the healthy lifespan and provide a normative reference for the spatial distribution of PVS enlargement patterns to which pathological alterations can be compared.

The paravascular pathway, also known as the \"glymphatic\" pathway, is a recently described system for waste clearance in the brain. According to this model, cerebrospinal fluid (CSF) enters the paravascular spaces surrounding penetrating arteries of the brain, mixes with interstitial fluid (ISF) and solutes in the parenchyma, and exits along paravascular spaces of draining veins. Studies have shown that metabolic waste products and solutes, including proteins involved in the pathogenesis of neurodegenerative diseases such as amyloid-beta, may be cleared by this pathway. Consequently, a growing body of research has begun to explore the association between glymphatic dysfunction and various disease states. However, significant controversy exists in the literature regarding both the direction of waste clearance as well as the anatomical space in which the waste-fluid mixture is contained. Some studies have found no evidence of interstitial solute clearance along the paravascular space of veins. Rather, they demonstrate a perivascular pathway in which waste is cleared from the brain along an anatomically distinct perivascular space in a direction opposite to that of paravascular flow. Although possible explanations have been offered, none have been able to fully reconcile the discrepancies in the literature, and many questions remain. Given the therapeutic potential that a comprehensive understanding of brain waste clearance pathways might offer, further research and clarification is highly warranted.

Microvascular blood volume pulsations due to the cardiac and respiratory cycles induce brain tissue deformation and, as such, are considered to drive the brain’s waste clearance system. We have developed a high-field magnetic resonance imaging (MRI) technique to quantify both cardiac and respiration-induced tissue deformations, which could not be assessed noninvasively before. The technique acquires motion encoded snapshot images in which various forms of motion and confounders are entangled. First, we optimized the motion sensitivity for application in the human brain. Next, we isolated the heartbeat and respiration-related deformations, by introducing a linear model that fits the snapshot series to the recorded physiological information. As a result, we obtained maps of the physiological tissue deformation with 3mm isotropic spatial resolution. Heartbeat and respiration-induced volumetric strain were significantly different from zero in the basal ganglia (median (25–75% interquartile range): 0.85·10−3 (0.39·10−3–1.05·10−3), p ​= ​0.0008 and −0.28·10−3 (−0.41·10−3–0.06·10−3), p ​= ​0.047, respectively. Smaller volumetric strains were observed in the white matter of the centrum semi ovale (0.28·10−3 (0–0.59·10−3) and −0.06·10−3 (−0.17·10−3–0.20·10−3)), which was only significant for the heartbeat (p ​= ​0.02 and p ​= ​0.7, respectively). Furthermore, heartbeat-induced volumetric strain was about three times larger than respiration-induced volumetric strain. This technique opens a window on the driving forces of the human brain clearance system. •Cardiac and respiration-induced brain deformations simultaneously measured with MRI.•Single-shot 2D DENSE is suitable to unravel cardiac and respiration induced brain tissue strain.•Tissue deformation of the brain is mainly driven by the cardiac cycle.•Inspiration induces tissue compression, probably due to venous outflow.

Abstract Poor sleep quality might contribute to the risk and progression of neurodegenerative disorders via deficient cerebral waste clearance functions during sleep. In this retrospective cross-sectional study, we explore the link between enlarged perivascular spaces (PVS), a putative marker of sleep-dependent glymphatic clearance, with sleep quality and motor symptoms in patients with Parkinson’s disease (PD). T2-weighted magnetic resonance imaging (MRI) images of 20 patients and 17 healthy control participants were estimated visually for PVS in the basal ganglia (BG) and centrum semiovale (CSO). The patient group additionally underwent a single-night polysomnography. Readouts included polysomnographic sleep features and slow-wave activity (SWA), a quantitative EEG marker of sleep depth. Associations between PVS counts, PD symptoms (MDS-UPDRS scores), and sleep parameters were evaluated using correlation and regression analyses. Intra- and inter-rater reproducibility was assessed with weighted Cohen`s kappa coefficient. BG and CSO PVS counts in both patients and controls did not differ significantly between groups. In patients, PVS in both brain regions was negatively associated with SWA (1–2 Hz; BG: r(15) = −.58, padj = .015 and CSO: r(15) = −.6, padj = .015). Basal ganglia PVS counts were positively associated with motor symptoms of daily living (IRR = 1.05, CI [1.01, 1.09], p = .007, padj = .026) and antidepressant use (IRR = 1.37, CI [1.05, 1.80], p = .021, padj = .043) after controlling for age. Centrum Semiovale PVS counts in patients were positively associated with a diagnosis of REM sleep behavior disorder (IRR = 1.39, CI [1.06, 1.84], p = .018, padj = .11). These results add to evidence that sleep deterioration may play a role in impairing glymphatic clearance via altered perivascular function, potentially contributing to disease severity in PD patients. Graphical Abstract Graphical Abstract

Waste from the brain has been shown to be cleared via the perivascular spaces through the so-called glymphatic system. According to this model the cerebrospinal fluid (CSF) enters the brain in perivascular spaces of arteries, crosses the astrocyte endfoot layer, flows through the parenchyma collecting waste that is subsequently drained along veins. Glymphatic clearance is dependent on astrocytic aquaporin-4 (AQP4) water channels that are highly enriched in the endfeet. Even though the polarized expression of AQP4 in endfeet is thought to be of crucial importance for glymphatic CSF influx, its role in extracellular solute clearance has only been evaluated using non-quantitative fluorescence measurements. Here we have quantitatively evaluated clearance of intrastriatally infused small and large radioactively labeled solutes in mice lacking AQP4 ( Aqp4 –/– ) or lacking the endfoot pool of AQP4 ( Snta1 –/– ). We confirm that Aqp4 –/– mice show reduced clearance of both small and large extracellular solutes. Moreover, we find that the Snta1 –/– mice have reduced clearance only for the 500 kDa [ 3 H]dextran, but not 0.18 kDa [ 3 H]mannitol suggesting that polarization of AQP4 to the endfeet is primarily important for clearance of large, but not small molecules. Lastly, we observed that clearance of 500 kDa [ 3 H]dextran increased with age in adult mice. Based on our quantitative measurements, we confirm that presence of AQP4 is important for clearance of extracellular solutes, while the perivascular AQP4 localization seems to have a greater impact on clearance of large versus small molecules.

Cerebral small vessel disease (SVD) is recognized as a major vascular contributor to cognitive decline, ultimately leading to dementia and stroke. While the pathogenesis of SVD remains unclear, emerging evidence suggests that waste clearance involving perivascular space (PVS) – also known as the glymphatic system – dysfunction may play a role. Among SVD radiological markers, the increased presence of dilated PVS is recognized as a marker of waste clearance disruption. Recently developed neuroimaging methods have been proposed as indirect measures of brain fluid dynamics, but they currently lack formal validation. Here, we provide a comprehensive overview of the latest neuroimaging advancements for assessing brain fluid dynamics, including waste clearance involving PVS function in SVD. We review the mechanisms by which clearance dysfunction might contribute to SVD. Finally, we argue that robust, multimodal, and longitudinal studies are essential for understanding the waste clearance (involving PVS) function and for establishing a diagnostic gold standard. Highlights The majority of PVS are not visible on MRI, making it crucial to understand how and why they become dilated. The origin of waste clearance involving PVS disruption in SVD may be multifactorial. The BBB and waste clearance (involving PVS) dysfunction likely affect each other, forming a vicious cycle, promoting further amyloid beta accumulation. Yet their direct association in humans over time remains to be studied. Comparative studies can aid in the standardization of methods for assessing waste clearance involving PVS function.

The intricate mechanisms governing brain health and function have long been subjects of extensive investigation. Recent research has shed light on two pivotal systems, the glymphatic system and the endocannabinoid system, and their profound role within the central nervous system. The glymphatic system is a recently discovered waste clearance system within the brain that facilitates the efficient removal of toxic waste products and metabolites from the central nervous system. It relies on the unique properties of the brain’s extracellular space and is primarily driven by cerebrospinal fluid and glial cells. Conversely, the endocannabinoid system, a multifaceted signaling network, is intricately involved in diverse physiological processes and has been associated with modulating synaptic plasticity, nociception, affective states, appetite regulation, and immune responses. This scientific review delves into the intricate interconnections between these two systems, exploring their combined influence on brain health and disease. By elucidating the synergistic effects of glymphatic function and endocannabinoid signaling, this review aims to deepen our understanding of their implications for neurological disorders, immune responses, and cognitive well-being.

INTRODUCTION Inflammatory bowel disease triggers extraintestinal manifestations, including in the central nervous system (CNS). However, the direct impact of peripheral inflammation on the CNS is largely unknown. METHODS Using a mouse model of colitis with pain and anxiety‐like behavior, we investigated the intricate pathogenic link between colonic inflammation, disruptions in circadian rhythmicity and impaired glymphatic circulation. RESULTS By in vivo magnetic resonance imaging, we observed a derangement of brain fluid dynamics, with a significant enlargement of the cerebral lateral ventricles and waste deposition within the brain parenchyma. Proteomics revealed changes in cerebrospinal fluid (CSF) composition, enriched in proteins related to inflammation, immune response, complement, neuronal, and lipid metabolic pathways. Alterations in brain metabolite concentrations and in inhibitory control mechanisms and excitatory transmission were detected. DISCUSSION Colonic inflammation induces remodeling in CSF volume distribution, clearance, and metabolism, with derangement of the crosstalk between neurons and astrocytes, priming synaptopathy. HIGHLIGHTS An acute peripheral inflammatory trigger affects the central level by remodeling central nervous system (CNS) fluid distribution and priming early signals of synaptopathy. A single dextran sulfate sodium (DSS) challenge disrupts the circadian clock machinery and alters CNS fluid distribution, a so far neglected system, thereby impairing glymphatic clearance of waste products and indirectly altering neurotransmitter release dynamics. These combined effects ultimately impact brain function, extending to the regulation of behavior. Understanding how an intestinal inflammatory insult may derange the daily rhythm of the mechanisms controlling brain waste disposal may help identify specific groups of subjects at high risk of developing neurological disorders.

As the most metabolically active organ in the body, there is a recognized need for pathways which remove waste proteins and neurotoxins from brain. Previous research has indicated potential associations between clearance system in the brain and pathologic conditions of the central nervous system (CNS), due to its importance, which has attracted considerable attention recently. In the last decade, studies of clearance system have been restricted to glymphatic system. However, removal of toxic and catabolic waste byproducts can’t be completed independently by glymphatic system, while no known research or paper has focused on a comprehensive overview over structure and function of clearance system. This thesis addresses a neglected aspect of linkage between the structural composition and main components as well as the role of neural cell throughout the clearance system, which found evidence that components of CNS including glymphatic system and meningeal lymphatic system interact with neural cell such as astrocytes and microglia in order to carry out vital clearance functions. As a result of these evidence that can contribute to a better understanding of the clearance system, suggestions were identified for further clinical intervention development of severe conditions caused by accumulation of metabolic waste products and neurotoxins in brain such as Alzheimer’s disease (AD) and Parkinson’s disease (PD).

As a leading economic center in China and an international metropolis, Shenzhen has great significance in promoting sustainable urban development. To predict its amount of domestic waste clearance, a new multivariable grey prediction model with combinatorial optimization of parameters is established in this paper. Firstly, the new model expands the value range of the order r of a grey accumulation generation operator from positive real numbers (R +) to all real numbers (R), which enlarges the optimization space of parameter and has positive significance for improving model performance. Secondly, the dynamic background-value coefficient λ is introduced into the new model to improve the smoothing effect of the nearest neighbor generated sequences. Thirdly, with the objective function of minimizing the mean absolute percentage error (MAPE), the particle swarm optimization (PSO) is employed to optimize parameters r and λ to improve the overall performance of the new model. The new model is used to simulate and predict the amount of domestic waste clearance in Shenzhen, and the MAPE of the new model is only 0.27%, which is far superior to several other similar models. Lastly, the new model is applied to predict the amount of domestic waste clearance in Shenzhen. The results indicate the amount of domestic waste clearance in 2028 could be 9.96 million tons, an increase of 20.58% compared to 2021.This highlights the significant challenge that Shenzhen faces in terms of urban domestic waste treatment. Therefore, some targeted countermeasures and suggestions have been proposed to ensure the sustainable development of Shenzhen's economy and society.