Spatially localized phosphorous metabolism of skeletal muscle in Duchenne muscular dystrophy patients: 24-month follow-up

PLoS One. 2017 Aug 1;12(8):e0182086. doi: 10.1371/journal.pone.0182086. eCollection 2017.

Abstract

Objectives: To assess the changes in phosphodiester (PDE)-levels, detected by 31P magnetic resonance spectroscopy (MRS), over 24-months to determine the potential of PDE as marker for muscle tissue changes in Duchenne Muscular Dystrophy (DMD) patients.

Methods: Spatially resolved phosphorous datasets were acquired in the right lower leg of 18 DMD patients (range: 5-15.4 years) and 12 age-matched healthy controls (range: 5-14 years) at three time-points (baseline, 12-months, and 24-months) using a 7T MR-System (Philips Achieva). 3-point Dixon images were acquired at 3T (Philips Ingenia) to determine muscle fat fraction. Analyses were done for six muscles that represent different stages of muscle wasting. Differences between groups and time-points were assessed with non-parametric tests with correction for multiple comparisons. Coefficient of variance (CV) were determined for PDE in four healthy adult volunteers in high and low signal-to-noise ratio (SNR) datasets.

Results: PDE-levels were significantly higher (two-fold) in DMD patients compared to controls in all analyzed muscles at almost every time point and did not change over the study period. Fat fraction was significantly elevated in all muscles at all time points compared to healthy controls, and increased significantly over time, except in the tibialis posterior muscle. The mean within subject CV for PDE-levels was 4.3% in datasets with high SNR (>10:1) and 5.7% in datasets with low SNR.

Discussion and conclusion: The stable two-fold increase in PDE-levels found in DMD patients in muscles with different levels of muscle wasting over 2-year time, including DMD patients as young as 5.5 years-old, suggests that PDE-levels may increase very rapidly early in the disease process and remain elevated thereafter. The low CV values in high and low SNR datasets show that PDE-levels can be accurately and reproducibly quantified in all conditions. Our data confirms the great potential of PDE as a marker for muscle tissue changes in DMD patients.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Female
  • Follow-Up Studies
  • Humans
  • Magnetic Resonance Spectroscopy
  • Male
  • Middle Aged
  • Muscle, Skeletal / metabolism*
  • Muscular Atrophy / diagnosis
  • Muscular Dystrophy, Duchenne / metabolism*
  • Phosphorus / metabolism*
  • Phosphorus Isotopes / chemistry
  • Reproducibility of Results
  • Signal-To-Noise Ratio

Substances

  • Phosphorus Isotopes
  • Phosphorus

Grants and funding

MTH reports a grant from the Netherlands Organization for Health Research and Development (ZonMW) (grant number 113302001) and a grant from the European Union (FP7-HEALTH-2013-INNOVATION-1, grant agreement no. 602485) during conduct of the research. JJGMV and EHN report grants from Duchenne Parent Project, ZonMW and AFM, and trial support from BioMarin, GSK, Lilly and Santhera, outside the submitted work. JJGMV reports grants from European Union and consultancy for Biomarin. EHN reports consultancies for BioMarin and Summit. HEK reports grants from ZonMW, AFM, Duchenne Parent Project, and Gratama Stichting, and consultancy for BioMarin and aTyr Pharma, outside the submitted work. AGW reports grants from NWO and a European Advanced Grant. ND reports a grant from Dutch Duchenne Parent Project (grant Brain imaging and cognition in Duchenne muscular dystrophy-2010) and a grant from Gratama Foundation (University of Leiden, grant number nr 10.13) CB reports a grant from the European Union (FP7-HEALTH-2013-INNOVATION-1, grant agreement no. 602485). No personal financial benefits were received. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.