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• Correlation between MEMRI and DTI was found in P301L tau mice. • Axonal transport deficits in tauopathy were correlated with the loss of myelin. • Myelin loss may contribute to the axonal degeneration in tauopathy. Diffusion Tensor Imaging (DTI) and Manganese Enhanced MRI (MEMRI) are noninvasive tools to characterize neural fiber microstructure and axonal transport. A combination of both may provide novel insights into the progress of neurodegeneration. To investigate the relationship of DTI and MEMRI in white matter of tauopathy, twelve optic nerves of 11-month-old p301L tau mice were imaged and finished with postmortem immunohistochemistry. MEMRI was used to quantify Mn2+ accumulation rates in the optic nerve (ON, termed ONAR) and the Superior Colliculus (SC, termed SCAR), the primary terminal site of ON in mice. We found that both ONAR and SCAR revealed a significant linear correlation with mean diffusion (mD) and radial diffusion (rD) but not with other DTI quantities. Immunohistochemistry findings showed that ONAR, mD, and rD are significantly correlated with the myelin content (Myelin Basic Protein, p < 0.05) but not with the axonal density (SMI-31), tubulin density, or tau aggregates (AT8 staining). In summary, slower axonal transport appeared to have less myelinated axons and thinner remaining axons, associated with reduced rD and mD of in vivo DTI. A combination of in vivo MEMRI and DTI can provide critical information to delineate the progress of white matter deficits in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

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]

Purpose: Diffusion tensor imaging (DTI) is commonly used to evaluate white matter integrity in multiple sclerosis (MS), but the relationship between DTI measures and functional changes during disease remains ambiguous. Using a mouse model of MS, we tested the hypothesis that DTI measures would correlate to the visual evoked potential (VEPs) dynamically at different disease stages. Methods: In vivo DTI, gadolinium-enhanced T1WI (Gd-T1WI) and VEPs were performed in 5 control and 25 mice after 2-12 weeks of experimental autoimmune encephalomyelitis (EAE). DTI indices, including fractional anisotropy (FA), axial and radial diffusivities (AD and RD), and Gd-T1WI enhancement, were measured in the optic nerve and tract (ON and OT), which were compared with measured VEPs. Results: Gd-T1WI showed a 3- to 4-fold enhancement over controls beginning after 2 weeks of EAE. Across the time course, we found progressive reductions in FA and increases in RD with increases in VEP latency and reductions in amplitude. Significant correlations between DTI (FA and RD) and VEP evolved; in control/early asymptomatic EAE mice, both FA and RD were highly correlated with VEP latency (but not amplitude), while in late EAE, both DTI indices were highly correlated with VEP amplitude (but not latency). Conclusion: DTI measures FA and RD are associated to VEP latency in early stages of EAE but associated to VEP amplitude in later stages, suggesting that the patterns of DTI related to the functional decline may depend on the stage of disease progression. [ABSTRACT FROM AUTHOR]

Background: Diffusion tensor imaging (DTI) suggests the presence of white matter abnormality at the prodromal stage in human Alzheimer's disease (AD).Objective: To use a mouse model of AD to determine whether the white matter abnormality detected by in vivo DTI is associated with functional deficits and axon damage.Methods: Amyloid-β1-42 (Aβ1-42) was injected into the left lateral ventricle in mice. Two months after the injection, in vivo DTI and visual evoked potential (VEP) recordings were performed, followed by immunohistochemistry of phosphorylated neurofilament and myelin basic protein.Results: DTI of Aβ1-42-treated mice showed a significant increase of radial diffusivity in white matter including the optic nerves and tracts. The abnormality was associated with decreased amplitude and increased latency of VEP. Immunohistochemistry confirmed a significant loss of axons and myelin integrity.Conclusion: White matter damage induced by Aβ1-42 in mice can be detected non-invasively by DTI. [ABSTRACT FROM AUTHOR]

Background: Diffusion tensor imaging (DTI) suggests the presence of white matter abnormality at the prodromal stage in human Alzheimer's disease (AD). Objective: To use a mouse model of AD to determine whether the white matter abnormality detected by in vivo DTI is associated with functional deficits and axon damage. Methods: Amyloid-β1-42 (Aβ1-42) was injected into the left lateral ventricle in mice. Two months after the injection, in vivo DTI and visual evoked potential (VEP) recordings were performed, followed by immunohistochemistry of phosphorylated neurofilament and myelin basic protein. Results: DTI of Aβ1-42-treated mice showed a significant increase of radial diffusivity in white matter including the optic nerves and tracts. The abnormality was associated with decreased amplitude and increased latency of VEP. Immunohistochemistry confirmed a significant loss of axons and myelin integrity. Conclusion: White matter damage induced by Aβ1-42 in mice can be detected non-invasively by DTI. [ABSTRACT FROM AUTHOR]

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: In the current study, the feasibility and reproducibility of in vivo diffusion tensor imaging (DTI) of the spinal cord in normal mice are illustrated followed by its application to mice with experimental allergic encephalomyelitis (EAE) to detect and differentiate axon and myelin damage. Axial diffusivity, describing water movement along the axonal fiber tract, in all regions of spinal cord white matter from EAE-affected C57BL/6 mice was significantly decreased compared to normal mice, whereas there was no statistically significant change in radial diffusivity, describing water movement across the fiber tract. Furthermore, a direct comparison between DTI and histology from a single mouse demonstrated a decrease in axial diffusivity that was supported by widespread staining of antibody against β-amyloid precursor protein. Regionally elevated radial diffusivity corresponded with locally diminished Luxol fast blue staining in the same tissue from the EAE mouse cord. Our findings suggest that axonal damage is more widespread than myelin damage in the spinal cord white matter of mice with EAE and that in vivo DTI may provide a sensitive and specific measure of white matter injury. [Copyright &y& Elsevier]

Background: Synaptic deficits and neuronal loss are the major pathological manifestations of Alzheimer's disease. However, the link between the early synaptic loss and subsequent neurodegeneration is not entirely clear. Cell culture studies have shown that amyloid-β (Aβ) applied to axonal terminals can cause retrograde degeneration leading to the neuronal loss, but this process has not been demonstrated in live animals. Objective: To test if Aβ applied to retinal ganglion cell axonal terminals can induce axonal damage in the optic nerve and optic tract in mice. Methods: Aβ was injected into the terminal field of the optic tract, in the left lateral geniculate nucleus of wildtype C57BL/6 mice. Following the injection, monthly diffusion tensor imaging was performed. Three months after the injection, mice underwent visual evoked potential recordings, and then sacrificed for immunohistochemical examination. Results: There were no significant changes seen with diffusion tensor imaging in the optic nerve and optic tract 3 months after the Aβ injection. The myelin and axons in these regions remained intact according to immunohistochemistry. The only significant changes observed in this study were delayed transduction and reduced amplitude of visual evoked potentials, although both Aβ and its reversed form caused similar changes. Conclusion: Despite the published in vitro studies, there was no significant axonal damage in the optic nerve and optic tract after injecting Aβ onto retinal ganglion cell axonal terminals of wildtype C57BL/6 mice. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Correlation of diffusion tensor imaging (DTI) with histochemical staining for demyelination and axonal damage in multiple sclerosis (MS) ex vivo human cervical spinal cords. Background: In MS, demyelination, axonal degeneration, and inflammation contribute to disease pathogenesis to variable degrees. Based upon in vivo animal studies with acute injury and histopathologic correlation, we hypothesized that DTI can differentiate between axonal and myelin pathologies within humans. Methods: DTI was performed at 4.7 T on 9 MS and 5 normal control fixed cervical spinal cord blocks following autopsy. Sections were then stained for Luxol fast blue (LFB), Bielschowsky silver, and hematoxylin and eosin (H&E). Regions of interest (ROIs) were graded semi-quantitatively as normal myelination, mild (<50%) demyelination, or moderate–severe (>50%) demyelination. Corresponding axonal counts were manually determined on Bielschowsky silver. ROIs were mapped to co-registered DTI parameter slices. DTI parameters evaluated included standard quantitative assessments of apparent diffusion coefficient (ADC), relative anisotropy (RA), axial diffusivity and radial diffusivity. Statistical correlations were made between histochemical gradings and DTI parameters using linear mixed models. Results: Within ROIs in MS subjects, increased radial diffusivity distinguished worsening severities of demyelination. Relative anisotropy was decreased in the setting of moderate–severe demyelination compared to normal areas and areas of mild demyelination. Radial diffusivity, ADC, and RA became increasingly altered within quartiles of worsening axonal counts. Axial diffusivity did not correlate with axonal density (p =0.091). Conclusions: Increased radial diffusivity can serve as a surrogate for demyelination. However, radial diffusivity was also altered with axon injury, suggesting that this measure is not pathologically specific within chronic human MS tissue. We propose that radial diffusivity can serve as a marker of overall tissue integrity within chronic MS lesions. This study provides pathologic foundation for on-going in vivo DTI studies in MS. [Copyright &y& Elsevier]