Longitudinal Assessment of Brain Structure and Function in Juvenile Onset Huntington's Disease

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PROJECT SUMMARY: Huntington's disease (HD) is a genetic neurodegenerative disorder caused by an abnormal expansion of a trinucleotide CAG repeat region of the huntingtin gene (HTT). The majority of patients with HD do not present with symptoms until the age of 40-50 years old, on average, which is referred to as Adult-Onset HD (AOHD). A much smaller percentage of patients with HD receive a motor diagnosis prior to the age of 21, which is referred to as Juvenile-Onset HD (JOHD). Although patients with JOHD have the same core triad of cognitive, behavior, and motor symptoms, there are unique clinical characteristics that are distinct from AOHD. Specifically, patients with JOHD have less chorea compared to patients with AOHD, often presenting with rigidity and bradykinesia. However due to the rarity, there is a paucity of data regarding the symptom characterization, the neurobiology, and the progression of JOHD. Large-scale observational studies have been performed in AOHD, which have broadened our understanding of HD and opened the doors for the development and conduct of clinical trials. Patients with JOHD have been excluded from clinical trials, leaving patients and their families feeling hopeless and abandoned by the scientific community. Large-scale, longitudinal studies in patients with JOHD are critical to bettering our understanding of this devastating disease and providing hope to patients who have felt left behind as therapeutic strategies advance in AOHD. We propose here the first ever comprehensive, clinical and neuroimaging study of JOHD. At the University of Iowa, we have performed a pilot longitudinal clinical and neuroimaging study to understand the progression of JOHD. We compared JOHD subjects to age and sex matched controls. In addition, we compared rate of change over time to AOHD subjects from the large PREDICT-HD study. Results from our pilot are striking: First, standard measures of cognition, and standard measures of motor dysfunction (United Huntington's Disease Rating Scale or UHDRS) show significant decline over time, supporting the notion that these measures accurately track disease. This includes a `hypokinesis' sub-score of the UDRS that is particularly relevant for JOHD subjects. Second, patients with JOHD demonstrate impressive striatal atrophy even in very early stages after motor onset. However, the striatum and other subcortical structures continue to degenerate, suggesting that they can be used for quantitative measures of disease progression. Third, striatal volume is closely related to clinical symptoms, showing strong correlations to the UHDRS, and cognitive symptoms are associated with thalamus volume. Fourth, in all of these observations, the rate of progression is faster and less variable in JOHD compared to patients with AOHD. These findings suggest JOHD may be a superior group for clinical trials.