Posted Sept 19, 2008 by LaVonne Veatch Goodman M.D.

A couple of years ago we reviewed articles on eye movement abnormalities as potential biomarkers for use in Huntington clinical trials. This week we report on a pilot study out of Imperial College in London that combines specific eye movements with a cognitive (thinking) task.  This type of test appears sensitive to predicted disease stage even before symptoms.  And in more good news, a further refinement of this test is already being studied in the much larger 360-person CHDI-sponsored TRACK-HD trial begun January 2008.

TRACK-HD is designed to look for and refine best biomarker tests that can speed HD drug trials.  Dr. Dan van Kammen, chief medical officer at CHDI, has suggested we might have the answers about this test --and several others that could be used with it -- in the one or two year time frame.

Research into eye movement (or saccade) disorders in Huntington's has a long history, dating back to 1979 [Avanzini 1979].  Results from study of PREDICT-HD participants sparked new interest in eye movements for use as HD biomarkers [Golding 2006] [Blekher 2006].

In an article in the September, 2008 issue of Progress in Brain Research, Dr. Stephen Hicks and colleagues from London show that a more complex eye movement test has good potential to become an important biomarker for Huntington's, both before and after symptoms develop [Hicks 2008]. If these pilot results are confirmed in a similar (refined) eye movement test in TRACK-HD, we may have one of the biomarkers that could greatly reduce the time it takes to do clinical trials.  This of course translates to faster times to get successful drugs to HD people.

The Research Goal: The authors compared 3 types of eye movement tasks to identify the best one for predicting disease stage among individuals who were divided into four groups:

• gene positive more than 10 years from predicted onset of symptoms
• gene positive less than 10 years from predicted onset of symptoms
• individuals who had symptoms of early disease (less than 7 years from onset)
  
• gene negative control individuals

The Method: Each participant performed three tests of increasing complexity using a laser device worn on their heads that records eye movement in response to dots presented on a testing screen. The most complex test combined eye movement with a cognitive (thinking) task.

The Results:  The investigators showed that results from the most complex task was best predictor of disease stage (for those with symptoms) and years to predicted onset (for those presymptomatic).    

Comments: This was a pilot study done on small numbers of participants, each studied at one time point. To qualify as a biomarker that could be accepted by the FDA in drug trials, it must be shown that this eye movement abnormality increases over time and tracks with disease progression in a sufficiently large number of people. Fortunately this study (begun in January 2008) is already underway as part of TRACK-HD, a trial sponsored by CHDI Inc.

If these results are confirmed in TRACK-HD, complex eye movements could be a clinical biomarker or one that directly measures loss of function caused by the disease, so it would not need more trials (and time) for validation that a blood or x-ray biomarker would require.  Dr. Dan van Kammen, leader of CHDI clinical trial program, suggests that this or other biomarkers may be ready for use in the 1 to 2 year time. As we learned at the recent June 2008 HDSA convention, he is already working with the FDA to define measures that will be accepted by the FDA for Huntington clinical trials.  This 1 to 2 year time frame coincides with that predicted for first CHDI clinical trials.

And Gratitude: We all owe gratitude to all investigators and sponsors for work on biomarkers.  But the equally special heroes are the study participants:  those in PREDICT-HD whose work led up to the present study, those in this London pilot study, and those (including some of my own patients) in TRACK-HD.  They show us that progress toward HD treatments is made possible by their participation in clinical studies.

References

Avanzini G, Girotti F, Caraceni T, Spreafico R. Oculomotor disorders in Huntington's chorea. J Neurol Neurosurg Psychiatry 1979 Jul;42(7):581-9. PubMed abstract

Golding CV, Danchaivijitr C, Hodgson TL, Tabrizi SJ, Kennard C. Identification of an oculomotor biomarker of preclinical Huntington disease. Neurology 2006 Aug 8;67(3):485-7. PubMed abstract

Blekher T, Johnson SA, Marshall J, White K, Hui S, Weaver M, Gray J, Yee R, Stout JC, Beristain X, Wojcieszek J, Foroud T. Saccades in presymptomatic and early stages of Huntington disease. Neurology 2006 Aug 8;67(3):394-9. PubMed abstract

Hicks SL, P A Robert M, V P Golding C, Tabrizi SJ, Kennard C. Oculomotor deficits indicate the progression of Huntington's Disease. Prog Brain Res 2008;171():555-8. PubMed abstract