Associations of neuroinflammatory IL-6 and IL-8 with brain atrophy, memory decline, and core AD biomarkers - in cognitively unimpaired older adults.

Concentrations of pro-inflammatory cytokines -interleukin-6 (IL-6) and interleukin-8 (IL-8) - are increased with age and in Alzheimer's disease (AD). It is not clear whether concentrations of IL-6 and IL-8 in the central nervous system predict later brain and cognitive changes over time nor whether this relationship is mediated by core AD biomarkers. Here, 219 cognitively healthy older adults (62-91 years), with baseline cerebrospinal fluid (CSF) measures of IL-6 and IL-8 were followed over time - up to 9 years - with assessments that included cognitive function, structural magnetic resonance imaging, and CSF measurements of phosphorylated tau (p-tau) and amyloid-ß (Aß-42) concentrations (for a subsample). Higher baseline CSF IL-8 was associated with better memory performance over time in the context of lower levels of CSF p-tau and p-tau/Aß-42 ratio. Higher CSF IL-6 was related to less CSF p-tau changes over time. The results are in line with the hypothesis suggesting that an up-regulation of IL-6 and IL-8 in the brain may play a neuroprotective role in cognitively healthy older adults with lower load of AD pathology.

Longitudinal trajectories of functional recovery after hip fracture.

BACKGROUND: There is limited evidence regarding predictors of functional trajectories after hip fracture. We aimed to identify groups with different trajectories of functional recovery the first year after hip fracture, and to determine predictors for belonging to such groups. METHODS: This longitudinal study combined data from two large randomized controlled trials including patients with hip fracture. Participants were assessed at baseline, four and 12 months. We used the Nottingham Extended Activities of Daily Living (NEADL) as a measure of instrumental ADL (iADL) and Barthel Index for personal ADL (pADL). A growth mixture model was estimated to identify groups of patients following distinct trajectories of functioning. Baseline characteristics potentially predicting group-belonging were assessed by multiple nominal regression. RESULTS: Among 726 participants (mean age 83.0; 74.7% women), we identified four groups of patients following distinct ADL trajectories. None of the groups regained their pre-fracture ADL. For one of the groups identified in both ADL outcomes, a steep decline in function was shown the first four months after surgery, and none of the groups showed functional recovery between four and 12 months after surgery. CONCLUSIONS: No groups regained their pre-fracture ADL. Some of the patients with relatively high pre-fracture function, had a steep ADL decline. For this group there is a potential for recovery, but more knowledge and research is needed in this group. These findings could be useful in uncovering groups of patients with different functioning after a hip fracture, and aid in discharge planning.

Plasma neurofilament light chain protein as a predictor of days in delirium and deep sedation, mortality and length of stay in critically ill patients.

BACKGROUND: Delirium predicts poor outcomes, however identifying patients with the worst outcomes is challenging. Plasma neurofilament light protein (NfL) is a sensitive indicator of neuronal damage. We undertook an exploratory observational study to determine the association between plasma NfL and delirium in the critically ill. METHODS: MoDUS was a randomised placebo-controlled delirium trial of simvastatin done in an UK adult general ICU. We measured NfL levels in plasma samples using a Single molecule array (Simoa) platform. We explored associations between patient's plasma NfL levels and number of delirium days, and clinical outcomes. The control group for baseline NfL were preoperative patients undergoing major surgery. FINDINGS: The majority of critically ill patients already had a high NfL level on admission. Patients with higher plasma NfL levels at days one and three spent more days in delirium or deep sedation. Patients with zero or one day in delirium or deep sedation had day one mean concentrations of 37.8 pg/ml (SD 32.6) compared with 96.5 pg/ml (SD 106.1)) for patients with two days or more, p-value 0.002 linear mixed effects model. Survivors discharged before 14 days had lower mean plasma NfL concentrations compared to those with longer hospital stays and/or who died within six months. The area under ROC curve for predicting death within six months using day one NfL was 0.81 (0.7,0.9). INTERPRETATION: Measurement of plasma NfL within three days of admission may be useful to identify those patients with worse clinical outcomes, and as an enrichment strategy for future delirium interventional trials in the critically ill. FUNDING: Alzheimer's Society UK, UK Dementia Research Institute.

Low Heart Rate Variability Predicts Stroke and Other Complications in the First Six Postoperative Months After a Hip Fracture Operation.

Background: One-year mortality after hip fractures is underestimated and is reported as 25%. An improved risk stratifying could contribute to a better follow up of these patients. Heart Rate Variability (HRV) is an easy point-of-care investigation and is been used in cardiology, endocrinology, and perioperative care. This observational study intended to explore relevant associations between HRV parameters and 6-months mortality and morbidity after a hip fracture. Methods: One hundred and sixty-five patients admitted to two hospitals were included, and short-time HRV measurements (5 min, and 10 min at the two hospitals, respectively) were obtained. Mortality data were gathered by means of the Norwegian central address register. Patients, close relatives of patients, and in some cases their general physicians or nursery home physicians were interviewed 6 months postoperatively regarding the incidence of pneumonia, cardiac events, or stroke. Results: One and hundred fifty-seven (95.2%) patients were followed up after 6 months post-surgery. Twenty-one (13%) died during this period. Twenty patients (13%) developed pneumonia, eight (5 %) stroke, and four (2%) myocardial infarction. No HRV parameter was associated with 6-month general mortality. However, patients who developed stroke had significantly lower High Frequency Power (HF, p < 0.001) and lower Very Low Frequency Power (VLF, p = 0.003) at inclusion compared to patients without complications. Patients who developed pneumonia had at the inclusion lower root mean square of successive differences (RMSSD, p = 0.044). Patients with a history of coronary heart disease (n = 41) showed a mortality of 7%. Mortality in this group was associated with standard deviation of beat-to-beat intervals (SDNN, p = 0.006), Total Power (TP, p = 0.009), HF (p = 0.026), and Low Frequency Power (LF, p = 0.012). Beta-blocker intake was associated with lower heart rate, but not with differences in HRV parameters. Conclusion: In this exploratory study, we present for the first-time significant associations between different preoperative HRV parameters and stroke, myocardial infarction, and pneumonia during a 6-month period after hip fracture. HRV might be a simple and effective tool to identify patients at risk that would warrant better follow-up.

Cerebrospinal Fluid Concentration of Neurogranin in Hip Fracture Patients with Delirium.

BACKGROUND: Delirium is associated with an increased risk of incident dementia and accelerated progression of existing cognitive symptoms. Reciprocally, dementia increases the risk of delirium. Cerebrospinal fluid (CSF) concentration of the dendritic protein neurogranin has been shown to increase in early Alzheimer's disease (AD), likely reflecting synaptic dysfunction and/or degeneration. OBJECTIVE: To elucidate the involvement of synaptic dysfunction in delirium pathophysiology, we tested the association between CSF neurogranin concentration and delirium in hip fracture patients with different AD-biomarker profiles, while comparing them to cognitively unimpaired older adults (CUA) and AD patients. METHODS: The cohort included hip fracture patients with (n = 70) and without delirium (n = 58), CUA undergoing elective surgery (n = 127), and AD patients (n = 46). CSF was collected preoperatively and diagnostically in surgery and AD patients respectively. CSF neurogranin concentrations were analyzed in all samples with an in-house ELISA. Delirium was assessed pre-and postoperatively in hip fracture patients by trained investigators using the Confusion Assessment Method. Hip fracture patients were further stratified based on pre-fracture dementia status, delirium subtype, and AD fluid biomarkers. RESULTS: No association was found between delirium and CSF neurogranin concentration (main analysis: delirium versus no delirium, p = 0.68). Hip fracture patients had lower CSF neurogranin concentration than AD patients (p = 0.001) and CUA (p = 0.035) in age-adjusted sensitivity analyses. CONCLUSION: The findings suggest that delirium is not associated with increased CSF neurogranin concentration in hip fracture patients, possibly due to advanced neurodegenerative disease and age and/or because synaptic degeneration is not an important pathophysiological process in delirium.

Orthogeriatrics prevents functional decline in hip fracture patients: report from two randomized controlled trials.

BACKGROUND: The incidence of hip fractures are expected to increase in the following years. Hip fracture patients have in addition to their fracture often complex medical problems, which constitute a substantial burden on society and health care systems. It is thus important to optimize the treatment of these patients to reduce negative outcomes. The aim of this study was to assess the effect of comprehensive orthogeriatric care (CGC) on basic and instrumental activities of daily living (B-ADL and I-ADL). METHODS: This study is based on two randomized controlled trials; the Oslo Orthogeriatric Trial and the Trondheim Hip Fracture Trial. The two studies were planned in concert, and data were pooled and analyzed using linear mixed models. I-ADL function was assessed by the Nottingham Extended ADL Scale (NEADL) and B-ADL by the Barthel ADL (BADL) at four and twelve months after surgery. RESULTS: Seven hundred twenty-six patients were included in the combined database, of which 365 patients received OC and 361 patients received CGC. For the primary endpoint, I-ADL at four months was better in the CGC group, with a between-group difference of 3.56 points (95 % CI 0.93 to 6.20, p = 0.008). The between-group difference at 12 months was 4.28 points (95 % CI 1.57 to 7.00, p = 0.002). For B-ADL, between-group difference scores were only statistically significant at 12 months. When excluding the patients living at a nursing home at admission, both I-ADL and B-ADL function was significantly better in the CGC group compared to the OC group at all time points. CONCLUSIONS: Merged data of two randomized controlled trials showed that admitting hip fracture patients to an orthogeriatric care unit directly from the emergency department had a positive effect on ADL up to twelve months after surgery.

Fatty Acid-Binding Protein 3 in Cerebrospinal Fluid of Hip Fracture Patients with Delirium.

BACKGROUND: Delirium is associated with dementia and thus biomarkers reflecting neurodegeneration are of interest. Fatty acid-binding protein 3 (FABP3) is a cytoplasmic neuronal protein that has been isolated from the brain. It is released following brain injury and concentrations in cerebrospinal fluid (CSF) are also higher in neurodegenerative disorders such as Alzheimer's disease (AD). OBJECTIVE: To examine the relationship between CSF FABP3 concentration and delirium in hip fracture patients compared to a group of cognitively normal controls. METHODS: CFS FABP3 concentration was measured in 128 hip fracture patients with (n = 71) and without (n = 57) delirium, and in cognitively unimpaired adults ≥64 years (n = 124) undergoing elective surgery. RESULTS: CSF FABP3 (pg/ml) concentration (median (IQR)) was higher in hip-fracture patients compared to cognitively normal controls (5.7 (4.2-7.7) versus 4.5 (3.4-6.1), p < 0.001). There was a significant weak correlation between age and CSF FABP3 (ρ= 0.3, p < 0.001). After adjustment for age, the association between CSF FABP3 and hip-fracture was no longer statistically significant (ß= 0.05, p = 0.5). There were no significant differences in CSF FABP3 concentration between hip fracture patients with (5.4 (4.1-8.2)) and without (5.8 (4.2-7.2)) delirium. CSF FABP3 concentration correlated positively with CSF AD biomarkers p-tau (ρ= 0.7, p < 0.01) and t-tau (ρ= 0.7, p < 0.01). CONCLUSION: CSF FABP3 concentrations were higher in hip fracture patients compared with cognitively normal older adults, indicating ongoing age-related neurodegeneration in these patients. There were no differences of CSF FABP3 concentrations across delirium groups, suggesting that neuronal damage or degeneration reflected by FABP3 may not be directly linked to delirium pathophysiology.

Biomarker profiling beyond amyloid and tau: cerebrospinal fluid markers, hippocampal atrophy, and memory change in cognitively unimpaired older adults.

Brain changes occurring in aging can be indexed by biomarkers. We used cluster analysis to identify subgroups of cognitively unimpaired individuals (n = 99, 64-93 years) with different profiles of the cerebrospinal fluid biomarkers beta amyloid 1-42 (Aß42), phosphorylated tau (P-tau), total tau, chitinase-3-like protein 1 (YKL-40), fatty acid binding protein 3 (FABP3), and neurofilament light (NFL). Hippocampal volume and memory were assessed across multiple follow-up examinations covering up to 6.8 years. Clustering revealed one group (39%) with more pathological concentrations of all biomarkers, which could further be divided into one group (20%) characterized by tauopathy and high FABP3 and one (19%) by brain ß-amyloidosis, high NFL, and slightly higher YKL-40. The clustering approach clearly outperformed classification based on Aß42 and P-tau alone in prediction of memory decline, with the individuals with most tauopathy and FABP3 showing more memory decline, but not more hippocampal volume change. The results demonstrate that older adults can be classified based on biomarkers beyond amyloid and tau, with improved prediction of memory decline.

Cerebrospinal Fluid Levels of Interleukin-8 in Delirium, Dementia, and Cognitively Healthy Patients.

BACKGROUND: Delirium is a common and serious complication in geriatric patients. The pathophysiology of delirium is not known. OBJECTIVE: The objective of the current study was to test the hypothesis that cerebrospinal fluid (CSF) levels of inflammatory markers at the time of spinal anesthesia for hip surgery are associated with delirium. METHODS: In total 133 hip fracture patients and 125 cognitively healthy controls undergoing elective surgery, together with 73 Alzheimer's disease (AD) dementia patients, were recruited at Oslo University Hospital and Diakonhjemmet Hospital, Oslo, Norway. Delirium was evaluated daily in hip fracture patients by the Confusion Assessment Method (CAM). Depression was evaluated by Cornell Scale for Depression in Dementia (CSDD). Tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1ß), and interleukin-8 (IL-8) levels were measured in CSF using a Mesoscale Discovery (MSD) immunoassay. RESULTS: Hip fracture patients had significantly higher IL-8 levels (p < 0.001) compared to cognitively healthy controls or patients with stable AD dementia. Furthermore, preoperative IL-8 levels were significantly higher (p = 0.013) in hip fracture patients who developed delirium (incident delirium) after surgery as compared to patients with no delirium. However, subgroup analyses showed that IL-8 levels were only significantly higher in delirium patients without dementia (p = 0.006). In contrast, depression subgroup analysis showed that IL-8 concentration was significantly higher (p = 0.002) in delirium patients with depression. Both TNF-α and IL-1ß were undetected in most patients. CONCLUSIONS: Our study suggests that IL-8 levels are associated with delirium onset and that underlying depression or dementia influences IL-8 levels.

Neurofilament Light in Serum and Cerebrospinal Fluid of Hip Fracture Patients with Delirium.

BACKGROUND: Delirium is associated with new-onset dementia, suggesting that delirium pathophysiology involves neuronal injury. Neurofilament light (NFL) is a sensitive biomarker for neuroaxonal injury. METHODS: NFL was measured in cerebrospinal fluid (CSF) (n = 130), preoperative serum (n = 192), and postoperative serum (n = 280) in hip fracture patients, and in CSF (n = 123) and preoperative serum (n = 134) in cognitively normal older adults undergoing elective surgery. Delirium was diagnosed with the Confusion Assessment Method. RESULTS: Median serum NFL (pg/mL) was elevated in delirium in hip fracture patients (94 vs. 54 pre- and 135 vs. 92 postoperatively, both p < 0.001). Median CSF NFL tended to be higher in hip fracture patients with delirium (1,804 vs. 1,636, p = 0.074). Serum and CSF NFL were positively correlated (ρ = 0.56, p < 0.001). CONCLUSION: Our findings support an association between neuroaxonal injury and delirium. The correlation between serum and CSF NFL supports the use of NFL as a blood biomarker in future delirium studies.

CSF sTREM2 in delirium-relation to Alzheimer's disease CSF biomarkers Aß42, t-tau and p-tau.

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 (rS = 0.39, p = 0.002, n = 60) and correlated well with the CSF Alzheimer's disease biomarkers, Aß42, and t-tau/p-tau (rS = 0.40, p = 0.002, rS = 0.46, p < 0.001/ rS = 0.49, p < 0.001, n = 60). Among patients with dementia, the level of Aß38 and Aß40 also correlated positively with sTREM2 in CSF (Aß38MSDrS = 0.44, p = 0.001; Aß40MSDrS = 0.48, p < 0.001; Aß42MSDrS = 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.

Cerebrospinal Fluid S100B and Alzheimer's Disease Biomarkers in Hip Fracture Patients with Delirium.

OBJECTIVES: This study aimed to investigate the relationship between cerebrospinal fluid (CSF) S100B astrocyte-derived protein and delirium and to perform stratified analyses according to clinical and CSF markers of dementia. METHODS: We performed a prospective cohort study in a university hospital setting. The participants were patients admitted for hip fracture (n = 98) or for elective surgery (n = 50). Delirium was assessed daily perioperatively in hip fracture patients using the Confusion Assessment Method. A consensus-based diagnosis of prefracture dementia was made using all available information. CSF was drawn at the onset of spinal anesthesia. S100B and phosphorylated tau (P-tau) concentrations were measured using electrochemiluminescence immunoassay and enzyme-linked immunosorbent assays, respectively. RESULTS: In the hip fracture population (n = 98) there was no significant difference in CSF S100B concentrations between patients with ongoing preoperative (i.e., prevalent) delirium (n = 36, median [interquartile range] 1.11 µg/L [0.91-1.29]) and patients who never developed delirium (n = 46, 1.08 µg/L [0.92-1.28], p = 0.92). In patients without preoperative delirium, those who developed delirium postoperatively (i.e., incident delirium) (n = 16, 1.38 µg/L [1.08-1.62]) had higher concentrations of S100B than the 46 who never did (p = 0.013). This difference was confined to patients with pathological concentrations of P-tau (≥60 ng/L, n = 38). We also found that P-tau and S100B were correlated in CSF in the elective surgery patients. CONCLUSIONS: CSF S100B was elevated in patients with incident delirium who also had pathological levels of the Alzheimer disease biomarker P-tau, suggesting vulnerability caused by a preexisting process of astrocytic activation and tau pathology.

Cerebrospinal Fluid Phosphate in Delirium after Hip Fracture.

AIMS: Phosphate is essential for neuronal activity. We aimed to investigate whether delirium is associated with altered phosphate concentrations in cerebrospinal fluid (CSF) and serum. METHODS: Seventy-seven patients with hip fracture were assessed for delirium before and after acute surgery. Prefracture dementia was diagnosed by an expert panel. Phosphate was measured in CSF obtained immediately before spinal anesthesia (n = 77) and in serum (n = 47). CSF from 23 cognitively healthy elderly patients undergoing spinal anesthesia was also analyzed. RESULTS: Hip fracture patients with prevalent delirium had higher CSF phosphate concentrations than those without delirium (median 0.63 vs. 0.55 mmol/L, p = 0.001). In analyses stratified on dementia status, this difference was only significant in patients with dementia. Serum phosphate was ∼1 mmol/L; there was no association between serum phosphate concentration and delirium status. CSF phosphate did not correlate with serum levels. CONCLUSION: Patients with delirium superimposed on dementia have elevated phosphate levels.

Perioperative hemodynamics and risk for delirium and new onset dementia in hip fracture patients; A prospective follow-up study.

BACKGROUND: Delirium is common in hip fracture patients and many risk factors have been identified. Controversy exists regarding the possible impact of intraoperative control of blood pressure upon acute (delirium) and long term (dementia) cognitive decline. We explored possible associations between perioperative hemodynamic changes, use of vasopressor drugs, risk of delirium and risk of new-onset dementia. METHODS: Prospective follow-up study of 696 hip fracture patients, assessed for delirium pre- and postoperatively, using the Confusion Assessment Method. Pre-fracture cognitive function was assessed using the Informant Questionnaire of Cognitive Decline in the Elderly and by consensus diagnosis. The presence of new-onset dementia was determined at follow-up evaluation at six or twelve months after surgery. Blood pressure was recorded at admission, perioperatively and postoperatively. RESULTS: Preoperative delirium was present in 149 of 536 (28%) assessable patients, and 124 of 387 (32%) developed delirium postoperatively (incident delirium). The following risk factors for incident delirium in patients without pre-fracture cognitive impairment were identified: low body mass index, low level of functioning, severity of physical illness, and receipt of ≥ 2 blood transfusions. New-onset dementia was diagnosed at follow-up in 26 of 213 (12%) patients, associated with severity of physical illness, delirium, receipt of vasopressor drugs perioperatively and high mean arterial pressure postoperatively. CONCLUSION: Risk factors for incident delirium seem to differ according to pre-fracture cognitive status. The use of vasopressors during surgery and/or postoperative hypertension is associated with new-onset dementia after hip fracture.

Decreases in heart rate variability are associated with postoperative complications in hip fracture patients.

BACKGROUND: To explore relevant associations between deviations in linear and nonlinear heart rate variability (HRV) scores, and short-term morbidity and mortality in patients undergoing hip-surgery after a fracture. METHODS: 165 patients with hip fractures being admitted for surgery at two hospitals were included in a prospective cohort study. A short-term ECG was recorded within 24 hours of arrival. 15 patients had to be excluded due to insufficient quality of the ECG recordings. 150 patients were included in the final analysis. Linear parameters were calculated in time domain: standard deviation of NN intervals (SDNN), root mean square of successive differences (rMSSD); and frequency domain: Total Power (TP), High Frequency Power (HF), Low Frequency Power (LF), Very Low Frequency Power (VLF), and the ratio of LF/HF. Postoperative outcome was evaluated at the time of discharge. This included occurrence of pneumonia, overall infection rate, stroke, myocardial infarction, and all-cause mortality. RESULTS: Patients experiencing complications had significantly lower rMSSD (p = 0.04), and TP (p = 0.03) preoperatively. Postoperative infections were predicted by decreased VLF preoperatively (p = 0.04). There was a significant association between pneumonia and LF/HF<1 (p = 0.03). The likelihood ratio to develop pneumonia when LF/HF < 1 was 6,1. CONCLUSION: HRV seems to reflect the general frailty of the patient with hip fracture and might be used to identify patients in need of increased surveillance or prophylactic treatment.

Preclinical Amyloid-ß and Axonal Degeneration Pathology in Delirium.

BACKGROUND: The clinical relevance of brain ß-amyloidosis in older adults without dementia is not established. As delirium and dementia are strongly related, studies on patients with delirium may give pathophysiological clues. OBJECTIVE: To determine whether the Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers amyloid-ß 1-42 (Aß42), total tau (T-tau), and phosphorylated tau (P-tau) are associated with delirium in hip fracture patients with and without dementia. METHODS: CSF was collected in conjunction to spinal anesthesia in 129 patients. Delirium was assessed using the Confusion Assessment Method once daily in all patients, both pre- and postoperatively. The diagnosis of dementia at admission was based upon clinical consensus. CSF levels of Aß42, T-tau, and P-tau were analyzed. RESULTS: In patients without dementia, we found lower CSF Aß42 levels (median, 310 ng/L versus 489 ng/L, p = 0.006), higher T-tau levels (median, 505 ng/L versus 351 ng/L, p = 0.02), but no change in P-tau in patients who developed delirium (n = 16) compared to those who remained lucid (n = 49). Delirious patients also had lower ratios of Aß42 to T-tau (p < 0.001) and P-tau (p = 0.001) relative to those without delirium. CSF Aß42 and T-tau remained significantly associated with delirium status in adjusted analyses. In patients with dementia, CSF biomarker levels did not differ between those with (n = 54) and without delirium (n = 10). CONCLUSION: The reduction in CSF Aß42, indicating ß-amyloidosis, and increase in T-tau, indicating neurodegeneration, in hip fracture patients without dementia developing delirium indicates that preclinical AD brain pathology is clinically relevant and possibly plays a role in delirium pathophysiology.

Cerebrospinal fluid levels of neopterin are elevated in delirium after hip fracture.

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.

Associations Between Delirium and Preoperative Cerebrospinal Fluid C-Reactive Protein, Interleukin-6, and Interleukin-6 Receptor in Individuals with Acute Hip Fracture.

OBJECTIVES: To examine whether delirium in individuals with hip fracture is associated with high C-reactive protein (CRP), interleukin-6 (IL-6), and soluble IL-6 receptor (sIL-6R) levels in the cerebrospinal fluid (CSF). DESIGN: Prospective cohort study. SETTING: Two university hospitals in Oslo, Norway, and Edinburgh, United Kingdom. PARTICIPANTS: Individuals admitted with acute hip fracture (N = 151). MEASUREMENTS: Participants were assessed for delirium pre- and postoperatively using the Confusion Assessment Method. Prefracture cognitive impairment was detected using the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Serum was collected preoperatively and CSF just before the onset of spinal anesthesia. Cytokine levels in serum and CSF samples were determined using an enzyme-linked immunosorbent assay. Student t-tests or Mann-Whitney U-tests were used for between-group comparisons. Spearman rho was used for correlations. RESULTS: Sixty participants had prior cognitive impairment (IQCODE score ≥3.44). Delirium was diagnosed in 46 participants (77%) with prior cognitive impairment and 25 (29%) without. In participants without prior cognitive impairment, CSF CRP levels were higher in participants with delirium (median 0.05 µg/mL, interquartile range (IQR) 0.02-0.12 µg/mL) than in those without delirium (median 0.01 µg/mL, IQR 0.00-0.06 µg/mL) (P = .01); there were no differences in participants with prior cognitive impairment. In secondary analyses, in participants with prior cognitive impairment, the concentration of CSF sIL-6R was higher in those participants who developed delirium than in the other subgroups, but this difference was not statistically significant. Serum levels of CRP, IL-6, and sIL-6R were not different according to delirium in participants with or without prefracture cognitive impairment. CONCLUSION: High CSF levels of CRP and sIL-6R may be associated with delirium. Different pathophysiological mechanisms may operate in different subgroups, notably in relation to the presence of prior cognitive impairment.

A comparison of the revised Delirium Rating Scale (DRS-R98) and the Memorial Delirium Assessment Scale (MDAS) in a palliative care cohort with DSM-IV delirium.

OBJECTIVE: Assessment of delirium is performed with a variety of instruments, making comparisons between studies difficult. A conversion rule between commonly used instruments would aid such comparisons. The present study aimed to compare the revised Delirium Rating Scale (DRS-R98) and Memorial Delirium Assessment Scale (MDAS) in a palliative care population and derive conversion rules between the two scales. METHOD: Both instruments were employed to assess 77 consecutive patients with DSM-IV delirium, and the measures were repeated at three-day intervals. Conversion rules were derived from the data at initial assessment and tested on subsequent data. RESULTS: There was substantial overall agreement between the two scales [concordance correlation coefficient (CCC) = 0.70 (CI 95 = 0.60-0.78)] and between most common items (weighted κ ranging from 0.63 to 0.86). Although the two scales overlap considerably, there were some subtle differences with only modest agreement between the attention (weighted κ = 0.42) and thought process (weighted κ = 0.61) items. The conversion rule from total MDAS score to DRS-R98 severity scores demonstrated an almost perfect level of agreement (r = 0.86, CCC = 0.86; CI 95 = 0.79-0.91), similar to the conversion rule from DRS-R98 to MDAS. SIGNIFICANCE OF RESULTS: Overall, the derived conversion rules demonstrated promising accuracy in this palliative care population, but further testing in other populations is certainly needed.

The effect of a pre- and postoperative orthogeriatric service on cognitive function in patients with hip fracture: randomized controlled trial (Oslo Orthogeriatric Trial).

BACKGROUND: Delirium is a common complication in patients with hip fractures and is associated with an increased risk of subsequent dementia. The aim of this trial was to evaluate the effect of a pre- and postoperative orthogeriatric service on the prevention of delirium and longer-term cognitive decline. METHODS: This was a single-center, prospective, randomized controlled trial in which patients with hip fracture were randomized to treatment in an acute geriatric ward or standard orthopedic ward. Inclusion and randomization took place in the Emergency Department at Oslo University hospital. The key intervention in the acute geriatric ward was Comprehensive Geriatric Assessment including daily interdisciplinary meetings. Primary outcome was cognitive function four months after surgery measured using a composite outcome incorporating the Clinical Dementia Rating Scale (CDR) and the 10 words learning and recalls tasks from the Consortium to Establish a Registry for Alzheimer's Disease battery (CERAD). Secondary outcomes were pre- and postoperative delirium, delirium severity and duration, mortality and mobility (measured by the Short Physical Performance Battery (SPPB)). Patients were assessed four and twelve months after surgery by evaluators blind to allocation. RESULTS: A total of 329 patients were included. There was no significant difference in cognitive function four months after surgery between patients treated in the acute geriatric and the orthopedic wards (mean 54.7 versus 52.9, 95% confidence interval for the difference -5.9 to 9.5; P = 0.65). There was also no significant difference in delirium rates (49% versus 53%, P = 0.51) or four month mortality (17% versus 15%, P = 0.50) between the intervention and the control group. In a pre-planned sub-group analysis, participants living in their own home at baseline who were randomized to orthogeriatric care had better mobility four months after surgery compared with patients randomized to the orthopedic ward, measured with SPPB (median 6 versus 4, 95% confidence interval for the median difference 0 to 2; P = 0.04). CONCLUSIONS: Pre- and postoperative orthogeriatric care given in an acute geriatric ward was not effective in reducing delirium or long-term cognitive impairment in patients with hip fracture. The intervention had, however, a positive effect on mobility in patients not admitted from nursing homes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01009268 Registered November 5, 2009.