Glymphatic Function and White Matter Integrity in Cerebral Venous Disorders

Glymphatic Function and White Matter Integrity in Cerebral Venous Disorders: A Prospective Cohort Study

Cerebral venous disorders, including cerebral venous sinus stenosis (CVSS) and cerebral venous sinus thrombosis (CVST), can obstruct venous blood drainage, leading to intracranial hypertension. However, their effects on glymphatic function and white matter integrity in the brain remain poorly understood.

Therefore, this study will enroll healthy controls, CVSS patients, and CVST patients to compare differences in glymphatic function and white matter microstructural integrity. Additionally, CVSS and CVST patients will undergo a 3-month follow-up to investigate the interrelationships and longitudinal changes among clinical parameters, glymphatic function, and white matter integrity.

Previously, researchers widely believed that the brain lacked a dedicated lymphatic system for clearing metabolic byproducts and wastes. However, recent studies have confirmed the existence of the glymphatic system along perivascular spaces (PVS), which plays a crucial role in metabolic waste clearance, nutrient and neuroactive substance exchange, regulation of central immune responses, and maintenance of cerebral fluid homeostasis. Emerging evidence suggests that dilated draining veins, elevated venous pressure, and increased intracranial pressure may impede glymphatic flow. Consequently, downstream venous pressure alterations-such as local stenosis or thrombosis in cerebral venous sinuses and/or internal jugular veins-could affect parenchymal venule pressure and volume, thereby influencing glymphatic system dynamics.

Preserved myelin integrity is essential for maintaining synchronized and efficient interregional neural communication. Demyelination compromises brain network integration. Diffusion tensor imaging (DTI), an advanced magnetic resonance imaging (MRI) technique for assessing white matter microstructure, can sensitively detect integrity changes. Our preliminary studies identified characteristic bilateral symmetrical cloudy white matter alterations in patients with cerebral venous sinus stenosis, predominantly in periventricular and centrum semiovale regions. However, the precise pathological mechanism remains unclear, and direct evidence linking these changes to chronic venous outflow obstruction is lacking. Although similar imaging findings have not been reported in cerebral venous thrombosis patients, DTI may reveal early microstructural damage, suggesting potential pathological connections.

White matter tracts serve not only as anatomical pathways for glymphatic flow but also depend on glymphatic clearance for metabolic homeostasis. This establishes a bidirectional regulatory relationship: glymphatic dysfunction may induce white matter injury, while white matter lesions could exacerbate glymphatic obstruction. Research indicates that glymphatic impairment may closely correlate with declining white matter integrity, with both potentially forming a mutually reinforcing feedback loop in disease progression across multiple pathologies.

Therefore, this prospective cohort study aims to systematically evaluate glymphatic function and white matter integrity in cerebral venous diseases (including cerebral venous sinus stenosis and thrombosis), further exploring multidimensional correlations among clinical parameters, glymphatic activity, and white matter integrity. The findings may elucidate potential mechanisms of venous-related neural injury.

1. Subjects with Cerebral Venous Sinus Stenosis

   Inclusion Criteria:

   • Age ≥18 years, any gender;
   • Definite diagnosis of cerebral venous sinus stenosis confirmed by clinical and imaging examinations;
   • Stenosis limited to the transverse sinus and/or sigmoid sinus, presenting as moderate to severe localized stenosis or occlusion (stenosis degree ≥50%), with or without internal jugular vein stenosis;
   • The subject or their legal representative signs a written informed consent form.

   Exclusion Criteria:

   • Simple anatomical variation or physiological narrowing of the cerebral venous sinus/internal jugular vein without definitive evidence of localized stenosis;
   • Complicated by cerebral venous sinus/cortical vein/internal jugular vein thrombosis;
   • Prior receipt of endovascular treatment for cerebral venous sinus/internal jugular vein, ventricular puncture drainage, or lumbar cistern drainage before enrollment;
   • Presence of moderate to severe stenosis (≥50%) in intracranial or extracranial arteries;
   • History of cerebral infarction, cerebral hemorrhage, or neurosurgery;
   • Complicated by other neurological structural abnormalities such as cerebral small vessel disease, intracranial vascular malformation, dural arteriovenous fistula, intracranial infection, intracranial space-occupying lesion, severe cerebral atrophy, or hydrocephalus;
   • Presence of other diseases affecting glymphatic function (e.g., multiple sclerosis, neuromyelitis optica spectrum disorders, systemic lupus erythematosus, obstructive sleep apnea-hypopnea syndrome, Parkinson's disease, or Alzheimer's disease);
   • Contraindications to MRI (e.g., metal implants, claustrophobia, etc.) or allergy to gadolinium-based contrast agents;
   • Other conditions deemed unsuitable for enrollment by the investigator.

2. Subjects with Cerebral Venous Sinus Thrombosis

   Inclusion Criteria:

   • Age ≥18 years, any gender;
   • Definite diagnosis of acute or subacute phase (onset to diagnosis ≤28 days) cerebral venous sinus thrombosis, with or without internal jugular vein thrombosis, confirmed by clinical and imaging examinations;
   • The subject or their legal representative signs a written informed consent form.

   Exclusion Criteria:

   • Isolated cortical vein thrombosis or isolated cavernous sinus thrombosis;
   • Recurrent intracranial venous sinus thrombosis;
   • Complicated by venous cerebral infarction;
   • Prior receipt of endovascular treatment for cerebral venous sinus/internal jugular vein, ventricular puncture drainage, or lumbar cistern drainage before enrollment;
   • Presence of moderate to severe stenosis (≥50%) in intracranial or extracranial arteries;
   • History of cerebral infarction, cerebral hemorrhage, or neurosurgery;
   • Complicated by other neurological structural abnormalities such as cerebral small vessel disease, intracranial vascular malformation, dural arteriovenous fistula, intracranial infection, intracranial space-occupying lesion, severe cerebral atrophy, or hydrocephalus;
   • Presence of other diseases affecting glymphatic function (e.g., multiple sclerosis, neuromyelitis optica spectrum disorders, systemic lupus erythematosus, obstructive sleep apnea-hypopnea syndrome, Parkinson's disease, or Alzheimer's disease);
   • Presence of severe impaired consciousness, hearing impairment, or aphasia preventing cooperation with examinations or assessments;
   • Contraindications to MRI (e.g., metal implants, claustrophobia, etc.) or allergy to gadolinium-based contrast agents;
   • Other conditions deemed unsuitable for enrollment by the investigator.

3. Healthy Control Subjects:

Inclusion Criteria:

• Gender and age-matched;
• No central nervous system diseases;
• Normal scores on the HAMD-24, HAMA-14, MMSE, MoCA, and PSQI scales;
• No cerebral venous sinus thrombosis, cerebral venous sinus stenosis, or moderate to severe intracranial/extracranial arterial stenosis;
• No contraindications to MRI (e.g., metal implants, claustrophobia, etc.);
• The subject or their legal representative signs a written informed consent form.