A systematic review of normal tissue neurovascular unit damage following brain irradiation – factors affecting damage severity and timing of effects

Radiotherapy is key in the treatment of primary and secondary brain tumours. However, normal tissue is inevitably irradiated, causing toxicity and contributing to cognitive dysfunction. The relative importance of vascular damage to cognitive decline is poorly understood. Here, we systematically review the evidence for radiation-induced damage to the entire neurovascular unit (NVU), particularly focusing on establishing the factors that influence damage severity, and timing and duration of vascular effects relative to effects on neural tissue. Using PubMed and Web of Science, we searched preclinical and clinical literature published between 1st January 1970 and 1st December 2022 and evaluated factors influencing NVU damage severity and timing of NVU effects resulting from ionising radiation. Seventy-two rodent, four canine, one rabbit, and five human studies met inclusion criteria. Radiation increased blood-brain-barrier (BBB) permeability, reduced endothelial cell number and extracellular matrix proteoglycans, reduced tight junction proteins, upregulated cellular adhesion molecule expression, reduced activity of glucose and BBB efflux transporters and activated glial cells. In the brain parenchyma, increased metalloproteinases 2 and 9 levels, demyelination, cell death, and inhibited differentiation were observed. Effects on the vasculature and neural compartment were observed across acute, delayed, and late timepoints, and damage extent was higher with low linear energy transfer (LET) radiation, higher doses, lower dose-rates, broader beams, and in the presence of a tumour. Irradiation of normal brain tissue leads to widespread and varied impacts on the NVU. Data indicates that vascular damage is in most cases an early effect that does not quickly resolve. More studies are needed to confirm sequence of damages, and mechanisms that lead to cognitive dysfunction.