Post-operative cognitive impairment: a cognitive epidemiology perspective

Cognitive epidemiology investigates cognitive predictors of health and disease outcomes. Post-operative cognitive impairment is a common complication of surgery but has been neglected as a health outcome in cognitive epidemiology research. This is despite the fact that knowledge of cognitive predictors of post-operative cognitive impairment can be utilized for risk stratification, informed decision-making (in elective surgery), and personalized care of patients during the postoperative period. In this narrative review, the current literature on cognitive predictors of post-operative cognitive impairment and gaps therein are summarized

Hypertension and risk of post-operative cognitive dysfunction (POCD): a systematic review and meta-analysis

BACKGROUND: Post-operative cognitive dysfunction (POCD) occurs frequently after major surgery. Hypertension is well-established as a risk factor for age-related cognitive impairment, but it is unclear whether or not it also increases the risk of POCD. OBJECTIVE: To evaluate the role of hypertension in POCD risk in a systematic review and meta-analysis. METHOD: PubMed, Ovid SP and the Cochrane Database of Systematic Reviews were searched for longitudinal studies of adults undergoing surgery with reporting of hypertension, blood pressure and/or anti-hypertensive treatment associations with POCD as relative risks or odds ratios. Fixed-effects meta-analyses were performed using Review Manager (version 5.3). RESULTS: Twenty-four studies on 4317 patients (mean age 63 years) were included. None of the studies had set out to assess hypertension as a risk factor for POCD. Hypertension was used as a categorical predictor throughout and only 2 studies adjusted for potential confounders. Across all 24 studies, hypertension was not significantly associated with POCD risk (RR 1.01; 95% CI 0.93, 1.09; p=0.82), though among 8 studies with >75% males, we found hypertension associations with a 27% increased risk of POCD (RR 1.27, 95% CI 1.07, 1.49; p=0.005). CONCLUSION: Our findings do not support the hypothesis that hypertension is a risk factor for POCD. However, since none of the studies included in our analysis were hypothesis-driven and most did not adjust for potential confounders, further systematic investigations are needed to evaluate the role of hypertension in the epidemiology of POCD

Associations of dyslipidaemia and lipid-lowering treatment with risk of postoperative cognitive dysfunction: a systematic review and meta-analysis

BACKGROUND: Lipid imbalance is linked to age-related cognitive impairment, but its role in postoperative cognitive dysfunction (POCD) is unknown. Here, we present a systematic review and meta-analysis on dyslipidaemia, lipid-lowering treatment and POCD risk. METHODS: PubMed, Ovid SP and Cochrane databases were searched for longitudinal studies that reported on associations of any measure of dyslipidaemia and/or lipid-lowering treatment with POCD as relative risks (RRs) or ORs. Fixed-effects inverse variance models were used to combine effects. RESULTS: Of 205 articles identified in the search, 17 studies on 2725 patients (grand mean age 67 years; mean age range 61-71 years) with follow-up periods of 1 day to 4 years (median 7 days; IQR 1-68 days) were included. Studies focused almost exclusively on hypercholesterolaemia as a measure of dyslipidaemia and on statins as lipid-lowering treatment. Across 12 studies on hypercholesterolaemia, we found no association with POCD risk (RR 0.93; 95% CI 0.80 to 1.08; P=0.34). Statin use before surgery was associated with a reduced POCD risk across eight studies (RR 0.81; 95% CI 0.67 to 0.98; P=0.03), but data on treatment duration were lacking. CONCLUSION: Statin users appear to be at reduced risk of POCD although hypercholesterolaemia per se may not be associated with POCD risk. Trial studies are needed to evaluate the usefulness of statins in POCD prevention

Plasma leptin, but not adiponectin, is associated with cognitive impairment in older adults

BACKGROUND: Leptin and adiponectin are adipose-tissue derived hormones primarily involved in glucose, lipid, and energy metabolism, inflammation, and atherosclerosis. Both adipokines may cross the blood-brain barrier but evidence on their roles in cognitive impairment is limited and conflicting. Here, we determined associations of plasma adipokine concentration with cognitive impairment in older adults. METHODS: Cross-sectional analysis of baseline data from 669 participants aged ≥65 years of the Biomarker Development for Postoperative Cognitive Impairment in the Elderly (BioCog) study were recruited 2014–2017 at study sites in Berlin, Germany and Utrecht, the Netherlands. Cognitive impairment was defined as the lowest tertile of a cognitive summary score derived from six neuropsychological tests. RESULTS: After adjustment for age, sex, fasting, BMI, diabetes, hypertension, cerebrovascular disease, and coronary heart disease, higher leptin concentrations and a higher leptin/adiponectin ratio (LAR) were associated with a higher odds of cognitive impairment (OR per 1 SD higher leptin concentration, 1.33; 95 % CI 1.05, 1.69; p = 0.02; OR per 1 SD higher LAR, 1.26; 95 % CI 1.01, 1.57; p = 0.04). Sensitivity analyses determined that these findings were driven by the non-obese group (BMI < 30 kg/m2), whereas leptin and LAR were not associated with cognitive impairment in the obese group (BMI ≥ 30 kg/m2). Soluble leptin receptor, leptin/soluble leptin receptor ratio, total adiponectin and high-molecular weight adiponectin concentrations were each not associated with impairment. CONCLUSIONS: With leptin as a known promoter of atherosclerosis and inflammation, our findings point to a pathogenic role of leptin in age-related cognitive impairment that may be limited to non-obese individuals and warrants further investigation

Associations of the metabolic syndrome and its components with cognitive impairment in older adults

BACKGROUND: The metabolic syndrome (MetS) is an established cardiovascular risk factor. Here, we investigated its role in cognitive impairment. METHODS: Baseline data from 202 participants (aged 65 to 87 years) of the BioCog study were used. All were free of clinical dementia (MMSE≥24/30). Cognitive impairment was defined as the lowest tertile of a cognitive summary score. Multiple logistic regression analyses examined associations of body mass index (BMI), triglycerides (TG), high-density lipoprotein (HDL-C), glucose and glycated hemoglobin A1c (HbA1c) levels with the odds of cognitive impairment. MetS was defined as ≥3 of its 5 components obesity (BMI ≥ 30 kg/m2), elevated TG (TG ≥1.7 mmol/L), reduced HDL-C (males:  0.05). Results for HDL-C were similar when HDL-C, glucose, BMI and TG were entered into a single model (OR 2.56 per 1 mmol/L reduction, 95% CI 1.09, 5.88, p = 0.031) and when cerebrovascular disease and coronary heart disease were additionally controlled for (OR 2.56 per 1 mmol/L reduction, 95% CI 1.06, 6.25, p = 0.036). Among the 5 MetS components, participants with elevated TG were at 2-fold increased odds of impairment (OR 2.09, 95% CI 1.08, 4.05, p = 0.028) including when the remaining 4 MetS components were entered (OR 2.23, 95% CI 1.07, 4.65, p = 0.033), but the finding was no longer statistically significant when cerebrovascular disease and coronary heart disease were additionally controlled for (p = 0.11). Presence of MetS and of obesity, reduced HDL-C, elevated glucose or elevated blood pressure were not significantly associated with impairment (all p > 0.05). CONCLUSION: Our findings support low HDL-C as an independent risk marker of cognitive impairment in older age. The need for research into mediatory and confounding factors, and re-evaluation of traditional cut-off points is highlighted. TRIAL REGISTRATION: The study was registered on 15th October 2014 at clinicaltrials.gov (NCT02265263)

Plasma amyloid concentration in Alzheimer's disease: performance of a high-throughput amyloid assay in distinguishing Alzheimer's disease cases from controls

BACKGROUND: Collection of cerebrospinal fluid (CSF) for measurement of amyloid-β (Aβ) species is a gold standard in Alzheimer's disease (AD) diagnosis, but has risks. Thus, establishing a low-risk blood Aβ test with high AD sensitivity and specificity is of outmost interest. OBJECTIVE: We evaluated the ability of a commercially available plasma Aβ assay to distinguish AD patients from biomarker-healthy controls. METHOD: In a case-control design, we examined plasma samples from 44 AD patients (A + N+) and 49 controls (A-N-) from a memory clinic. AD was diagnosed using a combination of neuropsychological examination, CSF biomarker analysis and brain imaging. Total Aβ40 and total Aβ42 in plasma were measured through enzyme-linked immunosorbent assay (ELISA) technology using ABtest40 and ABtest42 test kits (Araclon Biotech Ltd.). Receiver operating characteristic (ROC) analyses with outcome AD were performed, and sensitivity and specificity were calculated. RESULTS: Plasma Aβ42/40 was weakly positively correlated with CSF Aβ42/40 (Spearman's rho 0.22; p = 0.037). Plasma Aβ42/40 alone was not able to statistically significantly distinguish between AD patients and controls (AUC 0.58; 95% CI 0.46, 0.70). At a cut-point of 0.076 maximizing sensitivity and specificity, plasma Aβ42/40 had a sensitivity of 61.2% and a specificity of 63.6%. CONCLUSION: In this sample, the high-throughput blood Aβ assay was not able to distinguish well between AD patients and controls. Whether or not the assay may be useful in large-scale epidemiological settings remains to be seen

Metabolic syndrome and the risk of postoperative delirium and postoperative cognitive dysfunction: a multi-centre cohort study

BACKGROUND: Metabolic syndrome and its components are risk factors for cognitive impairment, but their contribution to perioperative neurocognitive disorders is unknown. We examined their associations with the risk of postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) in older patients. METHODS: In 765 male and female participants aged =65 years, we measured preoperative metabolic parameters and screened for POD for 7 days or until discharge. POCD was defined through comparison of cognitive change on six neuropsychological tests with non-surgical controls. Multiple logistic regression analyses examined the association of metabolic parameters with risk of POD and POCD with adjustment for age, sex, and surgery type. RESULTS: A total of 149 patients (19.5% of 765) developed POD and 53 (10.1% of 520 attendees) had POCD at 3 months. Patients with metabolic syndrome were at 1.85-fold higher risk of POD (95% confidence interval [CI] 1.26-2.70). Each 1 mmol L(-1) higher high-density lipoprotein cholesterol (HDL-C) was associated with a 0.47-fold lower POD risk (95% CI 0.30-0.74). Each 1 kg m(-2) higher body mass index (BMI) was associated with a 1.09-fold higher POCD risk (95% CI 1.02- 1.16). CONCLUSIONS: Older surgical patients with metabolic syndrome were at increased risk of POD. Only reduced HDL-C was significantly associated with POD. For POCD, a higher preoperative BMI was identified as a risk factor. These findings add to mounting evidence of a distinct epidemiology of POD and POCD. Screening programmes taking advantage of HDL-C and BMI measurements and of metabolic interventions in reducing perioperative neurocognitive disorders should be evaluated

Diabetes, but not hypertension and obesity, is associated with postoperative cognitive dysfunction

BACKGROUND/AIMS: Older people undergoing surgery are at risk of developing postoperative cognitive dysfunction (POCD), but little is known of risk factors predisposing patients to POCD. Our objective was to estimate the risk of POCD associated with exposure to preoperative diabetes, hypertension, and obesity. METHODS: Original data from 3 randomised controlled trials (OCTOPUS, DECS, SuDoCo) were obtained for secondary analysis on diabetes, hypertension, baseline blood pressure, obesity (BMI ≥30 kg/m(2)), and BMI as risk factors for POCD in multiple logistic regression models. Risk estimates were pooled across the 3 studies. RESULTS: Analyses totalled 1,034 patients. POCD occurred in 5.2% of patients in DECS, in 9.4% in SuDoCo, and in 32.1% of patients in OCTOPUS. After adjustment for age, sex, surgery type, randomisation, obesity, and hypertension, diabetes was associated with a 1.84-fold increased risk of POCD (OR 1.84; 95% CI 1.14, 2.97; p = 0.01). Obesity, BMI, hypertension, and baseline blood pressure were each not associated with POCD in fully adjusted models (all p > 0.05). CONCLUSION: Diabetes, but not obesity or hypertension, is associated with increased POCD risk. Consideration of diabetes status may be helpful for risk assessment of surgical patients

Basal forebrain cholinergic system volume is associated with general cognitive ability in the elderly

OBJECTIVE: At the present, it is unclear whether association of basal forebrain cholinergic system (BFCS) volume with cognitive performance exists in healthy as well as in cognitively impaired elderly subjects. Whereas one small study reported an association of BFCS volume with general cognitive ability 'g' in healthy ageing, effects on specific cognitive domains have only been found in subjects with cognitive decline. Here we aim to clarify whether an association of BFCS volume and 'g' is present in a larger sample of elderly subjects without obvious symptoms of dementia and whether similar associations can also be observed in specific cognitive domains. METHODS: 282 pre-surgical patients from the BioCog study (aged 72.7±4.9 years with a range of 65-87 years, 110 women) with a median MMSE score of 29 points (range 24-30) were investigated. BFCS and brain volume as well as brain parenchymal fraction were assessed in T1-weighted MR images using SPM12 and a probabilistic map of the BFCS. Neuropsychological assessment comprised the CANTAB cognitive battery and paper-and-pencil based tests. For data analysis, generalised linear models and quantile regression were applied. RESULTS: Significant associations of BFCS volume with 'g' and several cognitive domains were found, with the strongest association found for 'g'. BFCS volume explained less variance in cognitive performance than brain volume. The association was not confounded by brain parenchymal fraction. Furthermore, the association of BFCS volume and 'g' was similar in high- and low-performers. CONCLUSION: Our results extend previous study findings on BFCS volume associations with cognition in elderly subjects. Despite the observed associations of BFCS volume and cognitive performance, this association seems to reflect a more general association of brain volume and cognition. Accordingly, a specific association of BFCS volume and cognition in non-demented elderly subjects is questionable

Stability of neuropsychological test performance in older adults serving as normative controls for a study on postoperative cognitive dysfunction

OBJECTIVE: Studies of postoperative cognitive dysfunction (POCD) rely on repeat neuropsychological testing. The stability of the applied instruments, which are affected by natural variability in performance and measurement imprecision, is often unclear. We determined the stability of a neuropsychological test battery using a sample of older adults from the general population. Forty-five participants aged 65 to 89 years performed six computerized and non-computerized neuropsychological tests at baseline and again at 7 day and 3 months follow-up sessions. Mean scores on each test were compared across time points using repeated measures analyses of variance (ANOVA) with pairwise comparison. Two-way mixed effects, absolute agreement analyses of variance intra-class correlation coefficients (ICC) determined test-retest reliability. RESULTS: All tests had moderate to excellent test-retest reliability during 7-day (ICC range 0.63 to 0.94; all p < 0.01) and 3-month intervals (ICC range 0.60 to 0.92; all p < 0.01) though confidence intervals of ICC estimates were large throughout. Practice effects apparent at 7 days eased off by 3 months. No substantial differences between computerized and non-computerized tests were observed. We conclude that the present six-test neuropsychological test battery is appropriate for use in POCD research though small sample size of our study needs to be recognized as a limitation. Trial registration ClinicalTrials.gov Identifier NCT02265263 (15th October 2014)