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1H NMR spectroscopy studies of Huntington's disease: correlations with CAG repeat numbers
B G Jenkins1, H D Rosas, Y C Chen
1Department of Radiology, MGH-NMR Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, USA.
Insights
Huntington's disease (HD) involves a gene defect causing impaired energy metabolism. Studies show significantly elevated lactate in HD patients, even in presymptomatic individuals, suggesting early metabolic changes.
Area of Science:
- Neuroscience
- Genetics
- Metabolic Disorders
Background:
- Huntington's disease (HD) is a genetic disorder caused by an expanded CAG repeat in a gene on chromosome 4.
- A potential consequence of this genetic defect is progressive impairment of cellular energy metabolism.
Purpose of the Study:
- To investigate energy metabolism abnormalities in the brain of Huntington's disease patients.
- To assess lactate levels and neuronal degeneration markers in both symptomatic and presymptomatic HD individuals.
Main Methods:
- Utilized localized 1H spectroscopy to measure occipital cortex and striatal lactate levels.
- Assessed N-acetylaspartate (NAA)/creatine and choline/creatine ratios as markers of neuronal degeneration.
- Correlated metabolic changes with disease duration and CAG repeat length.
Main Results:
- HD patients exhibited a nearly threefold increase in occipital cortex lactate compared to controls.
- Elevated striatal lactate was observed in some presymptomatic gene-positive individuals.
- Striatal lactate and NAA loss correlated significantly with symptom duration and CAG repeat number.
Conclusions:
- These findings provide further evidence for impaired energy metabolism in Huntington's disease.
- The data suggest an interaction between neuronal activation and metabolic defects that may be present even before symptom onset.
- Metabolic abnormalities correlate with genetic and clinical disease severity.
Abstract:
Huntington's disease (HD) is the result of an expanded (CAG) repeat in a gene on chromosome 4. A consequence of the gene defect may be progressive impairment of energy metabolism. We previously showed increased occipital cortex lactate in HD using localized 1H spectroscopy. We have now extended these studies to show an almost threefold elevation in occipital cortex lactate in 31 HD patients as compared with 17 normal control subjects (p < 10(-11)). The spectra in three presymptomatic gene-positive patients were identical to normal control subjects in cortical regions, but three in eight showed elevated lactate in the striatum. Similar to recently reported increases in task-related activation of the striatum in the dominant hemisphere, we found that striatal lactate levels in HD patients were markedly asymmetric (higher on the left side). Markers of neuronal degeneration, decreased N-acetylaspartate (NAA)/creatine and increased choline/creatine levels, were symmetric. Both decreased NAA and increased lactate in the striatum significantly correlated with duration of symptoms. When divided by his or her age, an individual's striatal NAA loss and lactate increase were found to directly correlate with the subject's CAG repeat number, with correlation coefficients of 0.8 and 0.7, respectively. Similar correlations were noted between postmortem cell loss and age versus CAG repeat length. Together, these data provide further evidence for an interaction between neuronal activation and a defect in energy metabolism in HD that may extend to presymptomatic subjects.