Cellular correlates of longitudinal diffusion tensor imaging of axonal degeneration following hypoxic–ischemic cerebral infarction in neonatal rats

Abstract

Ischemically damaged brain can be accompanied by secondary degeneration of associated axonal connections e.g. Wallerian degeneration. Diffusion tensor imaging (DTI) is widely used to investigate axonal injury but the cellular correlates of many of the degenerative changes remain speculative. We investigated the relationship of DTI of directly damaged cerebral cortex and secondary axonal degeneration in the cerebral peduncle with cellular alterations in pan-axonal neurofilament staining, myelination, reactive astrocytes, activation of microglia/macrophages and neuronal cell death. DTI measures (axial, radial and mean diffusivity, and fractional anisotropy (FA)) were acquired at hyperacute (3 h), acute (1 and 2 d) and chronic (1 and 4 week) times after transient cerebral hypoxia with unilateral ischemia in neonatal rats. The tissue pathology underlying ischemic and degenerative responses had a complex relationship with DTI parameters. DTI changes at hyperacute and subacute times were smaller in magnitude and tended to be transient and/or delayed in cerebral peduncle compared to cerebral cortex. In cerebral peduncle by 1 d post-insult, there were reductions in neurofilament staining corresponding with decreases in parallel diffusivity which were more sensitive than mean diffusivity in detecting axonal changes. Ipsilesional reductions in FA within cerebral peduncle were robust in detecting both early and chronic degenerative responses. At one or four weeks post-insult, radial diffusivity was increased ipsilaterally in the cerebral peduncle corresponding to pathological evidence of a lack of ontogenic myelination in this region. The detailed differences in progression and magnitude of DTI and histological changes reported provide a reference for identifying the potential contribution of various cellular responses to FA, and, parallel, radial, and mean diffusivity.

Translational MR Neuroimaging of Stroke and Recovery

“…In densely packed white matter bundles, axonal membranes and myelination both contribute to FA, with the former arguably producing a greater contribution [49]. Focal ischemia models have correlated FA reductions with both axonal loss and demyelination [50, 51]. More generally following tissue damage, and particularly in gray matter, several studies have cautioned against interpreting FA as a simple combination of axonal density and white matter myelination.…”

Dietary Docosahexaenoic Acid Improves Cognitive Function, Tissue Sparing, and Magnetic Resonance Imaging Indices of Edema and White Matter Injury in the Immature Rat after Traumatic Brain Injury

“…In both stroke models, histologic axonal damage correlated with decreased FA and increased RD. 40,41 DTI indices of white matter injury, including decreased FA and increased RD, correlated with poor neurologic outcome in adult humans after TBI and in neonates after hypoxic ischemic injury. 82,83 Interestingly, increased RD and decreased FA also correlated with poor neurologic outcomes in children after TBI.…”

Mesenchymal stem cells attenuate MRI‐identifiable injury, protect white matter, and improve long‐term functional outcomes after neonatal focal stroke in rats

“…When applied to living immature P3 rats subjected to H‐I, DTI at 24 and 72 hr shows changes in radial organization, disappearance of radial organization within the deep layers maturing earlier than the external layers, and associated changes in cortical architecture by histology (Sizonenko et al, ). DTI applied at 24 hr (Lodygensky et al, ) or from 3 hr to 4 weeks (Tuor et al, ) after H‐I in P7 rats shows region‐dependent and time‐dependent abnormalities. Changes are more subtle early and more extensive at 2 to 4 weeks after H‐I and are observed in a directly damaged region, the cerebral cortex, and in a region with secondary axonal degeneration, the cerebral peduncle.…”