Purpose To determine if neurochemical concentrations obtained at two MRI sites using clinical 3 T scanners can be pooled when a highly optimized, non-vendor short-echo, single voxel proton MRS pulse sequence is utilized in conjunction with identical calibration and quantification procedures. Methods A modified semi-LASER sequence (TE = 28 ms) was used to acquire spectra from two brain regions (cerebellar vermis and pons) on two Siemens 3 T scanners using the same B0 and B1 calibration protocols from two different cohorts of healthy volunteers (N=24–33 per site) matched for age and BMI. Spectra were quantified with LCModel using water scaling. Results The spectral quality was very consistent between the two sites and allowed reliable quantification of at least 13 metabolites in the vermis and pons compared to 3 – 5 metabolites in prior multi-site MRS trials using vendor-provided sequences. The neurochemical profiles were nearly identical at the two sites and showed the feasibility to detect inter-individual differences in the healthy brain. Conclusion Highly reproducible neurochemical profiles can be obtained on different clinical 3 T scanners at different sites, provided that the same, optimized acquisition and analysis techniques are utilized. This will allow pooling of multi-site data in clinical studies, which is particularly critical for rare neurological diseases.
Background Spinocerebellar Ataxias (SCAs) belong to polyglutamine repeat disorders and are characterized by a predominant atrophy of the cerebellum and the pons. Methods Proton magnetic resonance spectroscopy (1H MRS) using an optimised semiadiabatic localization by adiabatic selective refocusing (semi-LASER) protocol was performed at 3 T to determine metabolite concentrations in the cerebellar vermis and pons of a cohort of patients with SCA1 (n = 16), SCA2 (n = 12), SCA3 (n = 21), SCA7 (n = 12) and healthy controls (n = 33). Results Compared to controls, patients displayed lower total N-acetylaspartate and, to a lesser extent, lower glutamate, reflecting neuronal loss/dysfunction, while the glial marker, myo-inositol, was elevated. Patients also showed higher total creatine as reported in Huntington disease, another polyglutamine repeat disorder. There was a strong correlation between the Scale for the Assessment and Rating of Ataxia and the neurometabolites in both affected regions of patients. Principal component analyses confirmed that neuronal metabolites (total N-acetylaspartate and glutamate) were inversely correlated in the vermis and the pons to glial (myo-inositol) and energetic (total creatine) metabolites, as well as to disease severity (motor scales). Neurochemical plots with selected metabolites also allowed the separation of SCA2 and SCA3 from controls. Conclusion The neurometabolic profiles detected in patients underlie cell-specific changes in neuronal and astrocytic compartments that cannot be assessed by other neuroimaging modalities. The inverse correlation between metabolites from these two compartments suggests a metabolic attempt to compensate for neuronal damage in SCAs. Because these biomarkers reflect dynamic aspects of cellular metabolism, they are good candidates for proof-of-concept therapeutic trials.
ObjectiveAs gene-based therapies may soon arise for patients with spinocerebellar ataxia (SCA), there is a critical need to identify biomarkers of disease progression with effect sizes greater than clinical scores, enabling trials with smaller sample sizes.MethodsWe enrolled a unique cohort of patients with SCA1 (n = 15), SCA2 (n = 12), SCA3 (n = 20) and SCA7 (n = 10) and 24 healthy controls of similar age, sex and body mass index. We collected longitudinal clinical and imaging data at baseline and follow-up (mean interval of 24 months). We performed both manual and automated volumetric analyses. Diffusion tensor imaging (DTI) and a novel tractography method, called fixel-based analysis (FBA), were assessed at follow-up. Effect sizes were calculated for clinical scores and imaging parameters.ResultsClinical scores worsened as atrophy increased over time (p < 0.05). However, atrophy of cerebellum and pons showed very large effect sizes (>1.2) compared to clinical scores (<0.8). FBA, applied for the first time to SCA, was sensitive to microstructural cross-sectional differences that were not captured by conventional DTI metrics, especially in the less studied SCA7 group. FBA also showed larger effect sizes than DTI metrics.ConclusionThis study showed that volumetry outperformed clinical scores to measure disease progression in SCA1, SCA2, SCA3 and SCA7. Therefore, we advocate the use of volumetric biomarkers in therapeutic trials of autosomal dominant ataxias. In addition, FBA showed larger effect size than DTI to detect cross-sectional microstructural alterations in patients relative to controls.
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