Radiation-induced brain injury: low-hanging fruit for neuroregeneration

Abstract

<jats:p>Brain radiation is a fundamental tool in neurooncology to improve local tumor control, but it leads to profound and progressive impairments in cognitive function. Increased attention to quality of life in neurooncology has accelerated efforts to understand and ameliorate radiation-induced cognitive sequelae. Such progress has coincided with a new understanding of the role of CNS progenitor cell populations in normal cognition and in their potential utility for the treatment of neurological diseases. The irradiated brain exhibits a host of biochemical and cellular derangements, including loss of endogenous neurogenesis, demyelination, and ablation of endogenous oligodendrocyte progenitor cells. These changes, in combination with a state of chronic neuroinflammation, underlie impairments in memory, attention, executive function, and acquisition of motor and language skills. Animal models of radiation-induced brain injury have demonstrated a robust capacity of both neural stem cells and oligodendrocyte progenitor cells to restore cognitive function after brain irradiation, likely through a combination of cell replacement and trophic effects. Oligodendrocyte progenitor cells exhibit a remarkable capacity to migrate, integrate, and functionally remyelinate damaged white matter tracts in a variety of preclinical models. The authors here critically address the opportunities and challenges in translating regenerative cell therapies from rodents to humans. Although valiant attempts to translate neuroprotective therapies in recent decades have almost uniformly failed, the authors make the case that harnessing human radiation-induced brain injury as a scientific tool represents a unique opportunity to both successfully translate a neuroregenerative therapy and to acquire tools to facilitate future restorative therapies for human traumatic and degenerative diseases of the central nervous system.</jats:p>

Delayed effects of a single-dose whole-brain radiation therapy on glucose metabolism and myelin density: a longitudinal PET study

“…We observed a similar pattern in myelin density changes in irradiated rats as in controls, although there appeared to be a non-significant tendency toward an increase in myelin density 3 months after radiation therapy, as compared to day 60. In line with our data, previous studies suggested that demyelination after 25-Gy WBRT in rodents is a process that mainly occurs in the acute phase (Burns et al 2016), with myelin density recovering to normal levels after around 3-6 months (Panagiotakos et al 2007;Fu et al 2017). This recovery is hypothesized to occur mainly due to the capacity of oligodendrocyte progenitor cells to migrate to the sites of myelin damage and remyelinate the injured white matter tracts.…”

“…In this study, we used PET to assess the late-delayed changes in white matter after WBRT, using 11 C-MeDAS as a tracer for myelin density and 18 F-FDG as a tracer for brain glucose metabolism. Demyelination is directly related to the white matter damage after WBRT (Burns et al 2016;Torrens et al 2016;Li et al 2018), whereas glucose metabolism could be considered a surrogate marker for neurodegeneration. The tracer 11 C-MeDAS has previously successfully been used for PET imaging of myelin loss and regeneration in various rodent models for multiple sclerosis (Wu et al 2010(Wu et al , 2013de Paula Faria et al 2014a, 2014b, 2014cFaria et al 2014).…”

Radiation-Induced Alterations in the Recurrent Glioblastoma Microenvironment: Therapeutic Implications

“…Whether the more radiation-like polarization state of aged microglia contributes to such poorer outcomes remains unknown. However, given the recurrent theme of chronic inflammation, in GBM, radiation, aging, and neurodegeneration, efforts to modulate the inflammatory microenvironment of both primary and recurrent GBM are of broad interest to attenuate tumorigenesis and enhance cognitive outcomes following radiation ( 172 , 173 ). Given the differences in the neuroinflammatory phenotype of rodents and humans, mechanistic studies specifically interrogating human disease will be paramount ( 174 ).…”

Long-term effects of radiation therapy on white matter of the corpus callosum: a diffusion tensor imaging study in children

“…Cellular damage is not limited to neurons, but extends to glial cells, with oligodendrocytes being particularly vulnerable. Oligodendrocytes have high metabolic demands and mitochondrial content, making them sensitive to the oxidative stress caused by radiation [14, 15]. Damage to oligodendrocyte progenitor cells and fully differentiated oligodendrocytes with subsequent white matter necrosis due to axonal demyelination and degradation has been observed [3, 14, 16, 17].…”