Drivers and consequences of cognitive functioning in glioma

1. The occurrence of neurocognitive deficits in diffuse glioma Treatment-naive glioma patients Cognitive impairments occur in the large majority of glioma patients. Because neurocognitive functioning (NCF) in glioma patients mostly has been studied postoperatively in previous literature, neurocognitive deficits were mainly thought to associate with surgery and medical therapies. However, neurocognitive deficits occur prior to any anti-tumor treatment and impairments can be found across all main cognitive domains. In domain-specific analyses, executive functioning and attention, memory, and psychomotor speed appeared to be involved most frequently (chapter 3), which is comparable to previously published literature (chapter 2). An explanation for this finding can be that these cognitive domains rely on widespread neural networks with multiple brain regions involved. For this reason, they can be altered easily by a mechanical conflict between the tumor and important nodes (hubs) or pathways of these networks.2-6 Neurocognitive changes after awake surgery Furthermore, we found that neurocognitive functioning is mostly maintained after awake surgery across different domains (chapter 4). Our results show that the domain psychomotor speed appeared most vulnerable to the effects of surgery, both at group level and at (the proportion of) individual-level deficits. 2. Factors that modulate neurocognitive functioning Treatment-naive glioma patients In the previous paragraph we saw that neurocognitive deficits occur prior to any anti-tumor treatment and impairments can be found across all main cognitive domains. These findings support the hypothesis that, in addition to treatment-related effects, the tumor and the direct effect of this tumor affects NCF in diffuse glioma. Chapter 9 focusses on the relation between the tumoral expression level of several biological markers and cognition in our own cohort of treatment naive patients. Most importantly, we found P-STAT5b, CD163, CD3 and SEMA3 to be independently associated with cognitive performance in different domains after correction for histopathological grade. Furthermore, we found specific associations (after correcting for volume and location) between expression level of CD3, IDH and psychomotor speed; IDH, BDNF, ATRX, CSNK2B, GAT3, SRF and EAAT1 and memory performance and for P-STAT5b, CSNK2B and IDH and executive functioning (chapter 9). So, our results support the hypothesis that in addition to its size and location, the metabolism and tumor genetics of a tumor can alter neural function. 3. Influence of neurocognitive functioning on survival Cognitive functioning is of great influence on quality of life and several studies already revealed that these deficits are significantly associated with survival in diffuse glioma patients25,26. In chapter 5 we focused on the independent relationship between executive functioning and memory, and survival. We found that cognitive impairments in executive functioning and memory are negatively associated with survival in diffuse glioma patients, even after correcting for all known possible confounders. Additionally, we found extensive domain-specific neuropsychological assessment to be more strongly correlated to survival than an often clinically used cognitive screener for cognitive decay, the MMSE