The aim of the study is to evaluate in vivo fluorescence imaging of experimental inflammatory joint disease by applying two different near-infrared (NIR) dyes in a model of Borrelia-induced Lyme arthritis.
Forty mice, 20 with Lyme arthritis and 20 controls, were examined. Two nonspecific NIR carbocyanine dyes, indocyanine green (ICG) and a hydrophilic carbocyanine derivative (1,1'-bis-[4-sulfobutyl] indotricarbocyanine-5,5'-dicarboxylic acid diglucamide monosodium salt [SIDAG]), were administered intravenously at two doses. Fluorescence images were acquired before and during 120 seconds after injection of cyanine dyes. For both dyes, the area under the curve (AUC) was determined for the interval between 40 and 80 seconds after injection. In addition, the slope of the signal decrease was compared among animal groups. Results were compared with histological findings.
The general temporal fluorescence intensity course for ICG was characterized by a rapid increase, with a peak at 40-50 seconds followed by a decrease; conversely for SIDAG, by a slow increase. AUC analysis for both dyes showed that the fluorescence signal differed significantly between controls and arthritic animals (P < .05). Within these groups, there were significant differences between the two doses investigated. ICG differed significantly between control and arthritic animals in the slope of the signal decrease for both doses investigated (P < .05). Histological examination showed early stages of inflammation in arthritic animals.
NIR fluorescence imaging based on the pharmacokinetic behavior of ICG or SIDAG is a promising approach to detect inflammatory joint changes of experimental arthritis. Moreover, SIDAG is suited to differentiate inflammatory and noninflammatory joints 24 hours after dye application.
"Optical imaging recordings were analyzed using Matlab (The MathWorks). Quantitative analysis of ZsYellow1 expression was performed using in-house Matlab scripts by calculating the slope of fluorescence signals (Fischer et al. 2006; Euler et al. 2012; Srinivasan et al. 2012, 2013). Each single recording consisted of 10 frames, and these were averaged into one image in order to reduce the size of the dataset. "
[Show abstract][Hide abstract] ABSTRACT: Nerve injury induces long-term changes in neuronal activity in the primary somatosensory cortex (S1), which has often been implicated as the origin of sensory dysfunction. However, the cellular mechanisms underlying this phenomenon remain unclear. C-fos is an immediate early gene, which has been shown to play an instrumental role in plasticity. By developing a new platform to image real-time changes in gene expression in vivo, we investigated whether injury modulates the levels of c-fos in layer V of S1, since previous studies have suggested that these neurons are particularly susceptible to injury. The yellow fluorescent protein, ZsYellow1, under the regulation of the c-fos promoter, was expressed throughout the rat brain. A fiber-based confocal microscope that enabled deep brain imaging was utilized, and local field potentials were collected simultaneously. In the weeks following limb denervation in adult rats (n = 10), sensory stimulation of the intact limb induced significant increases in c-fos gene expression in cells located in S1, both contralateral (affected, 27.6 ± 3 cells) and ipsilateral (8.6 ± 3 cells) to the injury, compared to controls (n = 10, 13.4 ± 3 and 1.0 ± 1, respectively, p value <0.05). Thus, we demonstrated that injury activates cellular mechanisms that are involved in reshaping neuronal connections, and this may translate to neurorehabilitative potential.
"The major drawback of FOI is the limited tissue penetration of light; however, as inflammatory arthopathies typically affect the small joints of the hands and feet, this is not necessarily a significant limitation for this imaging method . Under various experimental conditions, FOI proved to correspond to synovitis [17,18,20-24]. In those experiments, early hyperemia of inflamed joints could be diagnosed by recording scattering and absorption patterns of light transmitted through inflamed finger joints. "
[Show abstract][Hide abstract] ABSTRACT: To prospectively evaluate quantitative assessment of fluorescence optical imaging (FOI) for differentiation of synovitic from non-synovitic joints in patients suffering from rheumatoid arthritis (RA).
FOI of the hands was performed in patients with active RA, and a stratified quantitative fluorescence readout (FLRO) of 3 phases (1-120 s; 121-240 s; 241-360 s) was generated for 5 individual joints of the clinical predominant hand (carpal joint, metacarpophalangeal and proximal interphalangeal joints of digits II & III). To dissect the effect of the overall perfusion of the hand from the perfusion due to synovitis, a fluorescence ratio (FLRA) was additionally calculated, dividing each FLRO by the readout of the eponychium of digit II. The mean FLRO and FLRA were compared between joints with absent vs. present synovitis determined by clinical examination, grayscale, color Doppler ultrasonography, or magnetic resonance imaging (MRI).
The analysis for 90 individual joints from 18 patients yielded FLRO ranging from 4.4 to 49.0 × 10(3), and FLRAs ranging from 0.37 to 2.27. Overall, the analyses based on the FLRA revealed a higher discrimination than the analyses related to the FLRO, demonstrating most significant differences in phases 2 and 3. A sensitivity of 26/39 (67%) and a specificity of 31/40 (77%) were calculated for FLRA of phase 3 using a cut-off value of more than 1.2 to detect MRI-confirmed synovitis with FOI.
FOI has a potential for visualizing synovitis in subjects with RA. For adequate FOI interpretation, quantitative analysis should be based on the novel FLRA calculated for phases 2 and 3.
"The NIR fluorophore Cy5.5 was visualised in arthritic knee joints following induction of antigen-induced arthritis in mice , and demonstrated an approximately 1.5-fold increase in signal in arthritic compared to non-arthritic joints. Two other NIR dyes were evaluated in a murine Borrelia-induced Lyme arthritis model . These techniques rely on the generalised increased blood perfusion and 'vascular leakiness' that are recognised to be present around the inflamed joint . "
[Show abstract][Hide abstract] ABSTRACT: Novel molecular imaging techniques are at the forefront of both preclinical and clinical imaging strategies. They have significant potential to offer visualisation and quantification of molecular and cellular changes in health and disease. This will help to shed light on pathobiology and underlying disease processes and provide further information about the mechanisms of action of novel therapeutic strategies. This review explores currently available molecular imaging techniques that are available for preclinical studies with a focus on optical imaging techniques and discusses how current and future advances will enable translation into the clinic for patients with arthritis.
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