Cervical Lymphatic Bypass Reduces Nodal Resistance And Restores CSF Clearance: A Preclinical Model

Purpose: It has been hypothesized that deep cervical lymph node (dcLN) dysfunction directly contributes to impaired glymphatic clearance and accumulation of neurotoxic waste in Alzheimer's disease (AD). We hypothesized that vascular diversion or bypass of the dcLN would reduce lymphatic resistance and improve central nervous system (CNS) waste clearance. To test this hypothesis, we established a preclinical model of cervical lymphatic bypass in aged mice to evaluate its impact on brain and systemic fluid dynamics. Methods: Aged C57BL/6J mice (18-24 months) underwent cervical lymphatic bypass to divert afferent lymphatic flow around the dcLN, modeling a translational approach to cervical lymphovenous anastomosis (LVA). Sham-operated animals served as controls. Four weeks post-surgery, bypass patency and vascular outgrowth were assessed using near-infrared imaging of Prox1-eGFP mice and intracisternal tracer delivery (DB53 and 3 kDa dextran). CSF-to-blood efflux was quantified by femoral vein fluorescence imaging. Upstream glymphatic clearance was evaluated by quantifying CSF tracer distribution to the brain surface and parenchyma. Global CSF dynamics were assessed by measuring CSF production via lateral ventricle cannulation, outflow resistance by constant-rate CSF infusion, and intracranial pressure (ICP). Results: Four weeks after bypass, we observed robust outgrowth of bypass vasculature capable of diverting CSF around the dcLN. Intracisternal injection of DB53 tracer showed significantly increased tracer levels in peripheral blood, indicating enhanced lymphatic efflux. These findings demonstrate that dcLN dysfunction directly contributes to impaired CSF clearance and that bypass restores both flow and transport capacity. Importantly, bypass restored both upstream glymphatic influx and downstream CSF outflow, as shown by enhanced femoral vein tracer signal and redistribution of CSF tracer to meningeal, basal skull, and nasal efflux pathways. This was accompanied by a significant reduction in CSF outflow resistance (p < 0.05), increased CSF production (p < 0.05), and preserved ICP (Fig 1). We also observed early signs of adaptive remodeling in meningeal lymphatic vessel structure, including increased vessel diameter, consistent with flow-responsive plasticity. Behaviorally, bypassed mice exhibited preserved motor and social performance with significant improvement in recognition memory (p < 0.05) (Fig 2). Conclusion: These results establish surgical lymphatic bypass of the dcLN as a viable approach to restore CNS fluid homeostasis in a mouse model. This work provides a mechanistic and physiologic basis for translational application of cervical LVA in humans as a disease-modifying intervention for AD. This study provides proof-of-concept evidence supporting the translational potential of afferent cervical lymphatic bypass as a disease-modifying intervention for Alzheimer's disease. Our findings support future clinical studies utilizing image-guided selection of dysfunctional nodes as surgical targets for bypass-based restoration of cervical lymphatic clearance. *Source: https://ps-rc.org/meeting/Program/2026/08.cgi*