Cervical lymphadenectomy impairs brain lymphatic clearance and synaptic proteostasis.

Meningeal lymphatic vessels drain brain fluid and waste into the cervical lymph nodes, but how removing these nodes during surgery affects brain health is unknown. Retrospective analysis of cancer patients who underwent neck lymphadenectomy without chemo-radiation therapy found that up to 25% developed mild-to-severe cognitive impairment, and neuroimaging showed accelerated temporal horn enlargement after bilateral surgery. To determine mechanistically how cervical lymphadenectomy contributes to cognitive impairment, mouse and rat models were utilized to phenocopy abrupt disruption of lymphatic flow to the cervical and submandibular nodes. Impaired lymphatic drainage induced a cerebrospinal fluid signature of metabolic stress and inflammation. In the hippocampus, redox stress drove oxidative posttranslational protein modifications and microaggregation with biochemical, molecular, and structural features distinct from amyloid aggregates in Alzheimer's models. Such changes were absent when lymphatic drainage was gradually reduced. The data link cognitive impairment following acute neck lymphadenectomy with the biochemical consequences of impaired metabolic waste clearance.