Noninvasive detection of presymptomatic and progressive neurodegeneration in a mouse model of spinocerebellar ataxia type 1

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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.

Original languageEnglish (US)
Pages (from-to)3831-3838
Number of pages8
JournalJournal of Neuroscience
Volume30
Issue number10
DOIs
StatePublished - Mar 10 2010

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Spinocerebellar Ataxias
Magnetic Resonance Spectroscopy
Inositol
Transgenic Mice
Disease Progression
Glutamic Acid
Asymptomatic Diseases
Ataxia
Neuroglia
Histology
Biomarkers
Pathology

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@article{c1239787199a40a7922ab9a5a224e2a4,
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.",
author = "Gulin Oz and Nelson, {Christopher D.} and Koski, {Dee M.} and Pierre-Gilles Henry and Malgorzata Marjanska and Deelchand, {Dinesh K} and Shanley, {Ryan M} and Eberly, {Lynn E} and Orr, {Harry T} and Clark, {H. Brent}",
year = "2010",
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doi = "10.1523/JNEUROSCI.5612-09.2010",
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T1 - Noninvasive detection of presymptomatic and progressive neurodegeneration in a mouse model of spinocerebellar ataxia type 1

AU - Oz, Gulin

AU - Nelson, Christopher D.

AU - Koski, Dee M.

AU - Henry, Pierre-Gilles

AU - Marjanska, Malgorzata

AU - Deelchand, Dinesh K

AU - Shanley, Ryan M

AU - Eberly, Lynn E

AU - Orr, Harry T

AU - Clark, H. Brent

PY - 2010/3/10

Y1 - 2010/3/10

N2 - 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.

AB - 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.

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U2 - 10.1523/JNEUROSCI.5612-09.2010

DO - 10.1523/JNEUROSCI.5612-09.2010

M3 - Article

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EP - 3838

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 10

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