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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: Wallerian degeneration plays a significant role in many central nervous system (CNS) diseases. Tracking the progression of Wallerian degeneration may provide better understanding of the evolution of many CNS diseases. In this study, a 28-day longitudinal in vivo DTI of optic nerve (ON) and optic tract (OT) was conducted to evaluate the temporal and spatial evolution of Wallerian degeneration resulting from the transient retinal ischemia. At 3–28 days after ischemia, ipsilateral ON and contralateral OT showed significant reduction in axial diffusivity (32–40% and 21–29% respectively) suggestive of axonal damage. Both ON and OT showed significant increase in radial diffusivity, 200–290% and 58–65% respectively, at 9–28 days suggestive of myelin damage. Immunohistochemistry of phosphorylated neurofilament (pNF) and myelin basic protein (MBP) was performed to assess axonal and myelin integrities validating the DTI findings. Both DTI and immunohistochemistry detected that transient retinal ischemia caused more severe damage to ON than to OT. The current results suggest that axial and radial diffusivities are capable of reflecting the severity of axonal and myelin damage in mice as assessed using immunohistochemistry. [Copyright &y& Elsevier]

Abstract: In this study, axial (λ ||) and radial (λ ⊥) diffusivities derived from diffusion tensor imaging (DTI) were used to evaluate white matter injury in brains of mice affected by experimental autoimmune encephalomyelitis (EAE). Sixteen female C57BL/6 mice were immunized with amino acids 35–55 of myelin oligodendrocyte glycoprotein (MOG35–55). Three months after immunization, optic nerve and tract were severely affected with 19% and 18% decrease in λ || respectively, suggesting the presence of axonal injury. In addition, a 156% and 86% increase in λ ⊥ was observed in optic nerve and tract respectively, suggestive of myelin injury. After in vivo DTI, mice were perfusion fixed and immunohistochemistry for the identification of myelin basic protein (MBP) and phosphorylated neurofilament (pNF) was performed to verify the presence of axonal and myelin injury. The present study demonstrated that the visual pathway is selectively affected in MOG35–55 induced murine EAE and these injuries are non-invasively detectable using λ || and λ ⊥. [Copyright &y& Elsevier]

Abstract: Decreased axial (λ ||) and increased radial (λ ⊥) diffusivity have been shown to reflect axonal and myelin injury respectively. In the present study, evolving white matter injury within the optic nerves of mice with retinal ischemia was examined by in vivo and ex vivo measurements of λ || and λ ⊥. The results show that at 3 days after retinal ischemia, a 33% decrease in vivo and a 38% decrease ex vivo in λ || without change in λ ⊥ was observed in the injured optic nerve compared to the control, suggestive of axonal damage without myelin injury. At 14 days, both in vivo and ex vivo measured λ ⊥ increased significantly to 220–240% of the control level in the injured optic nerve suggestive of myelin damage. In contrast, the axonal injury that was clearly detected in vivo as a significantly decreased λ || (33% decrease) was not as clearly detected by ex vivo λ || (17% decrease). The current findings suggest that ex vivo λ ⊥ is comparable to in vivo λ ⊥ in detecting myelin injury. However, the structural changes resulting from axonal damage causing the decreased in vivo λ || may not be preserved ex vivo in the fixed tissues. Despite the accurate depiction of the pathology using λ || and λ ⊥ in vivo, the use of ex vivo λ || to extrapolate the status of axonal injury in vivo would require further investigation. [Copyright &y& Elsevier]

Abstract: The inner product of the major eigenvectors of adjacent pixels, known as the directional correlation (DC), has been used previously as a quantitative index to investigate directional similarity in white matter (WM) tracts. A high degree of directional similarity (i.e., high DC) among pixels within individual WM tracts was observed. Based on this observation, a region growing algorithm was employed to propagate an area from a seed point as a function of the DC threshold (DCt) to manually identify WM tracts in two-dimensional (2D) slices from diffusion tensor imaging (DTI). In the present study, an improved unsupervised DC based region growing (DCRG) method was implemented to reduce the operator-dependent variance and to improve the ease of use of the technique. By employing improved method, a multi-slice DTI data set of an in vivo mouse brain was used to identify the external capsule, visual pathway, and corpus callosum. The resultant WM tracts are computer rendered in three-dimensional (3D) images with anatomical images as structural references. In addition, three sets of ex vivo mouse brain data were used to examine the effects of different slice thickness and the signal-to-noise ratio (SNR) to the outcome of DCRG. [Copyright &y& Elsevier]

Abstract: Using magnetic resonance diffusion tensor imaging (DTI), the present study investigates changes in both gray and white matter in the APPsw transgenic mouse (Tg2576), a model of β-amyloid plaque deposition associated with Alzheimer''s disease (AD). DTI analyses were performed in cross-sectional groups of transgene-positive and -negative mice at 8, 12, 16, and 18 months of age to assess the magnitude of water diffusion in gray matter (i.e., Tr(D)) and changes in diffusion in white matter that may be indicative of axonal degeneration (i.e., reduced water diffusion parallel to axonal tracts, λ‖) and myelin degradation (i.e., increased water diffusion perpendicular to axonal tracts, λ⊥). No appreciable changes in gray or white matter were observed between the APPsw and the age-matched control mice at 8 months of age. Reduced Tr(D) and λ‖ were observed in gray and white matter, respectively, for the APPsw mice at ages greater than 8 months, which coincides with the time period when appreciable amyloid plaque accumulation was confirmed by ex vivo histopathological studies. The decreases in λ‖ suggest the presence of axonal injury in multiple white matter tracts of APPsw mice. Unlike λ‖, λ⊥was unaltered between control and APPsw mice in most white matter tracts. However, in the corpus collosum (CC), λ⊥ increased at 16 and 18 months of age, suggesting the possibility of myelin damage in the CC at these later ages. This work demonstrates the potential for DTI as a noninvasive modality to detect evolving pathology associated with changes in tissue water diffusion properties in brain tissues. [Copyright &y& Elsevier]

Both axon and myelin degeneration have significant impact on the long-term disability of patients with white matter disorder. However, the clinical manifestations of the neurological dysfunction caused by white matter disorders are not sufficient to determine the origin of neurological deficits. A noninvasive biological marker capable of detecting and differentiating axon and myelin degeneration would be a significant addition to currently available tools. Directional diffusivities derived from diffusion tensor imaging (DTI) have been previously proposed by this group as potential biological markers to detect and differentiate axon and myelin degeneration. To further test the hypothesis that axial (λ&z.dfnc;) and radial (λ⊥) diffusivities reflect axon and myelin pathologies, respectively, the optic nerve was examined serially using DTI in a mouse model of retinal ischemia. A significant decrease of λ&z.dfnc;, the putative DTI axonal marker, was observed 3 days after ischemia without concurrently detectable changes in λ⊥, the putative myelin marker. This result is consistent with histological findings of significant axonal degeneration with no detectable demyelination at 3 days after ischemia. The elevation of λ⊥ observed 5 days after ischemia is consistent with histological findings of myelin degeneration at this time. These results support the hypothesis that λ&z.dfnc; and λ⊥ hold promise as specific markers of axonal and myelin injury, respectively, and, further, that the coexistence of axonal and myelin degeneration does not confound this utility. [Copyright &y& Elsevier]

Myelin loss and axonal damage are both observed in white matter injuries. Each may have significant impact on the long-term disability of patients. Currently, there does not exist a noninvasive biological marker that enables differentiation between myelin and axonal injury. We describe herein the use of magnetic resonance diffusion tensor imaging (DTI) to quantify the effect of dysmyelination on water directional diffusivities in brains of shiverer mice in vivo. The principal diffusion eigenvalues of eight axonal fiber tracts that can be identified with certainty on DTI maps were measured. The water diffusivity perpendicular to axonal fiber tracts, λ⊥, was significantly higher in shiverer mice compared with age-matched controls, reflecting the lack of myelin and the increased freedom of cross-fiber diffusion in white matter. The water diffusivity parallel to axonal fiber tracts, λ∥, was not different, which is consistent with the presence of intact axons. It is clear that dysmyelination alone does not impact λ∥. The presence of intact axons in the setting of incomplete myelination was confirmed by electron microscopy. Although further validation is still needed, our finding suggests that changes in λ⊥ and λ∥ may potentially be used to differentiate myelin loss versus axonal 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]