Sturrock, A; (2015) The assessment of proton MRS as a biomarker for Huntington disease. Doctoral thesis , UCL (University College London).

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Abstract

The development of effective therapies for Huntington disease will require the identification of reproducible and objective markers of disease progression and abrogation. Magnetic Resonance Spectroscopy (MRS), a method of measuring brain metabolism within a specified region of interest, has shown potential as one such biomarker modality. Presented is work that demonstrates that putaminal MRS is an important biomarker modality, specifically in the context of clinical trials. At all time-points N-acetyl aspartate (NAA) and total NAA (tNAA), neuronal integrity markers, were lower in early manifest HD than control subjects. tNAA was consistently lower in pre-manifest HD than Controls. The gliosis marker, myo-inositol (mI), was robustly elevated in Early HD. Metabolites showed no longitudinal change for any group over 24 months. While motor assessments were better longitudinal measures of disease progresson, the robustness of tNAA permitted development of a model in which this metabolite is an outcome measure for future clinical trials. Thus, if one were to test a therapeutic with efficacy to partially normalise tNAA based on the difference between Control vs. Early HD, around 350 or 52 subjects (split between two treatment arms) would be required depending on whether 20% or 50% normalization of tNAA levels are expected. Brain metabolites most consistently correlated with disease burden but less so with motor phenotype. Direct and indirect evaluations of gliosis markers in biosamples were performed based on spectroscopic findings, and these suggested significant biomarker potential for the oxidation product lipid peroxidase (LPO). MRS demonstrates robust and consistent group metabolite differences in HD- affected individuals that correlate with disease burden. This modality has potential utility as an outcome measure for future therapeutic trials in HD, and furthermore may be useful in identifying novel biosample markers of disease.

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