Assessment of Dysmyelination with RAFFn MRI: Application to Murine MPS I

Type I mucopolysaccharidosis(MPS I) is an autosomal recessive lysosomal storage disorderwith neurological features. Humans and laboratory animals with MPS I exhibit various white matter abnormalities involving the corpus callosumand other regions. In this study, we first validated a novel MRI technique, entitled Relaxation Along a Fictitious Field in the rotating frame of rank n (RAFFn), as a measure of myelinationand dysmyelination in mice. We then examined differences between MPS I mice and heterozygotes using RAFF5 and histology. RAFF5 (i.e., RAFFn with n = 5) relaxation time constants were highly correlated with histological myelindensity (R2 = 0.68, P<0.001), and RAFF5 clearly distinguished between the hypomyelinated and dysmyelinated shiverermouse and the wild-type mouse. Bloch-McConnell theoretical analysis revealed slower exchange correlation times and smaller exchange-induced relaxation rate constants for RAFF4 and RAFF5 compared to RAFF1-3, T1ρ, and T2ρ. These data suggest that RAFF5 may assess methylene protons in myelinlipids and proteins, though other mechanisms (e.g. detection of myelin- bound water) may also explain the sensitivity of RAFF5 to myelin. In MPS I mice, mean RAFF5 relaxation time constants were significantly larger for the striatum (P = 0.004) and internal capsule(P = 0.039), and marginally larger for the fornix(P = 0.15). Histological assessment revealed no differences between MPS I mice and heterozygotes in myelindensity or corpus callosumthickness. Taken together, these findings support subtle dysmyelination in the brains of mice with MPS I. Dysmyelination may result from myelinlipid abnormalities caused by the absence of α-L- iduronidase. Our findings may help to explain locomotor and cognitive deficits seen in mice with MPS I.