title: In vivo monitoring of recovery from neurodegeneration in conditional transgenic SCA1 mice.
abstract: Reliable and objective markers of neuronal function and pathology that can directly assess the effects of neuroprotective treatments in the brain are urgently needed for clinical trials in neurodegenerative diseases. Here we assessed the sensitivity of high field proton magnetic resonance spectroscopy ((1)H MRS) to monitor reversal of neurodegeneration by taking advantage of a well characterized conditional mouse model of spinocerebellar ataxia type 1 (SCA1), where the cerebellar pathology and ataxic phenotype are reversible by doxycycline administration. Transgene expression was suppressed by feeding the mice with chow that contains doxycycline from 6 to 12 weeks of age in an early stage group and from 12 to 24 weeks in a mid-stage group. Cerebellar neurochemical profiles of treated and untreated conditional mice were measured at 9.4 tesla (T) before and after treatment and compared to those of wild type (WT) controls, as well as to histology measures (molecular layer thickness in the primary fissure and a global pathological severity score). Concentrations of N-acetylaspartate (NAA) and myo-inositol in the treated mice trended toward normalization to WT levels in both the early and mid-stage groups. The NAA-to-myo-inositol ratio was significantly different between the treated vs. untreated SCA1 mice and demonstrated partial reversal to WT values both at early and mid-stage, consistent with the histological measures. Taurine and total creatine levels were completely normalized in early and mid-stage treatment groups, respectively. The MRS markers were a more sensitive measure of treatment response than the histological measures from the same volume-of-interest in the early stage group. NAA, myo-inositol and taurine levels were significantly correlated with the histology measures in data combined from all groups. These data demonstrate that MRS markers reliably detect rescue from neuronal pathology and imply that the neurochemical levels measured by MRS accurately reflect treatment efficacy. Therefore this study presents an important step in validating MRS biomarkers as potential surrogate markers to evaluate therapeutics in pre-clinical and clinical trials in SCA1.
authors.affiliation: Center for Magnetic Resonance Research, Department of Radiology, Medical School, University of Minnesota, Minneapolis, MN 55455, USA. gulin@cmrr.umn.edu
authors.forename: Gülin
authors.initials: G
authors.lastname: Oz
authors.forename: Manda L
authors.initials: ML
authors.lastname: Vollmers
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Nelson
authors.forename: Ryan
authors.initials: R
authors.lastname: Shanley
authors.forename: Lynn E
authors.initials: LE
authors.lastname: Eberly
authors.forename: Harry T
authors.initials: HT
authors.lastname: Orr
authors.forename: H Brent
authors.initials: HB
authors.lastname: Clark
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000067696:Ataxin-1; D000067528:Ataxins; D002531:Cerebellum / Q000473:pathology*; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009687:Nuclear Proteins / Q000235:genetics*; D011522:Protons; D020127:Recovery of Function / Q000187:drug effects; D020754:Spinocerebellar Ataxias / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D019076:Transgenes / Q000502:physiology
chemical_list: D000900:Anti-Bacterial Agents; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D011522:Protons; D004318:Doxycycline