11 General introduction and thesis outline the presence of BMs themselves, and due to previous systemic treatments.27–30 The extent and type of preradiotherapy cognitive impairment can vary depending on the lesion location. Lesion studies have demonstrated the topological organization of the brain, with different areas of the brain responsible for different cognitive processes such as memory, attention, language, and executive function.31 Most of the research has focused on patients with ischemic stroke. This population has become the gold standard in this field due to the acute and focal nature of the lesions that are well-defined on imaging. Moreover, as stroke is a relatively common medical condition32, this allows for the required large patient samples in lesion-symptom mapping studies. The reliance on this population, however, raises concerns regarding the applicability of these findings to other populations, such as those with BMs. Behavioral consequences of a lesion may vary as a result of how the brain is affected by the lesion.31,33 For example, lesion distributions differ between etiologies, with certain brain areas more likely to be damaged than others, thereby affecting the spatial accuracy of lesion-symptom analyses. BMs mostly affect the cortex and subcortical white matter areas corresponding to watershed areas of large arteries34, while a stroke most often occurs in subcortical areas in the territory of the middle cerebral artery.35–37 Moreover, the mechanism of injury could vary; where an ischemic stroke leads to cell death due to a lack of oxygen and nutrients from the blood, BMs form tumors cells within the brain. MRI BIOMARKERS FOR RADIOTHERAPY-EFFECTS Although advancements have been made to limit the radiation dose to surrounding brain tissue, it is currently impossible to entirely avoid it due to the physical limitations of the photon radiotherapy technique. Consequently, cranial irradiation can potentially lead to encephalopathy, a complex phenomenon which is influenced by both the dose and time since exposure to radiation.38 The dose- and timedependency of this process is attributed to the differential radiosensitivity of the various components of the brain tissue and the blood vessels. Cranial irradiation can lead to various sequelae, including changes to the neuronal architecture, suppression of neurogenesis, neuroinflammation and autoimmune responses.23,38,39 Considering this, the underlying cause of radiation-induced cognitive decline is most likely multifaceted. In this thesis I mostly focused on the vascular component of the radiation effect. Animal experiments have revealed widespread vascular changes following cranial radiotherapy, including reduced vessel density and destabilization of the vascular endothelium.22,40–43 Microvascular damage resulting in reduced blood perfusion has already been reported in brain areas exposed to low doses of 10-15 Gy.44,45 Moreover, age-related vascular changes have been linked to cognitive 1
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