Role of glia in delirium: proposed mechanisms and translational implications

Abstract

Delirium is a common acute onset neurological syndrome characterised by transient fluctuations in cognition. It affects over 20% of medical inpatients and 50% of those critically ill. Delirium is associated with morbidity and mortality, causes distress to patients and carers, and has significant socioeconomic costs in ageing populations. Despite its clinical significance, the pathophysiology of delirium is understudied, and many underlying cellular mechanisms remain unknown. There are currently no effective pharmacological treatments which directly target underlying disease processes. Although many studies focus on neuronal dysfunction in delirium, glial cells, primarily astrocytes, microglia, and oligodendrocytes, and their associated systems, are increasingly implicated in delirium pathophysiology. In this review, we discuss current evidence which implicates glial cells in delirium, including biomarker studies, post-mortem tissue analyses and pre-clinical models. In particular, we focus on how astrocyte pathology, including aberrant brain energy metabolism and glymphatic dysfunction, reactive microglia, blood-brain barrier impairment, and white matter changes may contribute to the pathogenesis of delirium. We also outline limitations in this body of work and the unique challenges faced in identifying causative mechanisms in delirium. Finally, we discuss how established neuroimaging and single-cell techniques may provide further mechanistic insight at pre-clinical and clinical levels.

Fig. 1. Schematic outline of glial dysfunction in delirium and technologies which can be used to further our understanding of their roles in its pathogenesis.

Glial dysfunction has been described in delirium, but the underlying pathophysiological mechanisms are not fully understood. Key risk factors for and triggers of delirium include older age, pre-existing neurodegeneration, systemic inflammation, surgery, new medications and drug withdrawal. Reactive astrocytes with increased inflammasome activity, altered metabolism and impaired glymphatic activity have been reported in patients and models with delirium. Similarly, microglia display elevated cytokine production and C1q-tagged signalling. Impaired blood-brain barrier function and white matter changes have also been noted. Exploiting existing technologies including single-cell transcriptomics, neuroimaging, liquid biomarkers and optogenetics would provide deeper mechanistic insight into the roles of dysregulated glia in delirium. The effects of these mechanisms on neuronal function should also be interrogated. GFAP: glial fibrillary acidic protein; CXCL10: C-X-C motif chemokine ligand 10; IL-6/1β: interleukin-6/1β; TNFα: tumour necrosis factor α; C1q: complement component 1q; CD68: cluster of differentiation 68; TLR2: toll-like receptor 2.