NEWS & VIEWS NEURODEGENERATIVE DISEASE
Dorsey et al. 3 also examined other, more specific features of HD, such as the chorea and dystonia components of the UHDRS (both of which increased—that is, worsened—by 0.3 units per year) and a range of cognitive tests, including changes in verbal fluency (which declined by 0.7 points per year), symbol digit modality (which declined by 1.5 points per year) and various aspects of the Stroop test. The investigators evaluated how these changes differed as a function of disease stage by grouping the HD cohort into four equalsized groups repr esenting early, mild, moderate and advanced disease stages, as defined by TFC. The small group size and, therefore, low statistical power limits the conclusions that can be drawn from this analysis. It did, however, highlight the fact that some aspects of HD change at different rates over the disease course. For example, chorea seems to advance more slowly in later than in earlier disease. This finding could influence which aspects of disease are monitored in pharmacological trials, as the parameter selected will depend on the disease stage of the cohort being studied. Moreover, some measures of disease progression probably cannot advance beyond a certain point owing to the ceiling effects observed with commonly adopted rating scales. Although Dorsey et al.3 suggest that HD declines in a monotonic fashion, other studies have suggested that the disease progresses nonlinearly. TRACK-HD showed that pre-HD participants who were estimated to be less than 10.8 years from
Mapping the natural history of Huntington disease Roger A. Barker and Sarah L. Mason
A key challenge to improving the design of clinical trials in Huntington disease (HD) has been the limited data on the natural history of HD. A recent prospective longitudinal study has provided important information in this regard, which could be useful for future translation of disease-modifying therapies for early-stage HD.
Huntington disease (HD) is an autosomal dominant condition that typically presents in middle age with a combination of movement, cognitive and psychiatric problems, and leads to death 20–25 years later. HD is currently incurable, and although the underlying gene defect was discovered 20 years ago, its pathogenesis remains the subject of debate. Considerable efforts have been made to develop disease-modifying treatments to slow down disease progression and even delay onset, with many promising therapies emerging from the laboratory.1 Translation of such therapies to the clinic, however, is not straightforward, largely because easily accessible measures by which to track p rogression of this CNS disease are not available.
‘‘
…tools are now becoming available to assess whether symptomatic therapies are effective
’’
A number of recent studies have sought to better define the natural history of HD, including the stages immediately before and leading up to diagnosis2—a particularly challenging task given the delay between the start of the disease process and its overt clinical manifestations. Any disease- modifying therapy in HD is likely to be most beneficial in patients with early-stage manifest disease, as later stages of disease are associated with problems of informed consent and the difficulty of retaining patients for prolonged follow-up periods.
A better understanding of how the disease changes over time during early stages, therefore, would be invaluable. A recent study by Dorsey et al. as part of the Huntington Study Group is helpful in this respect.3 In the new study, a cohort of patients with manifest disease (n = 334), from whom at least 3 years’ worth of follow-up data were available, was compared with a smaller age-matched and sex-matched control group (n = 142). This group of patients is a subset of those who were enrolled into the multicentre, prospective Cooperative Huntington’s Observational Research Trial (COHORT),4 which includes 1,514 parti cipants with clinically definite HD. All patients in COHORT were followed up over time, but 3 consecutive years’ worth of longitudinal data—which included standard motor, cognitive and behavioural measures, as well as BMI, heart rate and blood pressure—were available from only 334 participants. The study by Dorsey et al. 3 showed, not surprisingly, that patients deteriorate over time on all measures. Moreover, such changes occur in a monotonic fashion. The investigators found that commonly used measures of disease were suitable for tracking disease progression. For example, in this cohort, the total motor score of the Unified HD Rating Scale (UHDRS) declined by a mean of 3 points per year; on average, the Mini-Mental State Examination score worsened by 0.7 points per year; total functional capacity (TFC) dropped by 0.6 points per year; and BMI decreased by 0.1 points per year.
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Barker, R. A. & Mason, S. L. Nat. Rev. Neurol. advance online publication 10 December 2013; doi:10.1038/nrneurol.2013.253
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NEWS & VIEWS predicted disease onset had a faster rate of disease progression than did those estimated to be further away from development of manifest disease.5 A possible limitation of the new study 3 was that owing to its observational design, therapeutic interventions varied between patients, which could have affected how some aspects of the disease, such as chorea, change over time. Nevertheless, the nature of the study ensured that the data reflected ‘real life’ practice, with the caveat that symptomatic treatment of HD can differ substantially across the globe, especially in the USA compared with Europe.6 The study by Dorsey et al.3 adds to the small but growing list of published studies recording the natural history of HD, all of which help to provide the necessary background information to enable planning of future trials. Such trials can now be powered more confidently in terms of the sample sizes needed to see significant effects, together with better-defined end points. In recent years, the emphasis has been on trialling of
agents that modify disease progression, but tools are now becoming available to assess whether symptomatic therapies are effective. The challenges now are to decide what those therapies should be, to determine the length of time needed before significant effects can be seen, and to define the stage of HD at which such an intervention will be most beneficial. The study by Dorsey et al.3 has provided useful information in these last two areas. In conclusion, this study once more highlights the value of prospective observational studies in large cohorts of patients using standard measures, which provides the foundations for much-needed drug trials in HD. Moreover, this approach could help inform the design of all studies that aim to address the growing burden of neurodegenerative disorders of the ageing CNS. John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, Forvie Site, Robinson Way, University of Cambridge, Cambridge CB2 0PY, UK (R. A. Barker, S. L. Mason).
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Correspondence to: R. A. Barker
[email protected] Competing interests The authors declare no competing interests. 1.
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Mason, S. L. & Barker, R. A. Emerging drug therapies in Huntington’s disease. Expert Opin. Emerg. Drugs 14, 273–297 (2009). Tabrizi, S. J. et al. Biological and clinical changes in premanifest and early stage Huntington’s disease in the TRACK-HD study: the 12-month longitudinal analysis. Lancet Neurol. 10, 31–42 (2011). Dorsey, E. R. et al. Natural history of Huntington disease. JAMA Neurol. http://dx.doi.org/ 10.1001/jamaneurol.2013.4408. Huntington Study Group COHORT Investigators & Dorsey, E. Characterization of a large group of individuals with Huntington disease and their relatives enrolled in the COHORT study. PLoS ONE 7, e29522 (2012). Tabrizi, S. J. et al. Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington’s disease in the TRACK-HD study: analysis of 36-month observational data. Lancet Neurol. 12, 637–649 (2013). Burgunder, J. M. et al. An international surveybased algorithm for the pharmacologic treatment of chorea in Huntington’s disease. PLoS Curr. 3, RRN1260 (2011).
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