title: Power Doppler ultrasound phenotyping of expanding versus collapsed popliteal lymph nodes in murine inflammatory arthritis.
abstract: Rheumatoid arthritis is a chronic inflammatory disease manifested by episodic flares in affected joints that are challenging to predict and treat. Longitudinal contrast enhanced-MRI (CE-MRI) of inflammatory arthritis in tumor necrosis factor-transgenic (TNF-Tg) mice has demonstrated that popliteal lymph nodes (PLN) increase in volume and contrast enhancement during the pre-arthritic "expanding" phase of the disease, and then suddenly "collapse" during knee flare. Given the potential of this biomarker of arthritic flare, we aimed to develop a more cost-effective means of phenotyping PLN using ultrasound (US) imaging. Initially we attempted to recapitulate CE-MRI of PLN with subcutaneous footpad injection of US microbubbles (DEFINITY®). While this approach allowed for phenotyping via quantification of lymphatic sinuses in PLN, which showed a dramatic decrease in collapsed PLN versus expanding or wild-type (WT) PLN, electron microscopy demonstrated that DEFINITY® injection also resulted in destruction of the lymphatic vessels afferent to the PLN. In contrast, Power Doppler (PD) US is innocuous to and efficiently quantifies blood flow within PLN of WT and TNF-Tg mice. PD-US demonstrated that expanding PLN have a significantly higher normalized PD volume (NPDV) versus collapsed PLN (0.553 ± 0.007 vs. 0.008 ± 0.003; p<0.05). Moreover, we define the upper (>0.030) and lower (<0.016) quartile NPDVs in this cohort of mice, which serve as conservative thresholds to phenotype PLN as expanding and collapsed, respectively. Interestingly, of the 12 PLN phenotyped by the two methods, there was disagreement in 4 cases in which they were determined to be expanding by CE-MRI and collapsed by PD-US. Since the adjacent knee had evidence of synovitis in all 4 cases, we concluded that the PD-US phenotyping was correct, and that this approach is currently the safest and most cost-effective in vivo approach to phenotype murine PLN as a biomarker of arthritic flare.
authors.affiliation: Center for Musculoskeletal Research, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America ; Department of Biomedical Engineering, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America.
authors.forename: Echoe M
authors.initials: EM
authors.lastname: Bouta
authors.forename: Yawen
authors.initials: Y
authors.lastname: Ju
authors.forename: Homaira
authors.initials: H
authors.lastname: Rahimi
authors.forename: Karen L
authors.initials: KL
authors.lastname: de Mesy-Bentley
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Wood
authors.forename: Lianping
authors.initials: L
authors.lastname: Xing
authors.forename: Edward M
authors.initials: EM
authors.lastname: Schwarz
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000000981:diagnostic imaging* / Q000235:genetics; D015415:Biomarkers / Q000378:metabolism; D003287:Contrast Media / Q000008:administration & dosage; D006801:Humans; D007089:Image Enhancement; D007719:Knee Joint / Q000000981:diagnostic imaging / Q000378:metabolism; D008198:Lymph Nodes / Q000000981:diagnostic imaging* / Q000378:metabolism; D042601:Lymphatic Vessels / Q000000981:diagnostic imaging / Q000378:metabolism; D008279:Magnetic Resonance Imaging / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D045423:Microbubbles; D008854:Microscopy, Electron; D010641:Phenotype; D011859:Radiography; D015203:Reproducibility of Results; D013585:Synovitis / Q000000981:diagnostic imaging / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D018608:Ultrasonography, Doppler / Q000379:methods*
chemical_list: D015415:Biomarkers; D003287:Contrast Media; D014409:Tumor Necrosis Factor-alpha
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