Neurochemical correlates of caudate atrophy in Huntington's disease

Abstract

BACKGROUND The precise pathogenic mechanisms of Huntington disease (HD) are unknown, but can be tested in vivo using proton magnetic resonance spectroscopy (1H MRS) to measure neurochemical changes. OBJECTIVE To evaluate neurochemical differences in HD gene mutation-carriers (HGMC) vs. controls, and to investigate relationships among function, brain structure and neurochemistry in HD. Since previous 1H MRS studies have yielded varied conclusions about HD neurochemical changes, an additional goal was to compare two 1H MRS data analysis approaches. METHODS HGMC with pre-manifest to early HD and controls underwent evaluation of motor function, MR imaging and localized 1H MRS in caudate and frontal lobe. Analytical approaches tested included absolute quantitation (unsuppressed water signal as an internal reference) and relative quantification (calculating ratios of all neurochemical signals within a voxel). RESULTS We identified a suite of neurochemicals reduced in concentration proportionally to loss of caudate volume in HGMC. Caudate concentrations of NAA, creatine, choline, and caudate and frontal concentrations of glutamate+glutamine and glutamate correlated with caudate volume in HGMC subjects. The relative, but not the absolute quantitation approach revealed disease-related differences; the Glx signal was decreased relative to other neurochemicals in caudate of HGMC subjects vs. controls. CONCLUSIONS This is the first study to demonstrate correlation among structure, function and chemical measures in HD brain. Additionally, we demonstrate that a relative quantitation approach may enable magnification of subtle differences between groups. Observation of decreased glutamate-glutamine signals suggests that glutamate signaling may be disrupted relatively early in HD, with important implications for therapeutic approaches.

A longitudinal study of magnetic resonance spectroscopy Huntington's disease biomarkers

“…The suggestion that relative metabolite concentrations may obviate partial volume effects, making it possible to sample, for example, caudate, without these concerns may represent oversimplification. Even where CSF constituents are measured relative to Cr, absent in CSF, this may falsely reduce metabolite estimations because spectroscopy averages voxel constituents.…”

Longitudinal atrophy characterization of cortical and subcortical gray matter in Huntington’s disease patients

“…In this regard, despite previous cross‐sectional studies indicating that caudate volume decrease mainly correlates with cognitive outcomes (Harris et al, ; Kim et al, ; Rosas et al, ), other studies have reported that it also correlates with the TFC status (Rosas et al, ; Tabrizi et al, ), suggesting its influence on functionality for daily living performance. In regard to the correlation with the UHDRS‐TMS decline, cross‐sectional studies have showed that the caudate volume decrease not only correlates with the global UHDRS‐TMS score (Coppen et al, ; Galvez et al, ; Padowski et al, ; Domínguez et al, , ), but also with specific domains of this scale, including chorea degree and eye movements’ deficits (Coppen et al, ; Galvez et al, ). Besides, longitudinal studies have shown that progressive caudate atrophy correlates with the UHDRS‐TMS performance at baseline (Domínguez et al, , ).…”

Advances in clinical trials for movement disorders

“…These studies suggest outcome measures for testing new therapies in future clinical trials and facilitate the calculation of sample sizes. The PREDICT HD study identified potential predictors of disease worsening, which allows for the selection of appropriate participants . Indeed, randomized, placebo‐controlled trials using these data have already been reported …”