A pilot study of longitudinal changes in neurocognition, white matter hyperintensities, and cortical thickness in atrial fibrillation patients following catheter ablation vs medical management.

Background: Cerebral microembolization and atrophy complicate atrial fibrillation (AF). Objectives: We aimed to compare changes in neuroimaging findings between AF patients treated with catheter ablation and those treated with medical therapy. Methods: In this pilot study, we evaluated differences in the change in regional white matter hyperintensity burden (WMHb) and cognitive function from baseline to 6 weeks and 1 year in patients treated with AF ablation (n = 12) and patients treated with medical management alone (n = 11). Change in cortical thickness over time in Alzheimer's disease (AD) risk, aging-associated, and shared AD risk/aging regions was also compared between groups. Results: The mean age was 69.7 ± 5.0 years, 78% of patients were male, 39% had persistent AF, and all received oral anticoagulation. There were no significant differences between groups in the change in cognitive function. At 6 weeks, there were no significant differences in periventricular WMHb changes between groups (0.00 vs 0.04, P = .12), but changes in attention/concentration were inversely correlated with periventricular (P = .01) and total (P = .03) WMHb. Medical management patients demonstrated significantly greater cortical thinning in AD risk regions from baseline to 1 year (P = .003). Conclusions: AF patients who underwent ablation demonstrated less cortical thinning in regions associated with AD risk than patients treated with medical therapy. Larger, prospective studies are needed to better understand the relationship between AF therapies and the development of cognitive decline.

Next-generation sequencing data show rapid radiation and several long-distance dispersal events in early Costaceae.

The monocot family Costaceae Nakai consists of seven genera but their mutual relationships have not been satisfactorily resolved in previous studies employing classical molecular markers. Phylogenomic analyses of 365 nuclear genes and nearly-complete plastome data provide almost fully resolved insights into their diversification. Paracostus is identified as sister to all other taxa, followed by several very short branches leading to discrete lineages, suggesting an ancient rapid radiation of these early lineages and leaving the exact relationships among them unresolved. Relationships among Chamaecostus, Dimerocostus and Monocostus confirmed earlier findings that these genera form a monophyletic group. The Afro-American Costus is also monophyletic. By contrast, Tapeinochilos appeared as a well-supported crown lineage of Cheilocostus rendering it paraphyletic. As these two genera differ morphologically from one another owing to a shift from insect- to bird-pollination, we propose to keep both names. The divergence time within Costaceae was estimated using penalized likelihood utilizing two fossils within Zingiberales, †Spirematospermum chandlerae and †Ensete oregonense, indicated a relatively recent diversification of Costaceae, between 18 and 9 Mya. Based on these data, the current pantropical distribution of the family is hypothesized to be the result of several long-distance intercontinental dispersal events, which do not correlate with global geoclimatic changes.

A Draft Genome of the Ginger Species Alpinia nigra and New Insights into the Genetic Basis of Flexistyly.

Angiosperms possess various strategies to ensure reproductive success, such as stylar polymorphisms that encourage outcrossing. Here, we investigate the genetic basis of one such dimorphism that combines both temporal and spatial separation of sexual function, termed flexistyly. It is a floral strategy characterised by the presence of two morphs that differ in the timing of stylar movement. We performed a de novo assembly of the genome of Alpinia nigra using high-depth genomic sequencing. We then used Pool-seq to identify candidate regions for flexistyly based on allele frequency or coverage differences between pools of anaflexistylous and cataflexistylous morphs. The final genome assembly size was 2 Gb, and showed no evidence of recent polyploidy. The Pool-seq did not reveal large regions with high FST values, suggesting large structural chromosomal polymorphisms are unlikely to underlie differences between morphs. Similarly, no region had a 1:2 mapping depth ratio which would be indicative of hemizygosity. We propose that flexistyly is governed by a small genomic region that might be difficult to detect with Pool-seq, or a complex genomic region that proved difficult to assemble. Our genome will be a valuable resource for future studies of gingers, and provides the first steps towards characterising this complex floral phenotype.

First molecular phylogenetic insights into the evolution of Eriocaulon (Eriocaulaceae, Poales).

Eriocaulon is a genus of c. 470 aquatic and wetland species of the monocot plant family Eriocaulaceae. It is widely distributed in Africa, Asia and America, with centres of species richness in the tropics. Most species of Eriocaulon grow in wetlands although some inhabit shallow rivers and streams with an apparent adaptive morphology of elongated submerged stems. In a previous molecular phylogenetic hypothesis, Eriocaulon was recovered as sister of the African endemic genus Mesanthemum. Several regional infrageneric classifications have been proposed for Eriocaulon. This study aims to critically assess the existing infrageneric classifications through phylogenetic reconstruction of infrageneric relationships, based on DNA sequence data of four chloroplast markers and one nuclear marker. There is little congruence between our molecular results and previous morphology-based infrageneric classifications. However, some similarities can be found, including Fyson's sect. Leucantherae and Zhang's sect. Apoda. Further phylogenetic studies, particularly focusing on less well sampled regions such as the Neotropics, will help provide a more global overview of the relationships in Eriocaulon and may enable suggesting the first global infrageneric classification.

Securing a Network for a Research-Intensive, Referral Academic Medical Center: University of Kentucky HealthCare as a Case Study.

Over the last 15 years, UK HealthCare, the clinical enterprise of the University of Kentucky, has undertaken 3 clinical strategic plans to secure its position as a research-intensive, referral academic medical center. The first plan, titled Securing the Traditional Marketplace (2005-2010), focused on building advanced subspecialty programs on campus while pursuing partnerships with providers in UK HealthCare's traditional marketplace, eastern Kentucky. The second plan, Expanding the Footprint (2010-2015), recognized that UK HealthCare needed to cover a population base of 5 to 10 million people to support its subspecialty programs. These 2 strategic plans were successful and achieved 4 outcomes: a doubling of annual discharges, a dramatic increase of transfers/external referrals, a significant increase in the case mix index, and impressive growth in subspecialty programs. The third clinical strategic plan, Preparing for Change (2015-2020), has expanded UK HealthCare's gains in the face of rapidly changing reimbursement systems and delivery models. The pillars of this plan are responding to consumerism, strengthening hallmark programs through service lines, "hard wiring" relationships with partnering organizations including establishing the Kentucky Health Collaborative, and building infrastructure to deal with risk-based reimbursement. UK HealthCare is trying to spearhead a rational system of care for Kentucky rather than a system that rations care. Halfway through the third clinical strategic plan, UK HealthCare has seen increased discharges, transfers, and clinical expansion in its hallmark programs, building evidence that well-thought business practices can lead to improved public policy.

Typification of names in Kaempferia (Zingiberaceae) in the flora of Cambodia, Laos and Vietnam.

Neotypes are designated for five names in Kaempferia (Zingiberaceae) from Lao PDR, namely K.attapeuensis Picheans. & Koonterm, K.champasakensis Picheans. & Koonterm, K.gigantiphylla Picheans. & Koonterm, K.sawanensis Picheans. & Koonterm and K.xiengkhouangensis Picheans. & Phokham.

Intravenous Lidocaine Does Not Improve Neurologic Outcomes after Cardiac Surgery: A Randomized Controlled Trial.

BACKGROUND: Cognitive decline after cardiac surgery occurs frequently and persists in a significant proportion of patients. Preclinical studies and human trials suggest that intravenous lidocaine may confer protection in the setting of neurologic injury. It was hypothesized that lidocaine administration would reduce cognitive decline after cardiac surgery compared to placebo. METHODS: After institutional review board approval, 478 patients undergoing cardiac surgery were enrolled into this multicenter, prospective, randomized, double-blinded, placebo-controlled, parallel group trial. Subjects were randomized to lidocaine 1 mg/kg bolus after the induction of anesthesia followed by a continuous infusion (48 µg · kg · min for the first hour, 24 µg · kg · min for the second hour, and 10 µg · kg · min for the next 46 h) or saline with identical volume and rate changes to preserve blinding. Cognitive function was assessed preoperatively and at 6 weeks and 1 yr postoperatively using a standard neurocognitive test battery. The primary outcome was change in cognitive function between baseline and 6 weeks postoperatively, adjusting for age, years of education, baseline cognition, race, and procedure type. RESULTS: Among the 420 allocated subjects who returned for 6-week follow-up (lidocaine: N = 211; placebo: N = 209), there was no difference in the continuous cognitive score change (adjusted mean difference [95% CI], 0.02 (-0.05, 0.08); P = 0.626). Cognitive deficit (greater than 1 SD decline in at least one cognitive domain) at 6 weeks occurred in 41% (87 of 211) in the lidocaine group versus 40% (83 of 209) in the placebo group (adjusted odds ratio [95% CI], 0.94 [0.63, 1.41]; P = 0.766). There were no differences in any quality of life outcomes between treatment groups. At the 1-yr follow-up, there continued to be no difference in cognitive score change, cognitive deficit, or quality of life. CONCLUSIONS: Intravenous lidocaine administered during and after cardiac surgery did not reduce postoperative cognitive decline at 6 weeks.

Longitudinal Changes in Regional Cerebral Perfusion and Cognition After Cardiac Operation.

BACKGROUND: Cardiac operation has been associated with increased risk of postoperative cognitive decline, as well as dementia risk in the general population. Few studies, however, have examined the impact of coronary revascularization or valve replacement or repair operation on longitudinal cerebral perfusion changes or their association with cognitive function. METHODS: We examined longitudinal changes in cerebral perfusion among 54 individuals with cardiac disease; 27 undergoing cardiac operation and 27 matched control patients. Arterial spin labeling magnetic resonance perfusion imaging was used to quantify cerebral blood flow within the anterior communicating artery, middle cerebral artery (MCA), and posterior communicating artery vascular territories before operation and postoperatively at 6 weeks and 1 year. Cognitive performance was examined during the same intervals by using a battery of tests that tapped memory, executive, information processing and upper extremity motor functions. Repeated measures, mixed models were used to examine for perfusion changes and the association between perfusion changes and cognition. RESULTS: Significant postoperative increases in perfusion were observed at 6 weeks within the MCA vascular territory after cardiac operation (p = 0.035 for interaction). Perfusion changes were most notable in distal territories of the MCA and posterior communicating artery at 6 weeks, with no additional changes at 1 year. Postoperative increases in MCA perfusion at 6 weeks were associated with improved psychomotor speed (ß = 0.35, p = 0.016), whereas no important differences were found between the groups in vascular territory perfusion and cognition at 1 year. CONCLUSIONS: Cardiac operation is associated with important short-term increases in MCA perfusion with associated improvements in psychomotor speed.

Dual antiplatelet therapy for perioperative myocardial infarction following CABG surgery.

OBJECTIVES: Perioperative myocardial infarction (MI) after coronary artery bypass graft surgery (CABG) has been associated with adverse outcome. Whether perioperative MI should be treated with dual antiplatelet therapy (DAPT) is unknown. We compared the effect of DAPT versus aspirin alone on short-term outcomes among patients with perioperative MI following CABG. METHODS: We used data from 3 clinical trials that enrolled patients undergoing isolated CABG: PREVENT IV (2002-2003), MEND-CABG II (2004-2005), and RED-CABG (2009-2010) (n = 9117). Perioperative MI was defined as CK-MB >5 times the upper limit of normal within 24 h of surgery (n = 2052). DAPT was defined as DAPT given after surgery and prior to discharge. A Cox regression model was used to assess the association between DAPT and 30-day nonfatal MI, stroke, or mortality after adjustment for baseline covariates. RESULTS: DAPT (n = 527) and aspirin alone (n = 1525) cohorts were similar in baseline comorbidities. Off pump bypass was used in 5.2% (n = 106) of patients. There was no difference in the 30-day composite of death, MI or stroke between patients receiving DAPT versus aspirin alone, nor in any of the individual components. There were fewer all-cause re-hospitalizations at 30 days following surgery among patients in the DAPT group (adjusted HR 0.71, CI 0.52-0.97, P = .033). CONCLUSION: One-quarter of CABG patients who had perioperative MI were treated with DAPT. DAPT was not associated with a difference in MI, stroke, or mortality at 30 days, but was associated with fewer re-hospitalizations. Further studies are needed to determine the optimal antiplatelet regimen following perioperative MI. What is already known about this subject? Perioperative myocardial infarction portends poor outcome but optimal management is currently unclear. While dual antiplatelet therapy is standard of care for acute coronary syndrome, its role in perioperative myocardial infarction is unknown. What does this study add? Dual antiplatelet therapy use during perioperative myocardial infarction was not associated with a difference in myocardial infarction, stroke or mortality at 30 days. It was, however, associated with fewer re-hospitalizations at 30 days. How might this impact on clinical practice? Dual antiplatelet therapy may be a potential treatment option for perioperative myocardial infarction after CABG surgery. Further studies are needed to better understand treatment for this disease process.

Neurocognitive Function after Cardiac Surgery: From Phenotypes to Mechanisms.

For half a century, it has been known that some patients experience neurocognitive dysfunction after cardiac surgery; however, defining its incidence, course, and causes remains challenging and controversial. Various terms have been used to describe neurocognitive dysfunction at different times after cardiac surgery, ranging from "postoperative delirium" to "postoperative cognitive dysfunction or decline." Delirium is a clinical diagnosis included in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Postoperative cognitive dysfunction is not included in the DSM-5 and has been heterogeneously defined, though a recent international nomenclature effort has proposed standardized definitions for it. Here, the authors discuss pathophysiologic mechanisms that may underlie these complications, review the literature on methods to prevent them, and discuss novel approaches to understand their etiology that may lead to novel treatment strategies. Future studies should measure both delirium and postoperative cognitive dysfunction to help clarify the relationship between these important postoperative complications.

Predictive ability of perioperative atrial fibrillation risk indices in cardiac surgery patients: a retrospective cohort study.

PURPOSE: The Multicenter Study of Perioperative Ischemia (McSPI) AFRisk index predicts postoperative atrial fibrillation (POAF) after cardiac surgery, but requires pre-, intra-, and postoperative data. Other more abbreviated risk indices exist, but there is no consensus on which risk index is optimal. We compared the discriminatory capacity of the McSPI AFRisk index with three indices containing only preoperative data (the CHA2DS2Vasc score, POAF score, and Kolek clinical risk prediction model), hypothesizing that the McSPI AFRisk index would have superior predictive capacity. METHODS: We retrospectively evaluated 783 patients undergoing cardiac surgery using cardiopulmonary bypass. The predictive capacity of each index was assessed by comparing receiver-operating characteristic (ROC) curves, scaled Brier scores, net reclassification indices, and the integrated discrimination indices. RESULTS: The incidence of POAF was 32.6%. The area under the curve (AUC) of the ROC curve were 0.77, 0.58, 0.66, and 0.66 for the McSPI AFRisk index, CHA2DS2Vasc score, POAF score, and Kolek clinical risk prediction model, respectively. The McSPI AFRIsk index had the highest AUC (P < 0.0001). The scaled Brier scores for the McSPI AFRisk index, CHA2DS2Vasc score, POAF score, and Kolek clinical risk prediction model were 0.23, 0.02, 0.08, and 0.07, respectively. Both net reclassification indices and integrated discrimination indices showed that the McSPI AFRisk index more appropriately identified patients at high risk of POAF. CONCLUSIONS: The McSPI AFRisk index showed superior ability to predict POAF after cardiac surgery compared with three other indices. When clinicians and investigators wish to measure the risk of POAF after cardiac surgery, they should consider using the McSPI AFRisk index.

18F-florbetapir Positron Emission Tomography-determined Cerebral ß-Amyloid Deposition and Neurocognitive Performance after Cardiac Surgery.

BACKGROUND: Amyloid deposition is a potential contributor to postoperative cognitive dysfunction. The authors hypothesized that 6-week global cortical amyloid burden, determined by F-florbetapir positron emission tomography, would be greater in those patients manifesting cognitive dysfunction at 6 weeks postoperatively. METHODS: Amyloid deposition was evaluated in cardiac surgical patients at 6 weeks (n = 40) and 1 yr (n = 12); neurocognitive function was assessed at baseline (n = 40), 6 weeks (n = 37), 1 yr (n = 13), and 3 yr (n = 9). The association of 6-week amyloid deposition with cognitive dysfunction was assessed by multivariable regression, accounting for age, years of education, and baseline cognition. Differences between the surgical cohort with cognitive deficit and the Alzheimer's Disease Neuroimaging Initiative cohorts (normal and early/late mild cognitive impairment) was assessed, adjusting for age, education, and apolipoprotein E4 genotype. RESULTS: The authors found that 6-week abnormal global cortical amyloid deposition was not associated with cognitive dysfunction (13 of 37, 35%) at 6 weeks postoperatively (median standard uptake value ratio [interquartile range]: cognitive dysfunction 0.92 [0.89 to 1.07] vs. 0.98 [0.93 to 1.05]; P = 0.455). In post hoc analyses, global cortical amyloid was also not associated with cognitive dysfunction at 1 or 3 yr postoperatively. Amyloid deposition at 6 weeks in the surgical cohort was not different from that in normal Alzheimer's Disease Neuroimaging Initiative subjects, but increased over 1 yr in many areas at a rate greater than in controls. CONCLUSIONS: In this study, postoperative cognitive dysfunction was not associated with 6-week cortical amyloid deposition. The relationship between cognitive dysfunction and regional amyloid burden and the rate of postoperative amyloid deposition merit further investigation.

Task-related changes in degree centrality and local coherence of the posterior cingulate cortex after major cardiac surgery in older adults.

OBJECTIVES: Older adults often display postoperative cognitive decline (POCD) after surgery, yet it is unclear to what extent functional connectivity (FC) alterations may underlie these deficits. We examined for postoperative voxel-wise FC changes in response to increased working memory load demands in cardiac surgery patients and nonsurgical controls. EXPERIMENTAL DESIGN: Older cardiac surgery patients (n = 25) completed a verbal N-back working memory task during MRI scanning and cognitive testing before and 6 weeks after surgery; nonsurgical controls with cardiac disease (n = 26) underwent these assessments at identical time intervals. We measured postoperative changes in degree centrality, the number of edges attached to a brain node, and local coherence, the temporal homogeneity of regional functional correlations, using voxel-wise graph theory-based FC metrics. Group × time differences were evaluated in these FC metrics associated with increased N-back working memory load (2-back > 1-back), using a two-stage partitioned variance, mixed ANCOVA. PRINCIPAL OBSERVATIONS: Cardiac surgery patients demonstrated postoperative working memory load-related degree centrality increases in the left dorsal posterior cingulate cortex (dPCC; p < .001, cluster p-FWE < .05). The dPCC also showed a postoperative increase in working memory load-associated local coherence (p < .001, cluster p-FWE < .05). dPCC degree centrality and local coherence increases were inversely associated with global cognitive change in surgery patients (p < .01), but not in controls. CONCLUSIONS: Cardiac surgery patients showed postoperative increases in working memory load-associated degree centrality and local coherence of the dPCC that were inversely associated with postoperative global cognitive outcomes and independent of perioperative cerebrovascular damage.

The Effect of Propofol vs. Isoflurane Anesthesia on Postoperative Changes in Cerebrospinal Fluid Cytokine Levels: Results from a Randomized Trial.

INTRODUCTION: Aside from direct effects on neurotransmission, inhaled and intravenous anesthetics have immunomodulatory properties. In vitro and mouse model studies suggest that propofol inhibits, while isoflurane increases, neuroinflammation. If these findings translate to humans, they could be clinically important since neuroinflammation has detrimental effects on neurocognitive function in numerous disease states. MATERIALS AND METHODS: To examine whether propofol and isoflurane differentially modulate neuroinflammation in humans, cytokines were measured in a secondary analysis of cerebrospinal fluid (CSF) samples from patients prospectively randomized to receive anesthetic maintenance with propofol vs. isoflurane (registered with http://www.clinicaltrials.gov, identifier NCT01640275). We measured CSF levels of EGF, eotaxin, G-CSF, GM-CSF, IFN-α2, IL-1RA, IL-6, IL-7, IL-8, IL-10, IP-10, MCP-1, MIP-1α, MIP-1ß, and TNF-α before and 24 h after intracranial surgery in these study patients. RESULTS: After Bonferroni correction for multiple comparisons, we found significant increases from before to 24 h after surgery in G-CSF, IL-10, IL-1RA, IL-6, IL-8, IP-10, MCP-1, MIP-1α, MIP-1ß, and TNF-α. However, we found no difference in cytokine levels at baseline or 24 h after surgery between propofol- (n = 19) and isoflurane-treated (n = 21) patients (p > 0.05 for all comparisons). Increases in CSF IL-6, IL-8, IP-10, and MCP-1 levels directly correlated with each other and with postoperative CSF elevations in tau, a neural injury biomarker. We observed CSF cytokine increases up to 10-fold higher after intracranial surgery than previously reported after other types of surgery. DISCUSSION: These data clarify the magnitude of neuroinflammation after intracranial surgery, and raise the possibility that a coordinated neuroinflammatory response may play a role in neural injury after surgery.

Resting-State Functional Connectivity and Cognition After Major Cardiac Surgery in Older Adults without Preoperative Cognitive Impairment: Preliminary Findings.

OBJECTIVES: To look for changes in intrinsic functional brain connectivity associated with postoperative changes in cognition, a common complication in seniors undergoing major surgery, using resting-state functional magnetic resonance imaging. DESIGN: Objective cognitive testing and functional brain imaging were prospectively performed at preoperative baseline and 6 weeks after surgery and at the same time intervals in nonsurgical controls. SETTING: Academic medical center. PARTICIPANTS: Older adults undergoing cardiac surgery (n = 12) and nonsurgical older adult controls with a history of coronary artery disease (n = 12); no participants had cognitive impairment at preoperative baseline (Mini-Mental State Examination score >27). MEASUREMENTS: Differences in resting-state functional connectivity (RSFC) and global cognitive change relationships were assessed using a voxel-wise intrinsic connectivity method, controlling for demographic factors and pre- and perioperative cerebral white matter disease volume. Analyses were corrected for multiple comparisons (false discovery rate P < .01). RESULTS: Global cognitive change after cardiac surgery was significantly associated with intrinsic RSFC changes in regions of the posterior cingulate cortex and right superior frontal gyrus-anatomical and functional locations of the brain's default mode network (DMN). No statistically significant relationships were found between global cognitive change and RSFC change in nonsurgical controls. CONCLUSION: Clinicians have long known that some older adults develop postoperative cognitive dysfunction (POCD) after anesthesia and surgery, yet the neurobiological correlates of POCD are not well defined. The current results suggest that altered RSFC in specific DMN regions is positively correlated with global cognitive change 6 weeks after cardiac surgery, suggesting that DMN activity and connectivity could be important diagnostic markers of POCD or intervention targets for potential POCD treatment efforts.

Effect of intravenous lidocaine on the transcerebral inflammatory response during cardiac surgery: a randomized-controlled trial.

PURPOSE: Postoperative cognitive dysfunction (POCD) occurs frequently after cardiac surgery. The pathophysiology of POCD remains elusive, but previous work showed that intravenous lidocaine may be protective against POCD, possibly by modulating cerebral inflammation. We hypothesized that intravenous lidocaine would attenuate the cerebral inflammatory response to cardiopulmonary bypass (CPB) by reducing the transcerebral activation gradients of platelets, leukocytes, and/or platelet-leukocyte conjugates. METHODS: We studied 202 patients undergoing cardiac surgery with CPB in this prospective randomized double-blinded placebo-controlled trial. Subjects were randomized to receive either intravenous lidocaine (bolus + 48-hr infusion) or placebo (identical infusion volume and duration). Paired jugular venous and radial arterial blood samples were drawn at several time points and analyzed by fluorescence-activated cell sorting to identify activated platelets and platelet-leukocyte conjugates. Transcerebral activation gradients were calculated by subtracting arterial values from venous values and were compared between groups using repeated measures regression models with covariate adjustment for age, sex, surgery type, and CPB duration. RESULTS: Beginning after aortic cross-clamp release and peaking ten minutes after the termination of CPB, the mean (SD) transcerebral activation gradient of platelet-monocyte conjugates decreased in lidocaine-treated vs placebo-treated patients [-1.84 (11.47) mean linear fluorescence intensity (MLFI) vs 1.46 (13.88) MLFI, respectively; mean difference, -4.08 MLFI; 95% confidence interval, -7.86 to -0.29; P = 0.03). No difference was seen at any time point for activated platelets or for platelet-neutrophil conjugates. CONCLUSION: While lidocaine did not affect the systemic or transcerebral activation of platelets or leukocytes, we did observe a reduction in the transcerebral activation of platelet-monocyte conjugates after aortic cross-clamp release. This may be a manifestation of reduced cerebral inflammation during cardiopulmonary bypass in response to treatment with lidocaine. This trial was registered at ClinicalTrials.gov (NCT00938964).

The Effect of Propofol Versus Isoflurane Anesthesia on Human Cerebrospinal Fluid Markers of Alzheimer's Disease: Results of a Randomized Trial.

BACKGROUND: Preclinical studies have found differential effects of isoflurane and propofol on the Alzheimer's disease (AD)-associated markers tau, phosphorylated tau (p-tau) and amyloid-ß (Aß). OBJECTIVE: We asked whether isoflurane and propofol have differential effects on the tau/Aß ratio (the primary outcome), and individual AD biomarkers. We also examined whether genetic/intraoperative factors influenced perioperative changes in AD biomarkers. METHODS: Patients undergoing neurosurgical/otolaryngology procedures requiring lumbar cerebrospinal fluid (CSF) drain placement were prospectively randomized to receive isoflurane (n = 21) or propofol (n = 18) for anesthetic maintenance. We measured perioperative CSF sample AD markers, performed genotyping assays, and examined intraoperative data from the electronic anesthesia record. A repeated measures ANOVA was used to examine changes in AD markers by anesthetic type over time. RESULTS: The CSF tau/Aß ratio did not differ between isoflurane- versus propofol-treated patients (p = 1.000). CSF tau/Aß ratio and tau levels increased 10 and 24 h after drain placement (p = 2.002×10-6 and p = 1.985×10-6, respectively), mean CSF p-tau levels decreased (p = 0.005), and Aß levels did not change (p = 0.152). There was no interaction between anesthetic treatment and time for any of these biomarkers. None of the examined genetic polymorphisms, including ApoE4, were associated with tau increase (n = 9 polymorphisms, p > 0.05 for all associations). CONCLUSION: Neurosurgery/otolaryngology procedures are associated with an increase in the CSF tau/Aß ratio, and this increase was not influenced by anesthetic type. The increased CSF tau/Aß ratio was largely driven by increases in tau levels. Future work should determine the functional/prognostic significance of these perioperative CSF tau elevations.