Research PaperDiffusion tensor imaging and myelin composition analysis reveal abnormal myelination in corpus callosum of canine mucopolysaccharidosis I
Introduction
MPS I (a.k.a. “Hurler syndrome”) is an inherited disease that causes progressive loss of cognitive function and substantial physical disease in children. In MPS I, glycosaminoglycans accumulate intracellularly, due to the deficiency of the lysosomal enzyme alpha-l-iduronidase. However, glycosaminoglycans are not directly toxic, and the cause of neurological deterioration in children with MPS I is not presently clear. Brain histological findings in MPS I patients have shown neuronal cell loss, gliosis, swelling of cell bodies and dendrites, prominent perivascular (i.e., Virchow–Robin) spaces, leptomeningeal thickening, and gross atrophy (Naidoo, 1953). In addition, brain MR imaging findings show hydrocephalus, cribriform changes, and hyperintense lesions of white matter (Seto et al., 2001). Some investigators have speculated that the hyperintense lesions of white matter are caused by abnormal myelination (Gabrielli et al., 2004). In this study, we performed a controlled, preclinical study of MPS I and carrier control dogs to determine whether white matter abnormalities described in human MPS I could be detected in MPS I dogs. Canine studies are essential because humans affected with severe MPS I disease typically receive bone marrow transplantation and immune suppression therapy, which could confound observational imaging studies and studies of novel therapies.
In previous studies, we used a naturally-occurring canine model of MPS type I to study the neurological disease due to MPS I and its potential treatment (Dierenfeld et al., 2010, Shull et al., 1982, Vite et al., 2013). In one study, we used MR imaging to assess anatomic and structural features of the brains of three canine populations: nine adult MPS I dogs, four age-matched, unaffected carrier dogs and four MPS I dogs that had been treated beginning at four months of age with intrathecal recombinant human alpha-l-iduronidase at three month intervals (Vite et al., 2013). The study showed that the canine MPS I brain shares many anatomic features with human MPS I disease including ventriculomegaly, brain cortical atrophy, and volume loss in the corpus callosum that was prevented by treatment (Vite et al., 2013). The neuroimaging findings of volume loss in the corpus callosum (a major white matter structure) and hyperintense regions within the white matter suggested the possibility of white matter involvement, including demyelination. With this in mind, we set out to study brain microstructure in MPS I dogs using MR techniques that would reflect myelination changes on the microscopic level and correlate those findings with the composition of myelin and expression of myelin-related genes.
DTI is a MR technique that provides information about the microstructure of white matter through measurement of the microscopic, three-dimensional motion of water. DTI studies of the brain in MPS I children have shown reduced fractional anisotropy (FA) in the corpus callosum, a finding that has been correlated with reduced attention and suggests that abnormalities within white matter may underlie some aspects of the loss of function in MPS I patients (Shapiro et al., 2012). Another pertinent DTI metric is radial diffusivity, which has been shown to correlate with the absence of myelination (Song et al., 2002).
In the present study, we set out to correlate DTI findings and features of demyelination of the same dogs that were examined in our previous study. Our first hypothesis was that both FA values and RD values would be altered in the white matter of untreated MPS I dogs. Our second hypothesis was that these findings would correlate with degree of myelination (as measured by levels of myelin basic protein (MBP) as well as altered myelin composition and diminished expression of myelin-related genes). Our third hypothesis was that treatment with intrathecal recombinant human alpha-l-iduronidase would ameliorate both the altered DTI metrics and the pre-existent defects in myelin composition and gene expression. Finding of a correlation between DTI parameters and a quantitative measurement of degree of myelination is very important if DTI is to be useful as a means to measure therapeutic response in demyelinating diseases. As a representative white matter structure, we chose the corpus callosum, a highly anisotropic structure that is easily identified in the canine brain.
Section snippets
Research objectives
We performed a controlled, preclinical study of MPS I and carrier control dogs to determine whether white matter abnormalities described in human MPS I could be detected in MPS I dogs. Canine studies were essential, because patients affected with severe MPS I disease typically receive bone marrow transplantation and immune suppression which could confound observational imaging studies in human subjects. Following our initial determination of reduced fractional anisotropy in the corpus callosum
DTI suggests abnormal myelination in MPS I dogs
The study subjects are listed in Table 1. DTI demonstrated a 20–30% decrease in fractional anisotropy and an increase in radial diffusivity of up to 63% higher in the corpus callosum of MPS I dogs compared to carrier controls (P < 0.01; Fig. 1 and Table 2). Mean FA value in the genu of the corpus callosum in heterozygous (i.e., control) dogs was 0.437 and that in the splenium was 0.514. In comparison, mean value in the genu of untreated affected dogs was 0.348 and in the splenium was 0.361. These
Discussion
In this investigation, we proposed three study hypotheses. Our first hypothesis was that both FA values and radial diffusivity values would be altered in the white matter of untreated MPS I dogs. Our second hypothesis was that DTI findings would correlate with altered myelin composition and diminished expression of myelin-related genes. Third, we hypothesized that intrathecal recombinant human alpha-l-iduronidase treatment would ameliorate both the effects of the disease on myelin composition
Conflicts of interest
The Los Angeles Biomedical Research Institute at Harbor—UCLA Medical Center and the Department of Pediatrics at Harbor—UCLA (but not the authors) receive royalties from the sale of recombinant human alpha-l-iduronidase (laronidase). P.I.D., E.G.S. and N.M.E. receive research support from, and R.Y.W. has received travel support and served as a consultant for, BioMarin and/or Genzyme–Sanofi, which manufacture and distribute laronidase.
Acknowledgments
Catalina Guerra, Jenny Dancourt, and Amanda Todd at the Los Angeles Biomedical Research Institute at Harbor—UCLA Medical Center, and numerous undergraduate students at Iowa State University, provided assistance with animals. Daisy O'Brien and Shida Banakar operated the MRI scanner. Leonard White assisted with neuroanatomy. Funding was provided by NIH/NINDS NS085381 and NS05242 to P.I.D., T32 GM8243-28 to support S.-h.K., NIH/NCATS (UCLA CTSI) UL1TR000124, NIH/NIBIB (Duke Center for In Vivo
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