Dissertation
Brain structure and function in juvenile onset Huntington's disease
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2020
DOI: 10.17077/etd.005279
Abstract
Objective: To assess brain structure and function in a sample of JHD patients and several mice models of HD that likely represent the human JHD phenotype.
Methods: Despite sharing the mutation in the Huntingtin gene, adult-onset HD (AOHD) characteristically presents as a hyperkinetic motor disorder, while juvenile-onset HD (JHD) typically presents as a hypokinetic motor disease. The University of Iowa Kids-JHD program enrolled children 5-25 years of age who have already received the clinical diagnosis. A total of 19 children with JHD (mean CAG = 72) were studied. JHD patients were compared to healthy controls (n = 234) using cross-sectional study design. Volumetric data from structural MRI, fractional anisotropy (FA) from diffusion tensor imaging (DTI) and seed-to-seed correlations from resting state functional MRI (R-fMRI) were compared between groups. In addition, we used the same procedure to evaluate brain morphology of R6/2, zQ175, and HdhQ250 HD mice models.
Results: Patients with JHD had substantially reduced Intracranial Volumes (ICV). After controlling for the small ICV size, the volumes of subcortical regions (caudate, putamen, globus pallidus and thalamus) and cortical white matter were significantly decreased in JHD patients. However, the cerebellum was proportionately enlarged in the JHD sample. The cerebral cortex was largely unaffected. Likewise, HD mice had a lower volume of striatum and proportionally higher volume of cerebellum, mirroring the human MRI results. DTI and R-fMRI measures support abnormal structural and functional connectivity in the striatum of JHD participants. Finally, the size of the striatum, the strength of the internal capsule FA and the connectivity between the putamen and the globus pallidus were directly related to motor function abnormalities (small volume, low FA and poor striatal co-activation predicted worse motor scores).
Conclusions: AOHD and JHD share the same pathology, but striatal degeneration is more severe and starts earlier in JHD patients. The primary pathology of JHD extends beyond changes in striatal volume. Brain morphology in both mice and human JHD patients shows proportional cerebellar enlargement. Larger cerebellar size and hyper-connectivity support the notion that the cerebellum attempted to compensate for failing striatal circuitry, but was overwhelmed by the degree of abnormal striatal development. Smaller volume and worse connectivity of the putamen may shift the balance between direct (excitatory) and indirect (inhibitory) pathways in the striatum, driving the hypokinetic motor symptoms in JHD, not seen in the hyperkinetic chorea-like phenotype of AOHD.
Details
- Title: Subtitle
- Brain structure and function in juvenile onset Huntington's disease
- Creators
- Alexander Vladimirovich Tereshchenko
- Contributors
- Peg Nopoulos (Advisor)Aaron Boes (Committee Member)David Moser (Committee Member)Nandakumar Narayanan (Committee Member)John Kamholz (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Neuroscience
- Date degree season
- Spring 2020
- DOI
- 10.17077/etd.005279
- Publisher
- University of Iowa
- Number of pages
- x, 74 pages
- Copyright
- Copyright 2020 Alexander Vladimirovich Tereshchenko
- Language
- English
- Description illustrations
- color illustrations
- Description bibliographic
- Includes bibliographical references (pages 58-74).
- Public Abstract (ETD)
Huntington’s Disease (HD) is a fatal neurodegenerative disorder with no cure, which manifests in cognitive, behavioral and motor changes. HD is caused by a DNA triplet repeat (CAG) expansion in the huntingtin gene (HTT). It is not known why adult-onset HD patients present with hyperkinetic symptoms (chorea), while juvenile-onset HD patients display a hypokinetic phenotype (bradykinesia, rigidity, tremors). The overall purpose of this research is to evaluate brain structure, function and development in juvenile-onset Huntington’s disease patients.
The study evaluates volumes using structural Magnetic Resonance Imaging (MRI), white matter integrity using Diffusion Tensor Imaging, and brain function using resting state-functional connectivity MRI. The University of Iowa Kids-HD participants are rare, and the JHD participants are ultra-rare. The combination represents a truly unique study sample. The biggest advantage of our study is the ability to study the effects of mutant HTT on the developing brain across the entire spectrum of CAG repeats.
While the primary pathology of both AOHD and JHD is thought to be located in the striatum, the role of other brain regions in HD is virtually unexplored. Striatal degeneration is a key component in the disease process. Research in the past few years discovered novel anatomical connections between the cerebellum and the striatum. Our research supports the notion that the abnormal development of circuitry between the cerebellum and the striatum is a possible component of HD pathoetiology.
- Academic Unit
- Interdisciplinary Graduate Program in Neuroscience
- Record Identifier
- 9983949593702771
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