Axonal damage and neuronal loss are key factors leading to irreversible neurological impairment in patients with MS. Early axonal damage in MS is associated with the infiltration of immune cells, which release neurotoxic cytokines to injure axons. Prolonged injury can induce Wallerian degeneration, a process of neuronal apoptosis, resulting in damage that propagates along axons and leads to the cell body loss. It is critical to visualize and differentiate these two types of axonal damage, so that therapeutic approaches can be used effectively to targeting each pathological condition. Diffusion Tensor Imaging (DTI) is a clinically available imaging modality. Our previous studies have demonstrated that DTI can detect Wallerian degeneration as decreased axial diffusivity ( ?||, sensitive to axonal damage), which is followed by increased radial diffusivity (?-, sensitive to myelin loss) in some days or weeks later. Thus, it is critical to know if DTI can be used to differentiate immune-induced damage from Wallerian degeneration. We hypothesized that the immune-induced axonal damage is closely associated with simultaneously decreased || and increased;while the Wallerian degeneration, results in decreased ?-, which is then followed by increased. We will examine our hypothesis using an animal model of MS, the experimental autoimmune encephalomyelitis (EAE) on the slow Wallerian Degeneration (WldS) mutant and wild-type mice. Our preliminary longitudinal DTI on mouse EAE visual system supported our hypothesis. It has been speculated that immune-induced damage and Wallerian degeneration may have different inflammatory processes. Gd-enhanced T1-weighted imaging (Gd-T1WI) is commonly used for MS to reveal the immune-induced Blood-Brain Barrier (BBB) breakdown. However, Wallerian degeneration activates the residual microglia cells but might not necessarily induce BBB breakdown. We examined degenerative optic nerves after retinal ischemia and found that the injured nerves, though observable with DTI, appeared normal in Gd-T1WI. This finding suggests a fundamental limitation of Gd-T1WI to characterize axonal damage in MS and EAE. We will investigate the time course of DTI in EAE combined with Gd-T1WI (Aim 1). Since optic nerves are axons originated from retinal ganglion cells (RGC), we will evaluate whether DTI in optic nerves predicts the RGC loss in EAE mice (Aim 3). Beyond the pathological examinations, we will also evaluate the relation of DTI and neurofunctional deficits (Aim 2). Visual evoked potential (VEP) will be measured to quantify the visual pathway conductivity. Mn2+enhanced MRI (MEMRI) will also be used to monitor the axonal transport of RGC. In our preliminary studies, both VEP and MEMRI-derived axonal transport were significantly delayed in EAE mice. The findings of this study will provide significant clinical relevance as to move therapeutic strategies toward a better efficient and direct treatment to prevent permanent disability.

Public Health Relevance

The findings of this project will have significant clinical relevance. We will explore the DTI as imaging biomarkers for immune-induced axonal damage and Wallerian degeneration. We will also explore the changes of DTI in association with neural functional outcomes. The findings of this study will provide significant clinical relevance as to move therapeutic strategies toward a better efficient and direct treatment to prevent permanent disability for Multiple Sclerosis.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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Utz, Ursula
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Loma Linda University
Schools of Arts and Sciences
Loma Linda
United States
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Nishioka, Christopher; Liang, Hsiao-Fang; Chung, Chen-Fang et al. (2017) Disease stage-dependent relationship between diffusion tensor imaging and electrophysiology of the visual system in a murine model of multiple sclerosis. Neuroradiology 59:1241-1250
Sun, Shu-Wei; Nishioka, Christopher; Chung, Chen-Fang et al. (2017) Anterograde-propagation of axonal degeneration in the visual system of wlds mice characterized by diffusion tensor imaging. J Magn Reson Imaging 45:482-491
Sun, Shu-Wei; Nishioka, Christopher; Labib, Wessam et al. (2015) Axonal Terminals Exposed to Amyloid-? May Not Lead to Pre-Synaptic Axonal Damage. J Alzheimers Dis 45:1139-48
Nishioka, Christopher; Poh, Christina; Sun, Shu-Wei (2015) Diffusion tensor imaging reveals visual pathway damage in patients with mild cognitive impairment and Alzheimer's disease. J Alzheimers Dis 45:97-107
Sun, Shu-Wei; Liang, Hsiao-Fang; Mei, Jennifer et al. (2014) In vivo diffusion tensor imaging of amyloid-?-induced white matter damage in mice. J Alzheimers Dis 38:93-101
Sun, Shu-Wei; Mei, Jennifer; Tuel, Keelan (2013) Comparison of mouse brain DTI maps using K-space average, image-space average, or no average approach. Magn Reson Imaging 31:1532-6
Sun, Shu-Wei; Thiel, Tiffany; Liang, Hsiao-Fang (2012) Impact of repeated topical-loaded manganese-enhanced MRI on the mouse visual system. Invest Ophthalmol Vis Sci 53:4699-709
Sun, Shu-Wei; Campbell, Bruce; Lunderville, Chantal et al. (2011) Noninvasive topical loading for manganese-enhanced MRI of the mouse visual system. Invest Ophthalmol Vis Sci 52:3914-20
Xie, M; Wang, Q; Wu, T-H et al. (2011) Delayed axonal degeneration in slow Wallerian degeneration mutant mice detected using diffusion tensor imaging. Neuroscience 197:339-47
Sun, Shu-Wei; Chen, Yu-Jen; Chou, Kun-Hsien et al. (2010) Keyhole and zero-padding approaches for reduced-encoding diffusion tensor imaging of the mouse brains. Magn Reson Imaging 28:1413-9