Participants were recruited at 17 sites in the USA, four sites in Canada and three sites in Australia (see Paulsen and colleagues27 for an overview of recruitment procedures). Study activities were reviewed and approved by institutional review boards at all study and data processing sites. Participants underwent informed consent procedures and signed consents for both participation and to allow de-identified research data to be sent to collaborative institutions for analyses. To ascertain a comparison cohort, sites were asked to enrol a participant with a CAG repeat length in the reference range (eg, ,30 repeats) for every six participants enrolled with a CAG repeat length in the HD range (ie, >39 repeats). Inclusion criteria required participants to have previously undergone voluntary genetic testing for the presence of the CAG expansion in the HD gene, huntingtin, on the short arm of chromosome 4. Exclusion criteria included: (a) clinical evidence of unstable medical or psychiatric illness; (b) history of other central nervous system disease or event, such as seizures or head trauma; (c) pacemaker or metallic implants; and (d) prescribed antipsychotic or phenothiazine derivative antiemetic medica- tions within the past 6 months. Other prescribed, over the counter and natural remedies were not restricted. Although the intent was to enrol only participants who were prediagnosed, provisions were made to enrol the few otherwise eligible individuals who seemed to be having HD symptoms if those individuals had not been diagnosed as having HD. Procedure Participants underwent annual study visits at local sites, including blood draws, a neurological examination, cognitive assessment, psychiatric and psychological questionnaires, and brain MRI. Only a subset of data collected in these assessments is presented in the current report. Data and samples were sent from local sites to the Predict specialty sites, including blood samples to Harvard University for DNA analyses of CAG repeat lengths, cognitive assessment data to Indiana University at Bloomington for scoring and quality control, and MRI datasets to the University of Washington in Seattle for volumetric analyses of the caudate nucleus and putamen. These data, as well as general case report forms, were then forwarded to the Clinical Trials Coordination Center at the University of Rochester, where data were collated and missing data were queried. Finally, data sets were sent to the University of Iowa for construction of the comprehensive database and statistical analysis. Data included in the current report Motor scores The Unified HD Rating Scale26 motor examination consists of 15 primary items administered by movement disorder specialists who had undergone reliability training for the Predict-HD study. Total motor scores in this sample ranged from 0 to 34 (mean 5.53 (SD 5.40)) of a possible 124 points. HD diagnostic confidence rating After performing the motor examination, the movement disorder specialist assigned a diagnostic opinion, with level of certainty, according to the following scale: 0 = normal (no abnormalities); 1 = non-specific motor abnormalities (less than 50% confidence that the participant has manifest HD); 2 = motor abnormalities that may be signs of HD (50–89% confidence); 3 = motor abnormalities that are likely signs of HD (90–98% confidence); or 4 = motor abnormalities that are J Neurol Neurosurg Psychiatry 2008;79:874–880. doi:10.1136/jnnp.2007.128728 Research paper unequivocal signs of HD (>99% confidence). This scale is based on the currently accepted formal diagnostic process, which requires the emergence of an otherwise unexplained extrapyr- amidal movement disorder in someone at risk for HD. Thus the rating does not directly reflect the presence of cognitive or psychiatric manifestations of HD, which may also be present. By consensus, a rating of 4 is considered to be the point at which HD diagnosis is made. As we were focused on HD development before the point of diagnosis, we excluded 11 participants from this analysis who had a diagnostic rating of 4 on their initial examination. Of the remaining 438 participants analysed, confidence ratings were as follows: 148 (34%) rated 0, 198 (45%) rated 1, 68 (16%) rated 2 and 24 (5.5%) rated 3. Determination of CAG length A previous voluntary decision to undergo HD gene testing was a prerequisite for entry into the Predict-HD study and clinical predictive testing results were confirmed by CAG repeat lengths obtained via PCR, as described elsewhere.27 For the study sample, CAG expansions ranged from 39 to 50, with a mean of 42.3 (median 42). Estimation of time to HD diagnosis To examine relationships between proximity to HD diagnosis and motor, brain volumetric and cognitive measures, we used a CAG based prognostic model developed3 on the basis of nearly 3000 subjects. This survival formula can be transformed to a probability distribution for age of diagnosis that depends on both the subject’s CAG expansion length and current age (fig 1A). We give details, including assumptions and transfor- mations to estimate years until diagnosis, in appendix A online. Briefly, in order to estimate mean time until clinical diagnosis, we truncate the probability distribution to account for the fact that a subject has reached their current age without yet receiving a diagnosis. We then calculate the mean of this revised distribution (fig 1B). The study sample had a mean estimated time to diagnosis of 13.9 (SD 6.7) years. Cognitive assessment Cognitive testing included nine paper and pencil tests from the well established clinical neuropsychological literature and nine computerised tasks developed specifically for Predict-HD which were administered on standardised specially constructed pc based computer systems. All study personnel who administered the cognitive battery underwent in-person training until they reached the criterion for standardised administration, followed by annual reliability checks. Only four of 18 tests were used in the current report. Tests were selected to represent varying components of brain processes (motor speed, timing, memory and sensory processes). Motor speed The Speeded Tapping Test28 is a computerised test of finger tapping speed that requires a participant to press keys on a response box as quickly as possible. The value analysed for this study was the average tapping rate. Previous research has suggested that motor speed may be maintained by the motor/ premotor circuit. Self-paced timing consistency Participants tapped on a single key in time to a series of 11 evenly paced tones, after which they had to continue tapping at the same pace for another 31 taps. To capture the consistency in 875