Non-Invasive Quantitation of Cellular and Biochemical Changes in Hereditary Ataxi

Summary

Principal Investigator: GULIN OZ
Abstract: DESCRIPTION (provided by applicant): Successful application of potential neuroprotective agents will depend on early detection of neurodegenerative diseases. Biochemical and cellular processes that trigger and accompany the neuronal loss in these diseases are known to be active for years prior to irreversible structural changes and diagnosis. The long-term goal of this work is to establish non-invasive, quantitative magnetic resonance spectroscopy (MRS) measures sensitive to the cellular and biochemical processes associated with the progressive neuron loss in neurodegenerative diseases and to utilize these measures in early detection and management of disease. This application focuses on two processes common to many neurodegenerative diseases, gliosis and oxidative stress. Hereditary ataxias with known involvement of gliosis or oxidative stress were chosen as the test case to establish the utility of MRS. In Specific Aim 1, indicators of gliosis (myo-inositol and glutamine) will be quantified by high field (4 tesla) MRS in cerebella and pons of patients with spinocerebellar ataxias SCA2 and SCA6 in comparison to healthy controls. Associations will be sought between these MRS markers and glial fibrillary acidic protein levels in cerebrospinal fluid (CSF) as determined by ELISA as an independent measure of reactive gliosis. Additionally, cerebellar and pons atrophy will be assessed by three-dimensional (3D) MRI and clinical severity by a quantitative ataxia rating scale. In Specific Aim 2, indicators of oxidative stress (glutathione and vitamin C) will be quantified by high field MRS in cerebella and pons of patients with Friedreich's ataxia (FRDA) in comparison to healthy controls. Associations will be sought between these MRS markers and F2-isoprostane levels in CSF as measured by GC/MS as an independent measure of oxidative damage in the brain. Cerebellar and pons atrophy will be assessed by 3D MRI and clinical severity by a quantitative ataxia rating scale. In both aims, the goal is to validate the non-invasive MRS measures with more established, but invasive CSF biomarkers. The MRS measures are expected to correlate with the CSF and clinical severity measures. In Specific Aim 3, neurochemical profiles of cerebella and pons of asymptomatic carriers of SCA2 and SCA6 will be measured by high field MRS and compared to those of healthy controls. This aim will start addressing the long term goal of early detection. It is expected that pre-clinical biochemical abnormalities associated with neuron loss will be detected in these individuals. Reliable in vivo quantitation of biomarkers in the intact brain will have a high impact in the management (early detection, disease staging and treatment monitoring) of many common neurodegenerative diseases. RELEVANCE: This work intends to establish non-invasive, quantitative imaging measures of biochemical and cellular alterations in neurodegenerative diseases. Such measures can eventually be used in the clinic for early disease detection, which in turn will facilitate application of treatments to delay the onset of these diseases, as well as for monitoring treatment response. Successful application of such treatments is expected to reduce the burden caused by these diseases on individuals, their families and society.
Funding Period: 2008-03-01 - 2010-02-28
more information: NIH RePORT

Top Publications

  1. pmc Neurochemical alterations in spinocerebellar ataxia type 1 and their correlations with clinical status
    GULIN OZ
    Center for MR Research, Department of Radiology, Medical School, University of Minnesota, Minneapolis, Minnesota 55455, USA
    Mov Disord 25:1253-61. 2010
  2. pmc (1)H MR spectroscopy in Friedreich's ataxia and ataxia with oculomotor apraxia type 2
    Isabelle Iltis
    Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, Minneapolis, MN 55455, USA
    Brain Res 1358:200-10. 2010
  3. pmc Distinct neurochemical profiles of spinocerebellar ataxias 1, 2, 6, and cerebellar multiple system atrophy
    GULIN OZ
    Center for MR Research, Department of Radiology, Medical School, University of Minnesota, 2021 6th St S E, Minneapolis, MN 55455, USA
    Cerebellum 10:208-17. 2011
  4. pmc Short-echo, single-shot, full-intensity proton magnetic resonance spectroscopy for neurochemical profiling at 4 T: validation in the cerebellum and brainstem
    GULIN OZ
    Center for MR Research, Department of Radiology, Medical School, University of Minnesota, Minneapolis, Minnesota 55455, USA
    Magn Reson Med 65:901-10. 2011

Scientific Experts

Detail Information

Publications4

  1. pmc Neurochemical alterations in spinocerebellar ataxia type 1 and their correlations with clinical status
    GULIN OZ
    Center for MR Research, Department of Radiology, Medical School, University of Minnesota, Minneapolis, Minnesota 55455, USA
    Mov Disord 25:1253-61. 2010
    ..These data demonstrate that (1)H MRS biomarkers can be utilized to noninvasively assess neuronal and glial status in individual ataxia patients...
  2. pmc (1)H MR spectroscopy in Friedreich's ataxia and ataxia with oculomotor apraxia type 2
    Isabelle Iltis
    Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, Minneapolis, MN 55455, USA
    Brain Res 1358:200-10. 2010
    ..We aimed at assessing the neurochemical profile of the pons, the cerebellar hemisphere and the vermis in patients with FRDA and AOA2 to identify potential biomarkers of these diseases...
  3. pmc Distinct neurochemical profiles of spinocerebellar ataxias 1, 2, 6, and cerebellar multiple system atrophy
    GULIN OZ
    Center for MR Research, Department of Radiology, Medical School, University of Minnesota, 2021 6th St S E, Minneapolis, MN 55455, USA
    Cerebellum 10:208-17. 2011
    ..Studies with higher numbers of patients and other ataxias are warranted to further investigate the clinical utility of neurochemical levels as measured by high-field MRS as ataxia biomarkers...
  4. pmc Short-echo, single-shot, full-intensity proton magnetic resonance spectroscopy for neurochemical profiling at 4 T: validation in the cerebellum and brainstem
    GULIN OZ
    Center for MR Research, Department of Radiology, Medical School, University of Minnesota, Minneapolis, Minnesota 55455, USA
    Magn Reson Med 65:901-10. 2011
    ..A high correlation between metabolite concentrations obtained by these two proton (1) H MRS techniques indicated the sensitivity to detect intersubject variation in metabolite levels...