The overall goal of this work is to investigate lymphatic vascular mechanisms of tissue sodium handling using novel, noninvasive imaging tools sensitive to sodium and lymphatics in patients with well-characterized lymphatic disease. Findings are intended to inform mechanisms of lymphatic clearance of tissue sodium, and provide novel imaging biomarkers of lymphedema progression and treatment response. Recent evidence supports that lymphatics regulate interstitial sodium levels. When lymphatic clearance is impaired, hypertonic interstitial sodium results in tissue swelling, skin sodium storage, and poor blood pressure control. When lymphatic clearance is impaired in rodent models of lymphedema, lymph stasis and inflammation ensues, leading to tissue remodeling and fibrosis. These data suggest, but do not confirm, that impaired lymphatic clearance contributes to tissue sodium storage and fibrosis. However, this possibility has not been investigated rigorously owing to a lack of clinically-feasible measurement tools sensitive to sodium and lymphatics in humans. To address this need, we have developed noninvasive, in vivo MRI approaches to quantify lymphatic vasculature and dynamics, and interstitial measures of tissue sodium content. We have applied a subset of these methods (i) in patients with unilateral upper-extremity lymphedema and we confirmed lateralized lymph stasis and enlarged lymphatic collector cross-sectional area that reduced following manual lymphatic drainage therapy, and (ii) in patients with lower-extremity lymphatic impairment in whom we reported significantly elevated sodium in the skin and subcutaneous tissue, compared to age-, BMI-, and race-matched controls. In preliminary data presented here, we show that in patients with advanced lower-extremity lymphedema and fibrosis, sodium-rich tissue co-localizes with subcutaneous fibrosis, and tissue sodium reduces following complete decongestive therapy (CDT). Here, we will extend this work to test fundamental hypotheses regarding sodium storage, lymphatic dysfunction, and lymphatic mobilization therapy. Hypothesis (1): In patients at-risk for secondary lymphedema, tissue sodium content (TSC) is elevated and inversely correlates with lymphatic flow velocity. Hypothesis (2): Skin TSC positively correlates with lymphedema stage; deep subcutaneous sodium co-localizes with fibrotic tissue in patients with lymphedema and fibrosis. Hypothesis (3): TSC decreases and lymphatic flow velocity increases after a course of CDT in affected limbs with lymphedema; imaging metrics do not change in a similar time-period in healthy volunteers. Impact: Results will confirm how TSC relates to lymphatic dysfunction, and specifically whether TSC can be reduced by manual stimulation of lymphatic channels. This will motivate early intervention as a candidate treatment for reducing fibrosis onset, but more broadly will outline clinically-feasible biomarkers of intervention response which could have significance...