Postoperative Cognitive Dysfunction (POCD) and Inflammatory Markers in Elderly Patients

Introduction: Particularly in elderly patients, the brain responds to a systemic inflammatory response with an increased production of inflammatory mediators. This has hypothetically been linked to the development of postoperative cognitive dysfunction (POCD). Methods: We investigated 31 patients aged >65 yrs undergoing elective major surgery under standardized general anaesthesia (thiopental, sevoflurane, fentanyl, atracurium). Cognitive function was measured preoperatively and 7 days postoperatively using the extended version of the Consortium to Establish a Registry for Alzheimer's Disease - Neuropsychological Assessment Battery (CERAD-NAB, validated German version) for which we developed a diagnostic cut-off in healthy elderly volunteers. Systemic C-reactive protein (CRP) and interleukin 6 (IL-6) were measured preoperatively, 2 days postoperatively, and 7 days postoperatively. Values for CRP, IL-6, operative characteristics and hospital length of stay in patients with POCD and without POCD were compared using the Mann- Whitney U test and are shown as median [range]. Results: Fourteen patients (45%) developed POCD. Values for CRP were not statistically different in patients with POCD and without POCD but tended to be higher in patients with POCD 2 days postoperatively. Patients with POCD had significantly higher IL-6 values on postoperative days 2 and 7 (table 1). These patients also had a significantly longer duration of anaesthesia (305 [195-620] vs.190 [150-560] min, p = 0.034), larger intraoperative blood loss (425 [0-1600] vs. 100 [0-1500] ml, p = 0.018) and longer hospital stays (15 [8-45] vs. 8 [4-40] days, p = 0.008). Table 1 POCD (n = 14) No POCD (n = 17) p value CRP (mg/dl) preop. 4.0 [1.0-245] 4.2 [0.3-36.2] 0.6 2 days postop. 223 [20-318] 98 [4.5-384] 0.07 7 days postop. 58 [15-147] 44 [11-148] 0.2 IL-6 (U/ml) preop. 2[2-28.1] 2 [2-7.3] 0.8 2 days postop. 56 [17-315] 20 [2-123] 0.009 7 days postop. 9[2-77] 4 [2-16] 0.03 Interpretation: In this small group of patients, high IL-6 values postoperatively were associated with POCD supporting a role for systemic inflammation in the development of POCD. In patients with POCD, duration of anaesthesia was significantly longer, and intraoperative blood losses were larger. These risk factors will need to be confirmed in a larger group of patients. The difference in length of stay may be indicative of postoperative complications, which have been linked to POCD earlier

Plasma lipoprotein-associated phospholipase A2 activity in Alzheimer's disease, amnestic mild cognitive impairment, and cognitively healthy elderly subjects: a cross-sectional study.

ABSTRACT: INTRODUCTION: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a circulating enzyme with pro-inflammatory and oxidative activities associated with cardiovascular disease and ischemic stroke. While high plasma Lp-PLA2 activity was reported as a risk factor for dementia in the Rotterdam study, no association between Lp-PLA2 mass and dementia or Alzheimer's disease (AD) was detected in the Framingham study. The objectives of the current study were to explore the relationship of plasma Lp-PLA2 activity with cognitive diagnoses (AD, amnestic mild cognitive impairment (aMCI), and cognitively healthy subjects), cardiovascular markers, cerebrospinal fluid (CSF) markers of AD, and apolipoprotein E (APOE) genotype. METHODS: Subjects with mild AD (n = 78) and aMCI (n = 59) were recruited from the Memory Clinic, University Hospital, Basel, Switzerland; cognitively healthy subjects (n = 66) were recruited from the community. Subjects underwent standardised medical, neurological, neuropsychological, imaging, genetic, blood and CSF evaluation. Differences in Lp-PLA2 activity between the cognitive diagnosis groups were tested with ANOVA and in multiple linear regression models with adjustment for covariates. Associations between Lp-PLA2 and markers of cardiovascular disease and AD were explored with Spearman's correlation coefficients. RESULTS: There was no significant difference in plasma Lp-PLA2 activity between AD (197.1 (standard deviation, SD 38.4) nmol/min/ml) and controls (195.4 (SD 41.9)). Gender, statin use and low-density lipoprotein cholesterol (LDL) were independently associated with Lp-PLA2 activity in multiple regression models. Lp-PLA2 activity was correlated with LDL and inversely correlated with high-density lipoprotein (HDL). AD subjects with APOE-ε4 had higher Lp-PLA2 activity (207.9 (SD 41.2)) than AD subjects lacking APOE-ε4 (181.6 (SD 26.0), P = 0.003) although this was attenuated by adjustment for LDL (P = 0.09). No strong correlations were detected for Lp-PLA2 activity and CSF markers of AD. CONCLUSION: Plasma Lp-PLA2 was not associated with a diagnosis of AD or aMCI in this cross-sectional study. The main clinical correlates of Lp-PLA2 activity in AD, aMCI and cognitively healthy subjects were variables associated with lipid metabolism

Postoperative cognitive dysfunction POCD, serum anticholinergic activity and intraoperative cerebral perfusion in geriatric patients

Background: Inadequate intraoperative cerebral perfusion and increased serum anticholinergic activity (SAA) have been suggested as possible causes of postoperative cognitive dysfunction (POCD). Methods: 53 patients aged >65 yrs undergoing elective major surgical procedures under standardized general anaesthesia. Cerebral perfusion was monitored with transcranial Doppler and near-infrared spectroscopy. Mx, an index of cerebral autoregulation was calculated based on the correlation of spontaneous changes inmean arterial blood pressure (MAP) and cerebral blood flow velocity. Cognitive function was measured preoperatively and 7 days postoperatively using the CERAD-Neuropsychological Battery. A postoperative decline >1 z-score in at least 2 cognitive variables was defined as POCD. SAA was measured preoperatively and 7 days postoperatively (data available for 38 patients). CRP was measured at the same time points and 2 days postoperatively. Results: Age was 75_7 yrs (mean_SD). 23 patients (43%) developed POCD. There were no statistical significant differences between patients with POCD and without POCD in age (77_7 vs 73_6 yrs), MAP (74_12 vs 78_11 mmHg), cerebral tissue oxygenation indices (67_6 vs 69_4 %) SAA preoperatively (1.74_1.52 vs 1.74_1.21) and 7 days postoperatively (1.90_1.63 vs 1.84_1.39) and CRP preoperatively (32_72 vs 7_9), 2 days postoperatively (176_129 vs 111_69) and 7days postoperatively (53_43 vs 48_25). Patients with POCD had less efficient autoregulation than patients without POCD (Mx 0.55_0.15 vs 0.45_0.20, p = 0.046). However, the percentage of patients with clearly impaired autoregulation (ie, Mx>0.5) was statistically not different between groups (with POCD: 65%; without POCD: 38%; p = 0.06) but there seems to be a trend. Conclusions: Our data on the association between cerebral perfusion and POCD in elderly patients are inconclusive and more patients need to be investigated. In this small group of patients SAA seems not to be associated with POCD

Intraoperative cerebral perfusion and postoperative cognitive dysfunction in geriatric patients

Background: Inadequate intraoperative cerebral perfusion has been suggested as a possible cause of postoperative cognitive dysfunction (POCD). Methods: We investigated 35 patients aged 65 or older undergoing elective major non-cardiac surgery under standardized general anaesthesia (thiopental, sevoflurane, fentanyl, atracurium). Intraoperative cerebral perfusion was monitored with transcranial Doppler, and near-infrared spectroscopy (NIRS). Arterial blood pressure was monitored continuously with a Finapres device. Mx, an index allowing continuous monitoring of cerebrovascular autoregulation based on the changes in mean arterial blood pressure (MAP) and cerebral blood flow velocity was calculated. Mx >0.5 was defined as disturbed cerebrovascular autoregulation. Cognitive function was measured preoperatively and 7 days postoperatively using the CERAD-NAB Plus test battery. A postoperative decline >1 z-score in at least two of the tested domains was defined as POCD. Data are shown as mean } SD. Results: Mean age was 75 } 7 yrs. Sixteen patients (46%) developed POCD. These patients were older (77 } 8 vs 73 } 7 yrs), had lower MAP (77 } 12 vs 81 } 11 mm Hg), lower cerebral tissue oxygenation indices measured by NIRS (66.8 } 6.0 vs 68.6 } 4.3%) and less efficient cerebrovascular autoregulation (Mx 0.54 } 0.17 and 0.44 } 0.22) than patients without POCD. Disturbed intraoperative cerebrovascular autoregulation was found more often (56 vs 37%) in patients with POCD. However, none of these differences reached statistical significance. Conclusions: Our data show a trend towards subtle changes in intraoperative cerebral perfusion in elderly patients who develop POCD. However, a cause effect relationship must not be assumed and a greater number of patients needs to be investigated patients. However, more patients need to be investigated to confirm and characterize these differences

Serum anticholinergic activity and postoperative cognitive dysfunction in elderly patients

Background: Cerebral cholinergic transmission plays a key role in cognitive function and anticholinergic drugs are associated with impaired cognitive functions [1]. In the perioperative phase many substances with anticholinergic effects are administered and disturbed cholinergic transmission is a hypothetical cause of postoperative cognitive dysfunction (POCD). Serum anticholinergic activity (SAA; pmol/ml) may be measured as a summary marker of anticholinergic activity in an individual patient's blood. We hypothesised that an increase in SAA from preoperatively to one week postoperatively is associated with POCD in elderly patients. Methods: Thirty-two patients aged >65 yrs undergoing elective major surgery under standardized general anaesthesia (thiopental, sevoflurane, fentanyl) were investigated. Cognitive functions were measured preoperatively and 7 days postoperatively using the extended version of the Consortium to Establish a Registry for Alzheimer's Disease - Neuropsychological Assessment Battery. POCD was defined as a postoperative decline >1 z-score in at least 2 cognitive domains. SAA was measured preoperatively and 7 days postoperatively at the time of cognitive testing. Results: 50% of the investigated patients developed POCD. There were no statistically significant differences between patients with and without POCD regarding age, education, baseline cognitive function, duration of anaesthesia, SAA preoperatively (median (range) 1.0 (0.3 to 5.0) vs 1.5 (0.4 to 5.0), SAA 7 days postoperatively (median (range) 1.3 (0.1 to 7.0) vs 1.4 (0.6 to 5.5) or changes in SAA (median (range) 0.1 (-1.6 to 2.2) vs 0.2 (-1.4 to 2.8). The variability of SAA in individual patients was considerable and marked changes in SAA between the two examinations were observed in some patients. However, there was no significant relationship between changes in SAA and changes in cognitive function. Conclusion: In this preliminary analysis of a small group of patients, changes in SAA in the perioperative phase were highly variable. SAA was not associated with POCD suggesting that POCD is not simply caused by anticholinergic medications administered in the perioperative phase. A further analysis of a larger group of patients is in progress

General practitioners' attitudes towards early diagnosis of dementia: a cross-sectional survey.

Dementia is often underdiagnosed in general practice, which may be based on general practitioners' (GPs') knowledge and emotional factors as well as external problems. This study aimed to describe GPs' attitudes toward early diagnosis of dementia. Cross-sectional postal survey in Switzerland in 2017. Members of the Swiss Association of General Practitioners (N = 4460) were asked to participate in the survey. The questionnaire assessed attitudes, enablers and barriers to early dementia diagnosis and post-diagnostic intervention strategies. Exploratory factor analysis and linear regression were used. The survey response rate was 21%. 85% of GPs agreed with enablers of early dementia recognition (e.g. "Plan for the future, organize support and care", "Minimize the strain and insecurity of patients and their informal family caregivers"). On the other hand, 15% of respondents perceived barriers towards early dementia recognition (e.g. "Time constraints in carrying out the necessary procedures to diagnose dementia"). GPs who were more likely to agree with barriers would less often counsel family members (β = - 0.05, 95% CI = - 0.09 - -0.02) or test fitness to drive (β = - 0.05, 95% CI = - 0.09 - -0.02), and more often choose a watchful waiting strategy (β = 0.05, 95% CI = 0.02-0.09). The attitude of the majority of GPs is not characterized by diagnostic and therapeutic nihilism. However, negative attitudes were associated with sub-optimal management after the diagnosis. Thus, health systems are required to critically examine the use of available resources allowing GPs to look after patients and their relatives in a holistic way

Early diagnosis and management of dementia in general practice - how do Swiss GPs meet the challenge?

In general practice, the diagnosis of dementia is often delayed. Therefore, the Swiss National Dementia Strategy 2014 concluded that action was needed to improve patient care. Little is known about GPs’ confidence in and approach to the diagnosis, disclosure and post-diagnostic management of individuals with dementia in Switzerland. The aim of this survey is to assess these elements of dementia care and GPs’ views on the adequacy of health care services regarding dementia. Cross-sectional postal survey in Switzerland in 2017 supported by all academic institutes of general practice in Swiss universities. Members of the Swiss Association of General Practitioners (n = 4460) were asked to participate in the survey. In addition to the GPs’ demographic characteristics, the survey addressed the following issues: GPs’ views on the adequacy of health care services, clinical approach and confidence in the management of dementia. The survey response rate was 21%. The majority of GPs (64%) felt confident diagnosing dementia, but not in patients with a migration background (15%). For neuropsychological testing, three-quarters of GPs collaborated with memory clinics and were satisfied with the access to diagnostic services. At the time of first diagnosis, 62% of GPs diagnosed the majority of their patients with a mild stage of dementia, and 31% with a mild cognitive impairment. The most frequent actions taken by GPs after the diagnosis of mild dementia were giving advice to relatives (71%), testing fitness-to-drive (66%) and minimising cardiovascular risk factors (63%). While 65% of GPs felt confident taking care of patients with dementia, fewer (53%) felt confident in pharmacological treatment, coping with suicidal ideation (44%) or caring for patients with a migration background (16%). Half of GPs preferred to delegate the assessment of fitness-to-drive to an official authority. One in four GPs was not satisfied with the local provision of care and support facilities for patients with dementia. Overall, GPs reported confidence in establishing a diagnosis of dementia and sufficient access to diagnostic services. Post-diagnostic management primarily focused on counselling and harm reduction rather than pharmacological treatment. Future educational support for GPs should be developed, concentrating on coping with their patients’ suicidal ideation and caring for patients with a migration background

Associations Between Impaired Cerebral Blood Flow Autoregulation, Cerebral Oxygenation, and Biomarkers of Brain Injury and Postoperative Cognitive Dysfunction in Elderly Patients After Major Noncardiac Surgery.

Increasing evidence links postoperative cognitive dysfunction (POCD) to surgery and anesthesia. POCD is recognized as an important neuropsychological adverse outcome in surgical patients, particularly the elderly. This prospective cohort study aimed to investigate whether POCD is associated with impaired intraoperative cerebral autoregulation and oxygenation, and increased levels of biomarkers of brain injury. Study subjects were patients ≥65 years of age scheduled for major noncardiac surgery. Cognitive function was assessed before and 1 week after surgery. POCD was diagnosed if a decline of >1 standard deviation of z-scores was present in ≥2 variables of the test battery. The incidence of POCD 1 week after surgery was modeled as a multivariable function of the index of autoregulation (MxA) and tissue oxygenation index (TOI), adjusting for baseline neuropsychological assessment battery (Consortium to Establish a Registry for Alzheimer's Disease-Neuropsychological Assessment Battery [CERAD-NAB]) total score and the maximum C-reactive protein (CRP) concentration. The biomarkers of brain injury neuron-specific enolase and S100β protein, age, and level of education were included in secondary multivariable logistic regression analyses. Of the 82 patients who completed the study, 38 (46%) presented with POCD 1 week after surgery. In the multivariable regression analysis, higher intraoperative MxA (odds ratio [OR; 95% confidence interval (CI)], 1.39 [1.01-1.90] for an increase of 0.1 units, P = .08 after Bonferroni adjustment), signifying less effective autoregulation, was not associated with higher odds of POCD. The univariable logistic regression model for MxA yielded an association with POCD (OR [95% CI], 1.44 [1.06-1.95], P = .020). Tissue oxygenation index (1.12 [0.41-3.01] for an increase of 10%, P = 1.0 after Bonferroni adjustment) and baseline CERAD-NAB total score (0.80 [0.45-1.42] for an increase of 10 points, P = .45) did not affect the odds of POCD. POCD was associated with elevated CRP on postoperative day 2 (median [interquartile range]; 175 [81-294] vs 112 [62-142] mg/L, P = .033); however, the maximum CRP value (OR [95% CI], 1.35 [0.97-1.87] for a 2-fold increase, P = .07) had no distinct effect on POCD. Impairment of intraoperative cerebral blood flow autoregulation is not predictive of early POCD in elderly patients, although secondary analyses indicate that an association probably exists

Serum anticholinergic activity and postoperative cognitive dysfunction in elderly patients.

BACKGROUND: Cerebral cholinergic transmission plays a key role in cognitive function, and anticholinergic drugs administered during the perioperative phase are a hypothetical cause of postoperative cognitive dysfunction (POCD). We hypothesized that a perioperative increase in serum anticholinergic activity (SAA) is associated with POCD in elderly patients. METHODS: Seventy-nine patients aged >65 years undergoing elective major surgery under standardized general anesthesia (thiopental, sevoflurane, fentanyl, and atracurium) were investigated. Cognitive functions were assessed preoperatively and 7 days postoperatively using the extended version of the CERAD-Neuropsychological Assessment Battery. POCD was defined as a postoperative decline >1 z-score in at least 2 test variables. SAA was measured preoperatively and 7 days postoperatively at the time of cognitive testing. Hodges-Lehmann median differences and their 95% confidence intervals were calculated for between-group comparisons. RESULTS: Of the patients who completed the study, 46% developed POCD. Patients with POCD were slightly older and less educated than patients without POCD. There were no relevant differences between patients with and without POCD regarding gender, demographically corrected baseline cognitive functions, and duration of anesthesia. There were no large differences between patients with and without POCD regarding SAA preoperatively (pmol/mL, median [interquartile range]/median difference [95% CI], P; 1.14 [0.72, 2.37] vs 1.13 [0.68, 1.68]/0.12 [-0.31, 0.57], P = 0.56), SAA 7 days postoperatively (1.32 [0.68, 2.59] vs 0.97 [0.65, 1.83]/0.25 [-0.26, 0.81], P = 0.37), or changes in SAA (0.08 [-0.50, 0.70] vs -0.02 [-0.53, 0.41]/0.1 [-0.31, 0.52], P = 0.62). There was no significant relationship between changes in SAA and changes in cognitive function (Spearman rank correlation coefficient preoperatively of 0.03 [95% CI, -0.21, 0.26] and postoperatively of -0.002 [95% CI, -0.24, 0.23]). CONCLUSIONS: In this panel of patients with low baseline SAA and clinically insignificant perioperative anticholinergic burden, although a relationship cannot be excluded in some patients, our analysis suggests that POCD is probably not a substantial consequence of anticholinergic medications administered perioperatively but rather due to other mechanisms

Brain microstructure reveals early abnormalities more than two years prior to clinical progression from mild cognitive impairment to Alzheimer's disease

Diffusion imaging is a promising marker of microstructural damage in neurodegenerative disorders, but interpretation of its relationship with underlying neuropathology can be complex. Here, we examined both volumetric and brain microstructure abnormalities in 13 amnestic patients with mild cognitive impairment (MCI), who progressed to probable Alzheimer's disease (AD) no earlier than 2 years after baseline scanning, in order to focus on early, and hence more sensitive, imaging markers. We compared them to 22 stable amnestic MCI patients with similar cognitive performance and episodic memory impairment but who did not show progression of symptoms for at least 3 years. Significant group differences were mainly found in the volume and microstructure of the left hippocampus, while white matter group differences were also found in the body of the fornix, left fimbria, and superior longitudinal fasciculus (SLF). Diffusion index abnormalities in the SLF were the sign of a subtle microstructural injury not detected by standard atrophy measures in the corresponding gray matter regions. The microstructural measure obtained in the left hippocampus using diffusion imaging showed the most substantial differences between the two groups and was the best single predictor of future progression to AD. An optimal prediction model (91% accuracy, 85% sensitivity, 96% specificity) was obtained by combining MRI measures and CSF protein biomarkers. These results highlight the benefit of using the information of brain microstructural damage, in addition to traditional gray matter volume, to detect early, subtle abnormalities in MCI prior to clinical progression to probable AD and, in combination with CSF markers, to accurately predict such progression