Longitudinal Evaluation of Magnetic Resonance Spectroscopy Metabolites as Biomarkers in Huntington’s Disease

Abstract

Magnetic resonance spectroscopy (MRS) is a non-invasive method of exploring cerebral metabolism. In Huntingtons disease, altered MRS-determined concentrations of several metabolites have been described; however, findings are often discrepant and longitudinal studies of metabolite trajectory are lacking. MRS metabolites may represent a valuable source of biomarkers, thus their relationship with established biofluid and structural imaging markers of disease progression require further exploration to assess prognostic value and elucidate biochemical pathways associated with neurodegeneration. In a prospective single-site controlled cohort study with standardised collection of CSF, blood, phenotypic and imaging data, we used MRS to evaluate metabolic profiles in the putamen of 56 participants at baseline (15 healthy controls, 15 premanifest and 26 manifest gene expansion carriers) and at 2-year follow-up. Intergroup differences and associations with established measures were assessed cross-sectionally using generalized linear models and partial correlation, controlling for age and CAG repeat length. We report no significant groupwise differences in metabolite concentration but found several metabolites to be associated with measures of disease progression; however, only two relationships were replicated across both time points, with total Creatine (creatine + phosphocreatine) and myo-inositol displaying significant associations with reduced caudate volume. Although relationships were observed between MRS metabolites and biofluid measures, these were not consistent across time points. To further assess prognostic value of the metabolites, we examined whether baseline MRS values, or rate of change, predicted subsequent change in established measures of disease progression. Several associations were found but were inconsistent across known indicators of disease progression. Finally, longitudinal mixed effects models, controlling for age, revealed no significant change in metabolite concentration over time in gene expansion carriers. Altogether, our findings show some interesting cross-sectional associations between select metabolites, namely total creatine and myo-inositol, and markers of disease progression, potentially highlighting the proposed roles of neuroinflammation and metabolic dysfunction in disease pathogenesis. However, the absence of group differences, inconsistency between baseline and follow-up, and lack of clear longitudinal change over two years suggests that MRS metabolites have limited potential as biomarkers in Huntingtons disease.

Neuroimaging Biomarkers for Huntington’s Disease

“…Correlations have been made between alternations in metabolites and motor performance [121,125], neuropsychological performance [128], disease severity [133], and disease burden [121]. So far there have been two longitudinal MRS studies, both showing no longitudinal change of metabolites in their follow-up [135,136].…”

From Pathophysiology to Treatment of Huntington's Disease

“…Skeletal muscle atrophy is another hallmark of HD [134]. Muscle cells express mHTT and show inclusion bodies in animal models of HD [135,136] and in muscle cell cultures from HD patients [137]. In addition to aggregate formation, cultured cells from HD patients also show mitochondrial abnormalities [137][138][139], and the two may work together to cause muscle wasting in HD.…”

“…Cardiac failure is relatively common among HD patients, as it occurs in about 30% of cases [132]. Cardiac tissue expresses HTT and while mHTT inclusions are seen in HD mice [140], no aggregates have been reported in cardiac tissue from HD patients [136]. Altered autonomic input to the heart [141], calcium dysregulation [142], and conduction abnormalities [111] are all seen in HD patients and could contribute to heart conditions.…”