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

Ying Zhou1, Rui Xue1, Yifei Li1

  • 1Department of Neurology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|May 5, 2024
PubMed

Insights

White matter hyperintensity (WMH) is linked to cognitive decline. Impaired lymphatic drainage exacerbates WMH, but enhancing meningeal lymphangiogenesis may offer a new treatment strategy.

Area of Science:

  • Neuroscience
  • Vascular Biology
  • Immunology

Background:

  • White matter hyperintensity (WMH) is a significant concern associated with cognitive decline and dementia.
  • The precise mechanisms driving WMH progression remain largely unknown.
  • Dysfunction in brain clearance pathways, including meningeal lymphatics and the glymphatic system, is implicated.

Purpose of the Study:

  • To investigate the relationship between WMH burden and the function of meningeal lymphatic vessels (mLVs) and the glymphatic pathway.
  • To explore the role of lymphangiogenesis and glymphatic drainage in WMH pathogenesis using a rat model.
  • To evaluate the therapeutic potential of modulating mLVs for WMH treatment.

Main Methods:

  • Human studies correlating WMH burden with mLV and glymphatic drainage.
  • Longitudinal cohort analysis of glymphatic function and WMH progression.
  • Rat model of WMH to assess lymphangiogenesis, glymphatic drainage, microglial activation, and demyelination.
  • Intervention using adeno-associated virus (AAV)-mediated VEGF-C delivery to enhance mLVs.
  • VEGF-C trap strategy to inhibit mLV growth.

Main Results:

  • High WMH burden in humans is associated with delayed mLV and glymphatic drainage.
  • Glymphatic dysfunction predicts future WMH progression.
  • WMH model in rats showed impaired lymphangiogenesis, reduced glymphatic drainage, increased microglial activation, and demyelination.
  • Enhancing mLVs with AAV-VEGF-C reduced gliosis and demyelination.
  • Inhibiting mLVs exacerbated WMH pathology.

Conclusions:

  • Dysfunction of mLVs and the glymphatic pathway plays a crucial role in the progression of brain white matter injury.
  • Modulating meningeal lymphangiogenesis presents a promising therapeutic avenue for preventing and treating WMH.
Keywords:
glymphatic pathwaymeningeal lymphaticsneuroinflammationwhite matter hyperintensity

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