Schizophrenia (SZ) and bipolar (BD) spectrum disorders are severe mental illnesses (SMI) with possible aberrations in neurodevelopment, shared clinical characteristics and substantial genetic overlap. In addition to the classical symptoms, such as psychosis, mania and depression, people with SMI often suBer from cognitive impairment. This includes impaired aspects of brain functioning, such as the ability to learn, form memories, maintain focus, solve problems and process information rapidly. Cognitive impairment is a considerable barrier for functional outcomes, including educational attainment, employment, and recovery. Despite this awareness, our understanding of the pathophysiology of cognitive impairment remains limited. Increasing this knowledge is a critical step towards developing successful pro-cognitive interventions to improve functional outcomes in SMI. One of the most promising neurobiological contributors to cognitive impairment involves the immune system. Immune disturbances are well documented in SMI with evidence from genetic-, postmortem- and epidemiological data. The immune system is increasingly recognized for its role in shaping, maintaining, and surveying the connections between brain cells, which are fundamental for cognitive functioning. Disruption in immune-mediated processes, particularly during neurodevelopment, can negatively impact the brain at molecular-, structural- and functional levels. Additionally, chronic low-grade systemic inflammation, observed in both SZ and BD, may aBect the barriers between the blood and the brain. This can lead to increased transport of immune and inflammatory elements into the brain can potentially damage brain tissue and disrupt cognitive functioning. An increasing number of studies report that these barriers are aBected in SMI. A central hypothesis is that cognitive impairment in SMI may in part be influenced by immune dysregulation.
Our understanding of the specific immune-related mechanisms that are involved, and whether these are related to specific cognitive functions in SMI, is still limited. One issue is the substantial heterogeneity observed in SMI – not all individuals have cognitive impairment or immune dysregulation. Comparing the average patient with the average healthy control could therefore result in a weaker signal and may partly explain inconsistent findings across studies. An alternative approach is to rather focus on individuals that fall in the lower or higher ranges of cognitive functioning and immune dysregulation, regardless of diagnostic category. This approach has the potential to uncover immune-cognitive treatment targets, and help us identify individuals that are more likely to benefit from interventions. Further, there are challenges with translation of findings from blood-based biomarkers to potential mechanisms in the brain. Finally, our knowledge about how immune-cognitive processes develop over the course oftreatment of SMI is scarce, due to a lack of longitudinal studies. This PhD project aimed to address current challenges and advance our understanding of immune-cognitive associations in SMI. The thesis is based on three published papers (Molecular Psychiatry; Brain, Behavior and Immunity; Psychological Medicine) between 2022 and 2024. The first paper used a multivariate approach combined with unsupervised clustering in order to identify immune/inflammatory markers and cognitive domains with shared variance, and to capture heterogenous immune-cognitive subgroups across individuals with SMI and healthy controls. The second paper followed a similar approach, but had the additional aim of translating findings from blood-based markers to the brain, by using stem cell technology and postmortem brain tissue. The final paper followed up on the findings of immune-cognitive subgroups by investigating their longitudinal trajectory over the course of the first year of receiving adequate treatment for SMI.
We found that dysregulation in innate immune processes, implicating inflammasome activation, cell adhesion, tissue remodelling, and systemic inflammation covaried with impairments in verbal learning, fine-motor and psychomotor processing speed – a pattern that was augmented in SMI. Among the candidate blood-based markers, we found evidence of brain dysregulation of the tissue remodelling marker, YKL-40, in individuals with SMI. A consistent finding across the studies was the presence of two distinct immune-cognitive subgroups with diBering clinical severity. One subgroup consisted of more individuals with SMI (predominantly SZ) than healthy controls, and was characterised by lower cognition and higher immune dysregulation. The other subgroup consisted of more healthy controls than individuals with SMI, and was characterised by the reversed pattern, i.e. higher cognition and lower immune dysregulation. However, individuals with SZ, BD and healthy controls were represented in both subgroups, suggesting that immune-cognitive associations are heterogenous and transdiagnostic. At baseline, individuals with SMI in the first, more compromised, subgroup had more symptoms and lower functioning compared to the other subgroup. Although the compromised subgroup improved over the course of the first year in treatment, they were still compromised relative to the other subgroup at follow-up one year later. The stability of the subgroup diBerences over time suggests that we may have identified an ideal target group for future interventions.
The findings are limited to the immune/inflammatory markers and cognitive domains studied, and do not allow us to establish the direction of eBects, i.e. whether immune dysregulation cause cognitive impairment or vice versa. Immune-cognitive associations are probably both complex and bidirectional. Future studies should further investigate the identified candidate immune/inflammatory markers and cognitive domains, particularly in high-risk populations before the onset of illness. While our understanding is far from complete, the findings have fuelled new questions that set the stage for further research and hopefully development of novel pro-cognitive interventions in SMI.