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Hum Brain Mapp. 2019 Apr 1;40(5):1419-1433. doi: 10.1002/hbm.24456. Epub 2018 Oct 30.

Regional subcortical shape analysis in premanifest Huntington's disease.

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Department of Electrical and Electronic Engineering, Southern University of Science and Technology, Shenzhen, Guangdong, China.
Division of Neurobiology, Departments of Psychiatry, Neurology, Neuroscience and Pharmacology, and Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Departments of Neurology and Psychiatry, The University of Iowa Carver College of Medicine, Iowa City, Iowa.
Department of Applied Mathematics and Statistics, Johns Hopkins University, Baltimore, Maryland.
Center for Imaging Science, Johns Hopkins University, Baltimore, Maryland.
Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland.
Neurology Service and GRECC, VAAAHS, Ann Arbor, Michigan.
Department of Neurology, University of Michigan Medical School, Ann Arbor, Michigan.
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland.


Huntington's disease (HD) involves preferential and progressive degeneration of striatum and other subcortical regions as well as regional cortical atrophy. It is caused by a CAG repeat expansion in the Huntingtin gene, and the longer the expansion the earlier the age of onset. Atrophy begins prior to manifest clinical signs and symptoms, and brain atrophy in premanifest expansion carriers can be studied. We employed a diffeomorphometric pipeline to contrast subcortical structures' morphological properties in a control group with three disease groups representing different phases of premanifest HD (far, intermediate, and near to onset) as defined by the length of the CAG expansion and the participant's age (CAG-Age-Product). A total of 1,428 magnetic resonance image scans from 694 participants from the PREDICT-HD cohort were used. We found significant region-specific atrophies in all subcortical structures studied, with the estimated abnormality onset time varying from structure to structure. Heterogeneous shape abnormalities of caudate nuclei were present in premanifest HD participants estimated furthest from onset and putaminal shape abnormalities were present in participants intermediate to onset. Thalamic, hippocampal, and amygdalar shape abnormalities were present in participants nearest to onset. We assessed whether the estimated progression of subcortical pathology in premanifest HD tracked specific pathways. This is plausible for changes in basal ganglia circuits but probably not for changes in hippocampus and amygdala. The regional shape analyses conducted in this study provide useful insights into the effects of HD pathology in subcortical structures.


circuit; premanifest Huntington's disease; shape; subcortical structures; subregion


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