Expanded neurochemical profile in the early stage of Huntington disease using proton magnetic resonance spectroscopy

Abstract

The striatum is a well-known region affected in Huntington disease (HD). However, other regions, including the visual cortex, are implicated. We have identified previously an abnormal energy response in the visual cortex of patients at an early stage of HD using ³¹ P magnetic resonance spectroscopy (³¹ P MRS). We therefore sought to further characterize these metabolic alterations with ¹ H MRS using a well-validated semi-localized by adiabatic selective refocusing (semi-LASER) sequence that allows the measurement of an expanded number of neurometabolites. Ten early affected patients [Unified Huntington Disease Rating Scale (UHDRS), total motor score = 13.6 ± 10.8] and 10 healthy volunteers of similar age and body mass index (BMI) were recruited for the study. We performed ¹ H MRS in the striatum - the region that is primarily affected in HD - and the visual cortex. The protocol allowed a reliable quantification of 10 metabolites in the visual cortex and eight in the striatum, compared with three to five metabolites in previous ¹ H MRS studies performed in HD. We identified higher total creatine (p < 0.05) in the visual cortex and lower glutamate (p < 0.001) and total creatine (p < 0.05) in the striatum of patients with HD compared with controls. Less abundant neurometabolites [glutamine, γ-aminobutyric acid (GABA), glutathione, aspartate] showed similar concentrations in both groups. The protocol allowed the measurement of several additional metabolites compared with standard vendor protocols. Our study points to early changes in metabolites involved in energy metabolism in the visual cortex and striatum of patients with HD. Decreased striatal glutamate could reflect early neuronal dysfunction or impaired glutamatergic neurotransmission.

Keywords: 1H MRS; Huntington disease; movement disorders; neurochemical profile; neurometabolite; semi-LASER.

Figure 1

Voxel positioning, spectra quality and model fitting by LCModel in the visual cortex and striatum. Spectra were acquired in an acquisition voxel of 25 × 25 × 25 mm³ in the visual cortex and 34 × 19 × 23 mm³ in the striatum using the modified semi-LASER sequence (T_R = 5000 ms, T_E = 28 ms, averages = 64). The black lines are the raw spectra, whilst the red lines are the LCModel fits. Asp: aspartate; Gln: glutamine; Glu: glutamate; Lac: lactate; myo-Ins: myo-inositol; NAA: N-acetylaspartate; sIns: scyllo-inositol; tCho: total choline; tCr: total creatine; tNAA: total N-acetylaspartate.

Figure 2

Brain tissue volume fraction in VOI in the striatum and visual cortex. Gray matter (GM) was markedly reduced in the striatum and visual cortex whilst cerebrospinal fluid (CSF) was significantly increased. *p<0.05 and #p≤0.01 represent significant differences between patients with HD and controls.

Figure 3

Mean metabolite concentrations obtained in the A) visual cortex and B) striatum. Fewer metabolites are reported for the striatum since they did not meet the quality control threshold unlike in the visual cortex. Asp: aspartate, Gln: glutamine, Glu: glutamate, GSH: glutathione, myo-Ins: myo-inositol, sIns: scyllo-inositol, Tau: taurine, tCho: total choline, tCr: total creatine, tNAA: total N-acetylaspartate. Error bars represent standard deviations. *p< 0.05, †p≤ 0.001.

Figure 4

Neurometabolite correlations with brain volume fractions of patients. A) tCr correlated positively with CSF fraction (p = 0.001), and negatively with GM (p < 0.05) and WM (p < 0.001) volume fractions in the visual cortex. B) Glu correlated negatively with CSF fraction (p < 0.05) and positively with WM volume fraction (p < 0.05) in the striatum.