Brain atrophy correlates with functional outcome in a murine model of multiple sclerosis.
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.
Pirko
I
I
Mayo Clinic, Department of Neurology, College of Medicine, Rochester, MN 55905, USA. pirko@mayo.edu
Johnson
A J
AJ
Chen
Yi
Y
Lindquist
D M
DM
Lohrey
A K
AK
Ying
J
J
Dunn
R Scott
RS
D000818:Animals; D001284:Atrophy; D001921:Brain / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D009103:Multiple Sclerosis / Q000473:pathology* / Q000503:physiopathology
Neuroimage. 2009 Dec;48(4):637-51
19589388
Annu Rev Biomed Eng. 1999;1:377-99
11701494
J Neuroimmune Pharmacol. 2010 Sep;5(3):355-69
19894121
Ann Neurol. 2001 Jul;50(1):121-7
11456302
Neurosci Lett. 2008 May 30;437(2):121-4
18440142
Arch Neurol. 2004 Feb;61(2):226-30
14967771
Lancet Neurol. 2006 Feb;5(2):158-70
16426992
Radiology. 2008 Mar;246(3):790-5
18309014
Philos Trans R Soc Lond B Biol Sci. 1999 Oct 29;354(1390):1675-86
10603619
Neuroimage. 2006 Sep;32(3):1016-23
16806982
Neurology. 2000 Apr 25;54(8):1689-91
10762518
Curr Opin Neurol. 2002 Jun;15(3):239-45
12045719
Neurology. 2003 Apr 8;60(7):1157-62
12682324
J Neurol Sci. 2009 Jul 15;282(1-2):34-8
19162280
Arch Neurol. 2000 Sep;57(9):1289-92
10987895
J Neurol Neurosurg Psychiatry. 2002 Aug;73(2):141-7
12122170
Neurology. 2007 Feb 27;68(9):634-42
17325269
Lab Invest. 2010 May;90(5):774-86
20157291
J Neuroimaging. 2005;15(4 Suppl):10S-21S
16385015
Acta Neurol Scand. 2000 Aug;102(2):99-105
10949526
J Neuropsychiatry Clin Neurosci. 2002 Winter;14(1):44-51
11884654
N Engl J Med. 2000 Sep 28;343(13):938-52
11006371
Arch Neurol. 2002 Oct;59(10):1572-6
12374494
Springer Semin Immunopathol. 2002;24(2):105-25
12503060
Int MS J. 2004 Dec;11(3):95-9
15585167