224 Chapter 9 availability to the brain tissue, which then could reach a level below the metabolic requirements.95 Previous research has shown that patients with steno-occlusive disease who had impaired CVR and elevated CTH indeed had a significant reduction in CMRO2. 94 Thus, CTH could aid in understanding the underlying mechanisms for reduced CMRO2. Thereby, examining CTH can provide additional insights into the relationship between cerebral hemodynamics and cognitive changes following cranial radiotherapy. Ideally, all research should simultaneously investigate multiple physiological MRI measures. Especially since we know that due to the cerebral autoregulatory processes in the brain, one of these measures may be affected, but then balanced out by another factor. For example, if CBF can no longer increase due to maximized CVR, the OEF of the tissue can increase in order to still maintain adequate supply of oxygen to the underlying tissue. Thereby, radiation-related changes in hemodynamics may only manifest into cognitive decline when the autoregulatory process starts to fail, similar to the brain reserve theory mentioned previously (Figure 2).45 To investigate this, we could draw parallels from the cluster method I used in Chapter 3 to identify meaningful subgroups of patients among a heterogeneous pattern of cognitive functioning. Cluster analysis of multiple physiological MRI-measures has the potential to uncover the combined effects of various vascular and metabolic post-radiotherapy changes. Moreover, using this cluster analysis, specific sub-types could be identified which may be related to specific cognitive profiles. Considering the multifaceted nature of radiation-induced cognitive decline, within this cluster framework you can extend beyond physiological MRI measures. Additional valuable MRI biomarkers include changes in white matter microstructure56–63 and functional brain networks64–68, as demonstrated in previous research. This approach would be in line with the aim of understanding the complex interplay between factors underlying radiation-induced cognitive decline. Moreover, different brain regions may have varying thresholds, with certain areas, such as the hippocampus, being particularly vulnerable for radiation-damage. In accordance with this notion, the hippocampus is frequently excluded from WBRT in order to mitigate potential adverse effects on cognitive functioning.96,97 Recent research has also demonstrated that radiotherapy dose on the neurogenic niches is associated with poorer overall survival in patients with lung cancer BMs.98 As agerelated decrease in adult neurogenesis have been linked to cognitive performance99, radiotherapy-related damage to these neurogenic niches may also be linked to radiation-induced cognitive decline. Future research endeavors should investigate whether distinct brain regions, such as cortical grey matter, white matter and
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