Developing a method to assess axonal integrity in vivo is paramount for the further understanding of multiple sclerosis (MS). Although the importance of Magnetic Resonance Imaging (MRI) in MS is indisputable, the current conventional MRI images in clinical practice correlate only modestly with measures of disability. Axonal loss has been proposed to contribute a large component to MS disability and disease progression. The rationale for this 'MRI paradox'is that the current imaging techniques are neither sensitive nor specific for the varying pathologies. The hypothesis of this project is that Magnetic Resonance Diffusion Tensor Imaging (DTI) can be used to evaluate both the structural integrity of axons, as well as the degree of demyelination in the human optic nerve in vivo. We propose to translate DTI from the animal model to the optic nerves of humans. We also hypothesize that this technique could be used to distinguish clinical outcomes and predict prognosis.
Aim 1 will evaluate subjects with acute optic neuritis prospectively to determine if directional diffusivity correlates with clinical parameters. Imaging will be performed at 0, 0.5,1,3,6, and 12 months. The course for the diffusion parameters will be correlated with tests of visual function. These tests will include contrast sensitivity, visual acuity, visual evoked potentials, color vision, and retinal nerve fiber layer thickness.
Aim 2 will correlate the histopathologic axonal loss in MS optic nerve autopsy specimens with the findings of ex-vivo diffusion imaging. Axonal loss, quantified by neurofilament and beta-amyloid precursor protein staining, demyelination, quantified by myelin basic protein staining, and inflammation, quantified by hematoxylin and eosin staining, will be correlated with diffusivity parameters in individual regions of the nerve.
Aim 3 will compare directional diffusivity in a cross section of living MS patients with remote optic neuritis and poor visual recovery matched to patients with good visual recovery. Clinical parameters will include contrast sensitivity, visual acuity, color vision, visual-evoked potentials, and retinal nerve fiber layer thickness. Those patients who do not develop additional clinical episodes of optic neuritis in the next 12 months will be re-evaluated prospectively in regards to visual function and imaging to determine the stability of DTI measurements.
Aim 4 will evaluate directional diffusivity of the optic nerve in living human subjects who have had unilateral retinal ischemia and poor visual recovery. Retinal ischemia represents a condition of retinal cell death with primary axonal degeneration and secondary demyelination. Tests of visual function will include those included in Aim 3.
Aim 5 will determine the range of values for diffusivity parameters of normal optic nerves in healthy volunteers stratified by age and gender.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23NS052430-05
Application #
8117048
Study Section
NST-2 Subcommittee (NST)
Program Officer
Utz, Ursula
Project Start
2007-08-01
Project End
2012-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
5
Fiscal Year
2011
Total Cost
$144,736
Indirect Cost
Name
Washington University
Department
Neurology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Alvarez, Enrique; Piccio, Laura; Mikesell, Robert J et al. (2013) CXCL13 is a biomarker of inflammation in multiple sclerosis, neuromyelitis optica, and other neurological conditions. Mult Scler 19:1204-8
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Naismith, Robert T; Xu, Junqian; Klawiter, Eric C et al. (2013) Spinal cord tract diffusion tensor imaging reveals disability substrate in demyelinating disease. Neurology 80:2201-9
Wagner, Joanne M; Norris, Rosemary A; Van Dillen, Linda R et al. (2013) Four Square Step Test in ambulant persons with multiple sclerosis: validity, reliability, and responsiveness. Int J Rehabil Res 36:253-9
Naismith, Robert T; Xu, Junqian; Tutlam, Nhial T et al. (2012) Diffusion tensor imaging in acute optic neuropathies: predictor of clinical outcomes. Arch Neurol 69:65-71
Klawiter, Eric C; Xu, Junqian; Naismith, Robert T et al. (2012) Increased radial diffusivity in spinal cord lesions in neuromyelitis optica compared with multiple sclerosis. Mult Scler 18:1259-68
Qian, Peiqing; Lancia, Samantha; Alvarez, Enrique et al. (2012) Association of neuromyelitis optica with severe and intractable pain. Arch Neurol 69:1482-7
Qian, Peiqing; Cross, Anne H; Naismith, Robert T (2011) Lack of response to monoclonal antibody therapy in neuromyelitis optica. Arch Neurol 68:1207-9

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