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

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.

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.