Probing diffusion of water and metabolites to assess white matter microstructure in Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a progressive X-linked neuromuscular disorder caused by the absence of functional dystrophin protein. In addition to muscle, dystrophin is expressed in the brain in both neurons and glial cells. Previous studies have shown altered white matter microstructure in patients with DMD using diffusion tensor imaging (DTI). However, DTI measures the diffusion properties of water, a ubiquitous molecule, making it difficult to unravel the underlying pathology. Diffusion-weighted spectroscopy (DWS) is a complementary technique which measures diffusion properties of cell-specific intracellular metabolites. Here we performed both DWS and DTI measurements to disentangle intra- and extracellular contributions to white matter changes in patients with DMD. Scans were conducted in patients with DMD (15.5 ± 4.6 y/o) and age- and sex-matched healthy controls (16.3 ± 3.3 y/o). DWS measurements were obtained in a volume of interest (VOI) positioned in the left parietal white matter. Apparent diffusion coefficients (ADCs) were calculated for total N-acetylaspartate (tNAA), choline compounds (tCho), and total creatine (tCr). The tNAA/tCr and tCho/tCr ratios were calculated from the non-diffusion-weighted spectrum. Mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD), and fractional anisotropy of water within the VOI were extracted from DTI measurements. DWS and DTI data from patients with DMD (respectively n = 20 and n = 18) and n = 10 healthy controls were included. No differences in metabolite ADC or in concentration ratios were found between patients with DMD and controls. In contrast, water diffusion (MD, t = -2.727, p = 0.011; RD, t = -2.720, p = 0.011; AD, t = -2.715, p = 0.012) within the VOI was significantly higher in patients compared with healthy controls. Taken together, our study illustrates the potential of combining DTI and DWS to gain a better understanding of microstructural changes and their association with disease mechanisms in a clinical setting.