Introduction

Stroke is the second leading cause of death globally, with ischemic stroke (IS) comprising the vast majority1. In China, IS, accounting for about 69.6% of stroke cases2. Due to the high prevalence of morbidity and mortality after stroke, numerous studies primarily focused on therapies at ultra-early stage, such as thrombolysis, thrombectomy, and neuroprotective therapy. Despite efforts, still about 50% patients encounter reperfusion injury3, and face the significant challenge of unreversible motor dysfunction and potential cognitive decline.

The glymphatic system, a recently identified mechanism responsible for clearing waste from the nervous system, offers valuable insights into stroke recovery. This system operates by facilitating the exchange of cerebrospinal fluid (CSF) and interstitial fluid (ISF) through perivascular pathways, such as para-arterial influx channels, para-venous efflux channels, and astrocyte-mediated connections4. Previous studies have shown that glymphatic system dysfunction exacerbates brain edema in the early stages of IS. Metrics like CSF Influx and AQP4 polarization indicate impaired glymphatic function post-stroke, correlating with increased edema5,6. While these metrics start to recover around 7 days post-stroke and are linked to motor recovery at 3 months7, the dynamics of glymphatic function during stroke recovery and its impact on long-term cognitive outcomes, especially post-stroke cognitive impairment (PSCI), remain unclear.

Advances in neuroimaging permit non-invasive assessment of glymphatic system in stroke patients in clinical practice. To evaluate dynamics of glymphatic function during stroke recovery, we employed three non-invasive imaging markers for reflecting distinct aspects of the glymphatic system. First, choroid plexus (CP) volume is a hydrodynamic regulator propelling CSF-ISF exchange. Second, enlarged perivascular spaces (PVS), an established proxy for glymphatic stagnation, serve as structural indicators of impaired interstitial waste clearance, where severe PVS dilation correlates with glymphatic dysfunction8. Third, Diffusion Tensor Imaging Analysis along the Perivascular Space (DTI-ALPS) method, initially proposed by Taoka et al.9, quantifies the diffusion of water within PVS along deep medullary veins and has robust correlations with glymphatic clearance, as determined by dynamic contrast-enhanced imaging10. Emerging translational evidence highlights the clinical utility of these biomarkers in stroke populations. Jianming et al. have reported that the choroid plexus work as a site of damage in hemorrhagic and ischemic stroke11. PVS burden was also reported as a biomarker of neuropathological condition12. As for DTI-ALPS index, a recent clinical study has demonstrated that acute-phase DTI-ALPS reductions predict critical pathological cascades7. Importantly, preliminary longitudinal data suggest a potentially recovery of DTI-ALPS index during the subacute phase post-stroke. However, critical gaps persist regarding long-term glymphatic function: existing studies predominantly focus on acute-phase dysfunction, leaving the chronic-stage recovery patterns and their cognitive implications unexplored. Notably, no prior investigation has systematically examined whether glymphatic function, as captured by DTI-ALPS index, PVS or CP volume, modulates the risk of PSCI.

In this study, we evaluate the performance and change of glymphatic system, and its association with stroke outcome. We hypothesize that post-stroke glymphatic dysfunction exhibits time-dependent recovery patterns, and that this recovery correlates with stroke outcome. We aime to: (1) characterize the longitudinal evolution of DTI-ALPS indices, PVS burden, and CP volumes from subacute to chronic phases post-stroke; and (2) determine whether these biomarkers predict functional outcome and PSCI at 6-month follow-up.

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