The role of glymphatic system in idiopathic intracranial hypertension: a longitudinal DTI-ALPS study and scoping review

Backgound: Idiopathic Intracranial Hypertension (IIH) is a chronic condition characterized by elevated intracranial pressure in the absence of secondary causes. Although its pathophysiology remains multifactorial and only partially understood, emerging evidence suggests a possible involvement of the glymphatic system, a perivascular clearance network responsible for cerebrospinal fluid (CSF) circulation and metabolic waste removal. Objective: The aim of this PhD project was to investigate in vivo glymphatic function in IIH patients using Diffusion Tensor Image – Analysis Along the Perivascular Space (DTIALPS), a non-invasive MRI-based index reflecting perivascular water diffusivity. The study employed a longitudinal pre- and post-CSF drainage design, enrolling 15 patients with confirmed IIH and a group of age- and sex-matched healthy controls. Results: Results showed slightly higher DTI-ALPS values in IIH patients compared with controls, with no significant change following CSF removal. Multiple regression analyses revealed that lower ALPS indices were associated with chronic headache, venous sinus stenosis, and optic nerve sheath distension, suggesting a link between venous outflow alterations and perivascular microdynamics. Overall, glymphatic function did not appear globally impaired but may reflect compensatory mechanisms to intracranial pressure fluctuations. In parallel, a systematic scoping review of 135 studies employing the DTI-ALPS method across neurological disorders was conducted. The review highlighted the rapid expansion of ALPS-related research, but also significant methodological heterogeneity, limited integration with other imaging biomarkers, and a lack of physiological validation studies. Conclusions:Taken together, these findings emphasize both the potential and the current limitations of the DTI-ALPS technique in assessing CSF-related dynamics. The results advocate for standardized protocols and multimodal approaches to clarify the physiological meaning and translational applicability of this promising, yet still evolving, neuroimaging marker.