The Association of Plasma Leptin, Soluble Leptin Receptor and Total and High-Molecular Weight Adiponectin With the Risk of Perioperative Neurocognitive Disorders.

BACKGROUND: Perioperative neurocognitive disorders (NCD) are poorly characterized in terms of their risk factor profiles. Leptin and adiponectin are adipose-tissue-derived hormones with a role in inflammation and atherosclerosis whose function in perioperative NCD is unclear. Here, we used a cohort of older adults to examine the association of preoperative plasma concentrations of these biomarkers with the risk of perioperative NCD. METHODS: Prospective analysis of 768 participants aged ≥ 65 years of the BioCog study. Blood was collected before surgery for measurement of plasma total and high-molecular-weight (hmw) adiponectin, leptin, and soluble leptin receptor (sOB-R). The free leptin index (FLI, leptin:sOB-R) was calculated. Postoperative delirium (POD) was assessed twice daily until postoperative day 7/discharge. Five hundred twenty-six patients (68.5%) returned for 3-month follow-up and provided data on postoperative cognitive dysfunction (POCD). POCD was defined as a decline on six neuropsychological tests that exceeded that of a nonsurgical control group. Logistic regression analyses examined the associations of each exposure with POD and POCD risk, in separate models adjusted for age, sex, fasting, surgery type, and body mass index (BMI). RESULTS: Of 768 patients, 152 (19.8%) developed POD. Of 526 attendants of the follow-up, 54 (10.3%) had developed POCD. Leptin, sOB-R, and total and hmw adiponectin were each not associated with POD. For POCD, we observed reduced risk in patients in FLI quartile 4 compared with quartile 1 (odds ratio, 0.26; 95% CI 0.08, 0.89). Sensitivity analyses for the outcome POD revealed statistically significant interaction terms of sOB-R and total adiponectin with obesity (BMI≥30kg/m2 versus BMI<30kg/m2). For the outcome POCD, a higher sOB-R was associated with an increased risk in the obese subgroup (odds ratio, 4.00; 95% CI 1.01, 15.86). CONCLUSIONS: We did not find consistent evidence for the role of leptin, its receptor, and total and hmw adiponectin in POD and POCD risk. Future research should be used to support or refute our findings and to fully characterize any differences in the associations of these hormones with POD/POCD between obese and nonobese individuals.

Perioperative Levels of IL8 and IL18, but not IL6, are Associated with Nucleus Basalis Magnocellularis Atrophy Three Months after Surgery.

Past studies have observed that brain atrophy may accelerate after surgical procedures. Furthermore, an association of systemic inflammation with neurodegeneration has been described. We hypothesize that postoperative interleukin (IL) levels in circulation as well as the perioperative change in interleukin levels are associated with increased postoperative atrophy in the Nucleus basalis magnocellularis (of Meynert, NBM) which is the major source of cortical acetylcholine. We analyzed data from the BioCog cohort which included patients ≥ 65 years presenting for elective major surgery (≥ 60min). Blood samples were taken before surgery and on the first postoperative day. Magnetic resonance imaging of the brain and neuropsychological assessments were conducted before surgery and after three months follow-up. We used linear regression analysis to determine the association of three interleukins (IL6, IL8 and IL18) with NBM atrophy (in % volume change from baseline before surgery to follow-up), as well as to examine the associations of NBM atrophy and volume with postoperative cognitive ability and perioperative cognitive change. Receiver-operating curves were used to determine the prognostic value of preoperative interleukin levels. For IL8 (N = 97) and IL18 (N = 217), but not IL6 (N = 240), we observed significant associations of higher postoperative IL levels at the first postoperative day with higher NBM atrophy at three months after surgery. Subsequent analyses suggested that in both IL8 and IL18, this association was driven by a more general association of chronically elevated IL levels and NBM atrophy, reflected by preoperative IL concentrations, rather than IL response to surgery, measured as the difference between pre- and postoperative IL concentrations. At follow-up, NBM volume was positively associated with the level of cognitive performance, but NBM atrophy was not significantly related to perioperative cognitive change. Prognostic value of preoperative IL concentrations for NBM atrophy was low. Our results suggest that an association of postoperative interleukin levels with NBM atrophy is driven by preoperatively elevated interleukins due to pre-existing inflammation, rather than perioperative change in interleukin levels in response to surgery and anesthesia. The BioCog study has been registered at clinicaltrials.gov on Oct 15, 2014 (NCT02265263).

Structural disconnectivity in postoperative delirium: A perioperative two-center cohort study in older patients.

BACKGROUND: Structural disconnectivity was found to precede dementia. Global white matter abnormalities might also be associated with postoperative delirium (POD). METHODS: We recruited older patients (≥65 years) without dementia that were scheduled for major surgery. Diffusion kurtosis imaging metrics were obtained preoperatively, after 3 and 12 months postoperatively. We calculated fractional anisotropy (FA), mean diffusivity (MD), mean kurtosis (MK), and free water (FW). A structured and validated delirium assessment was performed twice daily. RESULTS: Of 325 patients, 53 patients developed POD (16.3%). Preoperative global MD (standardized beta 0.27 [95% confidence interval [CI] 0.21-0.32] p < 0.001) was higher in patients with POD. Preoperative global MK (-0.07 [95% CI -0.11 to (-0.04)] p < 0.001) and FA (0.07 [95% CI -0.10 to (-0.04)] p < 0.001) were lower. When correcting for baseline diffusion, postoperative MD was lower after 3 months (0.05 [95% CI -0.08 to (-0.03)] p < 0.001; n = 183) and higher after 12 months (0.28 [95% CI 0.20-0.35] p < 0.001; n = 45) among patients with POD. DISCUSSION: Preoperative structural disconnectivity was associated with POD. POD might lead to white matter depletion 3 and 12 months after surgery.

Assessing the impact of sex on high-frequency repetitive transcranial magnetic stimulation´s clinical response in schizophrenia - results from a secondary analysis.

BACKGROUND: The evidence for repetitive transcranial magnetic stimulation (rTMS) to treat negative symptoms in schizophrenia (SCZ) is increasing, although variable response rates remain a challenge. Subject´s sex critically influences rTMS´ treatment outcomes. Females with major depressive disorder are more likely to respond to rTMS, while SCZ data is scarce. METHODS: Using data from the 'rTMS for the Treatment of Negative Symptoms in Schizophrenia' (RESIS) trial we assessed the impact of sex on rTMS´ clinical response rate from screening up to 105 days after intervention among SCZ patients. The impact of resting motor threshold (RMT) on response rates was also assessed. RESULTS: 157 patients received either active or sham rTMS treatment. No significant group differences were observed. Linear mixed model showed no effects on response rates (all p > 0.519). Apart from a significant sex*time interaction for the positive subscale of the positive and negative syndrome scale (PANSS) scores (p = 0.032), no other significant effects of sex on continuous PANSS scores were observed. RMT had no effect on response rate. CONCLUSION: In the largest rTMS trial on the treatment of SCZ negative symptoms we did not observe any significant effect of sex on treatment outcomes. Better assessments of sex-related differences could improve treatment individualisation.

Influence of a chronic beta-blocker therapy on perioperative opioid consumption - a post hoc secondary analysis.

BACKGROUND: Beta-blocker (BB) therapy plays a central role in the treatment of cardiovascular diseases. An increasing number of patients with cardiovascular diseases undergoe noncardiac surgery, where opioids are an integral part of the anesthesiological management. There is evidence to suggest that short-term intravenous BB therapy may influence perioperative opioid requirements due to an assumed cross-talk between G-protein coupled beta-adrenergic and opioid receptors. Whether chronic BB therapy could also have an influence on perioperative opioid requirements is unclear. METHODS: A post hoc analysis of prospectively collected data from a multicenter observational (BioCog) study was performed. Inclusion criteria consisted of elderly patients (≥ 65 years) undergoing elective noncardiac surgery as well as total intravenous general anesthesia without the use of regional anesthesia and duration of anesthesia ≥ 60 min. Two groups were defined: patients with and without BB in their regular preopreative medication. The administered opioids were converted to their respective morphine equivalent doses. Multiple regression analysis was performed using the morphine-index to identify independent predictors. RESULTS: A total of 747 patients were included in the BioCog study in the study center Berlin. 106 patients fulfilled the inclusion criteria. Of these, 37 were on chronic BB. The latter were preoperatively significantly more likely to have arterial hypertension (94.6%), chronic renal failure (27%) and hyperlipoproteinemia (51.4%) compared to patients without BB. Both groups did not differ in terms of cumulative perioperative morphine equivalent dose (230.9 (BB group) vs. 214.8 mg (Non-BB group)). Predictive factors for increased morphine-index were older age, male sex, longer duration of anesthesia and surgery of the trunk. In a model with logarithmised morphine index, only gender (female) and duration of anesthesia remained predictive factors. CONCLUSIONS: Chronic BB therapy was not associated with a reduced perioperative opioid consumption. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov ( NCT02265263 ) on the 15.10.2014 with the principal investigator being Univ.-Prof. Dr. med. Claudia Spies.

An exploratory research report on brain mineralization in postoperative delirium and cognitive decline.

Delirium is a severe postoperative complication associated with poor overall and especially neurocognitive prognosis. Altered brain mineralization is found in neurodegenerative disorders but has not been studied in postoperative delirium and postoperative cognitive decline. We hypothesized that mineralization-related hypointensity in susceptibility-weighted magnetic resonance imaging (SWI) is associated with postoperative delirium and cognitive decline. In an exploratory, hypothesis-generating study, we analysed a subsample of cognitively healthy patients ≥65 years who underwent SWI before (N = 65) and 3 months after surgery (N = 33). We measured relative SWI intensities in the basal ganglia, hippocampus and posterior basal forebrain cholinergic system (pBFCS). A post hoc analysis of two pBFCS subregions (Ch4, Ch4p) was conducted. Patients were screened for delirium until the seventh postoperative day. Cognitive testing was performed before and 3 months after surgery. Fourteen patients developed delirium. After adjustment for age, sex, preoperative cognition and region volume, only pBFCS hypointensity was associated with delirium (regression coefficient [90% CI]: B = -15.3 [-31.6; -0.8]). After adjustments for surgery duration, age, sex and region volume, perioperative change in relative SWI intensities of the pBFCS was associated with cognitive decline 3 months after surgery at a trend level (B = 6.8 [-0.9; 14.1]), which was probably driven by a stronger association in subregion Ch4p (B = 9.3 [2.3; 16.2]). Brain mineralization, particularly in the cerebral cholinergic system, could be a pathomechanism in postoperative delirium and cognitive decline. Evidence from our studies is limited because of the small sample and a SWI dataset unfit for iron quantification, and the analyses presented here should be considered exploratory.

Cognitive reserve and the risk of postoperative neurocognitive disorders in older age.

Background: Postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) are postoperative neurocognitive disorders (PNDs) that frequently occur in the aftermath of a surgical intervention. Cognitive reserve (CR) is a concept posited to explain why cognitive health varies between individuals. On this qualitative understanding of cognitive health, factors like IQ, education level, and occupational complexity can affect the impact of neuropathological processes on cognitive outcomes. Methods: We investigated the association between CR and POD and CR and POCD on data from 713 patients aged≥65 years with elective surgery. Peak pre-morbid IQ was estimated from vocabulary. Occupational complexity was coded according to the Dictionary of Occupational Titles (DOT). Education level was classed according to the International Standard Classification of Education (ISCED). These three factors were used as proxies of CR. In a series of regression models, age, sex, depression, site of surgery, and several lifestyle and vascular factors were controlled for. Results: Patients with a higher IQ had lower odds of developing POD. We found no significant association between the other two CR markers with POD. None of the CR markers was associated with POCD. Conclusion: The significant association of a higher IQ with lower POD risk allows for the stratification of elderly surgical patients by risk. This knowledge can aid the prevention and/or early detection of POD. Further research should attempt to determine the lack of associations of CR markers with POCD in our study.