The Predict-HD Study Identifies Early Changes

HD Lighthouse Contributing Editor's Comment: 

The Predict-HD study continues to yield useful insights about the years leading up to clinical onset. Predict-HD is a multi-center observational study of volunteers who had previously tested positive for the HD gene but who had not reached the stage of manifest Huntington's Disease. The study is a longitudinal one, with participants being followed over time through yearly visits.

The study began enrolling participants in September of 2002 and more time will be needed to collect and analyze significant longitudinal data from individuals. In the meantime, researchers are doing an analysis which compares individuals on a variety of cognitive, motor, and other measures based on their estimated time to onset, using a formula to predict age of onset.

The formula is based on the individuals current age and their CAG count. Can this work? Let's review what we know about CAG counts and age of onset. We know that age of onset is inversely correlated with the CAG count. In other words, the average age of onset for a group of people with 49 repeats is earlier than the average age for a group with 48 repeats and the average age is earlier for a group with 48 than a group with 47.

On the other hand, it's not possible to predict the onset for a particular individual from their CAG count. Other factors also have an influence and the range in ages of onset for each expanded CAG count can be fairly large. One person with a CAG count of 40 might have an onset at 48 and another at 60, for example.

This means that a large sample will be needed. Fortunately, the study does have a large sample and can provide useful data based on group averages. This is called a cross sectional approach. Later, the results can be validated with data collected each year for seven years from each individual in the study - a true longitudinal approach.

The researchers looked at several measures, the volume of the striatum in the brain, motor scores on the United Huntington's Disease Rating Scale, speed of finger tapping, self timed finger tapping, recall of word lists, and identification of odors.

The researchers feel confident that there are changes in the variables measured which can be detected ten to twenty years before diagnosis.

Should these early changes be alarming to those with the gene and those at risk? I don't think so. It's important to remember that all the changes measured are curvilinear, not a straight line. In other words, the changes are small and the rate of increase is small until the person is getting close to diagnosis when the changes get larger and larger. These very early changes aren't going to be noticeable outside of the research setting but they will be important for individual treatment plans.

There are dozens of promising compounds in the research pipeline. Clinical trials for some are starting this year and hopefully, there will be treatments within the next few years. The Predict-HD study will be very important in determining when a person who is gene positive should start receiving treatments to prevent or delay onset. 

-- Marsha L. Miller, Ph.D.
Posted to the HDL: 01-01-2008

Jane S. Paulsen, Ph.D.

Detection of Huntington’s disease decades before diagnosis: The Predict HD study

J S Paulsen, D R Langbehn, J C Stout , E Aylward , C A Ross, M Nance, M Guttman , S Johnson , M McDonald, L J Beglinger, K Duff, E Kayson, K Biglan, I Shoulson, D Oakes and M Hayden

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 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 modeled nonlinearly, 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 timescale of measurable disease development, and suggest candidate disease markers for use in preventive HD trials.

Source: Journal of neurology, neurosurgery, and psychiatry 2007 Dec 20 [Epub ahead of print]