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.

Metabolic Imaging in Humans

“…An exploratory in vivo 7T MRS study characterized metabolite changes with respect to disease stage and pathophysiological changes in Huntington’s disease (HD) in three tested groups: premanifest gene carriers, manifest HD patients, and healthy volunteers (Figure 1) 13 . In the caudate nucleus and the putamen, manifest HD patients showed significantly reduced NAA ( p = 0.009 and 0.024) and Cr ( p = 0.001 and 0.027), compared with healthy volunteers.…”

“…Five different regions are displayed: hypothalamus, thalamus, caudate nucleus, putamen, prefrontal region. A Gaussian filter of 4 Hz was applied 13 .…”

The Search for Sensitive Biomarkers in Presymptomatic Huntington Disease

“…In addition to providing new insights into the disease process, these results provide a new candidate biomarker. Two recent proton magnetic resonance spectroscopy studies in HD patients, one at 3 T and the other one at 7 T, as well as earlier studies at lower magnetic field cited in those two papers, showed that significant neurochemical changes in HD brain occur only after the appearance of clinical symptoms (Sturrock et al, 2010;van den Bogaard et al, 2011). Therefore, further studies are now needed to determine how early changes in pH reported by Chaumeil et al (2012) occur in HD and whether pH is a sensitive biomarker at earlier stages of the disease and in presymptomatic individuals.…”

Porcine Model of Huntington's Disease

“…However, several studies have also used two-dimensional chemical shift imaging (2D-CSI) [33,40,41]. Studies measuring changes by MRS revealed different values of metabolite concentrations in patients with HD [34,35,42,43]. Recently, several longitudinal clinical studies have been performed.…”

“…Concentrations of metabolites, such as N-acetylaspartate, creatine, phosphocreatine, glutamate, glutamine, choline-containing compounds, inositol, γ-aminobutyric acid and others, can be determined by 1 H MRS [34]. 1 H MRS has previously been considered as a biomarker method in pre-manifest and early stages of HD [35][36][37].…”