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Abstract: The changes of directional diffusivities derived from diffusion tensor imaging (DTI), i.e. decreased axial diffusivity (λ ||) and increased radial diffusivity (λ ⊥), have shown significant correlation with axonal and myelin damage, respectively. However, after formalin fixation, reduced sensitivity of λ || in detecting axonal damage in tissue has raised the concern of applying DTI ex vivo. In order to distinguish whether death or the fixation process diminishes the sensitivity of DTI in detecting lesions, in vivo, pre-fixed postmortem, and fixed postmortem DTI were conducted on mouse optic nerves 3 and 14 days after transient retinal ischemia. Our data showed that, from in vivo to pre-fixed postmortem, λ || and λ ⊥ decreased by 50 to 70% in both healthy and injured optic nerves (3 and 14 day injury). From pre-fixed postmortem to fixed postmortem, λ || and λ ⊥ decreased by 40 to 50% in normal and 3-day injured optic nerves, but only by 15 to 25% in 14-day injured optic nerves. Consequently, for the 14-day injured optic nerves, the differences between healthy and injured nerves were not preserved after fixation: the 40% decreased λ|| and 200% increased λ⊥ in injured nerves as compared to the normal nerves were measured in vivo and pre-fixed postmortem, but after the fixation process, 300% increased λ⊥ and insignificant changes in λ|| were found in injured nerves as compared to the normal nerves. This study clarified that fixation process, but not death, could change the sensitivity of DTI in detecting injury. [Copyright &y& Elsevier]

Abstract 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. However, how DTI changes related to the development of Amyloid beta (Aβ) and tau pathology, two key hallmarks of AD, remain elusive. We hypothesized that tauopathy induced by Aβ could initiate an axonal degeneration, 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. Longitudinal DTI was conducted to detect changes in the optic tract (OT) and optic nerve (ON), containing the distal and proximal segments of RGC axons, respectively. Our results showed DTI changes in OT (significant 13.2% reduction in axial diffusion, AxD vs. vehicle controls) followed by 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 co-treatment 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 prevent the axon loss in AD. Highlights • Aβ injection into the Lateral Geniculate Nucleus of p301L mice precipitated degeneration of Retinal Ganglion Cells. • Degeneration induced by Aβ was detectable by Diffusion Tensor Imaging early in OT and later in ON, confirmed by histology. • Treating mice with microtubule stabilizer EpoD ameliorated Aβ-induced tauopathy, axonal damage, and neuronal loss. [ABSTRACT FROM AUTHOR]

Abstract: Myelin damage, as seen in multiple sclerosis (MS) and other demyelinating diseases, impairs axonal conduction and can also be associated with axonal degeneration. Accurate assessments of these conditions may be highly beneficial in evaluating and selecting therapeutic strategies for patient management. Recently, an analytical approach examining diffusion tensor imaging (DTI) derived parameters has been proposed to assess the extent of axonal damage, demyelination, or both. The current study uses the well-characterized cuprizone model of experimental demyelination and remyelination of corpus callosum in mouse brain to evaluate the ability of DTI parameters to detect the progression of myelin degeneration and regeneration. Our results demonstrate that the extent of increased radial diffusivity reflects the severity of demyelination in corpus callosum of mouse brain affected by cuprizone treatment. Subsequently, radial diffusivity decreases with the progression of remyelination. Furthermore, radial diffusivity changes were specific to the time course of changes in myelin integrity as distinct from axonal injury, which was detected by βAPP immunostaining and shown to be most extensive prior to demyelination. Radial diffusivity offers a specific assessment of demyelination and remyelination, as distinct from acute axonal damage. [Copyright &y& Elsevier]