Exploratory 7-Tesla magnetic resonance spectroscopy in Huntington's disease provides in vivo evidence for impaired energy metabolism

Abstract

Huntington's disease (HD) is a neurodegenerative genetic disorder that affects the brain. Atrophy of deep grey matter structures has been reported and it is likely that underlying pathologic processes occur before, or in concurrence with, volumetric changes. Measurement of metabolite concentrations in these brain structures has the potential to provide insight into pathological processes. We aim to gain understanding of metabolite changes with respect to the disease stage and pathophysiological changes. We studied five brain regions using magnetic resonance spectroscopy (MRS) using a 7-Tesla MRI scanner. Localized proton spectra were acquired to obtain six metabolite concentrations. MRS was performed in the caudate nucleus, putamen, thalamus, hypothalamus, and frontal lobe in 44 control subjects, premanifest gene carriers and manifest HD. In the caudate nucleus, HD patients display lower NAA (p = 0.009) and lower creatine concentration (p = 0.001) as compared to controls. In the putamen, manifest HD patients show lower NAA (p = 0.024), lower creatine concentration (p = 0.027), and lower glutamate (p = 0.013). Although absolute values of NAA, creatine, and glutamate were lower, no significant differences to controls were found in the premanifest gene carriers. The lower concentrations of NAA and creatine in the caudate nucleus and putamen of early manifest HD suggest deficits in neuronal integrity and energy metabolism. The changes in glutamate could support the excitotoxicity theory. These findings not only give insight into neuropathological changes in HD but also indicate that MRS can possibly be applied in future clinical trails to evaluate medication targeted at specific metabolic processes.

Fig. 1

Chemical shift at 7-Tesla using STEAM. Chemical shifts provided for an actual planning. Red box NAA, white box metabolite as stated below each figure. Only a minimal chemical shift exists. The chemical shift of water is almost zero, as the separate water file is planned according to the NAA-voxel. NAA N-acetylaspartate

Fig. 2

Localized proton MR spectra from different regions of the brain. On the left side the voxel is displayed in the transverse direction, a typical spectrum of that structure is shown on the right side for the three groups. Five different regions are displayed: hypothalamus, thalamus, caudate nucleus, putamen, prefrontal region. Cho choline, Cr creatine, NAA N-acetylaspartate, mI myo-inositol, Glx glutamate + glutamine, Lac lactate, PPM parts per million. A Gaussian filter of 4 Hz was applied

Fig. 3

LCModel output example. This figure depicts the output provided by the LCModel analysis. The black line is the raw spectrum and the red line is the fit by LCmodel. PPM parts per million