Detection of Huntington's disease decades before diagnosis: the Predict-HD study

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 measurable 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.

Figure 1. (A) Example estimated probability density function for age at diagnosis of Huntington’s disease (HD), calculated at birth, for a person with a CAG expansion length of 42. Line and circle illustrate the expected age of diagnosis (mean of the distribution), which is 52.2 years. (B) Example estimated probability density function for age at HD diagnosis, for a person with a CAG expansion length of 42, given that the person has reached age 42 years without being diagnosed. Distribution from (A) is truncated at the present age and the remaining area under the curve is rescaled to equal 1. Line and circle illustrate the expected age of diagnosis for this adjusted distribution (ie, the mean of the age conditional distribution), which is 54.5 years. Therefore, the expected time until diagnosis is 54.4–42 = 12.4 years.

Figure 2. Scatterplot of self-timed tapping consistency data and estimated years from diagnosis of Huntington’s disease (HD). The fitted spline relationship, including 95% confidence limits for the fit, is superimposed. The plotted data points are adjusted for age, gender, education and estimated IQ by linear regression and standardised to a female with mean values of the other values. As detailed in table 1, the adjusted per cent variance explained (R²) for this plot is 0.20.

Figure 3. Relationship between estimated years to diagnosis of Huntington’s disease (HD) and various other measures. Solid line plots the predicted response; broken lines are 95% confidence limits for the estimated mean response. All relationships are adjusted to a female with mean levels of the other variables for which we adjusted our models (age = 41.2 years, education = 14 years, premorbid IQ).