Translational imaging evidence for rapid reversal of amyloid and myelin pathology following deep cervical lymphatic-venous anastomosis in Alzheimer's disease.

BACKGROUND: Recently, microsurgical restoration of extracranial lymphatic outflow through lymphatic-venous anastomosis (LVA) has been explored as a potential, albeit controversial, therapeutic strategy to enhance glymphatic clearance in Alzheimer's disease (AD); however, its impact on AD-related neuropathology has not yet been quantitatively or longitudinally evaluated. In this study, we performed translational PET imaging to determine whether restoring extracranial lymphatic outflow can rapidly and reversibly modulate cerebral glucose metabolism, myelin integrity, and amyloid burden in relation to cognitive improvement. METHODS: A cervical lymphatic obstruction model was established in rats, followed by longitudinal [18F]FDG-PET and [11C]MeDAS-PET to assess cerebral glucose metabolism and myelin integrity before and after LVA, with imaging findings further validated by immunohistochemistry. A cohort of eight AD patients underwent LVA and received [11C]PIB and [11C]MeDAS PET imaging at baseline and follow-up. The imaging results were correlated with cognitive performance. RESULTS: In Sprague-Dawley rats, cervical lymphatic obstruction led to significantly elevated cerebral glucose metabolism and reduced myelin integrity, both of which were largely restored to near-normal levels following LVA treatment, as further validated by immunohistochemical analyses. Similarly, in AD patients, LVA produced a 36.0 ± 2.1% decrease in cortical amyloid burden on [11C]PIB-PET (p < 0.001) and a 59.8 ± 29.0% increase in [11C]MeDAS uptake (p = 0.005). Subsequent correlation with MMSE scores demonstrated that short-term cognitive improvement was associated with greater myelin restoration and greater amyloid reduction. CONCLUSION: These preliminary findings provide initial evidence that restoration of extracranial lymphatic outflow may modulate core neuropathological processes in AD, justifying further investigation in larger cohorts with appropriate control groups and randomized controlled designs to validate and extend these observations. TRIAL REGISTRATION: The study was registered on the Chinese Clinical Trial website on April 21, 2025 (Registration No. ChiCTR2500101149).