Biological and clinical manifestations of Huntington's disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data

Abstract

Summary Background Huntington’s disease (HD) is an autosomal dominant, fully penetrant, neurodegenerative disease that most commonly affects adults in mid-life. Our aim was to identify sensitive and reliable biomarkers in premanifest carriers of mutated HTT and in individuals with early HD that could provide essential methodology for the assessment of therapeutic interventions. Methods This multicentre study uses an extensive battery of novel assessments, including multi-site 3T MRI, clinical, cognitive, quantitative motor, oculomotor, and neuropsychiatric measures. Blinded analyses were done on the baseline cross-sectional data from 366 individuals: 123 controls, 120 premanifest (pre-HD) individuals, and 123 patients with early HD. Findings The first participant was enrolled in January, 2008, and all assessments were completed by August, 2008. Cross-sectional analyses identified significant changes in whole-brain volume, regional grey and white matter differences, impairment in a range of voluntary neurophysiological motor, and oculomotor tasks, and cognitive and neuropsychiatric dysfunction in premanifest HD gene carriers with normal motor scores through to early clinical stage 2 disease. Interpretation We show the feasibility of rapid data acquisition and the use of multi-site 3T MRI and neurophysiological motor measures in a large multicentre study. Our results provide evidence for quantifiable biological and clinical alterations in HTT expansion carriers compared with age-matched controls. Many parameters differ from age-matched controls in a graded fashion and show changes of increasing magnitude across our cohort, who range from about 16 years from predicted disease diagnosis to early HD. These findings might help to define novel quantifiable endpoints and methods for rapid and reliable data acquisition, which could aid the design of therapeutic trials. Funding CHDI/High Q Foundation.

An image‐based model of brain volume biomarker changes in Huntington's disease

“…The pre‐HD cohort is distributed throughout the sequence with peaks at the first and final events, indicating that premanifest subjects can be grouped as more “HC‐like” or more “HD‐like”. We further substantiate this by dividing the pre‐HD cohort into two subgroups, pre‐HD A and pre‐HD B, which are defined by the TRACK‐HD study according to the predicted time to onset 5. The predicted time to onset is based on an age‐ and CAG‐dependent empirical relation,26 with pre‐HD A subjects having predicted onset greater than 10.8 years and pre‐HD B subjects less than 10.8 years.…”

“…The TRACK‐HD dataset was used in all following analyses 5, 14. This study uses a total of 357 subjects with clinical diagnoses at baseline and quality‐controlled imaging data – 119 healthy control (HC), 120 premanifest (pre‐HD), and 118 manifest (HD) – from four different sites: Leiden (NL), London (UK), Paris (FR), and Vancouver (CA) (Table 1).…”

“…This is complicated by the difficulty in assigning gene‐positive subjects to suitable groups when conducting drug trials; within any group there may be a range of physiological and biophysical factors that cause a very different response to treatment. Furthermore, HD displays an extended premanifest period4, 5 during which therapeutic intervention is likely to be most effective. Identifying a suitable biomarker that captures disease stage may potentially aid trial efficiency when included in a stratified statistical analysis.…”

“…5, 14 This provides a uniquely fine‐grained data‐driven sequence of the regional appearance of brain volume abnormalities in HD and an image‐based staging system. Although the original EBM methods paper8 shows a HD model, it is for demonstration purposes only, using a small single‐centre study, and the work makes no evaluation of the potential for staging and prediction.…”

Structural and functional brain network correlates of depressive symptoms in premanifest Huntington's disease

“…It is characterized by cognitive, motor and neuropsychiatric impairment. Depression can precede the onset of motor symptoms by many years [Tabrizi et al, 2009] and has a significant impact on morbidity [Beglinger et al, 2010] with a lifetime prevalence of 20% in the pre‐symptomatic or premanifest stage [Julien et al, 2007]. Neuroimaging studies have identified specific brain variations associated with depression in HD including gray matter volume loss and white matter (WM) microstructural abnormalities in the rostral anterior cingulate [Hobbs et al, 2011; Sprengelmeyer et al, 2014], and abnormal task‐based activations in prefrontal cortex [Gray et al, 2013; Unschuld et al, 2012].…”