eISSN 2384-1109
Open Access, Peer-reviewed
    Investig Magn Reson Imaging. 2023 Dec;27(4):208-220. English.
    Published online Dec 26, 2023.
    https://doi.org/10.13104/imri.2023.0032
    Copyright © 2023 Korean Society of Magnetic Resonance in Medicine
    Review

    Glymphatic Magnetic Resonance Imaging: Part II—Applications in Sleep and Neurodegenerative Diseases

    Hyochul Lee,1,2 Roh-Eul Yoo,2 and Seung Hong Choi1,2,3
      • 1Interdisciplinary Program in Cancer Biology, Seoul National University College of Medicine, Seoul, Korea.
      • 2Department of Radiology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
      • 3Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul, Korea.
    • Correspondence: Roh-Eul Yoo, MD, PhD. Department of Radiology, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea. Email: roheul7@gmail.com
    Received October 31, 2023; Revised December 04, 2023; Accepted December 12, 2023.

    This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Abstract

    The glymphatic system plays a crucial role in brain waste clearance, with glymphatic magnetic resonance imaging (MRI) techniques highlighting its significance in understanding neurodegenerative diseases. This review emphasizes the intricate relationship between sleep, the glymphatic system, and the onset of conditions such as Alzheimer's disease (AD), idiopathic normal pressure hydrocephalus (iNPH), Parkinson's disease (PD), and other neurological diseases. Key findings revealed that sleep disruptions can impair the glymphatic system and potentially accelerate the progression of neurodegenerative diseases. In AD, amyloid β plaque accumulation correlates with glymphatic dysfunction, while in iNPH, impaired glymphatic functionality may result in waste accumulation, such as amyloid-beta accumulation in AD. Research on PD has underscored the potential role of the glymphatic system in α-synuclein clearance. In conclusion, as we delve into the glymphatic system using MRI techniques, we anticipate a richer understanding of neurodegenerative diseases, offering prospects for innovative therapeutic interventions.

    Keywords
    Glymphatic system; Sleep; Neurodegenerative disease; Magnetic resonance imaging; Alzheimer disease

    INTRODUCTION

    The interstitial space around brain cells contains proteins such as β-amyloid (Aβ), α-synuclein, and tau, which are known to have neurotoxic properties [1]. The brain relies on the glymphatic system for the clearance of this waste. Cerebrospinal fluid (CSF) circulates throughout the brain, exchanging content with interstitial fluid (ISF) [2]. During this process, CSF and ISF engage in convective exchange predominantly centered around the blood vessels of the brain [3]. The arterial system facilitates the influx of CSF into the brain, while the venous system allows for the exit of ISF [4, 5]. As these fluids move through the interstitial space, ISF is responsible for transporting solutes and waste products away from brain cells. These solutes and waste materials are channeled into the paravenous CSF space [6]. The aquaporin 4 (AQP4) water channels play a pivotal role in this process. AQP4 aids in the convective flow of ISF, ensuring the effective removal of solutes and neurotoxins [2, 7, 8]. Eventually, with the help of this circulatory dynamic between CSF and ISF, waste products are directed towards the veins, which then carry them away from the brain for clearance [2]. Crucial for visualizing this system, magnetic resonance imaging (MRI) offers minimally invasive and detailed views of CSF dynamics, especially in living humans [9, 10, 11]. Techniques like T1-weighted contrast-enhanced MRI and diffusion tensor imaging (DTI) help map the glymphatic pathways and understand their functions, providing key insights into various neurological conditions and facilitating future research [11, 12]. In particular, the glymphatic system is clinically important because of its association with neurodegenerative diseases [9, 13]. In this review, we introduce studies that highlight these related characteristics and review efforts towards diagnosis and treatment.

    CLINICAL IMPLICATIONS

    The glymphatic system is instrumental in the brain's primary mechanism of waste elimination [2, 13]. Its proper functioning is vital to prevent the accumulation of harmful substances. Any anomalies or interruptions in this system can enhance the deposition of Aβ plaques, accelerating the onset of Alzheimer’s disease (AD) (Fig. 1) [1, 9]. Moreover, as age advances, there is a discernible decline in the efficacy of the glymphatic system, potentially intensifying age-related neurodegenerative conditions [14]. A deficient glymphatic system has broader implications beyond AD. Conditions such as Parkinson’s disease (PD) [15, 16], Huntington’s disease [17], and certain sleep disturbances [18, 19, 20] have all been associated with glymphatic dysfunction, highlighting its overarching significance in preserving neurological health. Additionally, the role of the glymphatic system in the comprehensive removal of toxic metabolites suggests that targeting its fluid transport may reveal promising therapeutic avenues for a range of neurological disorders, including AD, PD, depression, epilepsy, and CNS-related inflammation [21, 22, 23, 24].

    Fig. 1
    Illustration of the glymphatic system for highlighting the interaction between perivascular space and waste clearance mechanisms. In the “Normal” section (A), we observe the standard functioning of the glymphatic system. Cerebrospinal fluid (CSF) in the para-arterial space interacts with interstitial fluid (ISF) through the aid of aquaporin 4 (AQP4) water channels on astroglial endfeet. This exchange process is guided by the para-arterial ISF bulk influx (red arrows), glymphatic ISF bulk influx (blue arrows), and para-venous CSF-ISF efflux (green arrows), demonstrating the brain's natural waste drainage pathway. In neurodegenerative disorders, which might refer to a pathological condition like Parkinson's disease (PD) (B), there is an evident disruption in the glymphatic system. The alterations might be due to factors such as neuroinflammation and systemic oxidative stress, which can compromise the integrity of the blood-brain barrier (BBB) and functionality of astrocytes, affecting the efficiency of waste clearance in the glymphatic system [113]. Reprinted under a CC BY license, Chen et al. [113], Oxid Med Cell Longev 2021;2021:4034509.

    SLEEP

    Sleep and Glymphatic Activity in Rodents

    Sleep plays a pivotal role in enhancing daily well-being and optimizing mental and physical processes [25]. Over the years, there has been increasing interest in delving into how sleep correlates with the brain's operations, especially how sleep deprivation might hinder cognitive functions [26, 27, 28]. In this context, the brain's glymphatic system has emerged as a focal point due to its association with sleep.

    Xie et al. [29] employed two-photon microscopy to study the effects of fluorescent markers introduced into the CSF of mice. In this study, the elimination of amyloid β in both healthy mice and AQP4-deficient mice revealed that both natural sleep and anesthesia led to a 60% expansion of the interstitial space [29]. This enlargement significantly enhanced the interchange between CSF and ISF. The efficiency of this system considerably increases during sleep as opposed to wakeful states [30]. This heightened efficiency was attributed to the decreased volume of glial cells during sleep, which led to the enlargement of the interstitial space [29]. This expansion, in turn, facilitates more effective transport of substances within tissues [12, 29]. Taoka et al. [31] reported that sleep significantly influenced the glymphatic system. Dynamic MRI experiments on rats demonstrated that the transition of gadodiamide, a contrast agent, from the blood to CSF via the choroid plexus was notably faster [31]. The distribution of gadodiamide in areas such as the cerebral cortex and deep cerebellar nuclei appeared to be influenced by both blood flow and CSF [31]. In addition, groups injected in the morning (at the beginning of the rest/sleep period) during long anesthesia periods showed the lowest residual tissue gadolinium concentrations [31]. These findings suggest that the glymphatic system may play a crucial role in the distribution and clearance of substances such as gadodiamide from brain tissue, with sleep and anesthesia being influential factors in its function.

    Anesthesia and Glymphatic Activity in Rodents

    Several studies have used anesthesia to simulate a sleep-like state [14, 29, 31, 32, 33, 34]. In these investigations, the administration of anesthesia resulted in noticeable variations in the glymphatic activity of rodents. A previous study suggested that the proportion of the interstitial space in mouse brain tissue is approximately 14% during wakefulness, which rises to approximately 24% during ketamine/xylazine anesthesia [29]. In one study, researchers discovered a 30% boost in glymphatic system transport using a mix of low-dose isoflurane and dexmedetomidine compared to isoflurane alone, which was linked to the expansion of ISF space and sleep-induced oscillations [14, 34]. Dexmedetomidine further amplified these effects by reducing the adrenergic tone and increasing CSF volume [14, 35]. This study visualized these changes using MRI with gadoterate meglumine, mapping the movement of the contrast agent through the key glymphatic routes of the rat brain over 60 min [14]. While some anesthetics, such as isoflurane and sevoflurane, may impair this system and hinder waste clearance from the brain, the lack of slow-wave sleep during anesthesia may also disrupt CSF flow and metabolic waste removal, potentially leading to neurotoxicity and cognitive issues [33, 36, 37]. The exact relationship between anesthesia, sleep, and the glymphatic system remains unclear, necessitating further research to elucidate the specific effects and underlying mechanisms.

    Sleep and Glymphatic MRI Techniques in Humans

    Clinical studies using MRI have found that sleep significantly influences glymphatic activity in humans [38]. Specifically, serial intravenous contrast-enhanced T1 mapping with MRI demonstrated that changes in T1 values, indicative of glymphatic activity, were pronounced during standard night sleep cycles [38]. Moreover, this MRI technique allows for the quantitative assessment of glymphatic activity across various brain regions, such as the cerebral and cerebellar gray matter and the putamen [38]. Additionally, several studies have utilized intrathecal administration of contrast agents [39, 40]. In a recent study, multimodal MRI techniques revealed that solute transport in the brain during sleep and sleep deprivation goes beyond just extracellular diffusion [40]. The brain uses a diffusion coefficient 3.5 times higher than that of extracellular diffusion, with sleep deprivation affecting this process [40]. Following intrathecal tracer injection, MRI tracked tracer transport for 48 h, and computational modeling of the data highlighted the complex relationship between sleep and brain solute transport (Fig. 2) [40, 41].

    Fig. 2
    Glymphatic dynamics in sleep quality. This figure presents the cerebrospinal fluid (CSF) tracer uptake in non-dementia individuals assessed for tentative CSF disorders. A: Normalized T1 MRI signals in subjects with good sleep quality (global PSQI score ≤5) are presented in mid-sagittal, axial, and coronal views. B: Comparable MRI signals for those with poor sleep quality (PSQI >6), matched by age and gender within the same diagnostic category. C: Difference in normalized T1 signal percentages between poor sleepers and good sleepers, with red indicating enhanced glymphatic activity and blue signaling rapid clearance. D, E: Plots show signal percentages within gray and white matter, respectively, underscoring significant differences between poor and good sleepers at designated time points (gray matter: 4–7 and 24 hours, white matter: 24 hours) [41]. Significance is denoted with asterisks (*p < 0.05, **p < 0.01), and the data are presented as means with 95% confidence intervals. Reprinted under a CC BY license, Eide et al. [41], J Cereb Blood Flow Metab 2022;42:1676-1692. The Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality, where a score of 5 or less indicates good sleep, and a score above 5 suggests poor sleep. MRI, magnetic resonance imaging.

    Numerous studies have utilized the diffusion tensor imaging-analysis along the perivascular space (DTI-ALPS) index as a noninvasive tool to assess the glymphatic system in humans [42, 43, 44, 45]. In a recent study on 84 older adults, factors such as age and N2 sleep duration, a stage of sleep known as non-rapid eye movement (REM) stage 2, significantly influenced glymphatic efficiency [43]. This efficiency, in turn, correlated with the enhanced language and memory performance of participants [43].

    Associations of Sleep with Glymphatic System and Neurodegeneration

    In summary, effective operation of the glymphatic system is closely linked to sleep. During sleep, the spaces in the brain expand, allowing CSF and ISF to move more freely. This expansion, combined with a decrease in the size of glial cells during sleep, helps substances move more effectively within the brain. Studies using advanced MRI techniques have shown that sleep affects glymphatic activity, highlighting the crucial connection between sleep and the glymphatic system. Anesthesia, which mimics sleep to some extent, has also been shown to cause changes in glymphatic activity in rodents. These findings emphasize the vital role of understanding how glymphatic problems relate to sleep, which can have important implications for various neurological conditions and diseases [46, 47]. In the next section, we review the interplay between the glymphatic system and the development and progression of conditions such as AD.

    AD

    Pathophysiology and Glymphatic System Implications

    AD is a leading form of dementia, predominantly observed in older adults and characterized by progressive cognitive impairment and memory loss [48]. The incidence of AD increases notably with age [49, 50]. While its exact origins are multifaceted, involving a combination of genetic, environmental, and lifestyle influences, a significant marker is the buildup of extracellular Aβ aggregates [48]. These aggregates predominantly form amyloid plaques, which result in neuronal damage and behavioral shifts [50, 51]. Intriguingly, traces of the Aβ protein have been discovered in the meningeal tissues of AD patients [52, 53]. The brain's glymphatic system, pivotal for waste clearance, including harmful amyloid β substances, stands out as a vital area of research [21, 54]. Dysfunction in this system leads to increased amyloid β plaque accumulation, a characteristic feature of AD [55]. Current research highlights the system's role in clearing harmful neurotoxins like amyloid β [9, 56]. Furthermore, age-related factors, such as decline in the paravascular flow of CSF/ISF and deteriorating function of lymphatic vessels, are believed to influence Aβ accumulation in brain tissue [2, 57, 58]. However, the possible age-related reduction in the ability of meningeal lymphatics to drain CSF and its consequent impact on AD amyloid pathology in the CNS is an area that still requires exploration [58, 59]. Understanding these connections could pave the way for innovative therapeutic approaches, underscoring the importance of the glymphatic system in brain waste removal.

    AD and Glymphatic MRI Techniques in Rodents and Humans

    In rodents, Iliff et al. [5] assessed the function of the glymphatic system in brain waste clearance using dynamic contrast-enhanced MRI to observe the exchange between CSF and ISF. This MRI technique illuminates key influx nodes, particularly in areas such as the pituitary and pineal gland recesses, suggesting its potential utility in evaluating the real-time risk and progression of AD [5, 60, 61]. One study applied MRI to evaluate the glymphatic system in a mouse model (Fig. 3) [62]. This study highlighted the potential influence of the glymphatic system on pathological tau accumulation in AD model [62]. These findings indicate that glymphatic system dysfunction may contribute to the accumulation of harmful plaques in AD [63].

    Fig. 3
    Altered glymphatic function in the rTg4510 mouse model of Alzheimer’s disease (AD). The glymphatic system, crucial for cerebrospinal fluid (CSF)-interstitial fluid (ISF) exchange, potentially exerts its influence on tau accumulation. A, B: Representative pseudo-colored sagittal images of wild-type (A) and rTg4510 (B) mouse brains after cisterna magna infusion of contrast agent, illustrating contrast agent infiltration into the brain tissue. C-F: MRI T1 signal intensity tracked over time from regions impacted by tau pathology in the rTg4510 model: the caudal cortex (C), rostral cortex (D), and hippocampus (E), contrasted with the cerebellum (F), devoid of tau pathology in this model. The caudal cortex of the AD mouse displays notably significant differences in T1 signal intensities, while the differences in the rostral cortex and hippocampus remain relatively insignificant. These variations suggest a diminished penetration of contrast agent, likely due to the compromised glymphatic function in the brain of the AD mouse model. The presented data encompass mean ± standard error of the mean and the corresponding fitted curves. Through these findings, the study accentuates the disrupted CSF-ISF exchange in tauopathy mouse models, hinting at the pivotal role this clearance pathway might play in pathological tau accumulation [62]. Specific levels of statistical significance are highlighted by asterisks (*p < 0.05, **p < 0.01, ***p < 0.001). Reprinted under a CC BY license, Harrison et al. [62], Brain 2020;143:2576-2593. MRI, magnetic resonance imaging.

    In several studies, AD patients exhibited a pronounced reduction in the DTI-ALPS index across various brain regions compared to cognitively healthy individuals [42, 64, 65]. Furthermore, negative correlation between the basal ganglia perivascular space (BG-PVS) volume fraction and the DTI-ALPS index was noted, suggesting a possible link between PVS enlargement (ePVS) and hindered glymphatic functionality in AD [42, 65]. Additionally, patients with AD presented with a larger BG-PVS volume fraction, indicating potential disturbances in the brain's waste removal system [65]. Collectively, these results imply that a malfunctioning glymphatic system, as indicated by the DTI-ALPS index, may significantly influence AD progression [66]. Consequently, the DTI-ALPS index has emerged as a promising biomarker for gauging glymphatic efficacy and monitoring the progression of AD [42].

    Perivascular Space Enlargement and AQP4 in AD

    Another study focused on ePVS in groups clinically and pathologically diagnosed with AD and dementia [67]. These studies focused on examining brain tissue samples postmortem, specifically through anatomical and immunofluorescence techniques, to understand the changes related to AD and mixed dementia [67]. The key finding was the notable enlargement of the perivascular space in AD cases when compared to individuals without cognitive impairments. Moreover, the study highlighted the characteristic reduction in the perivascular localization of AQP4 despite increased overall global AQP4 expression in the AD group. These observations reinforce the established connection between ePVS and AD and propose ePVS as a potential marker for glymphatic dysfunction in AD brains.

    This comprehensive view of the glymphatic system integrates findings from various imaging modalities and potentially offers valuable insights into the mechanisms underlying AD and related neurodegenerative diseases.

    IDIOPATHIC NORMAL PRESSURE HYDROCEPHALUS

    Pathophysiology and Glymphatic System Implications

    Idiopathic normal pressure hydrocephalus (iNPH) is a unique neurodegenerative disorder marked by ventricular enlargement and cognitive deficits [68, 69]. While its pathophysiological origins remain under investigation, abnormal CSF dynamics, hypoperfusion, and glymphatic system dysfunction are considered to be contributing factors [70, 71, 72]. Remarkably, iNPH differentiates itself from other dementias owing to its reversibility with CSF shunting, which not only alleviates symptoms in many patients but also offers a lens to study cognitive decline mechanisms [68]. However, the benefits of CSF shunting may be less enduring in iNPH than in other hydrocephalus [68]. Central to understanding iNPH is the glymphatic system, which, when impaired, may result in waste accumulation in the brain, analogous to the amyloid-beta accumulation observed in AD [71]. Research indicates that vascular changes can compromise this system, hinting at their relevance to iNPH [71, 73]. Because shunting has been shown to enhance CSF dynamics, it is pivotal to explore how it can optimize glymphatic function and potentially curtail iNPH progression [74].

    iNPH and Glymphatic MRI Techniques in Humans

    A Norwegian research group conducted several studies in which contrast agents were administered intrathecally to both individuals with normal pressure hydrocephalus and a control group [75, 76, 77, 78, 79, 80, 81]. In one study, MRI biomarkers were proposed with a ventricular reflux grade system, reflecting the combined impairment of glymphatic and meningeal lymphatic functions and indicating the redirection of CSF flow to the ventricles in patients with iNPH [80]. MRI biomarkers have revealed altered CSF tracer dynamics in iNPH patients, suggesting impaired glymphatic and meningeal lymphatic clearance functions (Fig. 4) [80]. These biomarkers offer insights into the pathophysiology of iNPH and may be pivotal in identifying shunt-responsive patients, with potential implications for diagnosing other dementias, such as AD [71, 80]. Further research is vital for understanding the clinical utility of these MRI indicators in neurodegenerative diseases.

    Fig. 4
    Altered cerebrospinal fluid (CSF) dynamics in idiopathic normal pressure hydrocephalus (iNPH). This series of T1-weighted MRI scans illustrate the varying ventricular reflux grades (0–4) after intrathecal administration of MR contrast agent in iNPH. The grading method categorizes the extent of supra-aqueductal reflux based on intensity and duration: Grade 0 indicates no observable supra-aqueductal reflux; Grade 1 shows signs of supra-aqueductal reflux; Grade 2 is characterized by transient enrichment of the lateral ventricles on Day 1; Grade 3 denotes lasting enrichment in the lateral ventricles on Day 2, not isointense with CSF in the subarachnoid space; and Grade 4 represents continuous enrichment in the lateral ventricles at 24 hours, isointense with subarachnoid CSF. This categorization aids in assessing the glymphatic MRI for an individual at each ventricular reflux grade, with Grades 3–4 being typical features of iNPH. The use of these modified MRI biomarkers, particularly in analyzing CSF tracer dynamics, highlights reduced intracranial compliance. This figure highlights the potential parallels in CSF molecular clearance issues observed in iNPH and other neurodegenerative diseases, such as Alzheimer’s disease [80]. Reprinted under a CC BY NC license, Eide et al. [80], Brain Commun 2020;2:fcaa187. MRI, magnetic resonance imaging.

    In iNPH research, DTI-ALPS has also been effectively utilized [72, 82]. In a study comparing diffusivities and the ALPS-index between iNPH patients and control subjects, patients with iNPH had significantly lower diffusivity along the x-axis and ALPS-index values, suggesting reduced perivascular water diffusion [72, 82]. These findings offer insights into the altered water diffusion patterns in the brain of NPH patients, which may have significant implications for diagnosing and understanding this condition [72, 82].

    Relations Among iNPH and Sleep Disorders

    iNPH has a notable connection with sleep-disordered breathing, especially obstructive sleep apnea (OSA), which can hinder proper drainage of CSF due to retrograde intracranial venous hypertension [83, 84, 85]. Frequent awakening from OSA also disrupts the flow of interstitial CSF into the glymphatic system, exacerbating hydrocephalus.

    PD

    Pathophysiology and Glymphatic System Implications

    PD is a progressive neurodegenerative condition primarily characterized by the loss of dopaminergic neurons in the brain, leading to motor symptoms such as tremors and rigidity [86, 87]. In addition to these motor challenges, PD patients also experience non-motor symptoms, including sleep disruptions and neuropsychiatric issues [87, 88, 89, 90]. A hallmark of PD is the accumulation of misfolded α-synuclein proteins in the brain, forming clumps known as Lewy bodies [87, 91]. Before significant motor symptoms manifest, a large number of dopaminergic neurons deteriorate [92]. An intriguing link has been observed between REM sleep behavior disorder (RBD) and PD, with idiopathic RBD (iRBD) emerging as a potential early marker of PD [93]. The development of accurate neuroimaging markers is crucial for predicting and managing the progression of PD [94]. The glymphatic system plays a potential role in clearing α-synuclein, which may influence its accumulation and clearance in PD [2, 3, 21].

    PD and Glymphatic MRI Techniques in Human

    Si et al. used T2-weighted and fluid-attenuated inversion recovery (FLAIR) images (Fig. 5) [87]. In this study, MRI-visible ePVS, defined as fluid-filled spaces similar in intensity to CSF, were analyzed in patients with iRBD and PD in various brain regions [87]. iRBD patients exhibit significantly higher ePVS burdens than PD patients, with these burdens in specific regions correlating with clinical symptom severity [87]. The differential ePVS burdens suggest a potential compensatory mechanism in the glymphatic system, emphasizing the need for further research on its relation with α-synuclein aggregation [87].

    Fig. 5
    MRI-visible enlarged perivascular spaces (EPVS) and their implication in the glymphatic system. The T2 and FLAIR imaging illustrate the variances in EPVS burdens among iRBD, HC, and PD patients. EPVS is considered part of the glymphatic system, hypothesized to be related to the clearance mechanism due to α-synuclein aggregation. Red arrows point to EPVS, characterized as fluid-filled spaces from 1 to 3 mm in diameter with high signal on T2 and low signal on FLAIR, without a surrounding halo. Yellow arrows highlight WMH, with lesions within the white matter displaying high signal on both T2 and FLAIR. Blue arrows indicate lacunes, which are lesions sized 3–15 mm showing high signal on T2 with a surrounding halo on FLAIR. A: iRBD group with frequent/severe grade CSO, BG-EPVS and EPVS in SN and BS. B: HC group with moderate grade CSO, BG-EPVS, and EPVS in SN and BS. C: PD group with none/mild grade CSO, BG-EPVS, but without EPVS in SN or BS. The imaging distinctively emphasizes the EPVS burdens in iRBD and PD, highlighting the significance of neuroimaging markers in elucidating the pathophysiologic relationship between these two conditions and their association with the glymphatic system [87]. Reprinted under a CC BY license, Si et al. [87], Front Aging Neurosci 2020;12:580853. MRI, magnetic resonance imaging; FLAIR, fluid-attenuated inversion recovery; iRBD, idiopathic rapid eye movement sleep behavior disorder; HC, healthy control; PD, Parkinson’s disease; WMH, white matter hyperintensity; CSO, centrum semiovale; BG-EPVS, basal ganglia enlarged perivascular spaces; SN, substantia nigra; BS, brainstem.

    Several studies have used the DTI-ALPS method [42, 95, 96, 97, 98, 99, 100, 101]. Shen et al. [97] found a decreased DTI-ALPS index in advanced PD patients, with an initially prominent decline in the left hemisphere. This decrease was correlated with factors such as longer disease duration and higher PD severity [97]. Additionally, an increased PVS burden, consistent with a lowered DTI-ALPS index, suggests that both may serve as potential imaging biomarkers of PD progression, indicating impaired glymphatic function [97].

    OTHER NEUROLOGICAL DISEASES ASSOCIATED WITH GLYMPHATIC DYSFUNCTION

    The connection between the glymphatic system and various neurological diseases remains a topic of discussion. Traumatic brain injury (TBI) is a brain dysfunction caused by an external force that leads to impaired glymphatic function, which affects the clearance of biomarkers and contributes to neurological and cognitive impairments [102]. In mouse models, TBI significantly impaired glymphatic function and AQP4 polarization, reducing glymphatic flow by approximately 60%, and sustaining this impairment for at least 28 days post-injury [103]. In a recent study, TBI in mice altered the AQP4 orientation in astrocytes within 12 h, increasing its membrane presence and reducing its polarized position on the endfeet, followed by a shift to the cytomembrane [104].

    Ischemic stroke, which involves mass depolarization of neurons starting in the ischemic core, can potentially lead to neuronal death in the surrounding hypoxic tissue [105]. This process has been implicated in impaired glymphatic flow, suggesting a connection between neuronal disruptions caused by stroke and subsequent dysfunction of glymphatic system activity [9]. An early animal study demonstrated that glymphatic system impairment occurs hours after subarachnoid hemorrhage (SAH) induction in mice and also observed glymphatic insufficiency in ischemic stroke, noting that intracerebroventricular or intravenous injection of a tissue-type plasminogen activator enhanced glymphatic perfusion following SAH or ischemic stroke, respectively [106].

    Dysfunction of the glymphatic system has also been implicated in various other neurodegenerative conditions, including amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis [102, 107, 108, 109].

    FUTURE DIRECTIONS AND CONCLUSION

    In conclusion, although the impact of the glymphatic system has been introduced in the context of sleep and neurodegenerative diseases, its implications extend far beyond studies investigating its role in neurological diseases [12, 106]. Furthermore, researchers are exploring the interactions of the system with factors such as alcohol [110] and diabetes [111, 112], utilizing a range of MRI techniques. As our understanding of the glymphatic system deepens through these studies, we anticipate greater insights into the pathophysiology of various diseases, paving the way for enhanced research and therapeutic approaches in the future.

    Notes

    Conflicts of Interest:Seung Hong Choi, the Editor-in-Chief of the Investigative Magnetic Resonance Imaging, was not involved in the editorial evaluation or decision to publish this article. All remaining authors have declared no conflicts of interest.

    Author Contributions:

    • Conceptualization: Roh-Eul Yoo, Seung Hong Choi.

    • Funding acquisition: Roh-Eul Yoo, Seung Hong Choi.

    • Writing—original draft: Hyochul Lee.

    • Writing—review & editing: Roh-Eul Yoo, Seung Hong Choi.

    Funding Statement:This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF-2021R1A4A1028713 and NRF-2023R1A2C3003250) and grant no 0320230270 from the SNUH Research Fund.

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    MeSH Terms
    Alzheimer Disease
    Amyloid
    Brain
    Glymphatic System
    Hydrocephalus, Normal Pressure
    Magnetic Resonance Imaging*
    Neurodegenerative Diseases*
    Parkinson Disease
    Metrics
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