Post-acute pathological changes in the thalamus and internal capsule in aged mice following controlled cortical impact injury: A magnetic resonance imaging, iron histochemical, and glial immunohistochemical study

Abstract

Traumatic brain injury (TBI) is a major cause of neurological disability across all ages, but the elderly are particularly vulnerable and have a worse prognosis than younger individuals. To advance the understanding of long-term pathogenesis induced by TBI in the elderly, aged mice (21-24 months) were given a controlled cortical impact (CCI) injury to the sensorimotor cortex, and their brains were analyzed by MRI and histopathology at 1 and 2 months after CCI injury, a post-acute period. A T2 hypointensity was observed in the ipsilateral thalamus but not in the contralateral thalamus or in the thalamus of sham operated, control mice. The hypointensity was colocalized with increased histochemical staining of iron, a paramagnetic substance that causes a shortening of the T2 relaxation time. Since iron catalyzes reactions that lead to toxic free radicals, the deposition of iron in the thalamus raises the possibility that it promotes pathogenesis following TBI. Astrocyte gliosis and microgliosis were also observed in the ipsilateral thalamus in the post-acute period. The ipsilateral internal capsule displayed a trend for a T2 hypointensity, however, unlike the thalamus it did not have an increase of iron or GFAP staining, but it did have evidence of microgliosis. In summary, areas of T2 hypointensity were revealed in both the thalamus and internal capsule during the post-*Corresponding author: Nancy E.J. Berman, Ph.D. Professor of Anatomy and Cell Biology, University of Kansas Medical Center, 3901 Rainbow Blvd. -Mail Stop 3038, Kansas City KS 66160, Phone 913-588-2712, Fax 913-588-2710.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 2030 [17], are more likely to experience TBI, and they have a worse prognosis, than younger individuals [9,28]. There is a lack of effective interventions following TBI, and advancing the understanding of neuropathological changes that are triggered by TBI has the potential to reveal new therapeutic targets. During the post-acute period following TBI, e.g., when patients have left the hospital and are undergoing outpatient therapy, ongoing pathogenesis is possibly of critical importance to long-term patient outcome [4] and yet has received very little study in animal models. A potentially important treatment target is iron due to its ability to act as a catalyst of redox reactions that lead to the production of toxic free radicals. CNS levels of iron increase with age as well as in a variety of neurological diseases [35], and in multiple sclerosis there is evidence that increases in iron are associated with brain atrophy or cognitive...

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