Research reportStriatal and white matter predictors of estimated diagnosis for Huntington disease
Introduction
Huntington disease (HD) is an autosomal dominant neurodegenerative disease caused by a polyglutamine expansion within the N-terminus of the huntingtin protein [13]. HD is characterized by loss of movement control, cognitive ability, and emotional regulation and results in death approximately 15–20 years following motor diagnosis [11], [35]. Overall loss of brain mass is substantial, on the order of 30% by the time of death [38]. The unique value of HD as a model for the development of neuroprotective therapies for neurodegenerative disorders hinges on the ability to know, with certainty and years prior to diagnosis, which individuals will develop the disease. PREDICT-HD is a long-term observational study of a large population of participants who are known to carry the HD gene mutation, but who were not yet diagnosed with the disease at the time of entry into the study. The goals of PREDICT-HD are to identify measurable and sensitive neuropsychological, clinical, or imaging changes that emerge prior to the somewhat coarse endpoint of disease diagnosis. It is reasonable to think that neuroprotective therapies will have more benefit the earlier they are provided, but demonstration of the benefits will require the development of sensitive clinical and imaging markers of disease progression in the prodromal stage of HD.
Previous MRI studies have documented striatal volume decrements long before diagnosis [3], [4], [29], as well as a steady progression of volume decrement as diagnosis approaches [2], [28]. In addition, imaging studies have identified changes in the cerebral cortex that also occur either prior to the diagnosis or early in the course of the disease [17], [24], [26], [27], [29], [32], [37]. However, most of these studies have been relatively small, single-site investigations.
The purpose of the current study was to cross-sectionally examine baseline imaging measures in a multi-national sample of prodromal HD participants [27], [28]. The utility of imaging for early disease assessment as a possible biomarker for clinical trial design was a primary focus. All participants had structural MRI scans at 1.5 T, followed by automated volumetric analysis of both cortical and subcortical brain regions.
Section snippets
Participants
Participants were recruited from the PREDICT-HD study, an ongoing longitudinal observational study conducted at 32 sites in the United States, Canada, Australia, Germany, Spain, and the United Kingdom. All aspects of the study were approved by the Institutional Review Board at each participating institution, and all aspects of the study are in compliance with national legislation and the Declaration of Helsinki. Participants underwent informed consent procedures and signed consents for both
Group comparisons
Mean brain tissue volumes for each group (Control, Far, Mid, Near) as well as analyses of structure ratios (i.e., volumes divided by ICV) adjusted for age and gender are shown in Table 2. Except cerebellum, group differences met our strict criteria for statistical significance for all structures. Planned post hoc comparisons showed that all prodromal subgroups differed significantly from Controls. Although most subgroups differed from one another in a stepwise fashion for most brain structures,
Discussion
This cross-sectional study of over 600 gene-positive participants in the prodromal stages of HD shows clearly that the volume of all brain structures (except cerebellum), including total brain, cerebral white matter, cortical gray matter, caudate, putamen, and thalamus, is less than that of Controls in all three prodromal subgroups (Near, Mid, and Far from estimated time of diagnosis). Our confidence in these results is enhanced by (1) the large sample size, (2) the stepwise reduction in brain
Conflict of interest statement
The authors declare that they have no competing financial interests.
Acknowledgements
We thank the PREDICT-HD sites, the study participants, and the National Research Roster for Huntington Disease Patients and Families. This research is supported by the National Institutes for Health, National Institute of Neurological Disorders and Stroke (NS40068) and CHDI Foundation, Inc.
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