Brain atrophy correlates with functional outcome in a murine model of multiple sclerosis
I. Pirko, A. J. Johnson, Yi Chen, D. M. Lindquist, A. K. Lohrey, J. Ying, R. Scott Dunn
White matter (WM) lesions are the classic pathological hallmarks of multiple sclerosis (MS). However, MRI-based WM lesion load shows relatively poor correlation with functional outcome, resulting in the "clinico-radiological paradox" of MS. Unlike lesion based measures, volumetric MRI assessment of brain atrophy shows a strong correlation with functional outcome, and the presence of early atrophy predicts a worse disease course. While extensive literature exists describing MRI characteristics of atrophy in MS, the exact pathogenesis and the substrate of atrophy-gray vs. WM loss, axonal/neuronal damage vs. demyelination, or a combination of the above-remain unclear. Animal models of atrophy would allow for detailed investigations of the pathomechanism, and would contribute to an enhanced understanding of structural-functional connections in this complex disease. We now report that in the Theiler's Murine Encephalitis Virus (TMEV) model of MS in SJL/J mice, significant brain atrophy accompanies the development of the progressive MS-like disease. We conducted volumetric MRI studies in 8 cases and 4 age, gender- and strain-matched control mice. While in controls we did not detect any brain atrophy, significant atrophy developed as early as 3. months into the disease course, and reached its peak by 6. months, resulting in ventricular enlargement by 118% (p=0.00003). A strong correlation (r=-0.88) between atrophy and disability, as assessed by rotarod assay, was also demonstrated. We earlier reported another neurodegenerative feature in this model, the presence of deep gray matter T2 hypointensity in thalamic nuclei. Future studies utilizing this model will allow us to investigate key components of MRI detectable neurodegenerative feature development, their tissue correlations and associations with functional outcome measures. These studies are expected to pave the way to a better understanding of the substrate of disability in MS models.
https://doi.org/10.1016/j.neuroimage.2010.08.055
Brain atrophy
Mouse model of multiple sclerosis
TMEV
Theiler's murine encephalitis virus
Volumetric MRI
10.1016/j.neuroimage.2010.08.055
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Multiple Sclerosis Medicine & Life Sciences 100%
Atrophy Medicine & Life Sciences 98%
Brain Medicine & Life Sciences 55%
White Matter Medicine & Life Sciences 34%
Encephalitis Viruses Medicine & Life Sciences 20%
Rotarod Performance Test Medicine & Life Sciences 18%
Thalamic Nuclei Medicine & Life Sciences 16%
Demyelinating Diseases Medicine & Life Sciences 13%
Pirko, I., Johnson, A. J., Chen, Y., Lindquist, D. M., Lohrey, A. K., Ying, J., & Dunn, R. S. (2011). Brain atrophy correlates with functional outcome in a murine model of multiple sclerosis. NeuroImage, 54(2), 802-806. https://doi.org/10.1016/j.neuroimage.2010.08.055
Brain atrophy correlates with functional outcome in a murine model of multiple sclerosis. / Pirko, I.; Johnson, A. J.; Chen, Yi; Lindquist, D. M.; Lohrey, A. K.; Ying, J.; Dunn, R. Scott.
In: NeuroImage, Vol. 54, No. 2, 15.01.2011, p. 802-806.
Pirko, I, Johnson, AJ, Chen, Y, Lindquist, DM, Lohrey, AK, Ying, J & Dunn, RS 2011, 'Brain atrophy correlates with functional outcome in a murine model of multiple sclerosis', NeuroImage, vol. 54, no. 2, pp. 802-806. https://doi.org/10.1016/j.neuroimage.2010.08.055
Pirko I, Johnson AJ, Chen Y, Lindquist DM, Lohrey AK, Ying J et al. Brain atrophy correlates with functional outcome in a murine model of multiple sclerosis. NeuroImage. 2011 Jan 15;54(2):802-806. https://doi.org/10.1016/j.neuroimage.2010.08.055
Pirko, I. ; Johnson, A. J. ; Chen, Yi ; Lindquist, D. M. ; Lohrey, A. K. ; Ying, J. ; Dunn, R. Scott. / Brain atrophy correlates with functional outcome in a murine model of multiple sclerosis. In: NeuroImage. 2011 ; Vol. 54, No. 2. pp. 802-806.
@article{165d27837dd84ec99bb79c85cb99ed9e,
title = "Brain atrophy correlates with functional outcome in a murine model of multiple sclerosis",
abstract = "White matter (WM) lesions are the classic pathological hallmarks of multiple sclerosis (MS). However, MRI-based WM lesion load shows relatively poor correlation with functional outcome, resulting in the {"}clinico-radiological paradox{"} of MS. Unlike lesion based measures, volumetric MRI assessment of brain atrophy shows a strong correlation with functional outcome, and the presence of early atrophy predicts a worse disease course. While extensive literature exists describing MRI characteristics of atrophy in MS, the exact pathogenesis and the substrate of atrophy-gray vs. WM loss, axonal/neuronal damage vs. demyelination, or a combination of the above-remain unclear. Animal models of atrophy would allow for detailed investigations of the pathomechanism, and would contribute to an enhanced understanding of structural-functional connections in this complex disease. We now report that in the Theiler's Murine Encephalitis Virus (TMEV) model of MS in SJL/J mice, significant brain atrophy accompanies the development of the progressive MS-like disease. We conducted volumetric MRI studies in 8 cases and 4 age, gender- and strain-matched control mice. While in controls we did not detect any brain atrophy, significant atrophy developed as early as 3. months into the disease course, and reached its peak by 6. months, resulting in ventricular enlargement by 118% (p=0.00003). A strong correlation (r=-0.88) between atrophy and disability, as assessed by rotarod assay, was also demonstrated. We earlier reported another neurodegenerative feature in this model, the presence of deep gray matter T2 hypointensity in thalamic nuclei. Future studies utilizing this model will allow us to investigate key components of MRI detectable neurodegenerative feature development, their tissue correlations and associations with functional outcome measures. These studies are expected to pave the way to a better understanding of the substrate of disability in MS models.",
keywords = "Brain atrophy, Mouse model of multiple sclerosis, Multiple sclerosis, TMEV, Theiler's murine encephalitis virus, Volumetric MRI",
author = "I. Pirko and Johnson, {A. J.} and Yi Chen and Lindquist, {D. M.} and Lohrey, {A. K.} and J. Ying and Dunn, {R. Scott}",
note = "Funding Information: This study was funded by the National Multiple Sclerosis Society and by the National Institutes of Health ( R01NS058698 ).",
doi = "10.1016/j.neuroimage.2010.08.055",
journal = "NeuroImage",
T1 - Brain atrophy correlates with functional outcome in a murine model of multiple sclerosis
AU - Pirko, I.
AU - Johnson, A. J.
AU - Chen, Yi
AU - Lindquist, D. M.
AU - Lohrey, A. K.
AU - Ying, J.
AU - Dunn, R. Scott
N1 - Funding Information: This study was funded by the National Multiple Sclerosis Society and by the National Institutes of Health ( R01NS058698 ).
N2 - White matter (WM) lesions are the classic pathological hallmarks of multiple sclerosis (MS). However, MRI-based WM lesion load shows relatively poor correlation with functional outcome, resulting in the "clinico-radiological paradox" of MS. Unlike lesion based measures, volumetric MRI assessment of brain atrophy shows a strong correlation with functional outcome, and the presence of early atrophy predicts a worse disease course. While extensive literature exists describing MRI characteristics of atrophy in MS, the exact pathogenesis and the substrate of atrophy-gray vs. WM loss, axonal/neuronal damage vs. demyelination, or a combination of the above-remain unclear. Animal models of atrophy would allow for detailed investigations of the pathomechanism, and would contribute to an enhanced understanding of structural-functional connections in this complex disease. We now report that in the Theiler's Murine Encephalitis Virus (TMEV) model of MS in SJL/J mice, significant brain atrophy accompanies the development of the progressive MS-like disease. We conducted volumetric MRI studies in 8 cases and 4 age, gender- and strain-matched control mice. While in controls we did not detect any brain atrophy, significant atrophy developed as early as 3. months into the disease course, and reached its peak by 6. months, resulting in ventricular enlargement by 118% (p=0.00003). A strong correlation (r=-0.88) between atrophy and disability, as assessed by rotarod assay, was also demonstrated. We earlier reported another neurodegenerative feature in this model, the presence of deep gray matter T2 hypointensity in thalamic nuclei. Future studies utilizing this model will allow us to investigate key components of MRI detectable neurodegenerative feature development, their tissue correlations and associations with functional outcome measures. These studies are expected to pave the way to a better understanding of the substrate of disability in MS models.
AB - White matter (WM) lesions are the classic pathological hallmarks of multiple sclerosis (MS). However, MRI-based WM lesion load shows relatively poor correlation with functional outcome, resulting in the "clinico-radiological paradox" of MS. Unlike lesion based measures, volumetric MRI assessment of brain atrophy shows a strong correlation with functional outcome, and the presence of early atrophy predicts a worse disease course. While extensive literature exists describing MRI characteristics of atrophy in MS, the exact pathogenesis and the substrate of atrophy-gray vs. WM loss, axonal/neuronal damage vs. demyelination, or a combination of the above-remain unclear. Animal models of atrophy would allow for detailed investigations of the pathomechanism, and would contribute to an enhanced understanding of structural-functional connections in this complex disease. We now report that in the Theiler's Murine Encephalitis Virus (TMEV) model of MS in SJL/J mice, significant brain atrophy accompanies the development of the progressive MS-like disease. We conducted volumetric MRI studies in 8 cases and 4 age, gender- and strain-matched control mice. While in controls we did not detect any brain atrophy, significant atrophy developed as early as 3. months into the disease course, and reached its peak by 6. months, resulting in ventricular enlargement by 118% (p=0.00003). A strong correlation (r=-0.88) between atrophy and disability, as assessed by rotarod assay, was also demonstrated. We earlier reported another neurodegenerative feature in this model, the presence of deep gray matter T2 hypointensity in thalamic nuclei. Future studies utilizing this model will allow us to investigate key components of MRI detectable neurodegenerative feature development, their tissue correlations and associations with functional outcome measures. These studies are expected to pave the way to a better understanding of the substrate of disability in MS models.
KW - Brain atrophy
KW - Mouse model of multiple sclerosis
KW - TMEV
KW - Theiler's murine encephalitis virus
KW - Volumetric MRI
U2 - 10.1016/j.neuroimage.2010.08.055
DO - 10.1016/j.neuroimage.2010.08.055
JO - NeuroImage
JF - NeuroImage