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Abstract
Background Magnetic resonance spectroscopy (MRS) is a non-invasive method of exploring cerebral metabolism. In Huntington’s disease (HD), altered concentrations of several metabolites have been described; however, findings are discrepant and longitudinal studies are lacking.
Aims To assess prognostic value and explore longitudinal trajectories of MRS metabolites in HD patients and controls.
Methods/Techniques We used 3T MRS to quantify seven metabolites (total n-acetylaspartate; tNAA, total-creatine; tCre, total-choline; tCho, myo-inositol; MI, GABA, glutamate; GLX, and glutathione; GSH) in the putamen of 56 participants (15 controls, 41 HD patients) at baseline and 48 (12 controls, 36 HD patients) at follow-up. Intergroup differences and associations with markers of disease progression were assessed using generalized linear models and partial correlation. Additionally, we examined whether baseline MRS values predicted subsequent change in measures of disease progression and generated mixed effects models to explore longitudinal metabolite trajectories.
Results/Outcomes We found tCre and tNAA to be significantly reduced in manifest compared with premanifest participants at follow-up. Additionally, tCre and MI displayed significant associations with reduced caudate volume across both time points. Baseline MRS values predicted change in measures of disease progression, but findings were inconsistent. Finally, longitudinal mixed effects models revealed glutamate to display a slow linear decrease over time in gene expansion carriers.
Voxel placement and LCModel output: (A) Example voxel placement in left putamen displayed at baseline and follow-up. For the voxel placement in the second MRS acquisition, the images from the first scanning were used to match the anatomical location. (B) LCModel output generated from healthy controls (CTR), premanifest (PreHD) and manifest (HD) Huntington’s disease patients, with black and red lines representing the raw spectrum and model fit overlaid on raw data, respectively. Output peaks represent specific metabolite concentrations. Several metabolites have been labelled on the PreHD spectra for illustrative purposes. ppm, parts per million; CTR, Controls; PreHD, Premanifest gene expansion carriers; HD, Manifest gene expansion carriers
Group differences in metabolite concentration at baseline and follow-up. General linear modes controlling for age and CSF PVE revealed statistically significant differences in tNAA (F(4,43) = [3.98], P < 0.01) and tCre (F(4,43) = [8.16], P < 0.001) concentration at follow-up. HD participants were shown to have reduced concentration compared with PreHD (tNAA, P = 0.03, 95% CIs = [-1.20, -0.07]; tCre, P < 0.01, 95% CIs = [-1.38, -0.34]). These results remained significant when additionally controlling for CAG repeat length (tNAA, P = 0.03, 95% CIs = [-1.40, -0.07]; tCre, P = 0.04, 95% CIs = [-1.34, -0.04]). Diamonds represent mean values and ‘*’ represents statistical significance at p < 0.05. Tests were not corrected for multiple comparisons. Iu, Institutional units; CTR, Controls; PreHD, Premanifest gene expansion carriers; HD, Manifest gene expansion carriers
Associations between metabolites and clinical, cognitive, volumetric and biofluid measures at baseline. tCre and MI displayed a significant association with caudate volume across all models at baseline (tCre, r = 0.45, P < 0.01; MI, r = -0.41, P < 0.01) and follow-up (tCre, r = 0.52, P < 0.01; MI, r = -0.44. P < 0.01). Correlation coefficients displayed in the figure are generated using Pearson’s partial correlation controlling for age and CSF PVE and bootstrapped with 1000 repetitions. Double stars and bold text (**) represent statistical significance (P < 0.05) across all correlation models and time-points
Longitudinal analysis of MRS metabolites. (A) General linear modes controlling for age, CSF PVE and CAG repeat length revealed no significant differences in annualised rate of change across groups. Tests were not corrected for multiple comparisons. (B) tCre correlated with change in cUHDRS (r = 0.47, P < 0.01), whole brain (r = 0.43, P = 0.03) and caudate volume (r = 0.39, P < 0.01), MI significantly predicted decline in white matter (r = -0.47, P < 0.01) and grey matter volume (r = -0.40, P < 0.01) and GSH was associated with change in whole brain volume (r = 0.39, P = 0.03) across all four correlation models. Scatter plots show uncorrected values. (C) Longitudinal trajectories of all metabolites were studied in controls and mutation carriers, with GLX displaying a slow linear reduction in gene expansion carriers only (β = -0.40, 95% CIs = [-0.80, -0.01]). Beta values and 95% confidence intervals were generated from generalized mixed-effects models controlling for age and CSF PVE and have been multiplied by 10 to show change/10yrs. ‘*’ indicates significance at P < 0.05. Iu, Institutional units; CTR, Controls; PreHD, Premanifest gene expansion carriers; HD, Manifest gene expansion carriers; HDMC, Huntington’s disease mutation carriers
Conclusion We show evidence of reduced MRS metabolites as the disease progresses and associations with markers of disease progression. However, the absence of consistent group differences, inconsistency across time-points, and lack of clear longitudinal change suggests MRS metabolites have limited biomarker potential in HD.