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Previously, we tested the prediction that axonal damage results in decreased axial diffusivity ( ʈ ) while demyelination leads to increased radial diffusivity ( Ќ ). Cuprizone treatment of C57BL/6 mice was a highly reproducible model of CNS white matter demyelination and remyelination affecting the corpus callosum (CC). In the present study, six C57BL/6 male mice were fed 0.2% cuprizone for 12 weeks followed by 12 weeks of recovery on normal chow. The control mice were fed normal chow and imaged in parallel. Biweekly in vivo DTI examinations showed transient decrease of ʈ in CC at 2-6 weeks of cuprizone treatment. Immunostaining for nonphosphorylated neurofilaments demonstrated corresponding axonal damage at 4 weeks of treatment. Significant demyelination was evident from loss of Luxol fast blue staining at 6 -12 weeks of cuprizone ingestion and was paralleled by increased Ќ values, followed by partial normalization during the remyelination phase Diverse central nervous system (CNS) disorders involve white matter pathology leading to myelin and axon dysfunction (1-6). However, current neurologic examinations are not capable of differentiating the underlying axon and myelin pathologies causing the deficits (7,8). Recently, an analytical approach interpreting magnetic resonance diffusion tensor imaging (DTI) data in light of white matter pathology has been proposed (9 -11). Briefly, directional diffusivities of water molecules in white matter derived from DTI are separated into two components, i.e., axial ( ʈ ) and radial ( Ќ ) diffusivities describing water diffusion along and across axonal tracts, respectively. It has been demonstrated that axonal injury, such as axonal swelling and Wallerian degeneration (10), results in reduced ʈ , while dysmyelination increases Ќ without changing ʈ (11).The development of an effective therapy targeted at repairing axons and the protective myelin sheath may benefit from improved diagnostic tools that are capable of detecting and differentiating axonal damage and demyelination in various CNS disorders. To validate the aforementioned DTI parameters as surrogate markers of axon and myelin injury, the well-characterized CNS demyelination and remyelination mouse model of cuprizone (bis-cyclohexanone oxaldihydrazone) ingestion has been examined serially in living mice in the present study. Cuprizone, 0.2% by weight, was mixed in ground rodent chow and fed to a group of male C57BL/6 mice. The corpus callosum (CC) is the only tract in this mouse model that has been consistently documented to undergo massive and unequivocal demyelination as a result of cuprizone toxicity and remyelination after removal of cuprizone from the feed (12-16). The myelin and axonal pathology of the CC in the cuprizone-treated mice was demonstrated by histopathology and correlated with ex vivo DTI (9). Thus, the CC is the target white matter tract of the current study to test the in vivo DTI sensitivity and specificity of Ќ to demyelination and remyelination along with ʈ to axonal damage associated with cupri...

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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% in ON and OT respectively, at 9 − 28 days suggestive of myelin damage. Immuohistochmistry 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.