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doi: 10.1097/01.NT.0000391390.43716.8b
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Biomarkers May Distinguish Early Onset Huntington Disease

Atlas, Susan J.

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Total N-acetyl aspartate (tNAA) was significantly decreased — 15 percent lower (p<0.001) — and myo-inositol was 50 percent higher in patients with early Huntington disease compared with healthy controls.

Putaminal measures of two brain metabolites — total N-acetyl aspartate (tNAA) and myoinositol (MI) — could be useful for tracking the onset and progression of Huntington disease, according to a study in the Nov. 9 Neurology.

Study authors Aaron Sturrock, MRCP, and Cornelia Laule, PhD, research fellows from the University of British Columbia in Vancouver, Canada, used magnetic resonance spectroscopy (MRS) to measure tNAA and MI and other metabolites in people who had the mutant HTT gene for HD including 25 who had no clinical signs of the disease (pre-HD) and 29 who had mild deficits. They compared results with 30 healthy controls, consisting of spouses of HD patients who had no family history of the disease and family members who had a negative HD gene test.

Among findings, tNAA was significantly decreased — 15 percent lower (p<0.001) — and myo-inositol was 50 percent higher in patients with early HD compared with healthy controls. “NAA is a marker of neuronal viability and integrity, so decreased levels are a sign of neuronal dysfunction [and axonal pathology]. The increase in MI probably represents elevated glial cell numbers or activation (astrogliosis), which often accompanies CNS neuronal damage,” explained the study authors via e-mail.

Several independent investigators found the report promising but said the differences were small and more longitudinal data from this cohort and other groups are needed to confirm these findings. What's more, several experts commented that more data are needed to understand whether metabolite changes are part of the underlying disease process or occur secondarily to the disease process.

Commenting on the paper in a telephone interview, Jane Paulsen, PhD, professor of neurology, psychiatry, psychology, and neuroscience at the University of Iowa, said: “I think it was an excellent study.”

Dr. Paulsen, an HD researcher who was not involved in this study, added: “Functional imaging is so compelling because you may be able to detect disease in a brain that is still working — perhaps not as well, but still functioning. Intervention may be more hopeful if we can treat before the structural changes show up as atrophy, suggesting death of neurons and less brain to treat.”

Although she praised the study, Dr. Paulsen was a bit surprised at the results. She said that she would have expected to see biomarker differences between the pre-HD and control groups that were closer to what they see with structural imaging. For example, in structural studies done by her group, the striatum shows a 31 percent decrease in volume in pre-HD compared with controls. In contrast, Dr. Sturrock and colleagues found only an 8 percent decrease in NAA in pre-HD compared with controls; differences in total NAA were even smaller.

Dr. Paulsen added, “I thought their findings would be more robust, but we need to see the longitudinal data to tell how much these markers change over time. That will give us the best indicator of whether this is a marker of disease progression.”

One of the downsides of functional imaging is making the methodology transparent and replicable, Dr. Paulsen said. “This group has the competence and knowledge about Huntington disease, so if they can get a handle on the error variance from year to year and capture the changes, they will be making a huge contribution to our understanding of MRS as a biomarker.”

In a joint telephone interview, Elizabeth Aylward, PhD, associate director of the Center for Integrative Brain Research at the Seattle Children's Research Institute, and Kevin E. Conley, PhD, professor of radiology at the University of Washington in Seattle, expressed their enthusiasm for this report. Neither commentator was involved in the study.

Dr. Conley said: “I think that they are on the right track. It is important to identify the markers that are changing with Huntington disease.” But, he added, it is important to know how these changes are related to fundamental aspects of the disease, such as accumulation of the huntingtin protein or cell loss with putamen volume decrease.

“Do the changes in these metabolites give an idea of the underlying disease processes, or are they just something that happens secondarily?” he asked. These are questions for future investigation, not something that should have been answered in this study.

Dr. Aylward emphasized: “A good biomarker is relatively stable in normal subjects, but changes relatively quickly and consistently across diseased subjects, which can only be confirmed through longitudinal studies.” The study data correlating total NAA concentration with disease burden score over combined pre-HD and early HD groups suggest this is true, but longitudinal data will have to confirm it, she said.

She added that structural changes appear 10 to 15 years before onset of HD motor symptoms. It is possible that MRS measures will reverse with effective treatment, while the structural changes will not. “If you could reverse this process, would you expect to see delayed onset of the symptoms or a slower progression of disease? Presumably you would, but there is no way that we can know that until we find an effective treatment.”

©2010 American Academy of Neurology

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