Early detection of whole body radiation induced microstructural and neuroinflammatory changes in hippocampus: A diffusion tensor imaging and gene expression study

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Ionizing radiation exposure has varied effects ranging from immediate effects seen within a few minutes after exposure to long‐term genetic effects. There are reports of enhanced inflammatory response and induction of cytokine release in the body within a few hours of radiation exposure (Ballesteros‐Zebadua et al., 2012). It is recognized that whole body radiation affects most of the tissues and results in a systemic inflammatory response that may further be observed as local neuroimmune and inflammatory response in CNS (Lucas et al., 2006). Among all the brain regions, the hippocampus is known to be highly sensitive to radiation injury (Monje et al., 2002; Rola et al., 2004). Its vulnerability in radiation injury is due primarily to hippocampal neurogenesis, which is influenced mainly by changes in its microenvironment. More recently, investigators have shown that the complex response to radiation consists of changes in the tissue microenvironment, infiltration of immune cells, and triggering of the molecular pathways that occur prior to the development of tissue injury that might lead to neuroinflammation (Ballesteros‐Zebadua et al., 2012). Proinflammatory cytokines such as interleukin (IL)‐1β, tumor necrosis factor (TNF)‐α, IL‐6, and IL‐18 along with other inflammatory markers such as cyclooxygenase‐2, prostaglandin E2, glial fibrillary acidic protein (GFAP), ICAM‐1, and nuclear factor (NF)‐κB appear to be involved in the brain's response to radiation and may influence the brain microenvironment as well. An altered microenvironment may bring about microstructural changes in the brain that can be detected using a sensitive technique.
Diffusion tensor imaging (DTI) is one such sensitive and promising noninvasive magnetic resonance (MR) technique that has potential in identifying changes in the brain at the microstructural level by measuring the diffusion property of water molecules in three‐dimensional (3D) space (Le Bihan et al., 2001; Chan et al., 2009). The change in diffusivity of water molecule is detected by alteration in biochemical and biophysical properties of brain tissue. DTI parameters mean diffusivity (MD) and fractional anisotropy (FA) measures average water diffusion within the tissue and degree of diffusion anisotropy within the axon, respectively. In addition, for better characterization of the tissue microstructure, parameters such as axial diffusivity (AD) and radial diffusivity (RD) are used. AD is sensitive to axon injury, whereas RD is sensitive to myelin injury (Kim et al., 2007; Sun et al., 2008). DTI is used predominantly to study white matter structural changes because diffusion of water is affected by the direction and compactness of the myelinated fibers in white matter tracts. However, the difference in DTI parameters is also found within cortical areas and represents alterations in water diffusion resulting from change in extracellular matrix, synaptic field, or lightly myelinated/demyelinated axons. DTI has shown its potential in revealing the pathophysiology of inflammatory pathologies as well as an immediate early response within a few hours postinjury in traumatic brain injury (Thiel et al., 2010; Xu et al., 2011). The CNS response immediately after radiation exposure, i.e., within 24 hr of exposure, has been poorly characterized. We have observed DTI based acute changes after whole body radiation exposure (Trivedi et al., 2012), but there are no such reports on early acute or immediate effects of whole body irradiation. This study hypothesizes that radiation induced neuroinflammatory changes may lead to microstructural changes. Therefore, the present study has been planned to characterize early acute microstructural changes in hippocampus noninvasively using DTI technique and to link the physiological neuroinflammatory response by analyzing real‐time mRNA gene expression after 5 Gy whole body irradiation.
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