Glymphatic System Dysfunction in Central Nervous System Diseases
Zahran A; Abu-Khazneh O; Bdair M; Hajjeh O; AbuBaha M; Shehadeh W; Awashra A; Alazizi I; Fuqha R; Saife S; Fuqha H; Milhem F; Hamshary H; Abuzahra D; Shuaib U
CNS Neuroscience & Therapeutics2026-03-06
Summary (paraphrased)
This 2026 review synthesizes mechanistic and clinical evidence for glymphatic impairment across acute brain injury and chronic neurological disorders (including Alzheimer's, Parkinson's, small-vessel disease, and multiple sclerosis). It organizes dysfunction into five mechanisms: AQP4 depolarization at astrocytic endfeet, perivascular-space compression or obstruction, loss of arterial pulsatility and vascular stiffening, blood–brain barrier disruption with neuroinflammation, and sleep/autonomic dysregulation (altered noradrenergic tone). The authors note emerging clinical probes of glymphatic function (DTI-ALPS, contrast MRI, enlarged perivascular spaces), their associations with cognition and mood, and translational strategies — sleep and circadian optimization, vascular risk control, anti-inflammatory approaches, AQP4/TRPV4 targets, and neuromodulation.
Why it’s in the systems review
The most current synthesis available, and the axis's only record that links glymphatic dysfunction explicitly to mood and cognition outcomes — the two symptom domains (brain fog, anhedonia) the axis is meant to explain. It also catalogues the measurable biomarkers (DTI-ALPS, enlarged perivascular spaces) and the clearance-restoring strategy space, giving the corpus both a way to test the brain-clearance hypothesis in post-drug patients and a set of mechanistically grounded treatment-candidate directions to track. It closes the axis from discovery (Iliff, Xie) through mechanism (Mogensen) to clinical translation.