Background: Clinical imaging modalities including Optical Coherence Tomography (OCT) and Diffusion Tensor Imaging (DTI) are vital in Multiple Sclerosis (MS), but their relationships during the different phases of Retinal ganglion cell (RGC) degeneration are not clear. We hypothesize that initial injury in optic nerve causes axonal degeneration leading to RGC loss in retina, which can be characterized by a combination of DTI and OCT. Our objective was to examine the correlation between noninvasive and histological data to chronicle the degeneration profile of RGCs in the retina and optic nerve in a mouse model of MS. Materials and Methods: Experimental Autoimmune Encephalomyelitis (EAE) was induced in 11 C57Bl/6 mice, with 8 mice reserved as controls. OCT and DTI was conducted 2–8 weeks after induction of EAE. The thickness of the retinal ganglion cell complex (GCC) was measured using OCT and compared to DTI indices measured in optic nerves. End-stage histology was used to quantify axon/myelin loss in the optic nerve and retinal thinning/RGC loss in the retina. Results: Significant changes in DTI-derived Axial Diffusivity (AD, −17.2%) and Trace Diffusivity (TR, −18.3%) began after 2 weeks of EAE. Later significant reductions in Fractional Anisotropy (FA) and AD, with increases in Radial Diffusion (RD) were apparent after 4 and 8 weeks. OCT-derived measures of GCC thickness were reduced after 4 weeks, and reached significant reduction after 8 weeks. Among EAE mice, DTI (FA, AD and RD measures) and OCT measures were all significantly correlated after 4 and 8 weeks. Among histology measures, RGC density (−23%), RGC size (−27%), and the number of SMI31+ axons (−54%) were reduced significantly. DTI measures of FA and AD along with GCC thinning were the best independent predictors of axon loss. Conclusions: DTI and OCT measures are tightly correlated during the chronic phase of axonal degeneration (4–8 weeks) in EAE mice. After 8 weeks of EAE, both OCT and DTI measures are strong predictors of axon loss in the Optic Nerve.

White matter abnormalities, revealed by Diffusion Tensor Imaging (DTI), are observed in patients with Alzheimer's Disease (AD), representing neural network deficits that underlie gradual cognitive decline in patients with AD. However, how DTI changes are related to the development of Amyloid beta (Aβ) and tau pathology, two key hallmarks of AD, remains elusive. We hypothesized that tauopathy induced by Aβ could initiate an axonal degeneration process, leading to DTI-detectable white matter abnormalities. We utilized the visual system of the transgenic p301L tau mice as a model system. Aβ was injected in Lateral Geniculate Nucleus (LGN), where the Retinal Ganglion Cell (RGC) axons terminate, and longitudinal DTI was conducted to detect changes in the optic tract (OT, containing the distal segment of RGC axons) and optic nerve (ON, containing the proximal segment of RGC axons). Our results showed early DTI changes in OT (significant 13.2% reduction in axial diffusion, AxD vs. vehicle controls) followed by later significant alterations in ON AxD and fractional anisotropy, FA. Histology data revealed loss of synapses, RGC axons and cell bodies resulting from the Aβ injection. We further tested whether microtubule-stabilizing compound Epothilone D (EpoD) could ameliorate the damage. EpoD cotreatment with Aβ was sufficient to prevent Aβ-induced axon and cell loss. Using an acute injection paradigm, our data suggest that EpoD may mediate its protective effect by blocking localized, acute Aβ-induced tau phosphorylation. This study demonstrates white matter disruption resulting from localized Aβ, the importance of tau pathology induction to changes in white matter connectivity, and the use of EpoD as a potential therapeutic avenue to block axon loss during disease.