Early impairment in brain metabolism detected by MR spectroscopy antedates structural changes in mouse models of spinocerebellar ataxias



Read the full articleNon-invasive detection of neurochemical changes prior to overt pathology in a mouse model of spinocerebellar ataxia type 1’ on doi: 10.1111/jnc.12435.

Abbreviations used

magnetic resonance imaging


magnetic resonance spectroscopy

Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) are used for evaluating patients with neurological problems [see http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1471-4159/homepage/virtual_issues.htm#molecularimaging]. Many neurological disorders are manifested by changes in concentration of specific metabolites in brain or in discrete brain regions. A number of these metabolites can be readily detected and quantified non-invasively using localized MRS. From the clinical point of view, this technique may help to diagnose the specific neurological problem and to monitor response to therapy.

Inherited or aging-associated neurodegenerative diseases can be modeled in mice by specific gene mutations. Mouse models are used for studying disease onset and progress, its pathophysiology and the effect of therapy. Transgenic mice often replicate many of the symptoms of the corresponding human disease, and are thus valuable models that can substantially improve efficiency of testing drugs in specific neurodegenerative conditions. MRI and MRS can provide valuable information. MRI can be used to detect morphological changes in the brain tissue, and variations in tissue structure and composition can be revealed based on relaxation times, diffusion constants and other physical parameters of tissues [e.g. magnetization transfer and chemical exchange saturation transfer (CEST) effects, susceptibility variation, etc.]. Blood perfusion can be measured with or without contrast agents and blood vessels can be visualized using MR angiography or venography.

MRS of brain is the only technique to non-invasively measure the concentration of local tissue metabolites that provide information about the structural and metabolic integrity of the brain. The metabolite profile can provide information regarding the density and functionality of neurons, gliosis, energy supplies and consumption, osmoregulation and other neurochemical aspects of the brain tissue. This information is obtained in vivo and longitudinally over time on the same animal. Because of the non-invasive character and the feasibility for the longitudinal in vivo experiments, this technique is also suitable for drug development and testing.

Recently, several MRS studies on patients with spinocerebellar ataxias have been reported in the literature (Guerrini et al. 2004; Öz et al. 2010a; Lirng et al. 2012). In the type 1 of ataxia (SCA1), a decrease in the concentration of N-acetyl aspartate and glutamate as well as an increase in the concentration of glutamine, myo-inositol and total creatine (creatine + phosphocreatine) was observed in cerebellum and brainstem of patients relative to control subjects. These changes in the neurochemical profile may indicate alterations in energy metabolism, dysfunction and/or loss of neurons, gliosis and impairment of the glutamate-glutamine cycle. However, before pre-clinical and clinical trials, correlation of these biomarkers with pathology and their sensitivity to the progression of the disease should be further investigated. Transgenic mouse models are extremely well suited for such a study. The conditional SCA1[82Q] mice over-expressing mutant human ataxin-1 protein showed a good correlation of concentration of the same metabolites as observed in patients (N-acetylaspartate, myo-inositol and glutamate) with global pathological severity score and with molecular layer thickness in the primary fissure (Öz et al. 2010b). Treatment of these mice with doxycycline to suppress transgene expression led to partial normalization of the N-acetylaspartate and myo-inositol concentrations both in early and mid-stage groups of animals. The MRS markers in the early stage of the disease were significantly different between the drug treated and untreated groups whereas the pathological measures were not different (Öz et al. 2011). This finding indicates that the MRS markers can be a particularly sensitive index of changes from treatment in the early disease stage.

A study of a knockin mouse model, the Sca1154Q/2Qline, which mimics early stages of SCA1, is reported in this issue (Emir et al. 2013). This model showed mild cerebral pathology even at 39 weeks of age; however, it could be distinguished very early from controls by the MRS profile. The concentrations of taurine and total choline were decreased compared with wild-type mice starting at 6 weeks of age, and glutamine and total creatine levels were increased starting at 12 weeks (Table 1). These alterations can be related to osmotic changes and to alterations in membrane phospholipids and energy metabolism. The results of this study by Emir et al. (2013) underscore the translational potential of using genetically modified mice for modeling specific neurological diseases and evaluating the efficacy of targeted neuroprotective strategies. MRS provides the capability for non-invasive longitudinal studies over an extended period of disease progression and correlating the changes observed by MRS with histology and specific biochemical alterations in neurons and glial cells. This study underscores the unparalleled potential of high resolution MRS in advancing the understanding of ataxia and other neurological diseases.

Table 1. Metabolites whose concentrations were different compared to controls in the SCA1[82Q] and Sca1154Q/2Q mouse models of spinocerebellar ataxia type 1
MetaboliteAge (weeks)
Total creatine   
  Sca1 154Q/2Q
Total creatine  


The authors declare no conflict of interest.