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DOI: 10.1055/s-0039-1698173
New Non-invasive Biomarkers in Duchenne Muscular Dystrophy: Translational Molecular Imaging with Multispectral Optoacoustic Tomography
Publication History
Publication Date:
11 September 2019 (online)
Introduction: Duchenne muscular dystrophy (DMD) is the most common X-linked lethal genetic muscular disease in newborns. It is caused by loss-of-function mutations in the dystrophin gene producing a dysfunctional protein leading to muscular degeneration and inflammation, followed by fibro-fatty transformation with loss of physical muscle function. Non-invasive imaging with multispectral optoacoustic tomography (MSOT) in the extended near-infrared range was used in a bench-to-bedside approach to assess subcellular components of affected muscles in a porcine DMD model and in pediatric DMD patients in vivo.
Methods: For optoacoustic imaging eleven wavelengths (680–1100 nm) were used to quantitatively assess deoxygenated (HbR), oxygenated hemoglobin (HbO2), lipids, mean (CMEAN), and maximum collagen (CMAX) contents in vivo by spectral unmixing. MSOT was performed in n = 7 transgenic DMD (deleted DMD exon 52) piglets and n = 10 corresponding wildtypes (WT) on day 1–3 after birth. Results were compared to corresponding ex vivo tissues. In parallel, a first-in-pediatric monocentric, open-label, parallelized clinical trial was performed with n = 10 ambulant DMD patients and n = 10 matched healthy volunteers (HV). Diagnostic performance was gauged by clinical standard physical examinations (timed function tests, e.g. 6-minute walk test) and B-Mode ultrasound.
Results: 2D MSOT detected fibrotic degeneration in DMD piglets by means of increased CMEAN (p<0.001) and CMAX (p<0.001) when compared to WT piglets. Ex vivo histopathology confirmed muscular dystrophy and a qualitative increase in collagen formation in DMD piglets. Similarly, increased CMEAN (p<0.001) and CMAX (p<0.001) was detected in all muscle regions of DMD patients when compared to HV. 3D MOST demonstrated significant increase in CMEAN and CMAX (all p<0.001) and decreased HbR (p = 0.008) and HbO2 (p<0.001) in DMD patients compared to HV. The degree of collagenMEAN/MAX corresponded well with physical performance (6-MWT vs. C2D/3D-MEAN/MAX, all p<0.001) and was independent from age (p = 0.58–0.98).
Conclusions: This study demonstrates the potential of 2D/3D MSOT imaging to visualize collagen in vivo and suggests its application as a non-invasive, age independent biomarker for the assessment of disease progression in DMD patients. (Animal Welfare Authority District Government of Upper Bavaria, Reference Number 55.2-1-54-2532-163-2014; clinicaltrial.gov ID: NCT03490214)