Neurochemical alterations in spinocerebellar ataxia type 1 and their correlations with clinical status

Abstract

Robust biomarkers of neurodegeneration are critical for testing of neuroprotective therapies. The clinical applicability of such biomarkers requires sufficient sensitivity to detect disease in individuals. Here we tested the sensitivity of high field (4 tesla) proton magnetic resonance spectroscopy ((1)H MRS) to neurochemical alterations in the cerebellum and brainstem in spinocerebellar ataxia type 1 (SCA1). We measured neurochemical profiles that consisted of 10 to 15 metabolite concentrations in the vermis, cerebellar hemispheres and pons of patients with SCA1 (N = 9) and healthy controls (N = 15). Total NAA (N-acetylaspartate + N-acetylaspartylglutamate, tNAA) and glutamate were lower and glutamine, myo-inositol and total creatine (creatine + phosphocreatine, tCr) were higher in patients relative to controls, consistent with neuronal dysfunction/loss, gliotic activity, and alterations in glutamate-glutamine cycling and energy metabolism. Changes in tNAA, tCr, myo-inositol, and glutamate levels were discernible in individual spectra and the tNAA/myo-inositol ratio in the cerebellar hemispheres and pons differentiated the patients from controls with 100% specificity and sensitivity. In addition, tNAA, myo-inositol, and glutamate levels in the cerebellar hemispheres and the tNAA and myo-inositol levels in the pons correlated with ataxia scores (Scale for the Assessment and Rating of Ataxia, SARA). Two other biomarkers measured in the cerebrospinal fluid (CSF) of a subset of the volunteers (F(2)-isoprostanes asa marker of oxidative stress and glial fibrillary acidic protein (GFAP) as a marker of gliosis) were not different between patients and controls. These data demonstrate that (1)H MRS biomarkers can be utilized to noninvasively assess neuronal and glial status in individual ataxia patients.

Conflict of interest statement

The authors have no conflicts of interest to disclose.

Figures

Figure 1. Localized proton MR spectra obtained from the vermis (A), cerebellar hemispheres (B) and pons (C)

Left: healthy volunteer (50 year old male); right: patient with SCA1 (55 year old female). The alterations in total NAA, glutamate, myo-inositol and total creatine visible in the spectra of the patient are shown.

Figure 2. Neurochemical profiles of control subjects and patients with SCA1

Only metabolites that were quantified with CRLB ≤ 50% in most subjects in a group are plotted. Error bars are 2 × S.E. (95% C.I.). * p

Figure 3. Separation of patients with SCA1 from controls based on total NAA, myo-inositol, glutamate and total creatine levels

The patient with the highest ataxia score (14.5) had the lowest tNAA and highest myo-inositol levels (shown with arrows).

Figure 4. Correlation of neurochemical levels and clinical status

Concentrations of total NAA, myo-inositol and glutamate in the cerebellar hemispheres and total NAA and myo-inositol in the pons are significantly correlated with the SARA score. Correlation coefficients and significance levels are shown.