The Molecular Effects of Ionizing Radiations on Brain Cells: Radiation Necrosis vs. Tumor Recurrence

Abstract

The central nervous system (CNS) is generally resistant to the effects of radiation, but higher doses, such as those related to radiation therapy, can cause both acute and long-term brain damage. The most important results is a decline in cognitive function that follows, in most cases, cerebral radionecrosis. The essence of radio-induced brain damage is multifactorial, being linked to total administered dose, dose per fraction, tumor volume, duration of irradiation and dependent on complex interactions between multiple brain cell types. Cognitive impairment has been described following brain radiotherapy, but the mechanisms leading to this adverse event remain mostly unknown. In the event of a brain tumor, on follow-up radiological imaging often cannot clearly distinguish between recurrence and necrosis, while, especially in patients that underwent radiation therapy (RT) post-surgery, positron emission tomography (PET) functional imaging, is able to differentiate tumors from reactive phenomena. More recently, efforts have been done to combine both morphological and functional data in a single exam and acquisition thanks to the co-registration of PET/MRI. The future of PET imaging to differentiate between radionecrosis and tumor recurrence could be represented by a third-generation PET tracer already used to reveal the spatial extent of brain inflammation. The aim of the following review is to analyze the effect of ionizing radiations on CNS with specific regard to effect of radiotherapy, focusing the attention on the mechanism underling the radionecrosis and the brain damage, and show the role of nuclear medicine techniques to distinguish necrosis from recurrence and to early detect of cognitive decline after treatment.

Assessment of Nuclear and Mitochondrial DNA, Expression of Mitochondria-Related Genes in Different Brain Regions in Rats after Whole-Body X-ray Irradiation

“…IR induces functional and morphological changes in brain tissues, vascular damage, cerebral radiation necrosis, increased oxidative stress, inhibition of neurogenesis and proliferation, changes in 2 of 15 synoptic plasticity, decreased cognitive functions and the development of secondary brain tumors [1][2][3]. Though pronounced damage to brain tissue is usually caused by exposure to relatively high doses of IR used in radiotherapy of tumors, markedly more significant morphological and functional changes in the brain may occur from exposure to moderate-and low-level ionizing radiation [4,5].…”

“…In many laboratories, active research is underway to elucidate the pathophysiological, molecular pathways and cellular effects of different doses of radiation on brain structures and their recovery. Nevertheless, the initial mechanisms of fixing the possible late effects of radiation on the brain structures are not well understood [1,[3][4][5]. At present, the induction of nuclear DNA damage (nDNA) and mitochondrial dysfunctions in irradiated cells can be considered critical events leading to the cell death or development of late effects in the form of neurodegenerative diseases, oncogenesis and other human pathologies.…”

[11C]Methionine and [11C]PBR28 as PET Imaging Tracers to Differentiate Metastatic Tumor Recurrence or Radiation Necrosis

“… 16 Although PBR-TSPO expression has not been directly evaluated in RN, the neuroinflammatory process, characterized by microglial activation and reactive gliosis, known to upregulate expression is well-established. 17 - 19 PBR-TSPO expression could therefore be a potential adjunctive marker to complement [ 11 C]MET in differentiating TR from RN. Previous generations of PBR-TSPO targeting PET tracers have been tested, such as [ 11 C]PK11195 but are currently replaced by newer, more selective agents, such as [ 11 C]PBR28.…”

An Iatrogenic Model of Brain Small-Vessel Disease: Post-Radiation Encephalopathy

“…Ions derived from electrons' ejection from either atoms or molecules, secondary to different stresses such as high temperature, electrical discharges, or electromagnetic and nuclear radiation [1,2], are the basis for radiation.…”