Huntington disease: natural history, biomarkers and prospects for therapeutics

Key Points

  • No disease-modifying treatments are currently available for Huntington disease (HD), but clinical trials of potential compounds are imminent; identification of suitable biomarkers to assess therapeutic efficacy is a research priority

  • Quantifiable measures of patient function, including motor and cognitive assessments, have shown disease-related change in early HD but still lack sensitivity in premanifest cohorts

  • Structural imaging measures such as striatal atrophy show the largest effect sizes both cross-sectionally and longitudinally, and have the potential to track disease progression even in the premanifest period

  • Functional MRI and magnetic resonance spectroscopy are also sensitive for detecting change, but have not yet been well-validated longitudinally

  • PET imaging is quantitative and shows sensitivity to early premanifest disease, and may be useful longitudinally, but has the disadvantage of being expensive and complex

  • Biochemical assays of relevant molecules provide a more direct reflection of disease mechanisms; such measures have not been fully validated, and future work will focus on their development

Abstract

Huntington disease (HD) can be seen as a model neurodegenerative disorder, in that it is caused by a single genetic mutation and is amenable to predictive genetic testing, with estimation of years to predicted onset, enabling the entire range of disease natural history to be studied. Structural neuroimaging biomarkers show that progressive regional brain atrophy begins many years before the emergence of diagnosable signs and symptoms of HD, and continues steadily during the symptomatic or 'manifest' period. The continued development of functional, neurochemical and other biomarkers raises hopes that these biomarkers might be useful for future trials of disease-modifying therapeutics to delay the onset and slow the progression of HD. Such advances could herald a new era of personalized preventive therapeutics. We describe the natural history of HD, including the timing of emergence of motor, cognitive and emotional impairments, and the techniques that are used to assess these features. Building on this information, we review recent progress in the development of biomarkers for HD, and potential future roles of these biomarkers in clinical trials.

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Figure 1: Natural history of clinical HD, and hypothesized changes in imaging biomarkers.
Figure 2: Longitudinal data from TRACK-HD.
Figure 3: Change with CAP score of clinical and imaging variables: data from TRACK-HD.
Figure 4: Change in clinical features: data from COHORT and REGISTRY databases.
Figure 5: Schematic diagram of Huntington disease cellular pathogenesis.
Figure 6: Conceptual diagram of possible circuitry-related degeneration in Huntington disease.

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Acknowledgements

We acknowledge the contributions of the REGISTRY and COHORT study investigators for their work in collecting the data displayed in Figure 4. A complete list of the COHORT study investigators appears in Huntington Study Group COHORT Investigators & Dorsey (2012),23 and a complete list of the REGISTRY study investigators appears in Orth, M. & The European Huntington's Disease Network (2010).17 In addition, we thank the European Huntington's Disease Network, the Huntington Study Group, the CHDI Foundation, and HP Therapeutics for providing financial support for the data collection efforts that led to Figure 4. We thank all the study participants and their families, including the Venezuela study, the JHU study, and the TRACK-HD, REGISTRY, PREDICT-HD, and COHORT studies, who made this work possible. We thank Simon Noble, Cristina Sampaio and Robi Blumenstein for comments and suggestions. We thank Sharon Blackburn for figure drawing.

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C.A.R., E.H.A, E.J.W., D.R.L., J.D.L., J.H.W., R.I.S., B.R.L., J.C.S., R.R., P.G.U., R.L.M. and S.J.T. researched the data for the article. C.A.R., E.H.A, E.J.W., D.R.L., J.D.L., J.H.W., R.I.S. and S.J.T. provided substantial contributions to discussions of the content. C.A.R., E.H.A, E.J.W., D.R.L., J.D.L., J.H.W., R.I.S., B.R.L., J.C.S., R.R., P.G.U., A.W., R.L.M. and S.J.T. wrote the article. All authors reviewed and/or edited the manuscript before submission.

Correspondence to Christopher A. Ross.

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Ross, C., Aylward, E., Wild, E. et al. Huntington disease: natural history, biomarkers and prospects for therapeutics. Nat Rev Neurol 10, 204–216 (2014). https://doi.org/10.1038/nrneurol.2014.24

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