Persistent delirium is associated with cerebrospinal fluid markers of neuronal injury

Abstract

Abstract Delirium is associated with the risk of future long-term cognitive impairment, but the degree to which markers of neuronal injury may be distinct or shared with dementia has yet to be comprehensively described. We investigated CSF biomarkers of dementia, astrocytosis and neuronal damage in a clinical cohort with persistent delirium, comparing them with an outpatient memory clinic sample. Our aim was to determine if different patterns of biomarker changes could implicate specific mechanisms for delirium-related neuronal injury over and above that attributable to co-morbid dementia. We recruited 35 participants from the Prince of Wales Hospital, Sydney, Australia. We included inpatients with delirium persisting for at least five days (n=15, 10 with underlying dementia) and participants from outpatient memory clinics (n=20, 17 with dementia). CSF assays were: amyloid-β42 (Aβ42), amyloid-β40 (Aβ40), phosphorylated tau181 (P-tau181), neurofilament light chain, and glial fibrillary acidic protein (GFAP). We used propensity score matching to estimate effect sizes for each standardised CSF biomarker separately for persistent delirium (irrespective of underlying dementia) and dementia (irrespective of superimposed delirium). Compared with individuals without delirium, persistent delirium was associated with elevated GFAP (normalised coefficient per transformed standard deviation (SD), β = 0.85; 95% confidence interval (CI): 0.03 to 1.68) and neurofilament light chain (β = 1.1; 95% CI: 0.5 to 1.6), but not P-tau181. Compared with individuals without dementia, GFAP, neurofilament light chain and P-tau181 were all increased to expected levels in dementia cases, with the former two biomarkers at levels comparable to those seen in persistent delirium (GFAP (β = 1.54; 95% CI: 1.05 to 2.0), neurofilament light chain β = 0.65; 95% CI: 0.24 to 1.1). Persistent delirium was linked with changes in CSF biomarkers not necessarily attributable to dementia. These findings support the potential that delirium is associated with direct neuronal injury independent of dementia pathophysiology. Whether this involves astrocyte dysfunction or direct axonal damage are both possibilities. Future work examining acute brain injury in delirium is needed.