Glymphatic System Dysfunction in Autism Spectrum Disorder: Neuroinflammation, Metabolic Clearance Rate, and Clinical Severity

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by persistent deficits in social interaction, communication impairments, and repetitive behaviors.Despite extensive research, the underlying pathophysiological mechanisms of ASD remain incompletely understood.Recent evidence suggests that glymphatic system dysfunction plays a critical role in ASD by impairing the clearance of metabolic waste, exacerbating neuroinflammation, and disrupting neural homeostasis.The glymphatic system, a macroscopic waste removal pathway in the central nervous system, facilitates cerebrospinal fluid (CSF)-interstitial fluid (ISF) exchange and relies on aquaporin-4 (AQP4) channels for optimal function.Dysfunction of this system has been linked to increased accumulation of neurotoxic metabolites, such as lactate, glutamate, and reactive oxygen species, which contribute to oxidative stress and neuronal dysregulation in ASD.Neuroinflammation, a hallmark of ASD, is aggravated by glymphatic impairment, leading to elevated levels of pro-inflammatory cytokines, microglial activation, and astrocyte dysfunction.Sleep disturbances commonly observed in ASD further compromise glymphatic clearance, creating a self-perpetuating cycle of metabolic imbalance and inflammation.Genetic factors, environmental influences, and glucocorticoid dysregulation have also been implicated in glymphatic dysfunction in ASD, highlighting the complexity of its pathophysiology.This review synthesizes current findings on the glymphatic system's involvement in ASD, discusses potential biomarkers of glymphatic dysfunction, and explores emerging therapeutic strategies to enhance glymphatic clearance.Understanding the interplay between glymphatic function and ASD pathogenesis may provide novel insights into targeted interventions, paving the way for improved diagnosis, treatment, and long-term outcomes for affected individuals.