Unraveling the basis of white matter disease in mucopolysaccharidosis type I – a DTI study

PI: Alena Svatkova

Institution: University of Minnesota

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Animal models showed that Mucopolysaccharidosis type I (MPSI) critically affects normal brain functioning by damaging highly organized brain fiber nets, i.e., white matter (WM). Thus, canine MPS studies further emphasized the need to accurately depict WM deficits using innovative MR method entitled diffusion tensor imaging (DTI) to quantify effects of novel brain-directed MPS therapies in clinical trials. Thus far, the automated DTI analysis techniques have not been established yet due to the existence of cystic liquor-filled spaces, brain shrinkage, and abnormal head shape in MPS patients. The principal goal of our project was to identify WM signatures of severe (Hurler, MPSIH) and attenuated (MPSIA) MPSI without spurious effects of structural brain deficits. Optimized DTI analysis indeed revealed distinctions in WM damage between MPSI subtypes. Results unraveled that MPSIH is mainly caused by destruction of myelin, which covers neuronal fibers in order to facilitate brain communication, while MPSIA is characterized by a combination of damage in neuronal fibers and myelin. The WM deficiency was essential in cognitive functioning in MPSIH and attention performance in both subtypes. Thus, our study clearly delineated distinct WM areas that are affected in MPSI subtypes and established WM analysis method for future clinical trials.