Abstract
Huntington's disease (HD) is an autosomal-dominant inherited neurodegenerative disorder that is caused by expansion of a CAG-repeat tract in the huntingtin gene and characterized by motor impairment, cognitive decline, and neuropsychiatric disturbances. Neuropathological studies show that disease progression follows a characteristic pattern of brain atrophy, beginning in the basal ganglia structures. The HD Regulatory Science Consortium (HD-RSC) brings together diverse stakeholders in the HD community—biopharmaceutical industry, academia, nonprofit, and patient advocacy organizations—to define and address regulatory needs to accelerate HD therapeutic development. Here, the Biomarker Working Group of the HD-RSC summarizes the cross-sectional evidence indicating that regional brain volumes, as measured by volumetric magnetic resonance imaging, are reduced in HD and are correlated with disease characteristics. We also evaluate the relationship between imaging measures and clinical change, their longitudinal change characteristics, and within-individual longitudinal associations of imaging with disease progression. This analysis will be valuable in assessing pharmacodynamics in clinical trials and supporting clinical outcome assessments to evaluate treatment effects on neurodegeneration.
Highlights
Huntington’s disease (HD) is an autosomal-dominant inherited neurodegenerative disorder characterized by motor impairment, cognitive decline, and neuropsychiatric disturbances
Neuropathological studies indicate that HD progression is accompanied by a characteristic pattern of brain atrophy, with the earliest and most dramatic changes evident in the basal ganglia, the caudate and putamen1 [6, 7]
Imaging studies in the 1990s demonstrated that reduced striatal volumes were detectable in vivo in the early stages of clinically-diagnosed HD [21, 23], and such volume loss has since been identified in individuals up to 24 years before clinical motor volumetric magnetic resonance imaging (vMRI) Biomarkers in Huntington’s Disease diagnosis [4, 22]
Summary
Huntington’s disease (HD) is an autosomal-dominant inherited neurodegenerative disorder characterized by motor impairment, cognitive decline, and neuropsychiatric disturbances. Reduced striatal volume is detectable more than 20 years prior to clinical motor diagnosis, whereas losses in other brain structures are more apparent in later disease stages [8, 24,25,26,27].
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