Brain Alterations in Aged OVT73 Sheep Model of Huntington's Disease: An MRI Based Approach

Toloo Taghian, Jillian Gallagher, Erin Batcho, Caitlin Pullan, Tim Kuchel, Thomas Denney, Raj Perumal, Shamika Moore, Robb Muirhead, Paul Herde, Daniel Johns, Chris Christou, Amanda Taylor, Thomas Passler, Sanjana Pulaparthi, Erin Hall, Sundeep Chandra, Charles A. O'Neill, Heather Gray-Edwards

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)


BACKGROUND: Huntington's disease (HD) is a fatal neurodegenerative autosomal dominant disorder with prevalence of 1 : 20000 that has no effective treatment to date. Translatability of candidate therapeutics could be enhanced by additional testing in large animal models because of similarities in brain anatomy, size, and immunophysiology. These features enable realistic pre-clinical studies of biodistribution, efficacy, and toxicity. OBJECTIVE AND METHODS: Here we non-invasively characterized alterations in brain white matter microstructure, neurochemistry, neurological status, and mutant Huntingtin protein (mHTT) levels in cerebrospinal fluid (CSF) of aged OVT73 HD sheep. RESULTS: Similar to HD patients, CSF mHTT differentiates HD from normal sheep. Our results are indicative of a decline in neurological status, and alterations in brain white matter diffusion and spectroscopy metric that are more severe in aged female HD sheep. Longitudinal analysis of aged female HD sheep suggests that the decline is detectable over the course of a year. In line with reports of HD human studies, white matter alterations in corpus callosum correlates with a decline in gait of HD sheep. Moreover, alterations in the occipital cortex white matter correlates with a decline in clinical rating score. In addition, the marker of energy metabolism in striatum of aged HD sheep, shows a correlation with decline of clinical rating score and eye coordination. CONCLUSION: This data suggests that OVT73 HD sheep can serve as a pre-manifest large animal model of HD providing a platform for pre-clinical testing of HD therapeutics and non-invasive tracking of the efficacy of the therapy.

Original languageEnglish
Pages (from-to)391-406
Number of pages16
JournalJournal of Huntington's disease
Issue number4
Early online date29 Sept 2022
Publication statusPublished or Issued - 2022


  • clinical translation
  • diffusion tensor imaging
  • Huntington’s disease
  • large animal model
  • magnetic resonance spectroscopy
  • transgenic OVT73 sheep model of Huntington’s disease

ASJC Scopus subject areas

  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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