In many muscle diseases, inflammation, fibrosis and/or fatty infiltration of muscle tissue are prominent features. Clinically, patients experience muscle weakness and loss of function. Muscle weakness often starts in specific muscles and spreads to others as the disease progresses. The pathophysiology of the selective muscle involvement is unknown, and many of these diseases lack full-market approved drugs. In addition, about 30% of patients with Duchenne muscular dystrophy (DMD) show cognitive impairment with an unknown etiology and prognosis.
In the LUMC, we have implemented quantitative MRI tools to study fatty infiltration and inflammation in several of these diseases where we are NFU expert center. These include DMD, Becker muscular dystrophy (BMD) and Myasthenia Gravis (MG). In DMD, we also perform quantitative MRI of the brain.
• Study the natural history of fatty infiltration, inflammation and other MR indices of histopathological features of DMD, BMD and MG using quantitative MRI
• Describe brain involvement in DMD using quantitative MRI
• Relate the MR findings to functional measures
Natural history of DMD and BMD
We have performed extensive natural history studies into DMD and BMD, starting with cross-sectional studies of the lower limbs and now longitudinal studies in both the lower and upper limbs. Fatty infiltration and edema/inflammation of muscular tissue are clearly visible using MRI and will be assessed quantitatively. Additionally, phosphorous MR spectroscopy (MRS) measurements at the 7T scanner have been applied to study changes in metabolism. There is a lot of interest in therapy development in both diseases and the field is in need of sensitive outcome measures. We hope that quantitative MRI or MRS can play a role in this.
Eye muscle imaging in MG
The auto-immune disease MG affects the neuromuscular junction and commonly starts with weakness of the extra-ocular muscles (EOMs), causing double vision. We will perform quantitative MRI of the individual EOMs to study pathophysiology, determine if this can predict treatment response and explore whether this can be used to aid differential diagnosis. Given the auto-immune nature of MG, local elevation of inflammatory markers (i.e. the T2 relaxation time) in the EOMs could be an MG hallmark that is present at early stages of the disease. It is likely that this inflammation causes degenerative changes to the muscles if it remains untreated, as this is the presumed order of pathophysiology in muscular dystrophies. This will be reflected in local increases in fatty infiltration.
Background of selective muscle involvement.
In this project we will explore the reason for the disease-specific order in which symptoms of muscle weakness occur in muscular dystrophies. Elucidation of this phenomenon could hold help the development of new therapies, by changing the constitution of muscles that are involved early in the disease process to resemble muscles that are preserved longest, for instance by enhancing intrinsic properties of these preserved muscles. We will assess exercise-physiological, micro-structural and molecular differences between muscles to identify factors that contribute to preserving muscle tissue until late in disease progression. We will develop new methodology to assess muscles during exercise, assess micro-structure and molecular signatures of different muscles and apply this knowledge to elucidate the pathophysiology of MDs.
Brain imaging and MRS in DMD
In 2010 we have started to perform brain MRI and MRS in patients with DMD. The first cross-sectional studies showed decreases in grey matter volume, changes in white matter structure and decreases in cerebral perfusion. All of these changes were larger in patients lacking more isoforms of dystrophin. No clear differences in brain metabolites were observed. While there was no direct correlation to cognitive and behavioral tests, these showed the same trends in relation to the isoforms. It has long been the assumption that the cognitive problems in DMD are not progressive. We are now addressing this by studying brain involvement by quantitative MRI in a longitudinal way, and have extended the cohort of patients by a collaboration with the University of Newcastle.
Erik Niks, Chiara Straathof, Jan Verschuuren, Martijn Tannemaat, Vered Raz, Annemieke Aartsma-Rus, Peter-Bram ‘t Hoen, Jos Hendriksen, Volker Straub
Fat (left) and water (right) Dixon image of the leg of a DMD patient
Dixon water images for an MG patient (top) and a GO patient (bottom), and the 3D-image after segmentation of the extraocular muscles. The lateral rectus (LR) and the medial rectus (MR) muscles are shown. Notice the enlarged LR muscle in the GO patient.
Schematic overview of the involvement pattern in two different muscular dystrophies: Duchenne muscular dystrophy (DMD) and Facioscapulohumeral dystrophy (FSHD). The figure depicts muscles that are infiltrated by fat at different stages of the disease, with the darkest colors for muscles that are involved early, and white for muscles that are preserved until late in the disease process. Abbreviations: Adductor Longus (AL) and Magnus (AM); Biceps Femoris long head (BFL) and short head (BFS); Extensor Digitorum Longus (EDL); Flexor Digitorum Longus (FDL); Flexor Hallucis Longus (FHL), Gastrocnemius Medialis (GCM) and Lateralis (GCL), Gracilis (G), Vastus medialis (VM), lateralis (VL) and intermedius (VI); Rectus femoris (RF); Sartorius (S); Semi tendinosus (ST); Soleus (SOL); Tibialis Anterior (TA) and posterior (TP).
Processing pipeline for volume measurements using T1 weighted imaging: skull extraction and then separation into white matter, grey matter and cerebrospinal fluid.
- Burakiewicz J, Hooijmans MT, Webb AG, Verschuuren JJ, Niks EH, Kan HE. Improved olefinic fat suppression in skeletal muscle DTI using a magnitude-based dixon method. Magn Reson Med. 2018 Jan;79(1):152-159
- Doorenweerd N, Mahfouz A, van Putten M, Kaliyaperumal R, T' Hoen PAC, Hendriksen JGM, Aartsma-Rus AM, Verschuuren JJGM, Niks EH, Reinders MJT, Kan HE, Lelieveldt BPF. Timing and localization of human dystrophin isoform expression provide insights into the cognitive phenotype of Duchenne muscular dystrophy. Sci Rep. 2017 Oct 3;7(1):12575
- Burakiewicz J, Sinclair CDJ, Fischer D, Walter GA, Kan HE, Hollingsworth KG. Quantifying fat replacement of muscle by quantitative MRI in muscular dystrophy. J Neurol. 2017 Oct;264(10):2053-2067.
- Hooijmans MT, Doorenweerd N, Baligand C, Verschuuren JJGM, Ronen I, Niks EH, Webb AG, Kan HE. Spatially localized phosphorous metabolism of skeletal muscle in Duchenne muscular dystrophy patients: 24-month follow-up. PLoS One. 2017 Aug 1;12(8):e0182086
- Hooijmans MT, Niks EH, Burakiewicz J, Anastasopoulos CA, van den Berg SI, van Zwet E, Webb AG, Verschuuren JJ, Kan HE. Non-uniform muscle fat replacement along the proximodistal axis in Duchenne Muscular Dystrophy. Neuromusc Disord. May;27(5):458-464.
- Doorenweerd N, Dumas EM, Gharic E, Schmid S, Straathof CSM, Roest AAW, Wokke BH, van Zwet EW, Webb AG, Hendriksen JGM, van Buchem MA, Verschuuren JJGM, Asllani I, Niks EH, van Osch MJP, Kan HE. Decreased cerebral perfusion in Duchenne muscular dystrophy patients. Neuromuscul Disord. 2017 Jan;27(1):29-37.
- Wokke BH, Hooijmans MT, van den Bergen JC, Webb AG, Verschuuren JJ, Kan HE. Muscle MR spectroscopy detects elevated PDE/ATP ratios prior to fatty infiltration in Becker muscular dystrophy. NMR Biomed. 2014 Nov;27(11):1371-7
- Doorenweerd N, Straathof CS, Dumas EM, Spitali P, Ginjaar IB, Wokke BH, Schrans DG, van den Bergen JC, van Zwet EW, Webb A, van Buchem MA, Verschuuren JJ, Hendriksen JG, Niks EH, Kan HE. Reduced cerebral gray matter and altered white matter in boys with Duchenne muscular dystrophy. Ann Neurol 2014, Sep;76(3):403-11
- Wokke BH, van den Bergen JC, Versluis MJ, Niks EH, Milles J, Webb AG, van Zwet EW, Aartsma-Rus A, Verschuuren JJ, Kan HE. Quantitative MRI and strength measurements in the assessment of muscle quality in Duchenne muscular dystrophy. Neuromuscul Disord. 2014; May; 24(5):409-16
- van den Bergen JC, Wokke BH, Janson AA, van Duinen SG, Hulsker MH, Ginjaar HB, van Deutekom JC, Aartsma-Rus A, Kan HE, Verschuuren JJ. Dystrophin levels and clinical severity in Becker muscular dystrophy patients. J Neurol Neurosurg Psychiatry. 2014 Jul;85(7):747-53