title: Noninvasive detection of presymptomatic and progressive neurodegeneration in a mouse model of spinocerebellar ataxia type 1.
abstract: Recent studies with a conditional mouse model of spinocerebellar ataxia type 1 (SCA1) suggest that neuronal dysfunction is reversible and neurodegeneration preventable with early interventions. Success of such interventions will depend on early detection of neuronal and glial abnormalities before cell loss and availability of objective methods to monitor progressive neurodegeneration. Cerebellar concentrations of N-acetylaspartate (NAA), myo-inositol, and glutamate as measured by magnetic resonance spectroscopy (MRS) correlate with ataxia scores of patients with SCA1, indicating their potential as reliable biomarkers of neurodegeneration. Here we investigated whether neurochemical levels are altered by early, presymptomatic disease and whether they gauge disease progression in a mouse model of SCA1. Cerebellar neurochemical profiles of transgenic mice that overexpress the mutant human ataxin-1 (the SCA1[82Q] line) were measured longitudinally up to 1 year by MRS at 9.4 T and compared to those of transgenic mice that overexpress the normal human ataxin-1 (the SCA1[30Q] line) and wild-type controls. Multiple neurochemicals distinguished the SCA1[82Q] mice from controls with no overlap at all ages. Six neurochemicals were significantly different in SCA1[82Q] mice at 6 weeks, before major pathological and neurological changes. Alterations in NAA, myo-inositol, and glutamate progressively worsened and were significantly correlated (p < 0.0001) with disease progression as assessed by histology (molecular layer thickness and an overall severity score). Therefore, the neurochemicals that correlate with clinical status in patients reflected progressive pathology in the mouse model. These data demonstrate that presymptomatic and progressive neurodegeneration in SCA1 can be noninvasively monitored using MRS.
authors.affiliation: Center for Magnetic Resonance Research, Department of Radiology, Medical School, University of Minnesota, Minneapolis, Minnesota 55455, USA. gulin@cmrr.umn.edu
authors.forename: Gülin
authors.initials: G
authors.lastname: Oz
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Nelson
authors.forename: Dee M
authors.initials: DM
authors.lastname: Koski
authors.forename: Pierre-Gilles
authors.initials: PG
authors.lastname: Henry
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Marjanska
authors.forename: Dinesh K
authors.initials: DK
authors.lastname: Deelchand
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; D000067696:Ataxin-1; D000067528:Ataxins; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D020449:Repetitive Sequences, Amino Acid / Q000235:genetics; D020754:Spinocerebellar Ataxias / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology*
chemical_list: C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine