Neurocognitive Decline Following Radiotherapy: Mechanisms and Therapeutic Implications

Abstract

The brain undergoes ionizing radiation (IR) exposure in many clinical situations, particularly during radiotherapy for malignant brain tumors. Cranial radiation therapy is related with the hazard of long-term neurocognitive decline. The detrimental ionizing radiation effects on the brain closely correlate with age at treatment, and younger age associates with harsher deficiencies. Radiation has been shown to induce damage in several cell populations of the mouse brain. Indeed, brain exposure causes a dysfunction of the neurogenic niche due to alterations in the neuronal and supporting cell progenitor signaling environment, particularly in the hippocampus—a region of the brain critical to memory and cognition. Consequent deficiencies in rates of generation of new neurons, neural differentiation and apoptotic cell death, lead to neuronal deterioration and lasting repercussions on neurocognitive functions. Besides neural stem cells, mature neural cells and glial cells are recognized IR targets. We will review the current knowledge about radiation-induced damage in stem cells of the brain and discuss potential treatment interventions and therapy methods to prevent and mitigate radiation related cognitive decline.

Animal Models for Radiotherapy Research: All (Animal) Models Are Wrong but Some Are Useful

“…The review from Farris et al [ 11 ] covers current preclinical studies aimed at investigating the biological basis of radiation-induced musculoskeletal toxicity, another major source of morbidity in patients receiving radiotherapy. Furthermore, Pazzaglia and colleagues [ 12 ] provide a comprehensive review of the mechanisms and therapeutic implications of neurocognitive decline following radiotherapy, with an emphasis on radiation-induced stem cell injury and its functional consequences.…”

Pharmacological Modulation of Blood–Brain Barrier Permeability by Kinin Analogs in Normal and Pathologic Conditions

“…Radiation therapy is part of the standard treatment paradigm for CNS tumors [ 57 ]. The short-term effects of prior radiotherapy on the BBB opening induced by Labradimil have been investigated in normal and focal-irradiated dog brains [ 58 ].…”

“…Our findings are in line with the known contribution of BK in delayed brain damage after injury [ 59 ]. As more information becomes available on the exact causal links between cerebrovascular inflammation, BBB permeability, and neuroinflammation all leading to an accelerated cognitive decline [ 57 ], it may prove useful to increase the delivery of MRI contrast agents and therapeutic drugs to improve early detection and/or symptomatology of the disease. Indeed, MRI is commonly used to investigate radionecrosis but possesses low sensitivity and specificity.…”

X-ray mediated scintillation increases synaptic activity via Cerium-doped LSO and Channelrhodopsin-2

“…Repeated X-ray exposure has been shown to abolish neurogenesis (Burghardt et al, 2012;Lacefield et al, 2012) and effect cognitive function, as seen for radiotherapy (Pazzaglia et al, 2020). Neurogenesis can be diminished even with a single X-ray exposure (Mizumatsu et al, 2003;Casciati et al, 2016).…”