173 Physiological MRI Biomarkers & Cognition after SRS for Brain Metastases INTRODUCTION Approximately twenty percent of the basal metabolic rate of the body is consumed by the human brain, making it the most energy demanding organ.1,2 The primary sources of energy for the brain include oxygen and glucose, which are delivered by the arterial blood. To ensure the adequate delivery of nutrient necessary for homeostasis, autoregulatory functions serve to maintain stable cerebral blood flow (CBF) in response to changes in perfusion pressure or other hemodynamic events.2,3 However, this autoregulatory system can be disturbed by the presence of brain metastases. Brain metastases represent a distressing aspect of cancer progression and occur in ten to thirty percent of the adult cancer population.4,5 To metastasize to the brain, cancer cells sequentially complete a series of processes (e.g. penetration of the blood-brain-barrier)6 that may lead to alterations in the surrounding metabolic and vascular microenvironment.7–10 Moreover both primary brain tumors and brain metastases are frequently surrounded by vasogenic edema, which is the result of local blood-brain-barrier disruptions, allowing protein-rich fluid to accumulate in the extracellular space.11 A previous study has reported a lower fractional extraction of oxygen in edema surrounding diffuse gliomas and lower regional blood flow in edema surrounding brain metastases.12 Moreover, impaired cerebrovascular reactivity (CVR) was observed within edema surrounding both diffuse gliomas 13 and brain metastases14, which could reflect a local pressure effect restricting the ability of vessels to dilate and maintain adequate perfusion. Treatment and management of edema is aimed at reducing swelling and alleviating symptoms. However, it is unknown whether the metabolic and vascular reserve within these regions also recovers once edema subsides. Radiotherapy is the cornerstone of (palliative) treatment for brain metastases, in combination with surgery, chemotherapy or immunotherapy.15 Unfortunately, brain radiation can also damage surrounding healthy tissue, as shown by largely reduced vessel density in the brain after fractionated radiotherapy in rats.16 Likewise, studies have found vascular damage resulting in reduced blood perfusion in brain areas that received at least 10-15 Gy.17 Other studies have even shown reduced CBF at radiation doses below 10 Gy.18 Research on metabolic changes after radiotherapy is rather limited. Hypothetically, radiation damage to vessels could decrease the ability to regulate CBF, leading to increased oxygen extraction fraction (OEF) in order to maintain sufficient cerebral metabolic rate of oxygen (CMRO2). On the other hand, irradiation of healthy brain tissue can also cause cell damage19, possibly resulting 7
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