Suppression of transgene expression in a conditional transgenic mouse model of spinocerebellar ataxia 1 (SCA1) reverses the Purkinje cell pathology and motor dysfunction that are hallmarks of SCA1. We previously showed that cerebellar neurochemical levels measured by magnetic resonance spectroscopy (MRS) correlate with progression of pathology and clinical status of patients and that abnormal neurochemical levels normalize upon suppression of transgene expression, indicating their potential as robust surrogate markers of treatment effects. Here we investigated the relative sensitivities of MRS, histology, transgene expression and motor behavioral testing to disease reversal in conditional SCA1 mice. Transgene expression was suppressed by doxycycline administration and treated and untreated mice were assessed by MRS at 9.4. tesla before and after treatment and with an accelerating Rotarod, histology and quantitative polymerase chain reaction (qPCR) for ataxin-1 transgene expression following doxycycline treatment. The MRS-measured N-acetylaspartate-to-. myo-inositol ratio (NAA/Ins) correlated significantly with the molecular layer (ML) thickness and transgene expression. NAA/Ins, ML thickness and transgene expression were highly significantly different between the treated vs. untreated groups (. p<. 0.0001), while the Rotarod assessment showed a trend for treatment effect. MRS, qPCR and histology had high sensitivity/specificity to distinguish treated from untreated mice, all with areas under the curve (AUC). =. 0.97-0.98 in receiver operating characteristic (ROC) analyses, while Rotarod had significantly lower sensitivity and specificity (AUC. =. 0.72). Therefore, MRS accurately reflects the extent of recovery from neurodegeneration with sensitivity similar to invasive measures, further validating its potential as a surrogate marker in pre-clinical and clinical treatment trials.
Bibliographical noteFunding Information:
This work was supported by the National Institute of Neurological Disorders and Stroke grants R01 NS070815 and R37 NS022920 . Additional support was received from NINDS Center Core at the University of Minnesota P30 NS062158 , National Center for Research Resources (NCRR) biotechnology research resource grant P41 RR008079 , National Institute of Biomedical Imaging and Bioengineering (NIBIB) grant P41 EB015894 , the Institutional Center Cores for Advanced Neuroimaging award P30 NS076408 and the W.M. Keck Foundation . We thank the staff of the Center for MR Research for maintaining and supporting the MR system, LuAnn Anderson for expert technical help with histology and Drs. Teresa Macheda and Mark Thomas for guidance on the Rotarod assessments.
- Magnetic resonance spectroscopy
- Outcome measures
- Receiver operating characteristic analysis
- Spinocerebellar ataxia