Impaired Meningeal Lymphatics and Glymphatic Pathway in Patients with White Matter Hyperintensity

Adv Sci (Weinh). 2024 Jul;11(26):e2402059. doi: 10.1002/advs.202402059. Epub 2024 May 5.

Abstract

White matter hyperintensity (WMH) represents a critical global medical concern linked to cognitive decline and dementia, yet its underlying mechanisms remain poorly understood. Here, humans are directly demonstrated that high WMH burden correlates with delayed drainage of meningeal lymphatic vessels (mLVs) and glymphatic pathway. Additionally, a longitudinal cohort study reveals that glymphatic dysfunction predicts WMH progression. Next, in a rat model of WMH, the presence of impaired lymphangiogenesis and glymphatic drainage is confirmed, followed by elevated microglial activation and white matter demyelination. Notably, enhancing meningeal lymphangiogenesis through adeno-associated virus delivery of vascular endothelial growth factor-C (VEGF-C) mitigates microglial gliosis and white matter demyelination. Conversely, blocking the growth of mLVs with a VEGF-C trap strategy exacerbates these changes. The findings highlight the role of mLVs and glymphatic pathway dysfunction in aggravating brain white matter injury, providing a potential novel strategy for WMH prevention and treatment.

Keywords: glymphatic pathway; meningeal lymphatics; neuroinflammation; white matter hyperintensity.

MeSH terms

  • Aged
  • Animals
  • Disease Models, Animal
  • Female
  • Glymphatic System* / metabolism
  • Humans
  • Longitudinal Studies
  • Lymphatic Vessels / metabolism
  • Magnetic Resonance Imaging / methods
  • Male
  • Meninges* / metabolism
  • Rats
  • White Matter* / metabolism
  • White Matter* / pathology