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Background The inflammatory cell product neopterin is elevated in serum before and during delirium. This suggests a role for disordered cell-mediated immunity or oxidative stress. Cerebrospinal fluid (CSF) neopterin levels reflect brain neopterin levels more closely than serum levels. Here we hypothesized that CSF neopterin levels would be higher in delirium. Methods In this prospective cohort study, 139 elderly patients with acute hip fracture were recruited in Oslo and Edinburgh. Delirium was diagnosed with the confusion assessment method performed daily pre-operatively and on the first 5 days post-operatively. Paired CSF and blood samples were collected at the onset of spinal anaesthesia. Neopterin levels were measured using high-performance liquid chromatography. Results Sixty-four (46 %) of 139 hip fracture patients developed delirium perioperatively. CSF neopterin levels were higher in delirium compared to controls (median 29.6 vs 24.7 nmol/mL, p  = 0.003), with highest levels in patients who developed delirium post-operatively. Serum neopterin levels were also higher in delirium (median 37.0 vs 27.1 nmol/mL, p  = 0.003). CSF neopterin remained significantly associated with delirium after controlling for relevant risk factors. Higher neopterin levels were associated with poorer outcomes (death or new institutionalization) 1 year after surgery ( p  = 0.02 for CSF and p  = 0.03 for serum). Conclusions This study is the first to examine neopterin in CSF from patients with delirium. Our findings suggest potential roles for activation of cell-mediated immune responses or oxidative stress in the delirium process. High levels of serum or CSF neopterin in hip fracture patients may also be useful in predicting poor outcomes.

BACKGROUNDThe kynurenine pathway (KP) has been identified as a potential mediator linking acute illness to cognitive dysfunction by generating neuroactive metabolites in response to inflammation. Delirium (acute confusion) is a common complication of acute illness and is associated with increased risk of dementia and mortality. However, the molecular mechanisms underlying delirium, particularly in relation to the KP, remain elusive.METHODSWe undertook a multicenter observational study with 586 hospitalized patients (248 with delirium) and investigated associations between delirium and KP metabolites measured in cerebrospinal fluid (CSF) and serum by targeted metabolomics. We also explored associations between KP metabolites and markers of neuronal damage and 1-year mortality.RESULTSIn delirium, we found concentrations of the neurotoxic metabolite quinolinic acid in CSF (CSF-QA) (OR 2.26 [1.78, 2.87], P < 0.001) to be increased and also found increases in several other KP metabolites in serum and CSF. In addition, CSF-QA was associated with the neuronal damage marker neurofilament light chain (NfL) (β 0.43, P < 0.001) and was a strong predictor of 1-year mortality (HR 4.35 [2.93, 6.45] for CSF-QA ≥ 100 nmol/L, P < 0.001). The associations between CSF-QA and delirium, neuronal damage, and mortality remained highly significant following adjustment for confounders and multiple comparisons.CONCLUSIONOur data identified how systemic inflammation, neurotoxicity, and delirium are strongly linked via the KP and should inform future delirium prevention and treatment clinical trials that target enzymes of the KP.FUNDINGNorwegian Health Association and South-Eastern Norway Regional Health Authorities.

Background Postoperative delirium is prevalent in older patients and associated with worse outcomes. Recent data in animal studies demonstrate increases in inflammatory markers in plasma and cerebrospinal fluid (CSF) even after aseptic surgery, suggesting that inflammation of the central nervous system may be part of the pathogenesis of postoperative cognitive changes. We investigated the hypothesis that neuroinflammation was an important cause for postoperative delirium and cognitive dysfunction after major non-cardiac surgery. Methods After Institutional Review Board approval and informed consent, we recruited patients undergoing major knee surgery who received spinal anesthesia and femoral nerve block with intravenous sedation. All patients had an indwelling spinal catheter placed at the time of spinal anesthesia that was left in place for up to 24 h. Plasma and CSF samples were collected preoperatively and at 3, 6, and 18 h postoperatively. Cytokine levels were measured using ELISA and Luminex. Postoperative delirium was determined using the confusion assessment method, and cognitive dysfunction was measured using validated cognitive tests (word list, verbal fluency test, digit symbol test). Results Ten patients with complete datasets were included. One patient developed postoperative delirium, and six patients developed postoperative cognitive dysfunction. Postoperatively, at different time points, statistically significant changes compared to baseline were present in IL-5, IL-6, I-8, IL-10, monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, IL-6/IL-10, and receptor for advanced glycation end products in plasma and in IFN-γ, IL-6, IL-8, IL-10, MCP-1, MIP-1α, MIP-1β, IL-8/IL-10, and TNF-α in CSF. Conclusions Substantial pro- and anti-inflammatory activity in the central neural system after surgery was found. If confirmed by larger studies, persistent changes in cytokine levels may serve as biomarkers for novel clinical trials.

Background Delirium and dementia share symptoms of cognitive dysfunctions, and mechanisms of neuroinflammation appear involved in both conditions. Triggering receptor expressed on myeloid cells 2 ( TREM2 ) is linked to dementia and neurodegenerative disease. It encodes expression of an innate immune receptor in the brain expressed by microglia. The level of the soluble fragment of TREM2 (sTREM2) is reported to increase in the cerebrospinal fluid (CSF) already in prodromal and asymptomatic Alzheimer’s disease. Methods We analyzed the level of CSF sTREM2 in relation to delirium and dementia. The study included patients with or without pre-existing dementia who underwent acute hip fracture surgery ( n  = 120), and some of the patients developed delirium ( n  = 65). A medical delirium cohort ( n  = 26) was also examined. ELISA was used to determine the level of sTREM2 in CSF. Results Delirium was associated with a higher level of CSF sTREM2 only among those without pre-existing dementia ( p  = 0.046, n  = 15, n  = 44), particularly among patients developing delirium after CSF sampling ( p  = 0.02, n  = 7, n  = 44). Between patients with dementia, there was no group difference, but the CSF sTREM2 level increased with waiting time for surgery ( r S  = 0.39, p  = 0.002, n  = 60) and correlated well with the CSF Alzheimer’s disease biomarkers, Aβ42, and t-tau/p-tau ( r S  = 0.40, p  = 0.002, r S  = 0.46, p  < 0.001/ r S  = 0.49, p  < 0.001, n  = 60). Among patients with dementia, the level of Aβ38 and Aβ40 also correlated positively with sTREM2 in CSF (Aβ38 MSD r S  = 0.44, p  = 0.001; Aβ40 MSD r S  = 0.48, p  < 0.001; Aβ42 MSD r S  = 0.43, p  < 0.001, n  = 60). Conclusion The findings reinforce the involvement of neuroinflammation in delirium, yet with separate responses in patients with or without pre-existing dementia. Our findings support the concept of primed microglia in neurodegenerative disease and central immune activation after a peripheral trauma in such patients. A CSF biomarker panel of neuroinflammation might be valuable to prevent delirium by identifying patients at risk.

INTRODUCTION Delirium has heterogeneous etiologies and clinical presentations and is often associated with poor outcomes. Its pathophysiological mechanisms remain largely hypothetical and without targeted pharmacological treatment. This work investigates subphenotypes of patients undergoing delirium assessment based on clinical features and fluid biomarkers. METHODS We performed latent class analysis of an observational cohort of older adults undergoing elective surgery. RESULTS Two classes were identified, both containing individuals experiencing delirium symptoms, with a higher number in Class 1 (p < 0.001). Class 1 were older, less educated, and had more depression (p < 0.001). They performed worse in all pre‐operative cognitive assessments (p < 0.001) and had more markers of central nervous system damage: cerebrospinal fluid glial fibrillary acidic protein, neurofilament light chain, and soluble triggering receptor expressed on myeloid cells 2 (p < 0.001); plasma phosphorylated tau (p = 0.024); and amyloid beta 42/40 ratio (p < 0.001). Class 2 experienced more pain (p = 0.006) and received more morphine equivalents (p = 0.018). DISCUSSION Delirium and neighboring phenotypes should be investigated thoroughly in the newly dawning era of precision medicine, to establish novel treatments. Highlights Latent class analysis identified two subphenotypes of patients. Both groups contained patients with delirium or its individual symptoms. Groups differed by age, education, depression, independent living, and pain levels. Groups differed by pre‐operative and post‐operative cognition. Groups differed by biomarker levels of neurodegeneration and neuronal injury. In post‐operative patients undergoing delirium assessment, two latent classes were identified, both containing people experiencing delirium symptoms, but with higher proportion in Class 1. Class 1 were also older, less educated and had more depression. They performed worse in all preoperative cognitive assessments and had more markers of CNS damage. Class 2 experienced more pain and received more morphine equivalents.

Background Studies suggest delirium is associated with neuronal injury, which may further raise mortality risk. Neuronal injury can be assessed by measuring neurofilament light chain (NFL) concentrations in cerebrospinal fluid (CSF). This study aimed to investigate the association of CSF-NfL with delirium and mortality in patients with hip fracture. Methods The study comprised two prospective cohorts of 548 hip fracture patients with per-operative CSF samples. CSF-NfL concentrations were measured using a commercial ELISA. Delirium was assessed daily from admission until the fifth postoperative day and survival censored at one year. The multivariable analyses (Logistic and Cox regression) were adjusted for age, sex, glomerular filtration rate, dementia status, comorbidity, and Activities of Daily Living. Additionally, Cox regression was adjusted for delirium. Results In total, 259 (52%) patients developed delirium. In univariate analysis, CSF-NfL was higher among patients with delirium (2116 pg/ml versus 1366 pg/ml, odds ratio (OR) 2.21, (95% confidence interval (CI) [1.75,2,78], P  < 0.001). In adjusted analysis, CSF-NfL was not significant (OR 1.29, [0.92,1.81], P  = 0.128) and only remained significantly associated with delirium in the subgroup of patients without dementia (OR 1.84, [1.17, 2.89], P  = 0.007). In unadjusted analysis of mortality, CSF-NfL was significantly associated with death at one year (hazard ratio (HR) 1.60, [1.37, 1.87], P  < 0.001) but not in adjusted analysis (HR 1.03 [0.84, 1.26], P  = 0.736). Conclusions Our findings show that CSF-NfL concentrations were associated with delirium in patients without pre-existing dementia, suggesting possible undiagnosed dementia or, less likely, delirium-related neuronal injury. The CSF-NfL-associated mortality hazard was non-significant after adjustment, mainly for delirium. Thus, the clinical context must be considered when studying CSF-NfL and delirium.

ObjectivesNeurogranin (Ng) has a role in synaptic plasticity and is considered a biomarker of synaptic dysfunction, a process hypothesised to be important in delirium. Few studies examining Ng in delirium exist, with mixed findings. This study aimed to investigate associations between cerebrospinal fluid (CSF) Ng concentrations and delirium in acutely admitted hip fracture patients.DesignCross-sectional study.SettingAcutely admitted orthopaedic patients with hip fracture recruited from four participating hospitals in eastern Norway, representing secondary and tertiary care settings.ParticipantsThis study included 392 hip fracture patients. All admitted hip fracture patients operated in spinal anaesthesia were, regardless of age, considered for inclusion.MethodsAn in-house ELISA was used to measure CSF Ng concentration in patients acutely admitted with a hip fracture (n=392). Delirium status was evaluated daily according to The Diagnostic and Statistical Manual of Mental Disorders, Fifth Editions criteria independently by two experienced geriatricians. A value > 3.44 on The Informant Questionnaire on Cognitive Decline in the Elderly was used as a surrogate marker of probable dementia.Results180 patients (46 %) developed delirium and 70% of these had dementia. CSF Ng concentration did not differ significantly between those with and without delirium (176 pg/mL vs 164 pg/mL), with an estimated difference in medians of 12 (95% CI −5.8 to 29.8), p=0.185. Analyses adjusted for age, gender and dementia status did not show a statistically significant difference in Ng concentrations between the patients.ConclusionsWe did not find an association between delirium and CSF concentrations of Ng. This could imply that synaptic dysfunction and degeneration, involving Ng, are not key processes in the development of delirium. Further studies on other synaptic proteins are warranted to better explore synaptic dysfunction’s potential role in the pathophysiology of delirium.

Purpose: To investigate the relationship between soluble platelet‐derived growth factor β receptor (sPDGFRβ) in cerebrospinal fluid (CSF) and Alzheimer's disease (AD) biomarkers, to determine whether high CSF sPDGGFRβ is a potential risk factor for postoperative delirium (POD), and to evaluate its predictive effect, so as to provide reference for clinical prevention and treatment. Patients and Methods: CSF samples were collected preoperatively from cognitively normal participants aged 50–90 years undergoing knee/hip replacement surgery under spinal‐epidural anesthesia. The concentrations of sPDGFRβ, β‐amyloid 42 (Aβ42), total tau protein (Ttau), and phosphorylated tau protein (Ptau) in CSF were detected by enzyme‐linked immunosorbent assay (ELISA). The confusion assessment method (CAM) was used to evaluate whether participants developed POD after surgery, and they were divided into the POD group and non‐POD group (NPOD). The relationship between CSF sPDGFRβ, AD biomarkers, and POD was analyzed. Results: The level of sPDGFRβ, a marker of brain pericyte injury, was significantly increased in POD patients (p < 0.05), and the difference was still statistically significant after adjusting for multiple confounders (p < 0.05). CSF Aβ42 showed a significant mediating effect between CSF sPDGFRβ level and POD (22.45%). The combination of AD biomarkers and CSF sPDGFRβ predicted POD better than that of AD biomarkers or CSF sPDGFRβ alone. Conclusion: The results suggest that the increase in CSF sPDGFRβ is associated with an increased risk of POD due to the blood–brain barrier (BBB) dysfunction and reduced Aβ42 clearance. In this study, the correlation between CSF sPDGFRβ and POD was investigated for the first time, providing a new reference index for POD prediction. However, this paper did not study other relevant indicators of the BBB and lacked follow‐up, which could be further improved in the future. Brain pericyte injury may contribute to the onset and progression of POD by influencing the blood–brain barrier's capacity to clear Aβ protein. The combination of CSF sPDGFRβ with CSF AD biomarkers exhibits improved predictive abilities for POD.

Aims Postoperative delirium (POD) is relatively common and is associated with poor outcomes. Age is a risk factor for POD. This single‐center observational study is designed to determine whether surgery is a major contributor to the development of POD and inflammatory response. Methods Patients with elective procedures to repair thoracic aortic aneurysm were recruited to the study. Confusion Assessment Method was used to assess POD. Their blood and cerebrospinal fluids were harvested for analysis of inflammatory and neuronal injury indicators. Results A total of 67 patients were included in this study: 32 had stent placement under general anesthesia and 35 had open surgery to repair the aneurysm. No patients in the stent placement group had POD, but 9 patients in the open surgery group had POD (25.7%). Patients with POD had a lower body temperature at the end of surgery than patients without POD [36.3°C (35.7°C–36.6°C) vs. 36.7°C (36.3°C–37.0°C), p = 0.046]. This parameter was identified as a risk factor for POD. Patients in the open surgery group had increased interleukin 1β and neurofilament light chain in the blood. However, there was no change in these biomarkers in the cerebrospinal fluids at 10 and 24 h after surgery. Conclusion Our results suggest that surgery is a major contributor to POD, inflammatory response, and neuronal injury. Low body temperature at the end of surgery is a potential risk factor for POD in patients with open repair for thoracic aortic aneurysm. Diagram of findings: Surgical trauma is a major contributor to postoperative delirium, inflammation, and neuronal injury. Low body temperature at the end of surgery may be a risk factor for postoperative delirium in patients with open surgery repair for thoracic aortic aneurysm.

Background Delirium is an acute cognitive disturbance that is linked to increased healthcare costs, extended hospitalization, and a greater incidence of adverse outcomes, including cognitive decline. Despite its clinical importance, existing strategies for predicting and managing delirium remain inadequate. This study, therefore, sought to investigate the potential relationship between cerebrospinal fluid proteins and delirium via Mendelian randomization (MR) and to identify potential therapeutic targets. Methods Genetic data related to delirium were obtained from the 11th iteration of the FinnGen Biobank, which includes a total of 431,880 individuals of Finnish ancestry consisting of 3827 cases and 428,053 controls. Data on 910 cerebrospinal fluid proteins from 970 samples were collected via the ONTIME platform (https://ontime.wustl.edu/hg38/). MR analysis was used to evaluate genetic associations between cerebrospinal fluid proteins and delirium. Additionally, enrichment analysis was performed on cerebrospinal fluid proteins with genetic associations to identify potential cellular pathways and therapeutic targets. Results We identified 46 cerebrospinal fluid proteins associated with the occurrence of delirium. Among these, insulin (odds ratio [OR]: 1.35, 95% confidence interval [CI]: 1.07–1.70, p = 0.01), interleukin‐7 (OR: 0.56, 95% CI: 0.37–0.85, p = 0.01), and B‐cell lymphoma/leukemia 2‐like protein 1 (OR: 0.63, 95% CI: 0.45–0.88, p = 0.01) were identified as key proteins. Horizontal pleiotropy had a minimal impact on establishing causal relationships, with p values of 0.08, 0.26, and 0.32, respectively. Additionally, no evidence of heterogeneity in genetic variation was found between these three cerebrospinal fluid proteins and delirium, with p values of 0.07, 0.45, and 0.96, respectively. Leave‐one‐out analysis further confirmed the stability and robustness of these associations. The enrichment analysis indicated that the cytokine‐mediated signaling pathway plays a significant role in the pathogenesis of delirium. Conclusion Our study identified a genetic causal relationship between specific cerebrospinal fluid proteins and delirium, with insulin being a key factor. We also found that cytokine‐mediated signaling pathways may contribute to the pathophysiology of delirium. Future research should focus on the roles of peripheral and central glucose metabolism, as well as cellular immunity, in the pathological processes of delirium. This graphical summarizes a Mendelian randomization study exploring the causal relationship between cerebrospinal fluid (CSF) plasma proteins and delirium. 1. Data Sources: The study uses 910 CSF plasma proteins as exposures, sourced from the ONTIME database, and examines their associations with delirium outcomes (non‐induced by alcohol or other psychoactive substances) using genetic data from FinnGen (3,827 cases and 428,053 controls). 2. Statistical Analysis: Various Mendelian randomization methods are applied, including weighted median, weighted mode, simple MR‐Egger, and inverse variance weighted methods. Sensitivity analyses include heterogeneity and pleiotropy assessments using the MR‐Egger intercept test and Q‐statistic test to ensure the robustness of results. 3. Pathway Analysis: Protein‐protein interaction networks and KEGG pathway enrichment analyses are conducted to identify inter‐protein relationships and key biological pathways involved. This workflow highlights the integration of genetic data, advanced statistical analyses, and pathway enrichment to investigate the molecular mechanisms underlying delirium.