Exposure to Environmental Toxicants: Glymphatic System Dysfunction and Its Implications on Neurodevelopmental Disorders

The glymphatic system has recently been shown to clear brain extracellular solutes and abnormalities in glymphatic clearance system may contribute to both initiation and progression of neurological diseases. Despite that diabetes is known as a risk factor for vascular diseases, little is known how diabetes affects the glymphatic system. The current study is the first investigation of the effect of diabetes on the glymphatic system and the link between alteration of glymphatic clearance and cognitive impairment in Type-2 diabetes mellitus rats. MRI analysis revealed that clearance of cerebrospinal fluid contrast agent Gd-DTPA from the interstitial space was slowed by a factor of three in the hippocampus of Type-2 diabetes mellitus rats compared to the non-DM rats and confirmed by florescence imaging analysis. Cognitive deficits detected by behavioral tests were highly and inversely correlated to the retention of Gd-DTPA contrast and fluorescent tracer in the hippocampus of Type-2 diabetes mellitus rats. Type-2 diabetes mellitus suppresses clearance of interstitial fluid in the hippocampus and hypothalamus, suggesting that an impairment of the glymphatic system contributes to Type-2 diabetes mellitus-induced cognitive deficits. Whole brain MRI provides a sensitive, non-invasive tool to quantitatively evaluate cerebrospinal fluid and interstitial fluid exchange in Type-2 diabetes mellitus and possibly in other neurological disorders, with potential clinical application.

The newly discovered glymphatic system acts as pseudolymphatic vessels subserving brain waste clearance and is functionally dependent on astrocytic aquaporin-4 channels. The glymphatic system primarily functions during sleep as an interchange between cerebrospinal fluid and interstitial fluid, with cerebrospinal fluid flowing into the parenchyma via the perivascular spaces and then exchanging with interstitial fluid. The discovery of meningeal lymphatics helps refine the conceptual framework of glymphatic pathway, as certain waste products collected alongside perivascular spaces ultimately drain into the cervical lymph nodes via meningeal lymphatics, whose function regulates the functioning of the glymphatic system. The glymphatic and meningeal lymphatic systems are critical for the homeostasis of central nervous system, and their malfunctions complicate cerebral dysfunction and diseases. The present review will shed light on the structure, regulation, functions, and interrelationships of the glymphatic system and meningeal lymphatics. We will also expound on their impairments and corresponding targeted intervention in neurodegenerative diseases, traumatic brain injury, stroke, and infectious/autoimmune diseases, offering valuable references for future research.

The glymphatic system within the central nervous system (CNS) facilitates the exchange and elimination of cerebrospinal fluid (CSF) and interstitial fluid (ISF), aiding in the removal of potentially poisonous metabolic wastes to maintain brain stability. Sleep and Aquaporin‐4 (AQP‐4) expression positively regulate the glymphatic system. When sleep is disturbed and AQP‐4 polarization is inhibited, the glymphatic system is impaired, leading to the inability to effectively eliminate soluble wastes from the brain. This disruption can potentially contribute to, or accelerate, the progression of various CNS diseases, such as Alzheimer's disease and Parkinson's disease, as well as non‐CNS diseases, like diabetes mellitus and hypertension. Therefore, the normal functioning of the glymphatic system is essential for the recovery from both CNS diseases and non‐CNS diseases. In this review, an overview of the constituents and functions of the glymphatic system in the brain, specifically highlighting the glymphatic system lesions in different diseases is provided. Additionally, currently unresolved questions pertaining to this topic are summarized. Ultimately, the cerebral glymphatic system is expected to be a novel and promising target for the diagnosis and treatment of multiple diseases.

Background Attention-Deficit/Hyperactivity Disorder (ADHD) is the most common neurodevelopmental disorder in children (Polanczyk, Willcutt, Salum, Kieling, & Rohde, 2014) and is highly comorbid with Autism Spectrum Disorder (ASD) (Green et al., 2015; Kotte et al., 2013). Although it is well established that children with ADHD or ASD and their families experience poorer functioning including child and parent mental health problems, child peer problems, poorer family quality of life (FQoL) and parenting difficulties, it is unknown how comorbid ASD symptoms contribute to child and family functioning in children with ADHD. It is important to understand which comorbidities contribute to poorer child and family functioning to guide treatment planning. Aims This study aimed to examine the prevalence of ASD symptoms in children with ADHD and the association between ASD symptoms and child and family functioning across three connected studies. The specific aims of each study are outlined below. Study 1. To examine the prevalence and type of ASD symptoms (social interaction, communication and stereotyped behaviour) in children with ADHD and non-ADHD controls. Within the ADHD group only, we also examined the relationship between ADHD subtype, hyperactive/impulsive and inattentive symptoms, ADHD symptom severity and child gender and ASD symptom severity. Study 2. To examine the association between ASD symptoms and (a) social functioning; (b) mental health; (c) quality of life and (d) sleep, in children with and without ADHD. Study 3. To examine the association between ASD symptoms (measured dimensionally) in children with and without ADHD and a broad range of family functioning variables and to examine differences between ADHD+ASD, ADHD and control groups on family functioning variables. Methods Participants were 6-10 year old children (164 ADHD; 198 non-ADHD control) attending 43 schools in Melbourne, Australia, who were participating in the Children’s Attention Project. ADHD was assessed in two stages using the parent and teacher Conners’ 3 ADHD index and the Diagnostic Interview Schedule for Children IV (DISC-IV). ASD symptoms were identified using the Social Communication Questionnaire (SCQ). Child functioning measures were social functioning (Strengths and Difficulties Questionnaire (SDQ), mental health (DISC-IV, SDQ), quality of life (QoL: Pediatric Quality of Life Inventory 4.0) and sleep problem severity. Family functioning outcome variables were parent mental health, family quality of life (FQoL), and scales assessing couple conflict, couple support and parenting behaviours. Unadjusted and adjusted linear and logistic regression examined continuous and categorical outcomes, respectively. Results Study 1. Children with ADHD had more ASD symptoms than non-ADHD controls (adjusted mean difference = 4.0, 95% confidence interval (CI) 2.8; 5.3, p < 0.001, effect size = 0.7). Boys with ADHD had greater ASD symptom severity than girls with ADHD (adjusted mean difference = 2.9, 95% CI 0.8; 5.2, p = 0.01, effect size = 0.4). Greater ADHD symptom severity was associated with greater ASD symptom severity (regression co-efficient = 1.6, 95% CI 1.2; 2.0, p < 0.001). No differences were observed by ADHD subtype. Greater hyperactive/impulsive symptoms were associated with greater ASD symptoms (regression coefficient = 1.0; 95% CI 0.0; 2.0, p = 0.04) however, this finding attenuated in adjusted analyses, which accounted for parent educational attainment, socioeconomic status, child internalising and externalising comorbidities (p = 0.45). Study 2. Each standard deviation (SD) increase in SCQ scores was associated with a 6.7 unit reduction in QoL (p < 0.001) and greater parent and teacher-reported peer problems, emotional and conduct problems. For every SD increase in SCQ scores, internalising (OR = 1.8, 95% CI 1.3, 2.6, p = 0.001) and externalising disorders (OR = 1.5, 95% CI 1.1, 2.1, p = 0.02) increased, as did moderate/severe sleep problems (OR = 1.5, 95% CI 1.0, 2.2, p = 0.04). Most findings held in analyses adjusting for socio-demographic factors, ADHD symptom severity, and comorbidities (when not the outcome), with the exception of externalising disorders and sleep problems. Study 3. In unadjusted dimensional analyses, higher ASD symptoms were associated with more couple conflict (p = 0.04) and poorer FQoL for all subscales (p ≤ 0.001), with non-significant trends for less couple support (R2 = 0.10, p = 0.06), more hostile parenting (R2 = 0.02, p = 0.06) and poorer parent mental health (R2 = 0.02, p = 0.07). In adjusted dimensional analyses, higher ASD symptoms were only associated with poorer FQoL, across all subscales only (p ≤ 0.01). The trend association between ASD symptoms and parent mental health attenuated due to meaningful associations with comorbid internalising disorder (p = 0.003) and ADHD symptom severity (p = 0.05). The trend association between ASD symptoms and hostile parenting attenuated due to significant associations with comorbid externalising disorders (p = 0.002), lower parent education attainment (p = 0.03) and greater ADHD symptom severity (p = 0.04). Less couple support attenuated due to a significant association with socioeconomic status (p = 0.004). In unadjusted categorical analyses, parents of children with ADHD+ASD reported more couple conflict (p = 0.04), less couple support (p = 0.001), poorer FQoL (p <0.001) and a non-significant trend for greater mental health difficulties (p = 0.07), compared to the ADHD group. In adjusted categorical analyses, parents of children with ADHD+ASD had poorer parent self-efficacy (p = 0.02), poorer FQoL (p < 0.05) (p < 0.05) and a non-significant trend for less couple support (p = 0.06), compared to parents of children with ADHD. In unadjusted categorical analyses, family functioning was significantly poorer for the ADHD and ADHD+ASD groups, compared to controls for most outcomes (p <0.001). In adjusted categorical analyses, all findings attenuated except FQoL was significantly poorer for the ADHD and ADHD+ASD groups, compared to controls. Conclusion ASD symptoms are common, and associated with poorer functioning in children with ADHD. It is important for clinicians working with children with ADHD to identify and manage ASD symptoms, given that they exacerbate functional impairments in this already vulnerable group. The relationship between ASD symptoms and broader family functioning appears to be largely driven by internalising and externalising disorders, ADHD severity, and socioeconomic status. Poorer FQoL appears to be independently associated with ASD symptoms in children with ADHD.

Introduction: The glymphatic system is the equivalent of the lymphatic system in the brain. This system is responsible for the exchange of metabolism waste products between the cerebrospinal fluid and the interstitial fluid. The glymphatic system functions mainly during sleep, and this is when the removal of interstitial metabolism waste products take place. A proper diet and physical activity are also needed for the glymphatic system to work effectively. Abnormal function of the glymphatic system can contribute to the development of diseases of the central nervous system, including neurodegenerative diseases and migraine. Aim of the study: The aim of our study is to review the latest knowledge linking the glymphatic system with the pathogenesis of selected neurological diseases and other lifestyle-related factors such as sleep, diet and physical activity. The study included Alzheimer’s disease, Parkinson’s disease, migraines and ischemic stroke. Materials and methods: We have reviewed the literature available in the pubmed database using keywords: “glymphatic system”; “aquaporin-4”; “Alzheimer’s disease”; “Parkinson’s disease”; “migraines”; “sleep” Conclusions: The studies discussed here show a clear correlation between the glymphatic system and neurological diseases. The glymphatic system may definitely be involved in the pathophysiology of neurological disorders. A thorough investigation of this issue will help uncover potentially new strategies for the prevention and treatment of neurological diseases. Key words: glymphatic system; aquaporin-4; Alzheimer’s disease; Parkinson’s disease; migraine; sleep

BackgroundThe continuous performance task (CPT) may help identify coexistent attention deficit hyperactivity disorder (ADHD) in autism spectrum disorder (ASD). The Quantified behavior Test (QbTest) combines a CPT and motion-tracking data to assess ADHD symptoms. This study aimed to evaluate the QbTest performance of children and adolescents with ASD plus ADHD, including estimating the effects of single-dose methylphenidate (MPH). To achieve these aims, (1) the QbTest performances were evaluated in ASD alone, ASD plus ADHD, and ADHD alone, and (2) the effects on the QbTest performance of single-dose MPH before and after intake were estimated across the groups. It was assumed that the ASD plus ADHD performance, including the MPH response, would preferably resemble the performance in ADHD alone, rather than ASD alone.MethodsRetrospective data were analyzed for 482 children and adolescents: 69 with ASD alone, 142 with ASD plus ADHD (ASD/ADHD), and 271 with ADHD alone. For 343 subjects, the QbTest was performed before and up to four hours after a single-dose MPH intake. A summary index of the CPT and motion-capture data was provided for QbTest cardinal parameters.ResultsOf 12 QbTest parameters assessed before given MPH, the ASD/ADHD group had scores in line with the ASD group regarding four parameters and the ADHD group regarding nine parameters. Significant differences between groups were seen with respect to QbInattention (p > 0.05); the lowest scores in ASD and the highest in ADHD. Those with ASD/ADHD and ADHD had similar QbActivity and QbImpulsivity scores, but significantly higher than those with ASD. After MPH intake, scores for QbActivity decreased similarly in ASD/ADHD and ADHD, as well as scores for QbImpulsivity. QbImpulsivity increased in ASD. QbInattention scores decreased similarly in all groups after MPH intake.ConclusionsChildren and adolescents with ASD plus ADHD exhibited more atypical QbTest performances than those with ASD alone, while most of their performances were similar to those observed in ADHD alone. In addition, a single dose of MPH mitigated attention deficits and decreased hyperactivity while improved impulsivity in these children. Prospective studies should further clarify the role of the QbTest in the diagnostic and therapeutic interventions in ASD with ADHD.

Prospective cohort study. To provide a primer of the glymphatic system, discuss its potential relevance in evaluating spinal diseases like cervical spondylotic myelopathy (CSM), and describe possible imaging markers of the glymphatic system derived from advanced diffusion-weighted imaging (dMRI), namely diffusion tensor imaging (DTI) and diffusion basis spectrum imaging (DBSI). The glymphatic system is a recently described physiological process that plays an integral role in macroscopic waste clearance in the CNS through cerebrospinal fluid (CSF)-interstitial fluid (ISF) exchange. Chronic spinal cord compression in CSM leads to pathophysiological consequences that theoretically affect the glymphatic system, and advanced dMRI may be well positioned to characterize these changes. This single-center study enrolled participants (control and CSM) from 2018 through 2020. All participants underwent clinical assessments and dMRI, followed by DTI and DBSI analyses, preoperatively and 2 years postoperatively. CSF flow was characterized by DTI-derived apparent diffusion coefficient (ADC) and ISF flow by DBSI-derived extra-axonal axial diffusivity (EA-AD) and radial diffusivity (EA-RD). Imaging parameters were compared among participants. Forty-two patients with CSM [23 (55%) mild, 9 (24%) moderate, 10 (21%) severe] and 20 control patients were included. Preoperatively, ADC was significantly lower in CSM (2.59±0.4µm 2 /ms) than control (3.08±0.34µm 2 /ms) patients ( P <0.01). Conversely, EA-AD and EA-RD were significantly higher in CSM (2.53±0.33; 0.48±0.13µm 2 /ms) compared with control (2.27±0.2; 0.40±0.04µm 2 /ms) patients (both P <0.01). Two years postoperatively, only EA-RD significantly decreased for CSM patients (Δ-0.04±0.12µm 2 /ms, P <0.01). More severe CSM preoperatively was associated with lower baseline ADC (ρ=0.49, P <0.001) and higher baseline EA-RD (ρ=-0.35, P =0.005). The pathophysiology of CSM may affect the glymphatic system because of chronic spinal cord compression that decreases CSF bulk flow, leading to compensatory increases in ISF flow. Although research in this topic remains nascent, greater glymphatic system function observed on dMRI may correspond with greater disease burden. Future studies examining the role of the glymphatic system in spinal cord pathology are critical to better understanding how these noninvasive imaging biomarkers can improve patient outcomes in CSM. Level II.

Background/Objectives: Autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and Tourette syndrome (TS) are neurodevelopmental disorders (NDDs) with overlapping symptoms, suggesting a partially shared genetic origin. This study investigates the prevalence of connective tissue-related conditions in individuals with ASD, ADHD, or TS. Methods: A questionnaire was administered to families of 120 individuals with ASD, ADHD, or TS, collecting sociodemographic data and examining 10 types of disorders affecting various organs and systems. Statistical analyses were performed using STATA 16.0, with the significance level set at 5%. Results: Among the 120 patients, 48 had ASD, 36 had ADHD, and 36 had TS. Flat feet were significantly more common in individuals with ASD (52.1%; OR 7.20; p < 0.001), ADHD (52.8%; OR 6.73; p = 0.001), and TS (38.9%; OR 3.70; p = 0.034) compared to controls (13.6%). Hypersensitivity was more frequent in individuals with ASD (56.3%; OR 5.90; p = 0.001), ADHD (50.0%; OR 4.11; p = 0.011), and TS (58.3%; OR 5.35; p = 0.003) compared to controls (18.2%). Myopia and ptosis were more common in ADHD (30.6%). There was a possible trend towards orthodontic device use in TS (OR 3.20; p = 0.076). Flat feet and hypersensitivity were also common in fathers (31.0% and 36.4%, respectively), mothers (31.0% and 15.2%), and patients (43.8% and 55%). Conclusions: The findings of this study highlight the significant associations between ASD, ADHD, and TS and specific physical symptoms, such as flat feet, sensory hypersensitivity, and other connective tissue-related manifestations. The familial prevalence of these symptoms suggests a potential genetic underpinning, further supporting the hypothesis of shared aetiological pathways. These insights underscore the need for interdisciplinary research to explore the mechanisms linking neurodevelopmental and connective tissue disorders, aiming to improve diagnosis and management strategies.

Objective:Autism Spectrum Disorders (ASD) and Attention Deficit Hyperactivity Disorder (ADHD) are neurodevelopmental disorders with overlapping symptomatology and shared genetic makeup. Numerous previous studies have investigated ASD and ADHD using resting state functional networks. One functional network of particular interest is the Default Mode Network (DMN), as it has been shown to be abnormal in several mental disorders. Previous studies have investigated the DMN in ASD and ADHD separately but reported mixed trends of increased and decreased functional connectivity (FC) in the DMN in ASD and increased FC in ADHD. Additionally, little studies have investigated executive and attentional network dysfunction in the DMN for ASD and ADHD populations. To better understand the shared characteristics between ASD and ADHD, this study analyzed the DMN FC in children with ASD and ADHD.Participants and Methods:Archival datasets from Autism Brain Imaging Data Exchange (ABIDE)-I and ADHD-200 datasets were used, with 33 ADHD, 35 ASD, and 32 typically developing (TD) males (ages = 7-17 years). After applying a standard pre-processing pipeline, 11 regions of interest (ROIs) from the Dosenbach-160 atlas were examined with 55 ROI pairs generated for the 100 subjects.Results:Significant differences were noted between ASD-ADHD groups in attentional networks and executive functioning networks. Specifically, significant Group x VIQ interactions were noted for FC between the following pairs of regions: medial prefrontal cortex - ventromedial prefrontal cortex, anterior cingulate cortex -ventromedial prefrontal cortex, inferior temporal lobe - ventromedial prefrontal cortex, angular -ventromedial prefrontal cortex, angular -anterior cingulate cortex, inferior temporal lobe -ventrolateral prefrontal cortex, angular -superior frontal lobe, and intraparietal sulcus -superior frontal lobe. In the above FC pairs, FC in ADHD was negatively correlated with VIQ, with no correlation for ASD and positive correlation for TD. Previous literature has indicated that ADHD individuals demonstrate increased executive functioning deficits compared to ASD individuals. This study provides evidence at a neural level for these findings by demonstrating decreased FC trends in ADHD in attentional and executive functioning networks compared to ASD individuals. Group and VIQ main effects demonstrated mixed patterns across the three groups, as well as shared decreased FC in attention/executive networks for both ASD and ADHD groups.Conclusions:In summary, this study found similar findings from previous studies regarding mixed connectivity patterns, as well as shared dysfunction between ASD and ADHD groups. These results help in solidifying the theory that ASD and ADHD share clinical and neural patterns which need to be examined further. Future directions include utilizing more ASD+ADHD comorbid individuals in studies comparing ASD and ADHD FC trends as well as seeking to further understand the neuropsychological and neuroimaging profiles in ASD and ADHD.

Modeling glymphatic system of the brain using MRI

The recently discovered glymphatic system (GS) ensures the efficient clearance of interstitial fluid and soluble compounds from the central nervous system into cerebrospinal fluid (CSF), which compensates for the lack of conventional lymphatic vessels in the brain parenchyma. This unique anatomical and physiological phenomenon had been unknown until 2012. GS lacks inherent proper vessels Р the current of CSF and interstitial fluid is carried out directly inside the arterial walls (the perivascular pathway) or near the walls of the cerebral arteries and veins (the paravascular pathway). Current biorheological technologies could establish a special role of aquaporin-4 in the filtration of CSF and interstitial fluid. The close link between GS and the CSF circulatory system allows the established views on fluid dynamics within the brain to be reconsidered. The discovery of GS can contribute to our understanding of the pathogenesis of increased intracranial pressure and neurodegenerative diseases, as well as to the elaboration of new therapeutic approaches to their treatment.

The glymphatic system is a fluid-transport system that accesses all regions of the brain. It facilitates the exchange of cerebrospinal fluid and interstitial fluid and clears waste from the metabolically active brain. Astrocytic endfeet and their dense expression of the aquaporin-4 water channels promote fluid exchange between the perivascular spaces and the neuropil. Cerebrospinal and interstitial fluids are together transported back to the vascular compartment by meningeal and cervical lymphatic vessels. Multiple lines of work show that neurological diseases in general impair glymphatic fluid transport. Insofar as the glymphatic system plays a pseudo-lymphatic role in the central nervous system, it is poised to play a role in neuroinflammation. In this review, we discuss how the association of the glymphatic system with the meningeal lymphatic vessel calls for a renewal of established concepts on the CNS as an immune-privileged site. We also discuss potential approaches to target the glymphatic system to combat neuroinflammation.

The potential existence and roles of the meningeal lymphatic system in normal and pathological brain function have been a long-standing enigma. Recent evidence suggests that meningeal lymphatic vessels are present in both the mouse and human brain; in mice, they seem to play a role in clearing toxic amyloid-beta peptides, which have been connected with Alzheimer disease (AD). Here, we review the evidence linking the meningeal lymphatic system with human AD. Novel findings suggest that the recently described meningeal lymphatic vessels could be linked to, and possibly drain, the efferent paravascular glial lymphatic (glymphatic) system carrying cerebrospinal fluid, after solute and immune cell exchange with brain interstitial fluid. In so doing, the glymphatic system could contribute to the export of toxic solutes and immune cells from the brain (an exported fluid we wish to describe as glymph, similarly to lymph) to the meningeal lymphatic system; the latter, by being connected with downstream anatomic regions, carries the glymph to the conventional cervical lymphatic vessels and nodes. Thus, abnormal function in the meningeal lymphatic system could, in theory, lead to the accumulation, in the brain, of amyloid-beta, cellular debris, and inflammatory mediators, as well as immune cells, resulting in damage of the brain parenchyma and, in turn, cognitive and other neurologic dysfunctions. In addition, we provide novel insights into APOE4—the leading genetic risk factor for AD—and its relation to the meningeal lymphatic system. In this regard, we have reanalyzed previously published RNA-Seq data to show that induced pluripotent stem cells (iPSCs) carrying the APOE4 allele (either as APOE4 knock-in or stemming from APOE4 patients) express lower levels of (a) genes associated with lymphatic markers, and (b) genes for which well-characterized missense mutations have been linked to peripheral lymphedema. Taking into account this evidence, we propose a new conceptual framework, according to which APOE4 could play a novel role in the premature shrinkage of meningeal lymphatic vessels (meningeal lymphosclerosis), leading to abnormal meningeal lymphatic functions (meningeal lymphedema), and, in turn, reduction in the clearance of amyloid-beta and other macromolecules and inflammatory mediators, as well as immune cells, from the brain, exacerbation of AD manifestations, and progression of the disease. Altogether, these findings and their potential interpretations may herald novel diagnostic tools and therapeutic approaches in patients with AD.

Cerebral glymphatic system: Structure, regulation, ageing, and mechanisms of encephalopathy.

The glymphatic system, a perivascular network responsible for the exchange of cerebrospinal (CSF) and interstitial (ISR) fluids, plays a critical role in the clearance of metabolic wastes, particularly neurotoxic proteins such as β-amyloid and microtubule-associated protein tau (MAPT). Disruption of its function is commonly associated with neurodegenerative diseases, including Alzheimer's disease. However, ethanol (C₂H₅OH), a widespread neurotoxic substance, has also been shown to cause profound structural and functional changes in the central nervous system (CNS); in particular, its effect on the glymphatic system cannot be ruled out, which is still poorly understood. This review examines ethanol-induced morpho-histological changes in the glymphatic pathways, focusing on astrocyte integrity, aquaporin-4 (AQP4) mislocalization, perivascular inflammation, and vascular dysfunction. A systematic review of available studies shows that ethanol consumption leads to redistribution of AQP4 away from perivascular astrocytic endings, impairing glymphatic flow and reducing the efficiency of waste clearance. Thus, histopathologic evidence suggests ethanol-induced gliosis (pathologic overgrowth of glial cells in the CNS), neuroinflammation, and oxidative stress further exacerbate glymphatic dysfunction. In addition, ethanol disrupts basic mechanisms of sleep, which in turn as a process is a critical regulator of glymphatic activity; thereby exacerbating the adverse effects on CNS homeostasis. These mechanisms suggest a potential link between chronic ethanol exposure and accelerated progression of neurodegenerative diseases associated with glymphatic dysfunction. Despite the accumulating evidence of ethanol's neurotoxicity, studies directly addressing its effects on the glymphatic system at the tissue-cellular level remain scarce. Future research, which is extremely promising, should focus on elucidating the reversibility of ethanol-induced glymphatic disturbances and identifying potential pharmacological and behavioral interventions to mitigate their effects. Understanding these interrelationships of these processes, as well as their overall analysis and awareness, is necessary for the development of targeted neuroprotective strategies, especially in populations with chronic alcohol use.