Neuroinflammation and cognitive impairment after aneurysmal subarachnoid hemorrhage

Abstract

In chapter 2, we systematically reviewed and meta-analyzed the literature on the effect of inflammation on post-stroke cognitive impairment in both human and animal studies. We showed that the inflammatory response is increased in patients who develop cognitive impairment after stroke, and that the concentration of serum biomarkers for inflammation is negatively correlated with cognitive function. We further show that anti-inflammatory interventions in animals had a positive effect on cognitive function after stroke, and that interventions using complement inhibition or fingolimod had the largest effect. In chapter 3, we studied the effect of a selective C5 receptor antagonist, Eculizumab, on the concentration of C5a in the cerebrospinal fluid (CSF) in a randomized controlled trial. We showed that in 31 included patients, of whom in 26 CSF was collected, there was no statistically significant difference in C5a concentration between patients who received the intervention compared to controls. While the concentration was lower in the group that received the intervention, it did not reach the prespecified therapeutic effect. Moreover, there was no difference in the number of adverse events between patients that received the intervention compared to those who did not. In chapter 4, we investigated whether patients with cognitive impairment >3 years after aSAH had increased inflammation through positron emission tomography (PET), using a tracer that measures neuroinflammation. Furthermore, we investigated whether there was a difference in microstructural white matter damage and brain volumes between these patients, and correlated imaging findings to cognition. We found that there was no difference in inflammatory signal between patients with and without cognitive impairment, and that the level of inflammation was not related to cognitive functioning. We did find that microstructural brain damage measured through diffusion kurtosis imaging (DKI) was increased in patients with cognitive impairment, and that this damage was related to cognitive functioning. In chapter 5, we studied the strategies used by patients to compensate for cognitive complaints after aSAH. We show that these strategies are diverse but can be classified into 3 main themes identified earlier: offset the mismatch between cognitive supply and demand by increasing the time or effort spent, using a substitute skill or adjusting or adapting to the reduced cognitive performance. Through thematic analysis, we identified 8 subthemes within these 3 previously identified themes: increasing the time and effort, increasing rest before or after an activity, removal of distractors, the use of alternative cognitive functions, the use of external aids, the use of others, adjusting to reduced cognitive performance and acceptance of reduced cognitive performance. In chapter 6, the implications of this thesis and the future directions are discussed. We discussed the potential to gain more insights on the pathophysiological response through basic research and observational studies, the potential of genetic discovery to guide future interventions and the methods of cohort enrichment to improve clinical trial design. Finally, we discussed the current gaps in literature regarding cognitive rehabilitation, and explore ways to address symptoms that are most important to patients themselves.