The precise pathogenic mechanisms of Huntington disease (HD) are unknown, but can be tested in vivo using proton magnetic resonance spectroscopy (¹H MRS) to measure neurochemical changes.

To evaluate neurochemical differences in HD gene mutation-carriers (HGMC) vs. controls, and to investigate relationships among function, brain structure and neurochemistry in HD. Since previous ¹H MRS studies have yielded varied conclusions about HD neurochemical changes, an additional goal was to compare two ¹H MRS data analysis approaches.

HGMC with pre-manifest to early HD and controls underwent evaluation of motor function, MR imaging and localized ¹H MRS in caudate and frontal lobe. Analytical approaches tested included absolute quantitation (unsuppressed water signal as an internal reference) and relative quantification (calculating ratios of all neurochemical signals within a voxel).

We identified a suite of neurochemicals reduced in concentration proportionally to loss of caudate volume in HGMC. Caudate concentrations of NAA, creatine, choline, and caudate and frontal concentrations of glutamate+glutamine and glutamate correlated with caudate volume in HGMC subjects. The relative, but not the absolute quantitation approach revealed disease-related differences; the Glx signal was decreased relative to other neurochemicals in caudate of HGMC subjects vs. controls.

This is the first study to demonstrate correlation among structure, function and chemical measures in HD brain. Additionally, we demonstrate that a relative quantitation approach may enable magnification of subtle differences between groups. Observation of decreased glutamate-glutamine signals suggests that glutamate signaling may be disrupted relatively early in HD, with important implications for therapeutic approaches.