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Two technologies are better than one for understanding Huntington's disease

In a work published in NMR in Biomedicine, Researchers from MIRCen (CEA-Jacob) combined the specificity of NMR spectroscopy and the high spatial resolution of glutamine metabolic imaging to observe brains in murine models of Huntington's disease and identify novel biomarkers therein. Their approach enables the monitoring of disease course and may prove useful for studying other neurodegenerative diseases or evaluating the efficacy of future treatments.

Published on 31 July 2020

The identification of biomarkers is essential for understanding the biological processes involved in neurodegenerative diseases. Historically, the atrophy of certain brain structures has been proposed as a biomarker of interest. However, despite its robustness and ease of measure, cerebral structure atrophy appears in reality to provide little pathophysiological information; it instead most likely reflects the long-term effects of long-past biological events.

In a study published in NMR in Biomedicine, the Magnetic Resonance Methods to Study the Brain In Vivo team from the Neurodegenerative Diseases Laboratory of MIRCen (CEA-Jacob) identified pertinent early biomarkers of neurodegeneration, particularly in the setting of Huntington's disease*. The team's researchers developed a high magnetic field (11.7 Tesla) acquisition protocol combining the biological specificity offered by proton magnetic resonance spectroscopy and the high spatial resolution offered by gluCEST imaging (metabolic imaging of glutamate).

They studied two murine models of Huntington's disease, each presenting specific characteristics. The first was the Ki140CAG model, characterized by slow disease progression similar to presymptomatic disease forms observed in humans, and the second the R6/1 model, which reflects juvenile, aggressive disease.

By combining the spectroscopy and metabolic imaging techniques, the team was able to demonstrate striking differences between those two models. In the R6/1 aggressive disease model, the quantity of the metabolite N‐acetyl‐aspartate, found mainly in neurons, was shown to be diminished, suggesting an alteration of the neuronal compartment. Furthermore, the reduction in N‐acetyl‐aspartate was correlated with atrophy of the striatum, a structure affected early in Huntington's disease. In contrast, the quantities of other metabolites remained stable, suggesting that astrocytes (another type of brain cell) were not affected and that energy metabolism was preserved. In the Ki140CAG progressive disease model, modifications in the rates of several metabolites may have reflected changes that were occurring gradually in the mice's brains to compensate for deficits that developed earlier in their lives. The GluCEST imaging studies provided measures that would have been inaccessible to NMR spectroscopy. For example, the former detected alterations in unexpected regions of the brain, such as the corpus callosum.

The MIRCen team showed that the combinatorial complementarity of the spectroscopy and metabolic imaging techniques can provide different angles of view on the course of Huntington's disease. Their results may contribute to improving the use of animal models to study a large spectrum of neurodegenerative diseases and evaluate the efficacy of future treatments. 

Metabolic imaging of glutamate (gluCEST) in Ki140CAG (top row) and R6/1 (bottom row) mice. Ki140CAG mice homozygous for the muted huntingtin gene (Homo., right column) show lower glutamate levels than do wild type mice (WT, left column). Heterozygous mice (Hetero., middle column) show intermediate levels, suggesting a correlation between glutamate levels and disease severity. In contrast, the glutamate levels in heterozygous R6/1 mice are comparable to those of wild type mice. This observation appears to be peculiar to the R6/1 model and was brought to light by the protocol developed for the study. © J. Flament / MIRCen

Huntington's disease is a rare hereditary disease for which there is currently no curative treatment. Patients with it experience neuronal degeneration in areas of the brain involved in motor, cognitive and/or behavioral functions. 

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