Muscle Perfusion as a Unique Biomarker for in Clinical Trials
Skeletal muscle can adapt to various stimuli. Physical activity and exercise represent different types of stresses to the muscle. Depending on the exact nature of the stress, muscle may increase in size, improve neuro-muscular performance and enhance endurance capabilities. This brief overview gives an introduction into the clinical research conducted by IA-Group and collaborators into the use of quantitative imaging biomarkers for the assessment of muscle size and perfusion in drug development.
Various musculoskeletal and neuro-muscular conditions rely on the exact assessment of the volume and perfusion of the skeletal muscle – from the very common ones like Osteoarthritis (OA) to relatively rare such as Duchenne Muscular Dystrophy (DMD).
Today, there is no cure for either OA or DMD, but a tremendous research effort is put towards better understanding of the role of exercise, the endocrine system and intramuscular signaling pathways.
Understanding the basic physiology of muscle allows us to appreciate its dramatic interface with hormones and cell-signaling systems. Clinical imaging techniques give anatomical understanding of various tissues and intra-tissue relations, as well as critical for the assessment of biological function.
Examples of Conditions where Quantification of Muscle Impacts Therapeutic Decisions
Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by progressive muscle degeneration and weakness. It is one of many types of muscular dystrophy. DMD is caused by an absence of dystrophin, a protein that helps keep muscle cells intact. Clinical research is focused on discovering gene therapies, driving muscle growth and repair, https://www.mda.org/disease/duchenne-muscular-dystrophy/research
Clinical Imaging researchers are focused on quantifying the lower limb muscle using signal intensity measurements on T(1)-weighted and gadolinium contrast-enhanced MR images and by measurement of muscle T(2) values, and to investigate the effect of exercise. Tremendous effort by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and the National Institute of Neurological Disorders and Stroke (NINDS) is going into investigating the potential of magnetic resonance imaging (MRI) to noninvasively monitor disease progression in Duchenne muscular dystrophy, http://www.imagingdmd.org/
Osteoarthritis is a condition that affects your joints, causing pain and disability. The most recent work shows that OA is a whole joint disease and not just the cartilage degeneration condition. OA assessment in clinical research involves reviewing radiography and then MRI findings on cartilage morphology, cartilage lesions and composition (T2), bone, meniscus, muscle and adipose tissue. https://www.boa.ac.uk/wp-content/uploads/2016/08/Advances-in-osteoarthritis-imaging-What-will-make-it-into-clinical-practice.pdf
Peripheral arterial disease (PAD) is a progressive atherosclerotic disease of the lower. There is a critical need for a standard non-invasive approach to assess response to treatment. The investigators evaluate lower extremity skeletal muscle perfusion using conventional sodium iodide SPECT/CT imaging, as well as dynamic SPECT/CT imaging with a unique cadmium zinc telluride (CZT) system. Such a comprehensive approach offer important new opportunities as targets for therapeutic intervention.
Imaging Biomarkers: Measuring Muscle Volume and Perfusion
Muscle ultrasound is sometimes used in the assessment of muscle disease to aid in the selection of muscles for biopsy. However, the utility of muscle ultrasound in clinical research studies is limited by the fact that this technique is highly operator-dependent and not all muscles can be adequately assessed.
Magnetic Resonance Imaging (MRI) is a non-invasive imaging method, without ionizing radiation, which has the ability to visualize muscle, fat, connective tissue and bone. MRI has several advantages over muscle ultrasound, including that MRI has minimal operator-dependence and allows for excellent visualization of all muscles. Added advantage of using MRI that the measurements for both volume and perfusion of muscle can be extracted from the scans.
Positron Emission Tomography (PET) / SPECT reveal the metabolism of glucose within the bone and joint system. There is a limited use of FDG-PET scans due to the high cost of examinations. The level of radioactivity to which the patient is exposed is higher for PET scans as compared to SPECT scans.
Our own work investigates the association between muscle perfusion in the peri-articular knee muscles assessed by dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) and symptoms in patients with knee OA. This effort let us to the conclusion that more widespread perfusion in the peri-articular knee muscles was associated with less pain in patients with Knee OA. These results give rise to investigations of the effects of exercise on muscle perfusion and its possible mediating role in the causal pathway between exercise and pain improvements in the conservative management of OA.
We will be presenting our ongoing work on better understanding of osteoarthrosis through imaging biomarkers at the upcoming OARSI meeting (Osteoarthritis Research Society International World Congress to be held in Las Vegas, USA from the 27th to the 30th April 2017). Link to the published work can be found here: https://www.ncbi.nlm.nih.gov/pubmed/26074362
Last week, IA-Group and collaborators from Dept. of Radiology of University of Basel Hospital, Universitäts-Kinderspital beider Basel, Institut für Radiologie und Nuklearmedizin, Department of Radiology, Klinik St. Anna, Luzern, Switzerland presented at UK Neuromuscular Translational Research Conference, ‘Towards objective and reproducible measures of thigh muscle fat fraction in patients with Duchenne Muscular Dystrophy’. This work focused on deploying more automated approaches for the evaluation of muscle Fat Fraction (FF) from MRI.
Novel Therapies and Patient Phenotyping based on Quantitative Measurement of Muscle
It is worth noting that during healthy muscle repair, inflammatory responses are activated and are known to aid in the cleanup and restoration of damaged muscle. In DMD, however, these inflammatory responses are chronically activated and therefore become detrimental to the repair process.
In OA, muscle perfusion links to the pain in patients, as measured by KOOS (IA-Group exploratory study: ClinicalTrials.giv: NCT:01545258).
Many investigators are working to understand and interfere with inflammation in and around muscle fibers that may contribute to the DMD disease course. Equally in OA, a major research effort in going into patient phenotyping, which is based on quantitative markers of the inflammatory activity inside the muscle and the joint.
Contact us at firstname.lastname@example.org to discuss strategic use of imaging in your clinical research studies.
- Current imaging techniques in rheumatology: MRI, scintigraphy and PET, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789933/
- Associations between muscle perfusion and symptoms in knee osteoarthritis: a cross sectional study. https://www.ncbi.nlm.nih.gov/pubmed/26074362
- Knee pain and inflammation in the infrapatellar fat pad estimated by conventional and dynamic contrast-enhanced magnetic resonance imaging in obese patients with osteoarthritis: a cross-sectional study. https://www.ncbi.nlm.nih.gov/pubmed/24821663
- Synovitis assessed on static and dynamic contrast-enhanced magnetic resonance imaging and its association with pain in knee osteoarthritis: A cross-sectional study. https://www.ncbi.nlm.nih.gov/pubmed/27161058
- Use of skeletal muscle MRI in diagnosis and monitoring disease progression in Duchenne Muscular Dystrophy https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3561672/
- Osteoarthritis as a Whole Joint Disease, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3295952/
- Advances in osteoarthritis imaging: What will make it into clinical practice? https://www.boa.ac.uk/wp-content/uploads/2016/08/Advances-in-osteoarthritis-imaging-What-will-make-it-into-clinical-practice.pdf
- Duchenne Muscular Dystrophy (DMD), https://www.mda.org/disease/duchenne-muscular-dystrophy/research
- ANG1 treatment reduces muscle pathology and prevents a decline in perfusion in DMD mice, http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0174315
- Shimizu-Motohashi Y, Asakura A. Angiogenesis as a novel therapeutic strategy for Duchenne muscular dystrophy through decreased ischemia and increased satellite cells. Front Physiol. 2014;5:50. doi: 10.3389/fphys.2014.00050. pmid:24600399
- Palladino M, Gatto I, Neri V, Straino S, Smith RC, Silver M, et al. Angiogenic impairment of the vascular endothelium: A novel mechanism and potential therapeutic target in muscular dystrophy. Arterioscler Thromb Vasc Biol. 2013;33(12):2867–76. doi: 10.1161/ATVBAHA.112.301172. pmid:24072696
- Abdel-Salam E, Abdel-Meguid I, Korraa S. Markers of degeneration and regeneration in Duchenne muscular dystrophy. Acta Myol. 2009;28(3):94–100. pmid:20476668
- Stewart E, Chen X, Hadway J and Lee T Y. Correlation between hepatic tumor blood flow and glucose utilization in a rabbit liver tumor model. Radiology. 2006 239(3):740–50. doi: 10.1148/radiol.2393041382. pmid:1662192
- Sahani DV, Holalkere NS, Mueller PR and Zhu AX. Advanced hepatocellular carcinoma: CT perfusion of liver and tumor tissue-initial experience. Radiology. 2007;243(3):736–43. doi: 10.1148/radiol.2433052020. pmid:17517931
- Regulation of skeletal muscle perfusion during exercise. https://www.ncbi.nlm.nih.gov/pubmed/9578387
Figure: Workflow diagram of the semi-automated segmentation algorithm. After Normalisation of the gray scale values, rectangular ROIs were manually drawn around the whole thigh (green square in a), the muscle compartment (white square in b and d) and the bone (white square in a). Subcutaneous fat is manually excluded, using a free hand ROI. The muscle outline is then calculated (blue ROI). Intramuscular fat (orange and red in d) is calculated in the muscle compartment, including the intermuscular fasciae.
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