Research paper c Appendices A and B are published online only at http:// jnnp.bmj.com/content/vol79/ issue8 For numbered affiliations see end of article Correspondence to: Dr J S Paulsen, University of Iowa, Roy J and Lucille A Carver College of Medicine Research, 1-305 Medical Education Building, Iowa City, IA 52242- 1000, USA; jane-paulsen@ uiowa.edu The Predict-HD Investigators, Coordinators and Cognitive Raters of the Huntington Study Group are listed in appendix B online. Received 29 June 2007 Revised 25 November 2007 Accepted 1 December 2007 Published Online First 20 December 2007 This paper is freely available online under the BMJ Journals unlocked scheme, see http:// jnnp.bmj.com/info/unlocked.dtl 874 Detection of Huntington’s disease decades before diagnosis: the Predict-HD study J S Paulsen,1 D R Langbehn,1 J C Stout,2 E Aylward,3 C A Ross,4 M Nance,5 M Guttman,6 S Johnson,2 M MacDonald,7 L J Beglinger,1 K Duff,1 E Kayson,8 K Biglan,8 I Shoulson,8 D Oakes,9 M Hayden,10 The Predict-HD Investigators and Coordinators of the Huntington Study Group11 ABSTRACT Objective: The objective of the Predict-HD study is to use genetic, neurobiological and refined clinical markers to understand the early progression of Huntington’s disease (HD), prior to the point of traditional diagnosis, in persons with a known gene mutation. Here we estimate the approximate onset and initial course of various measur- able aspects of HD relative to the time of eventual diagnosis. Methods: We studied 438 participants who were positive for the HD gene mutation, but did not yet meet the diagnostic criteria for HD and had no functional decline. Predictability of baseline cognitive, motor, psychiatric and imaging measures was modelled non- linearly using estimated time until diagnosis (based on CAG repeat length and current age) as the predictor. Results: Estimated time to diagnosis was related to most clinical and neuroimaging markers. The patterns of association suggested the commencement of detectable changes one to two decades prior to the predicted time of clinical diagnosis. The patterns were highly robust and consistent, despite the varied types of markers and diverse measurement methodologies. Conclusions: These findings from the Predict-HD study suggest the approximate time scale of measurable disease development, and suggest candidate disease markers for use in preventive HD trials. Huntington’s disease (HD) is a dominantly inher- ited disease for which predictive testing can inform whether, but not precisely when, the disorder will manifest itself. The onset ages for HD have non- linear inverse relationships with the number of polyglutamine repeat sequences in the gene muta- tion so that younger diagnosed patients tend to have longer repeat lengths.1 2 Current guidelines for genetic counselling recommend against using pre- dictions of diagnosis age, in part because no curative or preventive treatments are available, and also because such estimates have large confidence intervals,3 making it impossible to accurately predict when the clinical disease will become manifest. Nonetheless, DNA based prog- nostic stratification can play a useful role in characterising attributes at the group level among those with various lengths of the HD CAG expansion. For example, in samples of individuals with the HD CAG expansion but not yet meeting diagnostic criteria for HD, at least two studies have indicated that minor motor signs are evident several years prior to diagnosis,4 5 and more than 20 studies have shown measurable cognitive impairments.6–11 Psychiatric disturbances are pre- valent prior to diagnosis of HD.12–16 At least seven studies have evaluated volumetric MRI in CAG expanded individuals prior to diagnosis,17–21 with a recent report suggesting that striatal volume loss is evident at least 9–11 years prior to estimated onset.22 Studies using functional MRI have shown reduced activation patterns in the basal ganglia23 and cingulate cortex24 in the absence of volumetric loss in prediagnosed individuals, suggesting that abnormalities in cell function may be detectable prior to cell death. Data from animal studies are consistent with these findings and indicate that receptor changes and electrophysiological changes clearly precede the onset of behavioural pheno- type(s) in HD transgenic mouse models.25 Moreover, a few recent longitudinal studies have validated cross sectional findings of prediagnosis disease markers.12 22 To reach the goals of prevention and interven- tion prior to clinical manifestations of HD, we must build on this evidence of prediagnostic changes in the brain and behaviour and attempt to further infer the longitudinal course of changes prior to diagnosis. For example, testing of effective preventive treatments may only be practical once it is possible to measure early disease progress prior to manifest clinical debilitation, and then to track these measures in response to candidate interven- tions. In this report, we have utilised estimates of time until diagnosis to examine early declines in HD biomarker and refined clinical marker changes. We used a large cohort of prediagnosed partici- pants from the Predict-HD study, all of whom had verified and measured CAG expansions for HD. METHODS Participants Predict-HD is a longitudinal study of individuals known to be at genetic risk for HD. This report is based on baseline data from all participants (n = 449 with CAG expansions in the HD gene) who were enrolled from September 2002 until October 2004. Participants were primarily Caucasian (96%), right-handed (89%), married (70%) employed (77%) females (64%) with an average age of 42.1 (SD 9.9) years. Ninety per cent had at least a high school education; average years of education for this sample was 14.5 (SD 2.6) years. J Neurol Neurosurg Psychiatry 2008;79:874–880. doi:10.1136/jnnp.2007.128728