In a study sponsored by CHDI Foundation, an international group of TRACK-HD investigators, with the help of several hundred individuals from Huntington's (HD) families have described potential MRI biomarker tests that may point the way to speedier drug trials for pre-manifest (preHD) and early HD individuals. These are results for a one year study, but those from the second year -- now being analyzed -- will be necessary to confirm and extend these results.

They did this by correlating change in sensitive MRI scans to changes in motor and cognitive tests in ways that will be necessary for regulatory drug approvals.

NIH biomarker definition: A characteristic that objectively measures a disease state or response to treatment

Why TRACK-HD? Though data from PREDICT-HD has provided the important groundwork for identifying markers of progression in preHD individuals, the TRACK-HD study goes the next step of describing these (and other markers) in the form that regulatory agencies will more readily accept for use in clinical trials -- for both preHD and early symptomatic HD. Specifically, they showed that MRI measures, when combined may be sensitive biomarkers for both motor and cognitive change in these groups [Tabrizi SJ 2011].

Study Method: Investigators from Australia, Europe and North America compared data from 5 groups at a baseline visit and a one-year follow-up.

  • PreHD: 116 individuals split into two groups: those further from predicted onset and those more near predicted onset.
  • Early HD: 114 early HD patients split into 2 groups: Stage 1 (fewer symptoms) and Stage 2 (more symptoms).
  • 115 control individuals who were either spouses or siblings negative for the gene expansion.

TRACK-HD testing procedures included: different types of brain MRI imaging, both old (UHDRS) and new types of motor and cognitive testing, and several measures of emotional symptoms and overall function.

Results: Certain tests were more sensitive, or showed a greater change over the one-year time course: quantitative imagery (three types of MRI studies), along with specific motor and cognitive measures. The "best" test marker was not the same across all the groups.

  • MRI studies: Whole brain MRI, which showed significant change in the preHD group nearer to onset, and Stage 1 and 2 symptomatic individuals. Those in the preHD group far from onset showed only a slight change, not significantly different from controls. This means that this type of MRI measure - used alone - would be useful for three of the groups, but not for testing a drug benefit in far from onset individuals. However MRI measures that combined information of whole brain and caudate volume was most sensitive (or best test to measure change) across all the groups of preHD and early HD.
  • The change in chorea index, an objective 3-D measure of chorea is a potentially promising clinical marker for motor change within the group of preHD farther from predicted onset.
  • Total motor score change, as measured by UHDRS appeared to be a better measure across the groups of pre-HD and early HD than other motor tests.
  • An indirect circle-tracing test that utilizes motor, visio-motor (eye movements) and cognitive (planning) systems was the most sensitive measure of change, or best test marker in the pre-manifest groups. This test, that requires the individual to trace a circle onto a computer screen (which is visually hidden) while looking at the circle on another screen may be a very good test to use in a drug trial to measure prevention of progression in the preHD time period. However they show that circle tracing is not as good a test to measure change in those with early symptomatic HD, where UHDRS Stroop color and symbol digit testing was more sensitive.
  • Emotional or behavioral symptoms were not useful tests to measure progression in any of the HD populations tested.

Summary and Discussion: TRACK-HD has made important progress by:

  • Establishing that MRI (using combined measures) is a sensitive marker for disease progression in preHD and early HD by correlating change in motor and cognitive clinical tests to change in MRI. This is vitally important for acceptance of MRI as a potential biomarker for clinical trials in these groups.
  • Showing that the sensitivity of MRI measures can potentially decrease the numbers of participants and the time needed to complete clinical trials. For instance, in an editorial accompanying the Lancet publication "analysis of the number of patients needed for a clinical trial to show disease-modifying effects over a 1 year time period would be fewer than 100 for each experimental arm (or 100 each for testing different doses and 100 for placebo groups) - if it is assumed that a drug has from 25-50% neuroprotective benefit [de Yébenes JG 2011].

Editoral Comments: To make progress in neuroprotective treatments rapidly enough for this generation of Huntington's, we must have clinical trials that are shorter than our recent history has allowed. TRACK-HD-- through the cooperative work of scientists, clinical investigators and study participants -- is leading the way for change by correlating MRI markers to changes in both motor and cognitive testing. This is an important step toward treatments for HD.

But of course, good biomarkers by themselves won't get us across the finish line. We still need the 40% effective drugs, and we still need the people to test them in. For sure, our scientists and drug developers have more work to do. But we in the family community will play a big part in the next critical steps. We can participate, or help others participate in the critically important pretrial studies necessary to help predict drug efficacy. And we can be at the ready for drug trials even before they start by joining what is soon to become a global registry for HD. COHORT in North America, and Registry in Europe will soon be joined by groups in South America and Asia in a new registry study called Enroll-HD. Through Enroll-HD, our investigators will be able to quickly call on the HD individuals worldwide that are needed for clinical studies and trials.

By working together with our scientist drug developers -- just like these participants in TRACK-HD -- we can solve the HD puzzle in time for our generation.


Tabrizi SJ, Scahill RI, Durr A, Roos RA, Leavitt BR, Jones R, Landwehrmeyer GB, Fox NC, Johnson H, Hicks SL, Kennard C, Craufurd D, Frost C, Langbehn DR, Reilmann R, Stout JC; TRACK-HD Investigators. Biological and clinical changes in premanifest and early stage Huntington's disease in the TRACK-HD study: the 12-month longitudinal analysis. Lancet Neurol. 2011 Jan;10(1):31-42. doi: 10.1016/S1474-4422(10)70276-3. Epub 2010 Dec 2. PubMed abstract

de Yébenes JG. TRACK and attack Huntington's disease. Lancet Neurol. 2011 Jan;10(1):21-2. doi: 10.1016/S1474-4422(10)70307-0. Epub 2010 Dec 2. PubMed abstract