Presentation Title

Diffusion Tensor Imaging of Huntington’s Disease in Sheep at 3T MRI

Faculty Mentor

Thomas Denney

Start Date

17-11-2018 8:30 AM

End Date

17-11-2018 10:30 AM

Location

HARBESON 20

Session

POSTER 1

Type of Presentation

Poster

Subject Area

engineering_computer_science

Abstract

Huntington’s Disease (HD) is a dominantly inherited progressive neurogenerative disorder caused by an expansion of the CAG sequence of the huntingtin (HTT) gene in exon 1, and the expansion length correlates broadly with the onset and severity of disease. HD symptoms are typically characterized by chorea, dementia, and impairments in psychiatric competencies. Treatment is currently restricted to supportive care; however, development of new biologics like oligonucleotides and gene therapy designed to silence HTT expression show great promise in animal models of HD. In 2008, a humanized HD sheep transgenic model was developed for study of HD and to provide a model that recapitulates adult onset HD. This model contains a clinically relevant HD mutation, (CAG)74--CAA-CAG, and they express the expanded human mHTT throughout the brain and exhibit neutrophil aggregation as well as intranuclear neuronal inclusions. High field (3T) MRI was utilized to determine if the HD sheep exhibit the traditional neurodegenerative changes of HD, which has been previously shown as loss of connectivity and volume in white matter tracts of the brain. In previous studies, humans with HD have exhibited higher values of apparent diffusion coefficient (ADC) and lower values of fractional anisotropy (FA). Using diffusion tensor imaging (DTI), data was analyzed from both normal and transgenic sheep using a region of interest (ROI) analysis to detect white matter alterations. ROIs were segmented on the corpus callosum, midbrain, motor cortex, parietal cortex, occipital cortex, left and right internal capsules, and left and right caudal internal capsules. The diffusion images were acquired on a 3T SIEMENS Skyra scanner using a 2D EPI diffusion sequence. A HARDI scheme was used, and a total of 512 diffusion sampling directions were acquired for each image.

Summary of research results to be presented

For each region, the mean and standard deviation of the ADC, FA, Radial Diffusion, and Axial Diffusion was computed. There was a statistically significant difference in the ADC mean in the occipital cortex; the transgenic value was 0.86, the normal value was 0.80, and the p value was 0.039. Variability of parameters across the regions was assessed using measurements of standard deviation (SD), for which there were several statistically significant differences. For the ADC SD in the corpus callosum, the transgenic value was 0.59, the normal value was 0.30, and the p value was 0.021. For the Axial Diffusion SD in the corpus callosum, the transgenic value was 0.57, the normal value was 0.29, and the p value was 0.01. For the Radial Diffusion SD in the corpus callosum, the transgenic value was 0.61, the normal value was 0.33, and the p value was 0.032. For the Radial Diffusion SD in the right internal capsule, the transgenic value was 0.08, the normal value was 0.12, and the p value was 0.036. There was no statistical significance in the FA values between the groups, which implies that there was no damage to white matter tracts in these regions. While further studies are needed to validate these trends, DTI analysis has proven to be a potential biomarker for HD due to its ability to detect changes in white matter diffusion in sheep and other large-brained animal models with HD.

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Nov 17th, 8:30 AM Nov 17th, 10:30 AM

Diffusion Tensor Imaging of Huntington’s Disease in Sheep at 3T MRI

HARBESON 20

Huntington’s Disease (HD) is a dominantly inherited progressive neurogenerative disorder caused by an expansion of the CAG sequence of the huntingtin (HTT) gene in exon 1, and the expansion length correlates broadly with the onset and severity of disease. HD symptoms are typically characterized by chorea, dementia, and impairments in psychiatric competencies. Treatment is currently restricted to supportive care; however, development of new biologics like oligonucleotides and gene therapy designed to silence HTT expression show great promise in animal models of HD. In 2008, a humanized HD sheep transgenic model was developed for study of HD and to provide a model that recapitulates adult onset HD. This model contains a clinically relevant HD mutation, (CAG)74--CAA-CAG, and they express the expanded human mHTT throughout the brain and exhibit neutrophil aggregation as well as intranuclear neuronal inclusions. High field (3T) MRI was utilized to determine if the HD sheep exhibit the traditional neurodegenerative changes of HD, which has been previously shown as loss of connectivity and volume in white matter tracts of the brain. In previous studies, humans with HD have exhibited higher values of apparent diffusion coefficient (ADC) and lower values of fractional anisotropy (FA). Using diffusion tensor imaging (DTI), data was analyzed from both normal and transgenic sheep using a region of interest (ROI) analysis to detect white matter alterations. ROIs were segmented on the corpus callosum, midbrain, motor cortex, parietal cortex, occipital cortex, left and right internal capsules, and left and right caudal internal capsules. The diffusion images were acquired on a 3T SIEMENS Skyra scanner using a 2D EPI diffusion sequence. A HARDI scheme was used, and a total of 512 diffusion sampling directions were acquired for each image.