MRI-Based ALPS Index as a Biomarker of Glymphatic Dysfunction and Prognosis After Aneurysmal Subarachnoid Hemorrhage

The clinical relevance of glymphatic dysfunction in patients with subarachnoid hemorrhage (SAH) remains unclear. This study aimed to evaluate glymphatic system function in patients with aneurysmal SAH using the diffusion tensor imaging-based analysis along the perivascular space (ALPS) index and to investigate its association with the development of hydrocephalus and clinical outcomes. In particular, we explored whether hydrocephalus could act as a potential mediator of the relationship between glymphatic dysfunction and poor functional outcome.

We retrospectively analyzed 60 patients with aneurysmal SAH who underwent magnetic resonance imaging, including diffusion tensor imaging, at a median of 18 days after onset. The ALPS index was calculated from directional diffusivity values in the deep white matter, and its relationship with 3-month functional outcomes (modified Rankin Scale) and shunt-dependent hydrocephalus was examined. A logistic regression-based causal mediation analysis was performed to assess whether hydrocephalus statistically mediated the association between a low ALPS index (<1) and poor outcome (modified Rankin Scale score ≥3).

The ALPS index was significantly lower in patients with poor outcomes (median [interquartile range], 1.09 [0.91-1.17]) than in those with favorable outcomes (1.29 [1.16-1.44]; P=0.0002). Shunt-dependent hydrocephalus occurred more frequently in the poor outcome group and was associated with a markedly reduced ALPS index (median, 0.99). Mediation analysis with covariates including age and World Federation of Neurosurgical Societies grade revealed that the total effect of a low ALPS index on poor outcome was significant (odds ratio, 7.98 [95% CI, 1.12-56.79]), and this effect was largely mediated by hydrocephalus development (indirect effect odds ratio, 3.11 [95% CI, 1.23-7.89]; proportion mediated=0.78).

Reduced ALPS index, which may reflect impaired glymphatic transport, was associated with poor functional outcomes in patients with aneurysmal SAH. This relationship appeared to be largely mediated by the presence of shunt-dependent hydrocephalus. Although causality cannot be established in this observational study, these findings suggest that glymphatic dysfunction may play a clinically relevant role in the pathophysiology of SAH-related hydrocephalus and outcome.