based on estimated time to diagnosis cannot perfectly represent the relationship that would be seen if true years to diagnosis were known, it can be shown that an accurate expected time proxy leads to approximations providing useful bounds on the true average relationships. For example, the (essentially) uniformly concave or convex nature of each curve in fig 3 allows invocation of Jensen’s inequality33 to suggest that we are estimating an upper limit to the true time course of mean change. Further mathematical arguments beyond the realm of this paper also show that it is unlikely that this upper bound dramatically overestimates the true mean time of onset of these deficits. Hence while resisting the temptation to over interpret these curves, we feel comfortable in our claim that they are strong evidence that detectable deficits begin between 10 and 20 years before HD diagnosis in the average CAG expanded subject. A more detailed and mathematical exposition regarding the limits of interpretability for this class of prognostic model will also be forthcoming in a separate report. Which of the outcomes described here is the strongest marker of developing HD? Again, we must remember that the models we have presented actually reflect the relationship between these markers and another known marker—CAG repeat length (corrected for age). While the relative strengths of these relationships provide a tentative basis for judgment, they are not guaranteed to reflect the relative prognostic importance that we will eventually observe with actual clinical diagnosis times. Similarly, we cannot yet know to what extent each measure independently contributes prognostic information. For example, striatal volume shows the strongest relationship to estimated prognosis in our analyses. Given the well known central role of basal ganglia deterioration in HD, we will not be surprised if this measure remains the strongest individual predictor when we can analyse observed onset. Nonetheless, it is possible that its relative strength in the current analysis could be due to an especially tight CAG length association that does not necessarily translate into the best incremental independent prediction of true prognosis. Our findings of cognitive, sensory, motor and striatal volumetric changes well before disease diagnosis are unequi- vocal, but it remains unknown whether these changes are of functional significance until our longitudinal data are acquired. Also, it is not known whether there are very subtle abnorm- alities, perhaps imperfectly reflected in these markers, prior to the evident upper limits that we have estimated here. Although not included in the current report, the Predict-HD study includes a comparison group of participants who are from HD families but are known not to have the CAG expansion. Once sufficient data from this sample become available, it may be possible to detect subtle abnormalities even earlier than the current report suggests. Current hopes for reducing the burden of neurodegenerative disease rely on the idea of preventing disease onset and slowing progression so that people at risk may live out a longer portion of their lifespan as healthy, fully functioning individuals. For this to be possible, promising therapeutic agents must be tested for their ability to slow early disease progression. These cross sectional findings from Predict-HD indicate the approximate time scale of measurable disease development, and suggest disease markers which may be candidate surrogates for use in preventive trials. Furthermore, even markers that fail as treatment response surrogates will have great value for risk stratification in such trials. With validation and refinement through longitudinal study, it will be possible in just a few more years to confirm such markers, making it feasible to initiate the J Neurol Neurosurg Psychiatry 2008;79:874–880. doi:10.1136/jnnp.2007.128728 R e s e a r c h p a p e r first preventive trials in individuals with the expansion prior to functional decline and diagnosis. HD CAG Author affiliations: 1 University of Iowa, The Roy J and Lucille A Carver College of Medicine, Iowa City, Iowa, USA; 2 Indiana University, Department of Psychology, Bloomington, Indiana, USA; 3 University of Washington, Department of Radiology, Seattle, Washington, USA; 4 Johns Hopkins University School of Medicine, Department of Psychiatry, Division of Neurobiology, Baltimore, Maryland, USA; 5 Park Nicollet Clinic, Department of Neurosciences, St Louis Park, Minnesota, USA; 6 Center for Movement Disorders, Markham, Ontario, Canada; 7 Massachusetts General Hospital, Neuroscience Center, Boston, Massachusetts, USA; 8 University of Rochester, Clinical Trials Coordination Center, Rochester, New York, USA; 9 University of Rochester Medical Center, Department of Biostatistics, Rochester, New York, USA; 10 University of British Columbia, Medical Genetics, Vancouver, British Columbia, Canada; 11 Huntington Study Group, Rochester, New York, USA Funding: National Institute of Neurological Disorders and Stroke grant No 40068, the National Institutes of Mental Health grant No 01579, Roy J Carver Trust Medicine Research Initiative, Howard Hughes Medical Institute, and High Q Foundation grants to Jane S Paulsen, the Huntington’s Disease Society of America, the Huntington’s Society of Canada, the Hereditary Disease Foundation, and the High Q Foundation grants to the Huntington Study Group. National Institute of Neurological Disorders and Stroke grant No 16375 to CAR. The NIH HD Roster Contract to Indiana University. Competing interests: None. Ethics approval: Study activities were reviewed and approved by institutional review boards at all study and data processing sites. REFERENCES 1. Gusella JF, MacDonald ME. Huntington’s disease: CAG genetics expands neurobiology. Curr Opin Neurobiol 1995;5:656–62. 2. Paulson HL, Fischbeck KH. Trinucleotide repeats in neurogenetic disorders. Annu Rev Neurosci 1996;19:79–107. 3. Langbehn DR, Brinkman R, Faulush D, et al. A new model for prediction of the age of onset and penetrance for Huntington’s disease based on CAG length. Clin Genet 2004;65:267–77. 4. Penney JB, Jr, Young AB, Shoulson I, et al. Huntington’s disease in Venezuela: 7 years of follow-up on symptomatic and asymptomatic individuals. Mov Disord 1990;5:93–9. 5. Siemers E, Foroud T, Bill DJ, et al. Motor changes in presymptomatic Huntington disease gene carriers. Arch Neurol 1996;53:487–92. 6. Diamond R, White RF, Myers RH, et al. Evidence of presymptomatic cognitive decline in Huntington’s disease. J Clin Exp Neuropsychol 1992;14:961–75. 7. Foroud T, Siemers E, Kleindorfer D, et al. Cognitive scores in carriers of Huntington’s disease gene compared to noncarriers. Ann Neurol 1995;37:657–64. 8. Jason GW, Pajurkova EM, Suchowersky O, et al. Presymptomatic neuropsychological impairment in Huntington’s disease. Arch Neurol 1988;45:769– 73. 9. Kirkwood SC, Siemers E, Stout JC, et al. Longitudinal cognitive and motor changes among presymptomatic Huntington disease gene carriers. Arch Neurol 1999;56:563– 8. 10. Paulsen JS, Zhao H, Stout JC, et al. Clinical markers of early disease in persons near onset of Huntington’s disease. Neurology 2001;57:658–62. 11. Strauss ME, Brandt J. Are there neuropsychologic manifestations of the gene for Huntington’s disease in asymptomatic, at-risk individuals? Arch Neurol 1990;47:905–8. 12. Craufurd D, Thompson JC, Snowden JS. Behavioral changes in Huntington Disease. Neuropsychiatry Neuropsychol Behav Neurol 2001;14:219–26. 13. Duff K, Paulsen JS, Beglinger LJ, et al. Psychiatric symptoms in Huntington’s disease before diagnosis: The Predict-HD Study. Biol Psychiatry 2007;62:1341–6. 14. Marshall J, White K, Weaver M, et al. Specific psychiatric manifestations among preclinical Huntington disease mutation carriers. Arch Neurol 2007;64:116–21. 15. Nehl C, Ready RE, Hamilton J, et al. Effects of depression on working memory in presymptomatic Huntington’s disease. J Neuropsychiatry Clin Neurosci 2001;13:342–6. 16. Snowden JS, Craufurd D, Thompson J, et al. Psychomotor, executive, and memory function in preclinical Huntington’s disease. J Clin Exp Neuropsychol 2002;24:133– 45. 17. Aylward EH, Brandt J, Codori AM, et al. Reduced basal ganglia volume associated with the gene for Huntington’s disease in asymptomatic at-risk persons. Neurology 1994;44:823–8. 18. Aylward EH, Codori AM, Rosenblatt A, et al. Rate of caudate atrophy in presymptomatic and symptomatic stages of Huntington’s disease. Mov Disord 2000;15:552–60. 19. Campodonico JR, Aylward E, Codori AM, et al. When does Huntington’s disease begin? J Int Neuropsychol Soc 1998;4:467–73. 20. Harris GJ, Codori AM, Lewis RF, et al. Reduced basal ganglia blood flow and volume in pre-symptomatic, gene-tested persons at-risk for Huntington’s disease. Brain 1999;122:1667–78. 21. Thieben MJ, Duggins AJ, Good CD, et al. The distribution of structural neuropathology in pre-clinical Huntington’s disease. Brain 2002;125:1815–28. 879