Diffusion tensor imaging and myelin composition analysis reveal abnormal myelination in corpus callosum of canine mucopolysaccharidosis I

Provenzale, James M.; Nestrašil, Igor; Chen, Steven; Kan, Shih Hsin; Le, Steven Q.; Jens, Jacqueline K.; Snella, Elizabeth M.; Vondrak, Kristen N.; Yee, Jennifer K.; Vite, Charles H.; Elashoff, David; Duan, Lewei; Wang, Raymond; Ellinwood, N. Matthew; Guzmán, Miguel A.; Shapiro, Elsa; Dickson, Patricia I.

doi:10.1016/j.expneurol.2015.07.021

Cited by 15 publications

(18 citation statements)

References 25 publications

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“…Given that the ex vivo FA and RD changes in canines affected with MPS are similar to those found in vivo, 11,14 ex vivo imaging appears to show promise as a method for more definitive determination of alterations in the MPS brain. Furthermore, ex vivo imaging provides a means for more direct comparison between imaging findings and histological changes because images from MR scans can be co-registered with anatomical brain slices.…”

Section: Discussionmentioning

confidence: 92%

Diffusion tensor imaging findings suggestive of white matter alterations in a canine model of mucopolysaccharidosis type I

Middleton

Chen

et al. 2017

Neuroradiol J

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Purpose We investigated fractional anisotropy (FA) and radial diffusivity (RD) in a canine model of mucopolysaccharidosis (MPS). We hypothesized that canines affected with MPS would exhibit decreased FA and increased RD values when compared to unaffected canines, a trend that has been previously described in humans with white matter diseases. Methods Four unaffected canines and two canines with MPS were euthanized at 18 weeks of age. Their brains were imaged using high-resolution diffusion tensor imaging (DTI) on a 7T small-animal magnetic resonance imaging system. One hundred regions of interest (ROIs) were placed in each of four white matter regions: anterior and posterior regions of the internal capsule (AIC and PIC, respectively) and anterior and posterior regions of the centrum semiovale (ACS and PCS, respectively). For each specimen, average FA and RD values and associated 95% confidence intervals were calculated from 100 ROIs for each brain region. Results For each brain region, the FA values in MPS brains were consistently lower than in unaffected dogs, and the RD values in MPS dogs were consistently higher, supporting our hypothesis. The confidence intervals for affected and unaffected canines did not overlap in any brain region. Conclusion FA and RD values followed the predicted trend in canines affected with MPS, a trend that has been described in humans with lysosomal storage and dysmyelinating diseases. These findings suggest that the canine model parallels MPS in humans, and further indicates that quantitative DTI analysis of such animals may be suitable for future study of disease progression and therapeutic response in MPS.

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Section: Discussionmentioning

confidence: 92%

Diffusion tensor imaging findings suggestive of white matter alterations in a canine model of mucopolysaccharidosis type I

Middleton

Chen

et al. 2017

Neuroradiol J

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“…Mice heterozygous for MPS I have lower than wild‐type iduronidase enzymatic activity, but have no known MPS phenotype. In addition, MPS I dogs show reduced expression of myelin‐related genes compared to heterozygote controls both at older ages (21 months; Provenzale et al, 2015) and at 7 weeks (unpublished). We were not able to study mice older than 50 weeks, as this is essentially the end of the lifespan for MPS I mice.…”

Section: Discussionmentioning

confidence: 94%

“…We found a subtler alteration in myelin composition in MPS I mice compared to those we had found in MPS I dogs. Our previous work in MPS I dogs showed reduced fractional anisotropy and loss of volume in corpus callosum, elevated cholesterol, reduced levels of myelin basic protein, and reduced expression of myelin‐related genes (Provenzale et al, 2015; Vite et al, 2013). In our canine study, we had extracted myelin from the corpus callosum white matter for compositional analysis.…”

Section: Discussionmentioning

confidence: 95%

“…Using this modality, we found reduced fractional anisotropy (an index of the propensity of water molecules to move in a preferred direction as opposed to randomly) and increased radial diffusivity (diffusion that is perpendicular to an expected direction of motion) in affected, adult animals (Middleton et al, 2018;Provenzale et al, 2015). To study the potential causative factors, we extracted tissue from the corpus callosum post-mortem and found reduced expression of myelin-related genes and abnormal composition of myelin including myelin lipids (Provenzale et al, 2015). The abnormalities in lipids included significantly lower sphingomyelin, dihydrosphingomyelin, and phosphatidylserine (PtdSer) levels in MPS I dogs.…”

Section: Introductionmentioning

confidence: 99%

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Myelin and Lipid Composition of the Corpus Callosum in Mucopolysaccharidosis Type I Mice

Nestrašil

Kan

et al. 2020

Lipids

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Mucopolysaccharidosis type I (MPS I) is a lysosomal disease with progressive central nervous system involvement. This study examined the lipid, cholesterol, and myelin basic protein composition of white matter in the corpus callosum of MPS I mice. We studied 50 week-old, male MPS I mice and littermate, heterozygote controls (n = 12 per group). Male MPS I mice showed lower phosphatidylcholine and ether-linked phosphatidylcholine quantities than controls (p < 0.05). Twenty-two phospholipid or ceramide species showed significant differences in percent of total. Regarding specific lipid species, MPS I mice exhibited lower quantities of sphingomyelin 18:1, phosphatidylserine 38:3, and hexosylceramide d18:1(22:1) mH 2 O than controls. Principal components analyses of polar, ceramide, and hexosylceramide lipids, respectively, showed some separation of MPS I and control mice. We found no significant differences in myelin gene expression, myelin basic protein, or total cholesterol in the MPS I mice versus heterozygous controls. There was a trend toward lower proteolipid protein-1 levels in MPS I mice (p = 0.06). MPS I mice show subtle changes in white matter composition, with an unknown impact on pathogenesis in this model.

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“…Attention was chosen as previous studies have found abnormal attentional function in MPS disorders [15] , [16] , [17] . It has been hypothesized that attention is related to white matter abnormalities in MPS conditions [18] . Overall, attention scores were below the average range for the d prime, omission errors, and variability for all three groups.…”

Section: Discussionmentioning

confidence: 99%

Association of somatic burden of disease with age and neuropsychological measures in attenuated mucopolysaccharidosis types I, II and VI

Ahmed

Shapiro

Rudser

et al. 2016

Molecular Genetics and Metabolism Reports

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IntroductionThe mucopolysaccharidoses (MPSs) are a group of rare genetic lysosomal disorders with progressive multisystem involvement. An MPS-specific physical symptom scale was developed and introduced a Physical Symptom Score (PSS) to quantify the somatic disease burden across MPS I, II and VI.HypothesisSomatic burden of disease in patients with attenuated MPS I, II and VI as measured by the PSS will be positively associated with age and negatively associated with neuropsychological functions [i.e. full scale intelligence quotient (FSIQ) and attention].Materials and methodsForty-eight patients with attenuated MPS I (n = 24), II (n = 14), and VI (n = 10) aged 6 to 32 years on enzyme replacement therapy who were enrolled in “Longitudinal Studies of Brain Structure and Functions in MPS Disorders” across seven centers. Somatic disease burden was measured by the PSS. Neuropsychological functions were measured by the Wechsler Abbreviated Scale of Intelligence (WASI) and Test of Variables of Attention (TOVA).ResultsPSS was positively associated with age in attenuated MPS I (P < 0.001), MPS II (P < 0.01) and MPS VI (P < 0.05). There was a negative association of PSS with FSIQ in attenuated MPS I (P < 0.001) and in MPS VI (P < 0.001) but not with MPS II. Although attention scores were below average in all groups, a significant negative association between PSS and one measures of sustained attention (TOVA d prime) was found only in MPS VI.ConclusionsPhysical Symptom Score increased with age in attenuated MPS I, II and VI, reflecting progressive somatic burden of disease despite treatment with enzyme replacement therapy. Furthermore, the association of increased somatic disease burden with decreased neurocognitive ability suggests that both measures reflect disease severity and are not independent.

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Diffusion tensor imaging and myelin composition analysis reveal abnormal myelination in corpus callosum of canine mucopolysaccharidosis I

Cited by 15 publications

References 25 publications

Diffusion tensor imaging findings suggestive of white matter alterations in a canine model of mucopolysaccharidosis type I

Diffusion tensor imaging findings suggestive of white matter alterations in a canine model of mucopolysaccharidosis type I

Myelin and Lipid Composition of the Corpus Callosum in Mucopolysaccharidosis Type I Mice

Association of somatic burden of disease with age and neuropsychological measures in attenuated mucopolysaccharidosis types I, II and VI

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