Fast track — ArticlesBiological and clinical manifestations of Huntington's disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data
Introduction
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder with complete penetrance. HD is caused by a CAG repeat expansion in HTT, the gene that encodes huntingtin, which is on chromosome 4.1 Individuals who have inherited the expanded CAG trinucleotide repeat can be identified before symptom onset by predictive genetic testing. The prevalence of HD is about 4–10 per 100 000 in the general population of the western hemisphere, but many more are at risk of developing the disease. HD is characterised by a triad of signs: progressive motor dysfunction, cognitive decline, and psychiatric disturbance. The formal diagnosis of HD is made on the basis of motor signs that are regarded as diagnostic for HD in a person with a positive family history, confirmed by gene testing. The concept of “motor onset” or “phenoconversion” is defined as the unambiguous presence of an otherwise unexplained movement disorder;2 however, this does not account for the many individuals who show cognitive or behavioural disturbances several years before the onset of motor symptoms.3
The mean age at formal diagnosis is in the mid-40s, and most people with the CAG repeat expansion seem healthy until adulthood. The length of the CAG repeat accounts for 50–70% of the variability in age at clinical onset, whereby individuals with longer repeat lengths commonly have an earlier onset than those with shorter repeat lengths.4 However, subclinical changes precede the onset of overt clinical manifestations; cross-sectional evidence shows that individuals with clinically premanifest HD perform significantly worse on a variety of cognitive measures5 and motor and oculomotor assessments,6, 7 and have increased psychopathology.8 Structural neuropathology during the decade before the estimated age of symptom onset, including volume reduction in the striatum,9 loss of grey and white matter,10, 11 and cortical thinning,12 have been reported as well as reduced neural activation13 and a reduction in raclopride (D2 dopamine receptor) binding.14
Much remains unknown about the mechanisms that underlie the considerable variation in age of onset, rate of progression, and clinical phenotypical characteristics. Extrapolation from existing studies is problematic because many did not exclude individuals with premanifest HD who might have shown some soft motor signs; rather, these studies relied solely on the unified HD rating scale (UHDRS) diagnostic confidence score to measure a patient's prediagnosis status.2 This stratification score has high inter-rater variability and might also include individuals who do not have true pre-motor symptoms.
The optimum point at which to introduce neuroprotective drugs to delay symptom onset or slow the rate of disease progression is likely the premanifest stage, before the onset of rapid neuronal degeneration and the emergence of clinical symptoms. Data from a conditional HD mouse model suggest the potential reversibility of this neuronal dysfunction, leading to a full recovery when expression of the mutant gene is halted.15 To test potential treatments, sensitive and stable markers of change in individuals with premanifest and early HD must be identified. However, despite some encouraging results from in vitro studies and animal trials, disease-modifying therapeutic trials in HD are limited by a paucity of robust endpoints by which disease progression can be tracked. Current clinical rating scales lack sensitivity, have floor or ceiling effects, particularly in premanifest individuals, and require long observation periods to unequivocally show a change. Improvements in the efficiency and precision of objective measurements of disease progression in individuals in the premanifest and early stages of HD could lead to biomarkers that are better able to assess disease progression and measure the effects of therapeutic interventions.
The full penetrance of the HD mutation in people with an HD CAG expansion of more than 40 provides a unique opportunity to examine the pattern of signs, symptoms, and neurobiological changes as they emerge. In TRACK-HD we aim to exploit the certainty of disease manifestation to ascertain the biomarkers and endpoints required to test therapeutic interventions early in the disease.
TRACK-HD is a multinational longitudinal observational study designed with similar principles to a clinical trial, with rapid study preparation and data acquisition, rigorous quality assurance and quality control, and blinded data analysis. We report the baseline data from the TRACK-HD cohort with the aim of identifying the changes that occur from health to early stage 2 disease by assessing a wide range and novel combination of measurements (ie, genetic, clinical, cognitive, quantitative motor, oculomotor, neuropsychiatric, and 3T MRI). The cohort is evenly divided among HTT expansion carriers with no or minimum motor signs (pre-motor) who are up to about 16 years away from a predicted disease diagnosis,16 early manifest HD individuals, and age-matched and sex-matched controls.
Section snippets
Participants
We report the baseline cross-sectional data from a longitudinal study with three annual timepoints. Full enrolment and testing was completed over a period of 8 months. The first participant was enrolled in January, 2008, and all assessments were completed by August, 2008. Individuals with expansion of the HD gene were recruited from the National Hospital for Neurology and Neurosurgery, London, UK, the Department of Medical Genetics at the University of British Columbia, Vancouver, Canada, the
Results
385 potential participants were screened and 381 met the inclusion criteria and were enrolled. 14 of these were subsequently excluded: one owing to stage 3 disease and the rest because they were unable to undergo MRI; one further participant withdrew their consent. Owing to difficulties in recruiting the required number of individuals with premanifest HD who had total motor scores of 5 or less and a burden of pathology score of more than 250, waivers were granted for the inclusion for nine
Discussion
In the TRACK-HD study, 243 HD expansion mutation carriers and 123 age-matched controls were studied over an 8-month recruitment and data collection period by the use of a collection of rigorous assessments that included novel multi-site applications of 3T MRI, quantitative motor, cognitive, and neuropsychiatric methods. Our findings indicate an increasing separation of the disease course of preclinical HD from healthy individuals at an early stage, in a cohort of premanifest HD gene carriers
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