Magnetic resonance spectroscopy biomarkers in premanifest and early Huntington disease

Abstract

Objectives: To evaluate in vivo brain metabolite differences in control subjects, individuals with premanifest Huntington disease (pre-HD), and individuals with early HD using 1 H magnetic resonance spectroscopy (MRS) and to assess their relationship with motor performance.Methods: Eighty-five participants (30 controls, 25 pre-HD, and 30 early HD) were recruited as part of the TRACK-HD study. Eighty-four were scanned at 3 T with single-voxel spectroscopy in the left putamen. Disease burden score was Ͼ220 among pre-HD individuals. Subjects underwent TRACK-HD motor assessment including Unified Huntington's Disease Rating Scale (UHDRS) motor scoring and a novel quantitative motor battery. Statistical analyses included linear regression and one-way analysis of variance. Results:Total N-acetylaspartate (tNAA), a neuronal integrity marker, was lower in early HD (ϳ15%) vs controls (p Ͻ 0.001). N-acetylaspartate (NAA), a constituent of tNAA, was lower in pre-HD (ϳ8%) and early HD (ϳ17%) vs controls (p Ͻ 0.05). The glial cell marker, myo-inositol (mI), was 50% higher in early HD vs pre-HD (p Ͻ 0.01). In early HD, mI correlated with UHDRS motor score (R 2 ϭ 0.23, p Ͻ 0.05). Across pre-HD and early HD, tNAA correlated with performance on a tongue pressure task (R 2 ϭ 0.30, p Ͻ 0.0001) and with disease burden score (R 2 ϭ 0.17, p Ͻ 0.005). Conclusions:We demonstrate lower putaminal tNAA in early HD compared to controls in a crosssection of subjects. A novel biomarker role for mI in early HD was also identified. These findings resolve disagreement in the literature about the role of MRS as an HD biomarker. We conclude that putaminal MRS measurements of NAA and mI are promising potential biomarkers of HD onset and progression. Neurology ® 2010;75:1702-1710 GLOSSARY AD ϭ Alzheimer disease; Cr ϭ creatine; DBS ϭ disease burden score; Glu ϭ glutamate; GPC ϭ glycerophosphocholine; HD ϭ Huntington disease; mI ϭ myo-inositol; MR ϭ magnetic resonance; MRS ϭ 1 H magnetic resonance spectroscopy; NAA ϭ N-acetylaspartate; NAAG ϭ N-acetylaspartylglutamate; PC ϭ phosphocholine; PCr ϭ phosphocreatine; pre-HD ϭ premanifest Huntington disease; SNR ϭ signal-to-noise ratio; tCho ϭ total choline; tCr ϭ total creatine; TE ϭ echo time; tNAA ϭ total N-acetylaspartate; TR ϭ repetition time; UBC ϭ University of British Columbia; UHDRS ϭ Unified Huntington's Disease Rating Scale; VBM ϭ voxel-based morphometry.The eventual development of Huntington disease (HD) symptoms can be predicted through detection of CAG trinucleotide repeat expansion in the HTT gene 1 in premanifest gene carriers. However, definitive HD biomarkers, able to objectively identify disease onset and progression, are lacking. Evaluation of potential biomarkers are the focus of longitudinal studies such as TRACK-HD 2 and PREDICT-HD. H magnetic resonance spectroscopy (MRS) has previously been evaluated as a biomarker modality in premanifest and early HD. [4][5][6][7][8][9][10][11] However, the literature is conflicted with regard to the utility of metabolites such as total N-ac...

Cortical Metabolites as Biomarkers in the R6/2 Model of Huntington's Disease

“…Both Cr and PCr increased in striatum and cortex, suggesting that additional disease-related mechanisms beyond energy balance were perturbing their steady-state levels. In contrast to the current study, total creatine was reported to decrease beginning at presymptomatic stages in humans (Sturrock et al, 2010). The observed increase in cortical Lac was not present in the previous study (Tkac et al, 2007) but changes in Lac, both increases and decreases, have been noted by others (Jenkins et al, 2005;Tsang et al, 2006).…”

“…Elevated myo-Ins, principally found within astrocytes, is considered a marker for gliosis and is elevated in a number of neurodegenerative diseases (Fisher et al, 2002;Oz et al, 2010a). Similarly, increases in myo-Ins and decreases in NAA have been found in both R6/2 mice and presymptomatic and early stage HD patients (Jenkins et al, 2005;Tsang et al, 2006;Sturrock et al, 2010). In the human 3T MRS study, choline increased in early stage HD, consistent with the mouse data (Sturrock et al, 2010).…”

“…At high magnetic fields, 1 H MRS can reliably quantify up to 17 brain metabolites in mouse models of neurological disease (Tkac et al, 2007;Oz et al, 2010b). A different number of metabolites (from 3 to 17) can be reliably quantified in human brain based on the magnetic field strength (1.5 to 7 T), pulse sequence and data processing (Jenkins et al, 1998;Sturrock et al, 2010;Oz et al, 2010a). As a noninvasive measurement in both species, MRS has the potential to provide a scale for aligning progression in mouse models with the human disease.…”

Clinical Motor and Cognitive Neurobehavioral Relationships in the Basal Ganglia

“…PET studies of Huntington's patients without hyperactive behavior have shown frontal metabolism to be normal but with decreased caudate and putamen metabolism [49,50]. However is it thought that normal frontal metabolism in Huntington's may result from a coexistent neurological degeneration and the resultant thalamo-frontal hyper-stimulation.…”

Biomarkers for Huntington’s Disease

“…Lower neuronal markers (N-acetylaspartate) levels were shown in presymptomatic and early HD, whereas glial cell markers (myo-inositol) were increased (Surrock et al 2010). Elevated lactate and reduced creatine levels were shown in the striatum of presymptomatic HD gene carriers and early HD patients (Reynolds et al 2005).…”