Age-dependent brain responses to mechanical stress determine resilience in a chronic lymphatic drainage impairment model

The outflow of ‘dirty’ brain fluids from the glymphatic system drains via the meningeal lymphatic vessels to the lymph nodes in the neck, primarily the deep cervical lymph nodes (dcLN). However, it is unclear whether dcLN drainage is essential for normal cerebral homeostasis. Using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and computational fluid dynamics, we studied the impact of long-term mechanical stress from compromised dcLN drainage on brain solute and fluid outflow in anesthetized rats. We found that in young, but not middle-aged, rats, impairment of dcLN drainage was linked to moderately increased intracranial pressure and the emergence of extracranial perivenous drainage, with no evidence of hydrocephalus at any age. Surprisingly, both age groups showed enhanced brain solute clearance despite reduced glymphatic influx. CSF proteomic analysis revealed cellular stress in the form of low-grade inflammation and upregulation of pathways associated with neurodegeneration and blood brain barrier leakage in the rats with impaired lymphatic drainage. Our findings highlight that dcLN drainage is indeed a prerequisite for normal cerebral homeostasis in the rat and reveal the brain’s age-dependent compensatory responses to chronic impairment of its lymphatic drainage pathways.