Assessing recovery from neurodegeneration in spinocerebellar ataxia 1: Comparison of in vivo magnetic resonance spectroscopy with motor testing, gene expression and histology

Abstract

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.

Repeated Mesenchymal Stromal Cell Treatment Sustainably Alleviates Machado-Joseph Disease

“…Importantly, the levels of GABA and the glutamate-glutamine complex in the cerebella of Tg-ATXN3-69Q mice were positively correlated with their rotarod performance (r s = 0.59, p = 0.05 and r s = 0.77, p = 0.03; Figures 8D and 8E, respectively). 26 Even though, in the present study, no differences were observed in the levels of N-acetylasparate (NAA) and N-acetylaspartylglutamate (NAAG) (data not shown), there was a positive correlation between the levels of (NAA+NAAG)/INS and rotarod performance (measured 8 weeks after the first treatment course), as already shown for another SCA 41 (r s = 0.87, p = 0.01; Figure 8F). Finally, we highlight that two different subpopulations can be distinguished in every plot, with the MSC-treated group exhibiting higher metabolic levels and increased rotarod performance than controls ( Figures 8D-8F), suggesting that these biomarkers might be used to track the success of MSC transplantation.…”

Antisense oligonucleotide–mediated ataxin-1 reduction prolongs survival in SCA1 mice and reveals disease-associated transcriptome profiles

“…Neurochemical response to ASO treatment in Atxn1 154Q/2Q mice. Previously, we demonstrated that MRS accurately reflected recovery of cerebellar pathology in a conditional transgenic mouse model of ATX-N1[82Q]-induced cerebellar disease (10,11). Consequently, MRS was examined for its ability to detect ASO treatment effects on neurochemicals in the cerebella and brainstems in Atxn1 154Q/2Q mice.…”

“…Following recovery from the final scan, mice were euthanized via carbon dioxide asphyxiation, and brain tissue was harvested for RNA analysis. A quadrature surface coil and a horizontal 9.4 T magnet (Agilent) were used to acquire MRS measurements according to methods previously described (11,43). VOIs for the MRS measurement were selected using coronal and sagittal images acquired with a rapid acquisition with relaxation enhancement sequence (repetition time [TR] = 4 s; echo train length = 8; echo time (TE) = 60 ms; slice thickness = 1 mm).…”

“…expression significantly improved Purkinje cell pathology, behavior deficits (9), and neurochemical abnormalities (10,11). At an early stage of disease (6 weeks of age), Purkinje cell pathology and motor dysfunction were completely reversible.…”

Neurochemical abnormalities in premanifest and early spinocerebellar ataxias

“…21 Importantly, neurochemical alterations were also reflective of pathological progression 20 and reversal 22, 23 in SCA1 models.…”