Miles Berger

All Publications

• 2025 American Society of Anesthesiologists Practice Advisory for Perioperative Care of Older Adults Scheduled for Inpatient Surgery. Anesthesiology Sieber, F., McIsaac, D. I., Deiner, S., Azefor, T., Berger, M., Hughes, C., Leung, J. M., Maldon, J., McSwain, J. R., Neuman, M. D., Russell, M. M., Tang, V., Whitlock, E., Whittington, R., Marbella, A. M., Agarkar, M., Ramirez, S., Dyer, A., Friel Blanck, J., Uhl, S., Grant, M. D., Domino, K. B. 2025; 142 (1): 22-51

  View details for DOI 10.1097/ALN.0000000000005172

  View details for PubMedID 39655991

• Corrigendum to "A real-time neurophysiologic stress test for the aging brain: Novel perioperative and ICU applications of EEG in older surgical patients" Neurotherapeutics 20 (4) (2023) 975-1000. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics Berger, M., Ryu, D., Reese, M., McGuigan, S., Evered, L. A., Price, C. C., Scott, D. A., Westover, M. B., Eckenhoff, R., Bonanni, L., Sweeney, A., Babiloni, C. 2024: e00473

  View details for DOI 10.1016/j.neurot.2024.e00473

  View details for PubMedID 39482181

• Potential risks of nonoperative management of appendicitis in high-risk patients. Surgery Lunardi, N., Thornton, M., Zarzaur, B. L., Agarwal, S., Berger, M., Sharath, S., Kougias, P., Bhat, S., Frank, K., Pham, T. H., Balentine, C. J. 2024

  Abstract

  INTRODUCTION: The popularity of nonoperative management for acute appendicitis is based on the untested assumption that it offers a lower risk alternative to surgery in patients who are at high risk for morbidity and mortality with appendectomy. We hypothesized that patients who were at a high risk with appendectomy would also be at a high risk for complications following nonoperative management.METHODS: This is a retrospective cohort study of patients with acute, uncomplicated appendicitis in the 2004-2017 National Inpatient Sample. We used a logistic regression model to predict the risk of morbidity or mortality following appendectomy and applied this model to predict the risk of patients managed nonoperatively. High risk was defined as ≥2 standard deviations above the mean predicted risk of morbidity or mortality. We used inverse probability weighting of the propensity score to compare outcomes of nonoperative versus operative management for high-risk patients.RESULTS: The sample included 21,242 high-risk patients with a median age of 68years (interquartile range 57-78), and 31% were managed nonoperatively. Compared to surgery, nonoperative management was associated with a 9% decrease in complications (95% confidence interval [CI] 7%-10%), 2% increase in mortality (95% CI 2%-3%), $10,202 increase in hospital costs (95% CI $9,065-$11,339), 3-day increase in length of stay (95% CI 2-3), and 9% greater likelihood of discharge to skilled nursing facilities (95% CI 8%-10%).CONCLUSION: Nonoperative management of acute appendicitis in high-risk patients may reduce morbidity but increase mortality, duration of hospitalization, discharge to skilled facility, and costs. Surgeons should exercise caution when considering nonoperative management in these vulnerable patients.

  View details for DOI 10.1016/j.surg.2024.08.022

  View details for PubMedID 39327128

• Multi-level social determinants of health, inflammation, and postoperative delirium in older adults JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Vasunilashorn, S. M., Wolfson, E., Berger, M., Leung, J., Ware, E. B., Baccarelli, A., Jones, R. N., Ngo, L. H., Marcantonio, E. R., Inouye, S. K., Kind, A. H. 2024

  View details for DOI 10.1111/jgs.19159

  View details for Web of Science ID 001300732000001

  View details for PubMedID 39206865

• Prediction of Post-Operative Delirium in Older Adults from Preoperative Cognition and Alpha Power from Resting-State EEG. medRxiv : the preprint server for health sciences Ning, M., Rodionov, A., Ross, J. M., Ozdemir, R. A., Burch, M., Lian, S. J., Alsop, D., Cavallari, M., Dickerson, B. C., Fong, T. G., Jones, R. N., Libermann, T. A., Marcantonio, E. R., Santarnecchi, E., Schmitt, E. M., Touroutoglou, A., Travison, T. G., Acker, L., Reese, M., Sun, H., Westover, B., Berger, M., Pascual-Leone, A., Inouye, S. K., Shafi, M. M., SAGES II Study Group and the INTUIT/PRIME Study Groups 2024

  Abstract

  Postoperative Delirium (POD) is the most common complication following surgery among older adults, and has been consistently associated with increased mortality and morbidity, cognitive decline, and loss of independence, as well as markedly increased health-care costs. The development of new tools to identify individuals at high risk for POD could guide clinical decision-making and enable targeted interventions to potentially decrease delirium incidence and POD-related complications. In this study, we used machine learning techniques to evaluate whether baseline (pre-operative) cognitive function and resting-state electroencephalography could be used to identify patients at risk for POD. Pre-operative resting-state EEGs and the Montreal Cognitive Assessment (MoCA) were collected from 85 patients (age = 73 ± 6.4 years) undergoing elective surgery, 12 of whom subsequently developed POD. The model with the highest f1-score for predicting delirium, a linear-discriminant analysis (LDA) model incorporating MoCA scores and occipital alpha-band EEG features, was subsequently validated in an independent, prospective cohort of 51 older adults (age ≥ 60) undergoing elective surgery, 6 of whom developed POD. The LDA-based model, with a total of 7 features, was able to predict POD with area under the receiver operating characteristic curve, specificity and accuracy all >90%, and sensitivity > 80%, in the validation cohort. Notably, models incorporating both resting-state EEG and MoCA scores outperformed those including either EEG or MoCA alone. While requiring prospective validation in larger cohorts, these results suggest that prediction of POD with high accuracy may be feasible in clinical settings using simple and widely available clinical tools.

  View details for DOI 10.1101/2024.08.15.24312053

  View details for PubMedID 39185530

• Anesthesia Dose and Delirium-A Picture Coming Into Focus JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Berger, M., Neuman, M. D. 2024; 332 (2): 107-108

  View details for DOI 10.1001/jama.2023.26819

  View details for Web of Science ID 001247598800003

  View details for PubMedID 38857024

• Cognitive and Cerebrospinal Fluid Alzheimer's Disease-related Biomarker Trajectories in Older Surgical Patients and Matched Nonsurgical Controls ANESTHESIOLOGY Reese, M., Wong, M. K., Cheong, V., Ha, C. I., Wright, M., Browndyke, J., Moretti, E., Devinney, M. J., Habib, A. S., Moul, J. W., Shaw, L. M., Waligorska, T., Whitson, H. E., Cohen, H. J., Welsh-Bohmer, K. A., Plassman, B. L., Mathew, J. P., Berger, M., Markers Alzheimers Dis 2024; 140 (5): 963-978

  Abstract

  Anesthesia and/or surgery accelerate Alzheimer's disease pathology and cause memory deficits in animal models, yet there is a lack of prospective data comparing cerebrospinal fluid (CSF) Alzheimer's disease-related biomarker and cognitive trajectories in older adults who underwent surgery versus those who have not. Thus, the objective here was to better understand whether anesthesia and/or surgery contribute to cognitive decline or an acceleration of Alzheimer's disease-related pathology in older adults.The authors enrolled 140 patients 60 yr or older undergoing major nonneurologic surgery and 51 nonsurgical controls via strata-based matching on age, sex, and years of education. CSF amyloid β (Aβ) 42, tau, and p-tau-181p levels and cognitive function were measured before and after surgery, and at the same time intervals in controls.The groups were well matched on 25 of 31 baseline characteristics. There was no effect of group or interaction of group by time for baseline to 24-hr or 6-week postoperative changes in CSF Aβ, tau, or p-tau levels, or tau/Aβ or p-tau/Aβ ratios (Bonferroni P > 0.05 for all) and no difference between groups in these CSF markers at 1 yr (P > 0.05 for all). Nonsurgical controls did not differ from surgical patients in baseline cognition (mean difference, 0.19 [95% CI, -0.06 to 0.43]; P = 0.132), yet had greater cognitive decline than the surgical patients 1 yr later (β, -0.31 [95% CI, -0.45 to -0.17]; P < 0.001) even when controlling for baseline differences between groups. However, there was no difference between nonsurgical and surgical groups in 1-yr postoperative cognitive change in models that used imputation or inverse probability weighting for cognitive data to account for loss to follow up.During a 1-yr time period, as compared to matched nonsurgical controls, the study found no evidence that older patients who underwent anesthesia and noncardiac, nonneurologic surgery had accelerated CSF Alzheimer's disease-related biomarker (tau, p-tau, and Aβ) changes or greater cognitive decline.

  View details for DOI 10.1097/ALN.0000000000004924

  View details for Web of Science ID 001235375000022

  View details for PubMedID 38324729

  View details for PubMedCentralID PMC11003848

• Reply to "A Letter Concerning a Role for Blood-Brain Barrier Dysfunction in Delirium following Noncardiac Surgery in Older Adults" ANNALS OF NEUROLOGY Devinney, M. J., Berger, M. 2024; 95 (2): 411-413

  View details for DOI 10.1002/ana.26834

  View details for Web of Science ID 001154093500013

  View details for PubMedID 37994239

  View details for PubMedCentralID PMC11225806

• Preoperative electroencephalographic alpha-power changes with eyes opening are associated with postoperative attention impairment and inattention-related delirium severity BRITISH JOURNAL OF ANAESTHESIA Acker, L., Wong, M. K., Wright, M. C., Reese, M., Giattino, C. M., Roberts, K. C., Au, S., Colon-Emeric, C., Lipsitz, L. A., Devinney, M. J., Browndyke, J., Eleswarpu, S., Moretti, E., Whitson, H. E., Berger, M., Woldorff, M. G., , I. 2024; 132 (1): 154-163

  Abstract

  In the eyes-closed, awake condition, EEG oscillatory power in the alpha band (7-13 Hz) dominates human spectral activity. With eyes open, however, EEG alpha power substantially decreases. Less alpha attenuation with eyes opening has been associated with inattention; thus, we analysed whether reduced preoperative alpha attenuation with eyes opening is associated with postoperative inattention, a delirium-defining feature.Preoperative awake 32-channel EEG was recorded with eyes open and eyes closed in 71 non-neurological, noncardiac surgery patients aged ≥ 60 years. Inattention and other delirium features were assessed before surgery and twice daily after surgery until discharge. Eyes-opening EEG alpha-attenuation magnitude was analysed for associations with postoperative inattention, primarily, and with delirium severity, secondarily, using multivariate age- and Mini-Mental Status Examination (MMSE)-adjusted logistic and proportional-odds regression analyses.Preoperative alpha attenuation with eyes opening was inversely associated with postoperative inattention (odds ratio [OR] 0.73, 95% confidence interval [CI]: 0.57, 0.94; P=0.038). Sensitivity analyses showed an inverse relationship between alpha-attenuation magnitude and inattention chronicity, defined as 'never', 'newly', or 'chronically' inattentive (OR 0.76, 95% CI: 0.62, 0.93; P=0.019). In addition, preoperative alpha-attenuation magnitude was inversely associated with postoperative delirium severity (OR 0.79, 95% CI: 0.65, 0.95; P=0.040), predominantly as a result of the inattention feature.Preoperative awake, resting, EEG alpha attenuation with eyes opening might represent a neural biomarker for risk of postoperative attentional impairment. Further, eyes-opening alpha attenuation could provide insight into the neural mechanisms underlying postoperative inattention risk.

  View details for DOI 10.1016/j.bja.2023.10.037

  View details for Web of Science ID 001165348000001

  View details for PubMedID 38087743

  View details for PubMedCentralID PMC10797508

• Association between surgery and rate of incident dementia in older adults: A population-based retrospective cohort study JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Reich, K. M., Gill, S. S., Eckenhoff, R., Berger, M., Austin, P. C., Rochon, P. A., Nguyen, P., Goodarzi, Z., Seitz, D. P. 2024; 72 (5): 1348-1359

  Abstract

  The risk of incident dementia after surgery in older adults is unclear. The study objective was to examine the rate of incident dementia among older adults after elective surgery compared with a matched nonsurgical control group.We conducted a population-based, propensity-matched retrospective cohort study using data from linked administrative databases in Ontario, Canada. All community-dwelling individuals aged 66 years and older who underwent one of five major elective surgeries between April 1, 2007 and March 31, 2011 were included. Each surgical patient was matched 1:1 on surgical specialty of the surgeon at consultation, age, sex, fiscal year of entry, and propensity score with a patient who attended an outpatient visit with a surgeon of the same surgical specialty but did not undergo surgery. Patients were followed for up to 5 years after cohort entry for the occurrence of a new dementia diagnosis, defined from administrative data. Cause-specific hazard models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for the association between surgery and the hazard of incident dementia. Subgroup and sensitivity analyses were performed.A total of 27,878 individuals (13,939 matched pairs) were included in the analysis. A total of 640 (4.6%) individuals in the surgical group and 965 (6.9%) individuals in the control group developed dementia over the 5-year follow-up period. Individuals who underwent surgery had a reduced rate of incident dementia compared with their matched nonsurgical controls (HR 0.88; 95% CI 0.80-0.97; p = 0.01). This association was persistent in most subgroups and after sensitivity analyses.Elective surgery did not increase the rate of incident dementia when compared with matched nonsurgical controls. This could be an important consideration for patients and surgeons when elective surgery is considered.

  View details for DOI 10.1111/jgs.18736

  View details for Web of Science ID 001134796700001

  View details for PubMedID 38165146

  View details for PubMedCentralID PMC11090718

• Inflammatory changes in the plasma and cerebrospinal fluid of patients with persistent pain and postpartum depression after elective Cesarean delivery: an exploratory prospective cohort study CANADIAN JOURNAL OF ANESTHESIA-JOURNAL CANADIEN D ANESTHESIE Yurashevich, M., Cooter Wright, M., Sims, S. C., Tan, H., Berger, M., Ji, R., Habib, A. S. 2023; 70 (12): 1917-1927

  Abstract

  Severe acute pain after Cesarean delivery increases the risk of developing persistent pain (~20% incidence) and postpartum depression (PPD) (~15% incidence). Both conditions contribute to maternal morbidity and mortality, yet early risk stratification remains challenging. Neuroinflammation has emerged as a key mechanism of persistent pain and depression in nonobstetric populations. Nevertheless, most studies focus on plasma cytokines, and the relationship between plasma and cerebrospinal fluid (CSF) cytokine levels is unclear. Our primary aim was to compare inflammatory marker levels between patients who developed the composite outcome of persistent pain and/or PPD vs those who did not.We recruited term patients with singleton pregnancies undergoing elective Cesarean delivery under neuraxial anesthesia into an exploratory prospective cohort study. We collected baseline demographic, obstetric, and Edinburgh Postnatal Depression Scale information, and performed quantitative sensory tests. Plasma was collected preoperatively and 48 hr postoperatively. In the operating room, 10 mL of CSF was collected, followed by a standardized anesthetic. Intra- and postoperative management were according to standard practice. We obtained Edinburgh Postnatal Depression Scale and pain scores at six weeks and three months after delivery. The primary outcome was persistent pain and/or PPD at three months. We analyzed the difference in inflammatory marker levels between the groups (primary aim) using two-sided Mann-Whitney tests.Eighty participants were enrolled, and 63 patients completed the study; 23 (37%) experienced the primary outcome at three months. Preoperative plasma transforming growth factor beta 1 (TGF-β1) concentration was higher in patients who developed the primary outcome compared with those who did not (median [interquartile range (IQR)], 2,879 [2,241-5,494] vs 2,292 [1,676-2,960] pg·mL-1; P = 0.04), while CSF IL-1β concentration was higher in patients who developed the primary outcome than in those who did not (median [IQR], 0.36 [0.29-0.39] vs 0.30 [0.25-0.35] pg·mL-1; P = 0.03).We observed differential levels of plasma and CSF inflammatory biomarkers in patients who developed persistent pain and PPD compared with those who did not. We showed the feasibility of collecting plasma and CSF samples at Cesarean delivery, which may prove useful for future risk-stratification.ClinicalTrials.gov (NCT04271072); registered 17 February 2020.

  View details for DOI 10.1007/s12630-023-02603-2

  View details for Web of Science ID 001099924000005

  View details for PubMedID 37932648

  View details for PubMedCentralID PMC10842683

• Role of Blood-Brain Barrier Dysfunction in Delirium following Non-cardiac Surgery in Older Adults ANNALS OF NEUROLOGY Devinney, M. J., Wong, M. K., Wright, M., Marcantonio, E. R., Terrando, N., Browndyke, J. N., Whitson, H. E., Cohen, H. J., Nackley, A. G., Klein, M. E., Ely, E., Mathew, J. P., Berger, M., MADCO PC & INTUIT Study Teams 2023; 94 (6): 1024-1035

  Abstract

  Although animal models suggest a role for blood-brain barrier dysfunction in postoperative delirium-like behavior, its role in postoperative delirium and postoperative recovery in humans is unclear. Thus, we evaluated the role of blood-brain barrier dysfunction in postoperative delirium and hospital length of stay among older surgery patients.Cognitive testing, delirium assessment, and cerebrospinal fluid and blood sampling were prospectively performed before and after non-cardiac, non-neurologic surgery. Blood-brain barrier dysfunction was assessed using the cerebrospinal fluid-to-plasma albumin ratio (CPAR).Of 207 patients (median age = 68 years, 45% female) with complete CPAR and delirium data, 26 (12.6%) developed postoperative delirium. Overall, CPAR increased from before to 24 hours after surgery (median change = 0.28, interquartile range [IQR] = -0.48 to 1.24, Wilcoxon p = 0.001). Preoperative to 24 hours postoperative change in CPAR was greater among patients who developed delirium versus those who did not (median [IQR] = 1.31 [0.004 to 2.34] vs 0.19 [-0.55 to 1.08], p = 0.003). In a multivariable model adjusting for age, baseline cognition, and surgery type, preoperative to 24 hours postoperative change in CPAR was independently associated with delirium occurrence (per CPAR increase of 1, odds ratio = 1.30, 95% confidence interval [CI] = 1.03-1.63, p = 0.026) and increased hospital length of stay (incidence rate ratio = 1.15, 95% CI = 1.09-1.22, p < 0.001).Postoperative increases in blood-brain barrier permeability are independently associated with increased delirium rates and postoperative hospital length of stay. Although these findings do not establish causality, studies are warranted to determine whether interventions to reduce postoperative blood-brain barrier dysfunction would reduce postoperative delirium rates and hospital length of stay. ANN NEUROL 2023;94:1024-1035.

  View details for DOI 10.1002/ana.26771

  View details for Web of Science ID 001122271200001

  View details for PubMedID 37615660

  View details for PubMedCentralID PMC10841407

• PD-L1/PD-1 checkpoint pathway regulates hippocampal neuronal excitability and learning and memory behavior NEURON Zhao, J., Bang, S., Furutani, K., Mcginnis, A., Jiang, C., Roberts, A., Donnelly, C. R., He, Q., James, M. L., Berger, M., Ko, M., Wang, H., Palmiter, R. D., Ji, R. 2023; 111 (17): 2709-+

  Abstract

  Programmed death protein 1 (PD-1) and its ligand PD-L1 constitute an immune checkpoint pathway. We report that neuronal PD-1 signaling regulates learning/memory in health and disease. Mice lacking PD-1 (encoded by Pdcd1) exhibit enhanced long-term potentiation (LTP) and memory. Intraventricular administration of anti-mouse PD-1 monoclonal antibody (RMP1-14) potentiated learning and memory. Selective deletion of PD-1 in excitatory neurons (but not microglia) also enhances LTP and memory. Traumatic brain injury (TBI) impairs learning and memory, which is rescued by Pdcd1 deletion or intraventricular PD-1 blockade. Conversely, re-expression of Pdcd1 in PD-1-deficient hippocampal neurons suppresses memory and LTP. Exogenous PD-L1 suppresses learning/memory in mice and the excitability of mouse and NHP hippocampal neurons through PD-1. Notably, neuronal activation suppresses PD-L1 secretion, and PD-L1/PD-1 signaling is distinctly regulated by learning and TBI. Thus, conditions that reduce PD-L1 levels or PD-1 signaling could promote memory in both physiological and pathological conditions.

  View details for DOI 10.1016/j.neuron.2023.05.022

  View details for Web of Science ID 001073943100001

  View details for PubMedID 37348508

  View details for PubMedCentralID PMC10529885

• EEG pre-burst suppression: characterization and inverse association with preoperative cognitive function in older adults FRONTIERS IN AGING NEUROSCIENCE Reese, M., Christensen, S., Anolick, H., Roberts, K. C., Wong, M. K., Wright, M., Acker, L., Browndyke, J. N., Woldorff, M. G., Berger, M., MADCO-PC & INTUIT Investigators 2023; 15: 1229081

  Abstract

  The most common complication in older surgical patients is postoperative delirium (POD). POD is associated with preoperative cognitive impairment and longer durations of intraoperative burst suppression (BSup) - electroencephalography (EEG) with repeated periods of suppression (very low-voltage brain activity). However, BSup has modest sensitivity for predicting POD. We hypothesized that a brain state of lowered EEG power immediately precedes BSup, which we have termed "pre-burst suppression" (preBSup). Further, we hypothesized that even patients without BSup experience these preBSup transient reductions in EEG power, and that preBSup (like BSup) would be associated with preoperative cognitive function and delirium risk. Data included 83 32-channel intraoperative EEG recordings of the first hour of surgery from 2 prospective cohort studies of patients ≥age 60 scheduled for ≥2-h non-cardiac, non-neurologic surgery under general anesthesia (maintained with a potent inhaled anesthetic or a propofol infusion). Among patients with BSup, we defined preBSup as the difference in 3-35 Hz power (dB) during the 1-s preceding BSup relative to the average 3-35 Hz power of their intraoperative EEG recording. We then recorded the percentage of time that each patient spent in preBSup, including those without BSup. Next, we characterized the association between percentage of time in preBSup and (1) percentage of time in BSup, (2) preoperative cognitive function, and (3) POD incidence. The percentage of time in preBSup and BSup were correlated (Spearman's ρ [95% CI]: 0.52 [0.34, 0.66], p < 0.001). The percentage of time in BSup, preBSup, or their combination were each inversely associated with preoperative cognitive function (β [95% CI]: -0.10 [-0.19, -0.01], p = 0.024; -0.04 [-0.06, -0.01], p = 0.009; -0.04 [-0.06, -0.01], p = 0.003, respectively). Consistent with prior literature, BSup was significantly associated with POD (odds ratio [95% CI]: 1.34 [1.01, 1.78], p = 0.043), though this association did not hold for preBSup (odds ratio [95% CI]: 1.04 [0.95, 1.14], p = 0.421). While all patients had ≥1 preBSup instance, only 20.5% of patients had ≥1 BSup instance. These exploratory findings suggest that future studies are warranted to further study the extent to which preBSup, even in the absence of BSup, can identify patients with impaired preoperative cognition and/or POD risk.

  View details for DOI 10.3389/fnagi.2023.1229081

  View details for Web of Science ID 001066341900001

  View details for PubMedID 37711992

  View details for PubMedCentralID PMC10499509

• Awake Spinal Fusion Is Associated with Reduced Length of Stay, Opioid Use, and Time to Ambulation Compared to General Anesthesia: A Matched Cohort Study WORLD NEUROSURGERY Sykes, D. W., Tabarestani, T. Q., Chaudhry, N. S., Salven, D. S., Shaffrey, C. I., Bullock, W., Guinn, N. R., Gadsden, J., Berger, M., Abd-El-Barr, M. M. 2023; 176: E91-E100

  Abstract

  There is increasing interest in performing awake spinal fusion under spinal anesthesia (SA). Evidence supporting SA has been positive, albeit limited. The authors set out to investigate the effects of SA versus general anesthesia (GA) for spinal fusion procedures on length of stay (LOS), opioid use, time to ambulation (TTA), and procedure duration.The authors performed a retrospective review of a single surgeon's patients who underwent lumbar fusions under SA versus GA from June of 2020 to June of 2022. SA patients were compared to demographically matched GA counterparts undergoing comparable procedures. Analyzed outcomes include operative time, opioid usage in morphine milligram equivalents, TTA, and LOS.Ten SA patients were matched to 10 GA counterparts. The cohort had a mean age of 66.77, a mean body mass index of 27.73 kg/m2, and a median American Society of Anesthesiologists Physical Status Score of 3.00. LOS was lower in SA versus GA patients (12.87 vs. 50.79 hours, P = 0.001). Opioid utilization was reduced in SA versus GA patients (10.76 vs. 31.43 morphine milligram equivalents, P = 0.006). TTA was reduced in SA versus GA patients (7.22 vs. 29.87 hours, P = 0.022). Procedure duration was not significantly reduced in SA patients compared to GA patients (139.3 vs. 188.2 minutes, P = 0.089).These preliminary retrospective results suggest the use of SA rather than GA for lumbar fusions is associated with reduced hospital LOS, reduced opioid utilization, and reduced TTA. Future randomized prospective studies are warranted to determine if SA usage truly leads to these beneficial outcomes.

  View details for DOI 10.1016/j.wneu.2023.05.001

  View details for Web of Science ID 001052980500001

  View details for PubMedID 37164209

  View details for PubMedCentralID PMC10659088

• Amyloid beta and postoperative delirium: partners in crime or strangers in the dark? BRITISH JOURNAL OF ANAESTHESIA Reekes, T. H., Devinney, M. J., Berger, M. 2023; 131 (2): 205-208

  Abstract

  Postoperative delirium is a particularly debilitating complication of surgery and perioperative care. Although the aetiology of postoperative delirium is not entirely understood, recent evidence suggests that Alzheimer's disease and related dementias pathology plays an important role in the development of postoperative delirium. A recent study evaluating postoperative changes in plasma beta amyloid (Aβ) levels found increased Aβ across the postoperative period, but the association with postoperative delirium incidence and severity was variable. These findings support the idea that Alzheimer's disease and related dementias pathology in combination with blood-brain barrier dysfunction and neuroinflammation may impart risk for postoperative delirium.

  View details for DOI 10.1016/j.bja.2023.05.009

  View details for Web of Science ID 001147614800001

  View details for PubMedID 37330308

• Perioperative changes in neurocognitive and Alzheimer's disease-related cerebrospinal fluid biomarkers in older patients randomised to isoflurane or propofol for anaesthetic maintenance BRITISH JOURNAL OF ANAESTHESIA Villalobos, D., Reese, M., Wright, M., Wong, M., Syed, A., Park, J., Hall, A., Browndyke, J. N., Martucci, K. T., Devinney, M. J., Acker, L., Moretti, E. W., Talbot, L., Colin, B., Ohlendorf, B., Waligorska, T., Shaw, L. M., Whitson, H. E., Cohen, H. J., Mathew, J. P., Berger, M. 2023; 131 (2): 328-337

  Abstract

  Animal studies have shown that isoflurane and propofol have differential effects on Alzheimer's disease (AD) pathology and memory, although it is unclear whether this occurs in humans.This was a nested randomised controlled trial within a prospective cohort study; patients age ≥60 yr undergoing noncardiac/non-neurological surgery were randomised to isoflurane or propofol for anaesthetic maintenance. Cerebrospinal fluid (CSF) was collected via lumbar puncture before, 24 h, and 6 weeks after surgery. Cognitive testing was performed before and 6 weeks after surgery. Nonparametric methods and linear regression were used to evaluate CSF biomarkers and cognitive function, respectively.There were 107 subjects (54 randomised to isoflurane and 53 to propofol) who completed the 6-week follow-up and were included in the analysis. There was no significant effect of anaesthetic treatment group, time, or group-by-time interaction for CSF amyloid-beta (Aβ), tau, or phospho-tau181p levels, or on the tau/Aβ or p-tau181p/Aβ ratios (all P>0.05 after Bonferroni correction). In multivariable-adjusted intention-to-treat analyses, there were no significant differences between the isoflurane and propofol groups in 6-week postoperative change in overall cognition (mean difference [95% confidence interval]: 0.01 [-0.12 to 0.13]; P=0.89) or individual cognitive domains (P>0.05 for each). Results remained consistent across as-treated and per-protocol analyses.Intraoperative anaesthetic maintenance with isoflurane vs propofol had no significant effect on postoperative cognition or CSF Alzheimer's disease-related biomarkers within 6 weeks after noncardiac, non-neurological surgery in older adults.NCT01993836.

  View details for DOI 10.1016/j.bja.2023.04.019

  View details for Web of Science ID 001148259700001

  View details for PubMedID 37271721

  View details for PubMedCentralID PMC10375507

• A Real-Time Neurophysiologic Stress Test for the Aging Brain: Novel Perioperative and ICU Applications of EEG in Older Surgical Patients NEUROTHERAPEUTICS Berger, M., Ryu, D., Reese, M., McGuigan, S., Evered, L. A., Price, C. C., Scott, D. A., Westover, M., Eckenhoff, R., Bonanni, L., Sweeney, A., Babiloni, C. 2023; 20 (4): 975-1000

  Abstract

  As of 2022, individuals age 65 and older represent approximately 10% of the global population [1], and older adults make up more than one third of anesthesia and surgical cases in developed countries [2, 3]. With approximately > 234 million major surgical procedures performed annually worldwide [4], this suggests that > 70 million surgeries are performed on older adults across the globe each year. The most common postoperative complications seen in these older surgical patients are perioperative neurocognitive disorders including postoperative delirium, which are associated with an increased risk for mortality [5], greater economic burden [6, 7], and greater risk for developing long-term cognitive decline [8] such as Alzheimer's disease and/or related dementias (ADRD). Thus, anesthesia, surgery, and postoperative hospitalization have been viewed as a biological "stress test" for the aging brain, in which postoperative delirium indicates a failed stress test and consequent risk for later cognitive decline (see Fig. 3). Further, it has been hypothesized that interventions that prevent postoperative delirium might reduce the risk of long-term cognitive decline. Recent advances suggest that rather than waiting for the development of postoperative delirium to indicate whether a patient "passed" or "failed" this stress test, the status of the brain can be monitored in real-time via electroencephalography (EEG) in the perioperative period. Beyond the traditional intraoperative use of EEG monitoring for anesthetic titration, perioperative EEG may be a viable tool for identifying waveforms indicative of reduced brain integrity and potential risk for postoperative delirium and long-term cognitive decline. In principle, research incorporating routine perioperative EEG monitoring may provide insight into neuronal patterns of dysfunction associated with risk of postoperative delirium, long-term cognitive decline, or even specific types of aging-related neurodegenerative disease pathology. This research would accelerate our understanding of which waveforms or neuronal patterns necessitate diagnostic workup and intervention in the perioperative period, which could potentially reduce postoperative delirium and/or dementia risk. Thus, here we present recommendations for the use of perioperative EEG as a "predictor" of delirium and perioperative cognitive decline in older surgical patients.

  View details for DOI 10.1007/s13311-023-01401-4

  View details for Web of Science ID 001028417900002

  View details for PubMedID 37436580

  View details for PubMedCentralID PMC10457272

• A Role for Blood-brain Barrier Dysfunction in Delirium following Non-Cardiac Surgery in Older adults. medRxiv : the preprint server for health sciences Devinney, M. J., Wong, M. K., Wright, M. C., Marcantonio, E. R., Terrando, N., Browndyke, J. N., Whitson, H. E., Cohen, H. J., Nackley, A. G., Klein, M. E., Ely, E. W., Mathew, J. P., Berger, M., MADCO-PC & INTUIT Study Groups 2023

  Abstract

  Objective: Although animal models suggest a role for blood-brain barrier dysfunction in postoperative delirium-like behavior, its role in postoperative delirium and postoperative recovery in humans is unclear. Thus, we evaluated the role of blood-brain barrier dysfunction in postoperative delirium and hospital length of stay among older surgery patients.Methods: Cognitive testing, delirium assessment, and cerebrospinal fluid and blood sampling were prospectively performed before and after non-cardiac, non-neurologic surgery. Blood-brain barrier dysfunction was assessed using the cerebrospinal fluid-to-plasma albumin ratio (CPAR).Results: Of 207 patients (median age 68, 45% female) with complete CPAR and delirium data, 26 (12.6%) developed postoperative delirium. Overall, CPAR increased from before to 24-hours after surgery (median postoperative change 0.28, [IQR] [-0.48-1.24]; Wilcoxon p=0.001). Preoperative to 24-hour postoperative change in CPAR was greater among patients who developed delirium vs those who did not (median [IQR] 1.31 [0.004, 2.34] vs 0.19 [-0.55, 1.08]; p=0.003). In a multivariable model adjusting for age, baseline cognition, and surgery type, preoperative to 24-hour postoperative change in CPAR was independently associated with delirium incidence (per CPAR increase of 1, OR = 1.30, [95% CI 1.03-1.63]; p=0.026) and increased hospital length of stay (IRR = 1.15 [95% CI 1.09-1.22]; p<0.001).Interpretation: Postoperative increases in blood-brain barrier permeability are independently associated with increased delirium rates and postoperative hospital length of stay. Although these findings do not establish causality, studies are warranted to determine whether interventions to reduce postoperative blood-brain barrier dysfunction would reduce postoperative delirium rates and hospital length of stay.

  View details for DOI 10.1101/2023.04.07.23288303

  View details for PubMedID 37214925

• Awake spinal anesthesia facilitates spine surgery in poor surgical candidates: A case series NEUROCHIRURGIE Sykes, D. W., Tabarestani, T. Q., Salven, D. S., Chaudhry, N. S., Wang, T. Y., Gottfried, O. N., Shaffrey, C. I., Guinn, N. R., Gadsden, J., Ayoub, C. M., Bullock, W., Berger, M., Abd-El-Barr, M. M. 2023; 69 (3): 101444

  Abstract

  Annually, hundreds of thousands of patients undergo surgery for degenerative spine disease (DSD). This represents only a fraction of patients that present for surgical consideration. Procedures are often avoided due to comorbidities that make patients poor candidates for general anesthesia (GA) and its associated risks. With increasing interest in awake surgery under spinal anesthesia (SA), the authors have observed that SA may facilitate spine surgery in patients with relative contraindications to GA. With this in mind, the authors set out to summarize the outcomes of a series of highly comorbid patients who received surgery under SA.Case logs of a single surgeon were reviewed, and patients undergoing spine surgery under SA were identified. Within this group, patients were identified with relative contraindications to GA, such as advanced age and medical comorbidities. For these patients, for whom surgery was facilitated by SA, the medical records were consulted to report demographic information and patient outcomes.Ten highly comorbid patients were identified who received lumbar spine surgery for DSD under SA. Comorbidities included octogenarian status, obesity, and chronic health conditions such as heart disease. The cohort had a mean age of 75.5 and a mean American Society of Anesthesiologists Physical Status (ASA-PS) score of 3.1. The patients were predicted to have a 2.74-fold increase of serious complications compared to the average patient. There were no adverse events.For patients with symptomatic, refractory DSD and relative contraindications to GA, SA may facilitate safe surgical intervention with excellent outcomes.

  View details for DOI 10.1016/j.neuchi.2023.101444

  View details for Web of Science ID 000984384200001

  View details for PubMedID 37061179

• Perioperative neurocognitive and functional neuroimaging trajectories in older APOE4 carriers compared with non-carriers: secondary analysis of a prospective cohort study (vol 127, pg 917, 2021) BRITISH JOURNAL OF ANAESTHESIA Browndyke, J. N., Wright, M. C., Yang, R., Syed, A., Park, J., Hall, A., Martucci, K., Devinney, M. J., Shaw, L., Waligorska, T., Moretti, E. W., Whitson, H. E., Cohen, H. J., Mathew, J. P., Berger, M., MADCO PC Investigators 2023; 130 (5): 646

  View details for DOI 10.1016/j.bja.2023.02.009

  View details for Web of Science ID 000982209200001

  View details for PubMedID 36878808

  View details for PubMedCentralID PMC10170390

• Outcomes of Nonoperative vs Operative Management of Acute Appendicitis in Older Adults in the US JAMA SURGERY Meier, J., Stevens, A., Bhat, A., Berger, M., Balentine, C. 2023; 158 (6): 625-632

  Abstract

  Although the incidence of acute appendicitis among adults 65 years and older is high, these patients are underrepresented in randomized clinical trials comparing nonoperative vs operative management of appendicitis; it is unclear whether current trial data can be used to guide treatment in older adults.To compare outcomes following nonoperative vs operative management of appendicitis in older adults and assess whether they differ from results in younger patients.This retrospective cohort study used US hospital admissions data from the Agency for Healthcare Research and Quality's National Inpatient Sample from 2004 to 2017. Of 723 889 adult patients with acute uncomplicated appendicitis, 474 845 with known procedure date who survived 24 hours postprocedure and did not have inflammatory bowel disease were included (43 846 who were treated nonoperatively and 430 999 with appendectomy) were included. Data were analyzed from October 2021 to April 2022.Nonoperative vs operative management.The primary outcome was incidence of posttreatment complications. Secondary outcomes included mortality, length of stay, and inpatient costs. Differences were estimated using inverse probability weighting of the propensity score with sensitivity analysis to quantify effects of unmeasured confounding.The median (IQR) age in the overall cohort was 39 (27-54) years, and 29 948 participants (51.3%) were female. In patients 65 years and older, nonoperative management was associated with a 3.72% decrease in risk of complications (95% CI, 2.99-4.46) and a 1.82% increase in mortality (95% CI, 1.49-2.15) along with increased length of hospitalization and costs. Outcomes in patients younger than 65 years were significantly different than in older adults, with only minor differences between nonoperative and operative management with respect to morbidity and mortality, and smaller differences in length of hospitalization and costs. Morbidity and mortality results were somewhat sensitive to bias from unmeasured confounding.Nonoperative management was associated with reduced complications in older but not younger patients; however, operative management was associated with reduced mortality, hospital length of stay, and overall costs across all age groups. The different outcomes of nonoperative vs operative management of appendicitis in older and younger adults highlights the need for a randomized clinical trial to determine the best approach for managing appendicitis in older patients.

  View details for DOI 10.1001/jamasurg.2023.0284

  View details for Web of Science ID 000965391800002

  View details for PubMedID 37017955

  View details for PubMedCentralID PMC10077130

• Blood-brain barrier permeability and cognitive dysfunction after surgery - A pilot study JOURNAL OF CLINICAL ANESTHESIA Lascola, C. D., Cotter, S. F., Klinger, R. Y., Bisanar, T., Wright, M., Berger, M., Martin, G., Podgoreanu, M. V., Newman, M. F., Terrando, N., Mathew, J. P. 2023; 86: 111059

  View details for DOI 10.1016/j.jclinane.2023.111059

  View details for Web of Science ID 001010773500001

  View details for PubMedID 36739699

  View details for PubMedCentralID PMC10072905

• Comparison of Postoperative Outcomes of Laparoscopic vs Open Inguinal Hernia Repair JAMA SURGERY Meier, J., Stevens, A., Berger, M., Makris, K., Bramos, A., Reisch, J., Cullum, C., Lee, S. C., Skinner, C., Zeh, H., Brown, C. J., Balentine, C. J. 2023; 158 (2): 172-180

  Abstract

  Advocates of laparoscopic surgery argue that all inguinal hernias, including initial and unilateral ones, should be repaired laparoscopically. Prior work suggests outcomes of open repair are improved by using local rather than general anesthesia, but no prior studies have compared laparoscopic surgery with open repair under local anesthesia.To evaluate postoperative outcomes of open inguinal hernia repair under general or local anesthesia compared with laparoscopic repair.This retrospective cohort study identified 107 073 patients in the Veterans Affairs Surgical Quality Improvement Program database who underwent unilateral initial inguinal hernia repair from 1998 to 2019. Data were analyzed from October 2021 to March 2022.Patients were divided into 3 groups for comparison: (1) open repair with local anesthesia (n = 22 333), (2) open repair with general anesthesia (n = 75 104), and (3) laparoscopic repair with general anesthesia (n = 9636).Operative time and postoperative morbidity were compared using quantile regression and inverse probability propensity weighting. A 2-stage least-squares regression and probabilistic sensitivity analysis was used to quantify and address bias from unmeasured confounding in this observational study.Of 107 073 included patients, 106 529 (99.5%) were men, and the median (IQR) age was 63 (55-71) years. Compared with open repair with general anesthesia, laparoscopic repair was associated with a nonsignificant 0.15% (95% CI, -0.39 to 0.09; P = .22) reduction in postoperative complications. There was no significant difference in complications between laparoscopic surgery and open repair with local anesthesia (-0.05%; 95% CI, -0.34 to 0.28; P = .70). Operative time was similar for the laparoscopic and open general anesthesia groups (4.31 minutes; 95% CI, 0.45-8.57; P = .048), but operative times were significantly longer for laparoscopic compared with open repair under local anesthesia (10.42 minutes; 95% CI, 5.80-15.05; P < .001). Sensitivity analysis and 2-stage least-squares regression demonstrated that these findings were robust to bias from unmeasured confounding.In this study, laparoscopic and open repair with local anesthesia were reasonable options for patients with initial unilateral inguinal hernias, and the decision should be made considering both patient and surgeon factors.

  View details for DOI 10.1001/jamasurg.2022.6616

  View details for Web of Science ID 000903221100008

  View details for PubMedID 36542394

  View details for PubMedCentralID PMC9857280

• Hevin/Sparcl1 drives pathological pain through spinal cord astrocyte and NMDA receptor signaling JCI INSIGHT Chen, G., Xu, J., Luo, H., Luo, X., Singh, S. K., Ramirez, J. J., James, M. L., Mathew, J. P., Berger, M., Eroglu, C., Ji, R. 2022; 7 (23)

  Abstract

  High endothelial venule protein/SPARC-like 1 (hevin/Sparcl1) is an astrocyte-secreted protein that regulates synapse formation in the brain. Here we show that astrocytic hevin signaling plays a critical role in maintaining chronic pain. Compared with WT mice, hevin-null mice exhibited normal mechanical and heat sensitivity but reduced inflammatory pain. Interestingly, hevin-null mice have faster recovery than WT mice from neuropathic pain after nerve injury. Intrathecal injection of WT hevin was sufficient to induce persistent mechanical allodynia in naive mice. In hevin-null mice with nerve injury, adeno-associated-virus-mediated (AAV-mediated) re-expression of hevin in glial fibrillary acidic protein-expressing (GFAP-expressing) spinal cord astrocytes could reinstate neuropathic pain. Mechanistically, hevin is crucial for spinal cord NMDA receptor (NMDAR) signaling. Hevin-potentiated N-Methyl-D-aspartic acid (NMDA) currents are mediated by GluN2B-containing NMDARs. Furthermore, intrathecal injection of a neutralizing Ab against hevin alleviated acute and persistent inflammatory pain, postoperative pain, and neuropathic pain. Secreted hevin that was detected in mouse cerebrospinal fluid (CSF) and nerve injury significantly increased CSF hevin abundance. Finally, neurosurgery caused rapid and substantial increases in SPARCL1/HEVIN levels in human CSF. Collectively, our findings support a critical role of hevin and astrocytes in the maintenance of chronic pain. Neutralizing of secreted hevin with monoclonal Ab may provide a new therapeutic strategy for treating acute and chronic pain and NMDAR-medicated neurodegeneration.

  View details for DOI 10.1172/jci.insight.161028

  View details for Web of Science ID 000993865300001

  View details for PubMedID 36256481

  View details for PubMedCentralID PMC9746899

• Conserved YKL-40 changes in mice and humans after postoperative delirium BRAIN, BEHAVIOR, & IMMUNITY - HEALTH David-Bercholz, J., Acker, L., Caceres, A. I., Wu, P., Goenka, S., Franklin, N. O., Rodriguiz, R. M., Wetsel, W. C., Devinney, M., Wright, M., Zetterberg, H., Yang, T., Berger, M., Terrando, N. 2022; 26: 100555

  Abstract

  Delirium is a common postoperative neurologic complication among older adults. Despite its prevalence (14%-50%) and likely association with inflammation, the exact mechanisms that underpin postoperative delirium are unclear. This project aimed to characterize systemic and central nervous system (CNS) inflammatory changes following surgery in mice and humans. Matched plasma and cerebrospinal fluid (CSF) samples from the "Investigating Neuroinflammation Underlying Postoperative Brain Connectivity Changes, Postoperative Cognitive Dysfunction, Delirium in Older Adults" (INTUIT; NCT03273335) study were compared to murine endpoints. Delirium-like behavior was evaluated in aged mice using the 5-Choice Serial Reaction Time Test (5-CSRTT). Using a well established orthopedic surgical model in the FosTRAP reporter mouse we detected neuronal changes in the prefrontal cortex, an area implicated in attention, but notably not in the hippocampus. In aged mice, plasma interleukin-6 (IL-6), chitinase-3-like protein 1 (YKL-40), and neurofilament light chain (NfL) levels increased after orthopedic surgery, but hippocampal YKL-40 expression was decreased. Given the growing evidence for a YKL-40 role in delirium and other neurodegenerative conditions, we assayed human plasma and CSF samples. Plasma YKL-40 levels were similarly increased after surgery, with a trend toward a greater postoperative plasma YKL-40 increase in patients with delirium. However, YKL-40 levels in CSF decreased following surgery, which paralleled the findings in the mouse brain. Finally, we confirmed changes in the blood-brain barrier (BBB) as early as 9 h after surgery in mice, which warrants more detailed and acute evaluations of BBB integrity following surgery in humans. Together, these results provide a nuanced understanding of neuroimmune interactions underlying postoperative delirium in mice and humans, and highlight translational biomarkers to test potential cellular targets and mechanisms.

  View details for DOI 10.1016/j.bbih.2022.100555

  View details for Web of Science ID 001061600400001

  View details for PubMedID 36457825

  View details for PubMedCentralID PMC9706140

• Neuroimaging and immunological features of neurocognitive function related to substance use in people with HIV JOURNAL OF NEUROVIROLOGY Murdoch, D. M., Barfield, R., Chan, C., Towe, S. L., Bell, R. P., Volkheimer, A., Choe, J., Hall, S. A., Berger, M., Xie, J., Meade, C. S. 2023; 29 (1): 78-93

  Abstract

  This study sought to identify neuroimaging and immunological factors associated with substance use and that contribute to neurocognitive impairment (NCI) in people with HIV (PWH). We performed cross-sectional immunological phenotyping, neuroimaging, and neurocognitive testing on virally suppressed PWH in four substance groups: cocaine only users (COC), marijuana only users (MJ), dual users (Dual), and Non-users. Participants completed substance use assessments, multimodal MRI brain scan, neuropsychological testing, and blood and CSF sampling. We employed a two-stage analysis of 305 possible biomarkers of cognitive function associated with substance use. Feature reduction (Kruskal Wallis p-value < 0.05) identified 53 biomarkers associated with substance use (22 MRI and 31 immunological) for model inclusion along with clinical and demographic variables. We employed eXtreme Gradient Boosting (XGBoost) with these markers to predict cognitive function (global T-score). SHapley Additive exPlanations (SHAP) values were calculated to rank features for impact on model output and NCI. Participants were 110 PWH with sustained HIV viral suppression (33 MJ, 12 COC, 22 Dual, and 43 Non-users). The ten highest ranking biomarkers for predicting global T-score were 4 neuroimaging biomarkers including functional connectivity, gray matter volume, and white matter integrity; 5 soluble biomarkers (plasma glycine, alanine, lyso-phosphatidylcholine (lysoPC) aC17.0, hydroxy-sphingomyelin (SM.OH) C14.1, and phosphatidylcholinediacyl (PC aa) C28.1); and 1 clinical variable (nadir CD4 count). The results of our machine learning model suggest that substance use may indirectly contribute to NCI in PWH through both metabolomic and neuropathological mechanisms.

  View details for DOI 10.1007/s13365-022-01102-2

  View details for Web of Science ID 000880263300001

  View details for PubMedID 36348233

  View details for PubMedCentralID PMC10089970

• Intraoperative Anesthetic Probes of Brain Health: Ketamine as a Canary in the Coal Mine? Anesthesia and analgesia Reese, M., Heifets, B. D., Berger, M. 2022; 135 (4): 679-682

  View details for DOI 10.1213/ANE.0000000000005965

  View details for PubMedID 36108180

• The potential link between obstructive sleep apnea and postoperative neurocognitive disorders: current knowledge and possible mechanisms CANADIAN JOURNAL OF ANESTHESIA-JOURNAL CANADIEN D ANESTHESIE Devinney, M. J., VanDusen, K. W., Kfouri, J. M., Avasarala, P., Spector, A. R., Mathew, J. P., Berger, M. 2022; 69 (10): 1272-1287

  Abstract

  This narrative review examines the current evidence on whether obstructive sleep apnea (OSA) is associated with postoperative delirium (POD) and postoperative cognitive dysfunction (POCD). The mechanisms that could predispose OSA patients to these disorders are also explored.Relevant literature was identified by searching for pertinent terms in Medline®, Pubmed, ScopusTM, and Google scholar databases. Case reports, abstracts, review articles, original research articles, and meta-analyses were reviewed. The bibliographies of retrieved sources were also searched to identify relevant papers.Seven studies have investigated the association between OSA and POD, with mixed results. No studies have examined the potential link between OSA and POCD. If these relationships exist, they could be mediated by several mechanisms, including increased neuroinflammation, blood-brain barrier breakdown, cerebrovascular disease, Alzheimer's disease neuropathology, disrupted cerebral autoregulation, sleep disruption, sympathovagal imbalance, and/or disrupted brain bioenergetics.There is very limited evidence that OSA plays a role in postoperative neurocognitive disorders because few studies have been conducted in the perioperative setting. Additional perioperative prospective observational cohort studies and randomized controlled trials of sleep apnea treatment are needed. These investigations should also assess potential underlying mechanisms that could predispose patients with OSA to postoperative neurocognitive disorders. This review highlights the need for more research to improve postoperative neurocognitive outcomes for patients with OSA.

  View details for DOI 10.1007/s12630-022-02302-4

  View details for Web of Science ID 000842686800001

  View details for PubMedID 35982354

  View details for PubMedCentralID PMC9924301

• Regional vs General Anesthesia and Incidence of Postoperative Delirium in Older Patients Undergoing Hip Fracture Surgery JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Nobuhara, C., Devinney, M., Berger, M. 2022; 327 (17): 1707-+

  View details for DOI 10.1001/jama.2022.3538

  View details for Web of Science ID 000793675300025

  View details for PubMedID 35503352

• Pre- and Postoperative CSF Proteomic Signatures of Postoperative Delirium Thomas, J., Corcoran, D., Fuller, M., Moseley, A., Cooter, M., Lutz, M., Mathew, J. P., Berger, M., Devinney, M. LIPPINCOTT WILLIAMS & WILKINS. 2022: 467-470

  View details for Web of Science ID 000840283000179

• Cognitive and cerebrospinal fluid Alzheimer's Disease biomarker changes over time in older surgical patients and matched nonsurgical controls Wong, M., Reese, M., Cooter, M., Browndyke, J. N., Mathew, J. P., Cohen, H. J., Whitson, H. E., Berger, M. LIPPINCOTT WILLIAMS & WILKINS. 2022: 954-956

  View details for Web of Science ID 000840283001065

• Perioperative neurocognitive and CSF Alzheimer's biomarker trajectories in older patients randomized to Isoflurane or Propofol for Anaesthetic Maintenance Villalobos, D., Berger, M., Cooter, M., Browndyke, J. N., Syed, A., Moretti, E., Divinney, M. LIPPINCOTT WILLIAMS & WILKINS. 2022: 488-490

  View details for Web of Science ID 000840283000187

• The SANDMAN Study: Sleep Apnea, Neuroinflammation, and Cognitive Dysfunction Manifesting After Non-cardiac surgery Avasarala, P., Thomas, J., Spector, A. R., Browndyke, J. N., Smith, P. J., Dominguez, J., Cooter, M., Bunning, T., Eleswarpu, S., VanDusen, K. W., Cai, V., Whitson, H. E., Mathew, J. P., Berger, M., Devinney, M. LIPPINCOTT WILLIAMS & WILKINS. 2022: 1100-1102

  View details for Web of Science ID 000840283001116

• Preoperative EEG Inattention Signatures and Postoperative Delirium Acker, L., Au, S., Roberts, K., Giattino, C., Moretti, E., Devinney, M., Reese, M., Cohen, H. J., Mathew, J. P., Woldorff, M. G., Whitson, H. E., Berger, M. LIPPINCOTT WILLIAMS & WILKINS. 2022: 496

  View details for Web of Science ID 000840283000190

• Machine learning XGBoost classification of postoperative delirium by intraoperative EEG metrics Reese, M., Roberts, K., Woldorff, M. G., Cooter, M., Acker, L., Wu, S., Whitson, H. E., Berger, M. LIPPINCOTT WILLIAMS & WILKINS. 2022: 609-611

  View details for Web of Science ID 000840283000244

• Postoperative changes in cognition and cerebrospinal fluid neurodegenerative disease biomarkers ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY Berger, M., Browndyke, J. N., Wright, M., Nobuhara, C., Reese, M., Acker, L., Bullock, W., Colin, B. J., Devinney, M. J., Moretti, E. W., Moul, J. W., Ohlendorf, B., Laskowitz, D. T., Waligorska, T., Shaw, L. M., Whitson, H. E., Cohen, H. J., Mathew, J. P., MADCO-PC Investigators 2022; 9 (2): 155-170

  Abstract

  Numerous investigators have theorized that postoperative changes in Alzheimer's disease neuropathology may underlie postoperative neurocognitive disorders. Thus, we determined the relationship between postoperative changes in cognition and cerebrospinal (CSF) tau, p-tau-181p, or Aβ levels after non-cardiac, non-neurologic surgery in older adults.Participants underwent cognitive testing before and 6 weeks after surgery, and lumbar punctures before, 24 h after, and 6 weeks after surgery. Cognitive scores were combined via factor analysis into an overall cognitive index. In total, 110 patients returned for 6-week postoperative testing and were included in the analysis.There was no significant change from before to 24 h or 6 weeks following surgery in CSF tau (median [median absolute deviation] change before to 24 h: 0.00 [4.36] pg/mL, p = 0.853; change before to 6 weeks: -1.21 [3.98] pg/mL, p = 0.827). There were also no significant changes in CSF p-tau-181p or Aβ over this period. There was no change in cognitive index (mean [95% CI] 0.040 [-0.018, 0.098], p = 0.175) from before to 6 weeks after surgery, although there were postoperative declines in verbal memory (-0.346 [-0.523, -0.170], p = 0.003) and improvements in executive function (0.394, [0.310, 0.479], p < 0.001). There were no significant correlations between preoperative to 6-week postoperative changes in cognition and CSF tau, p-tau-181p, or Aβ42 changes over this interval (p > 0.05 for each).Neurocognitive changes after non-cardiac, non-neurologic surgery in the majority of cognitively healthy, community-dwelling older adults are unlikely to be related to postoperative changes in AD neuropathology (as assessed by CSF Aβ, tau or p-tau-181p levels or the p-tau-181p/Aβ or tau/Aβ ratios).clinicaltrials.gov (NCT01993836).

  View details for DOI 10.1002/acn3.51499

  View details for Web of Science ID 000749251400001

  View details for PubMedID 35104057

  View details for PubMedCentralID PMC8862419

• Developing a Real-Time Electroencephalogram-Guided Anesthesia-Management Curriculum for Educating Residents: A Single-Center Randomized Controlled Trial ANESTHESIA AND ANALGESIA Berger, M., Eleswarpu, S. S., Wright, M., Ray, A. M., Wingfield, S. A., Heflin, M. T., Bengali, S., Udani, A. D. 2022; 134 (1): 159-170

  Abstract

  Different anesthetic drugs and patient factors yield unique electroencephalogram (EEG) patterns. Yet, it is unclear how best to teach trainees to interpret EEG time series data and the corresponding spectral information for intraoperative anesthetic titration, or what effect this might have on outcomes.We developed an electronic learning curriculum (ELC) that covered EEG spectrogram interpretation and its use in anesthetic titration. Anesthesiology residents at a single academic center were randomized to receive this ELC and given spectrogram monitors for intraoperative use versus standard residency curriculum alone without intraoperative spectrogram monitors. We hypothesized that this intervention would result in lower inhaled anesthetic administration (measured by age-adjusted total minimal alveolar concentration [MAC] fraction and age-adjusted minimal alveolar concentration [aaMAC]) to patients ≥60 old during the postintervention period (the primary study outcome). To study this effect and to determine whether the 2 groups were administering similar anesthetic doses pre- versus postintervention, we compared aaMAC between control versus intervention group residents both before and after the intervention. To measure efficacy in the postintervention period, we included only those cases in the intervention group when the monitor was actually used. Multivariable linear mixed-effects modeling was performed for aaMAC fraction and hospital length of stay (LOS; a non-prespecified secondary outcome), with a random effect for individual resident. A multivariable linear mixed-effects model was also used in a sensitivity analysis to determine if there was a group (intervention versus control group) by time period (post- versus preintervention) interaction for aaMAC. Resident EEG knowledge difference (a prespecified secondary outcome) was compared with a 2-sided 2-group paired t test.Postintervention, there was no significant aaMAC difference in patients cared for by the ELC group (n = 159 patients) versus control group (N = 325 patients; aaMAC difference = -0.03; 95% confidence interval [CI], -0.09 to 0.03; P =.32). In a multivariable mixed model, the interaction of time period (post- versus preintervention) and group (intervention versus control) led to a nonsignificant reduction of -0.05 aaMAC (95% CI, -0.11 to 0.01; P = .102). ELC group residents (N = 19) showed a greater increase in EEG knowledge test scores than control residents (N = 20) from before to after the ELC intervention (6-point increase; 95% CI, 3.50-8.88; P < .001). Patients cared for by the ELC group versus control group had a reduced hospital LOS (median, 2.48 vs 3.86 days, respectively; P = .024).Although there was no effect on mean aaMAC, these results demonstrate that this EEG-ELC intervention increased resident knowledge and raise the possibility that it may reduce hospital LOS.

  View details for DOI 10.1213/ANE.0000000000005677

  View details for Web of Science ID 000730360200028

  View details for PubMedID 34709008

  View details for PubMedCentralID PMC8678191

• A Processed Electroencephalogram-Based Brain Anesthetic Resistance Index Is Associated With Postoperative Delirium in Older Adults: A Dual Center Study ANESTHESIA AND ANALGESIA Wright, M., Bunning, T., Eleswarpu, S. S., Heflin, M. T., McDonald, S. R., Lagoo-Deenadalayan, S., Whitson, H. E., Martinez-Camblor, P., Deiner, S. G., Berger, M. 2022; 134 (1): 149-158

  Abstract

  Some older adults show exaggerated responses to drugs that act on the brain. The brain's response to anesthetic drugs is often measured clinically by processed electroencephalogram (EEG) indices. Thus, we developed a processed EEG-based measure of the brain's resistance to volatile anesthetics and hypothesized that low scores on it would be associated with postoperative delirium risk.We defined the Duke Anesthesia Resistance Scale (DARS) as the average bispectral index (BIS) divided by the quantity (2.5 minus the average age-adjusted end-tidal minimum alveolar concentration [aaMAC] inhaled anesthetic fraction). The relationship between DARS and postoperative delirium was analyzed in 139 older surgical patients (age ≥65) from Duke University Medical Center (n = 69) and Mt Sinai Medical Center (n = 70). Delirium was assessed by geriatrician interview at Duke, and by research staff utilizing the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) instrument at Mt Sinai. We examined the relationship between DARS and delirium and used the Youden index to identify an optimal low DARS threshold (for delirium risk), and its associated 95% bootstrap confidence bounds. We used multivariable logistic regression to examine the relationship between low DARS and delirium risk.The relationship between DARS and delirium risk was nonlinear, with higher delirium risk at low DARS scores. A DARS threshold of 28.755 maximized the Youden index for the association between low DARS and delirium, with bootstrap 95% confidence bounds of 26.18 and 29.80. A low DARS (<28.755) was associated with increased delirium risk in multivariable models adjusting for site (odds ratio [OR] [95% confidence interval {CI}] = 4.30 [1.89-10.01]; P = .001), or site-plus-patient risk factors (OR [95% CI] = 3.79 [1.63-9.10]; P = .003). These associations with postoperative delirium risk remained significant when using the 95% bootstrap confidence bounds for the low DARS threshold (P < .05 for all). Further, a low DARS (<28.755) was associated with delirium risk after accounting for opioid, midazolam, propofol, phenylephrine, and ketamine dosage as well as site (OR [95% CI] = 4.21 [1.80-10.16]; P = .002). This association between low DARS and postoperative delirium risk after controlling for these other medications remained significant (P < .05) when using either the lower or the upper 95% bootstrap confidence bounds for the low DARS threshold.These results demonstrate that an intraoperative processed EEG-based measure of lower brain anesthetic resistance (ie, low DARS) is independently associated with increased postoperative delirium risk in older surgical patients.

  View details for DOI 10.1213/ANE.0000000000005660

  View details for Web of Science ID 000730360200027

  View details for PubMedID 34252066

  View details for PubMedCentralID PMC8678136

• Geriatric Preoperative Optimization: A Review AMERICAN JOURNAL OF MEDICINE Zietlow, K. E., Wong, S., Heflin, M. T., McDonald, S. R., Sickeler, R., Devinney, M., Blitz, D., Lagoo-Deenadayalan, S., Berger, M. 2022; 135 (1): 39-48

  Abstract

  This review summarizes best practices for the perioperative care of older adults as recommended by the American Geriatrics Society, American Society of Anesthesiologists, and American College of Surgeons, with practical implementation strategies that can be readily implemented in busy preoperative or primary care clinics. In addition to traditional cardiopulmonary screening, older patients should undergo a comprehensive geriatric assessment. Rapid screening tools such as the Mini-Cog, Patient Health Questionnaire-2, and Frail Non-Disabled Survey and Clinical Frailty Scale, can be performed by multiple provider types and allow for quick, accurate assessments of cognition, functional status, and frailty screening. To assess polypharmacy, online resources can help providers identify and safely taper high-risk medications. Based on preoperative assessment findings, providers can recommend targeted prehabilitation, rehabilitation, medication management, care coordination, and/or delirium prevention interventions to improve postoperative outcomes for older surgical patients. Structured goals of care discussions utilizing the question-prompt list ensures that older patients have a realistic understanding of their surgery, risks, and recovery. This preoperative workup, combined with engaging with family members and interdisciplinary teams, can improve postoperative outcomes.

  View details for DOI 10.1016/j.amjmed.2021.07.028

  View details for Web of Science ID 000732467300022

  View details for PubMedID 34416164

  View details for PubMedCentralID PMC8688225

• Perioperative neurocognitive and functional neuroimaging trajectories in older <i>APOE4</i> carriers compared with non-carriers: secondary analysis of a prospective cohort study BRITISH JOURNAL OF ANAESTHESIA Browndyke, J. N., Wright, M. C., Yang, R., Syed, A., Park, J., Hall, A., Martucci, K., Devinney, M. J., Shaw, L., Waligorska, T., Moretti, E. W., Whitson, H. E., Cohen, H. J., Mathew, J. P., Berger, M., MADCO-PC Investigators 2021; 127 (6): 917-928

  Abstract

  Cognitive dysfunction after surgery is a major issue in older adults. Here, we determined the effect of APOE4 on perioperative neurocognitive function in older patients.We enrolled 140 English-speaking patients ≥60 yr old scheduled for noncardiac surgery under general anaesthesia in an observational cohort study, of whom 52 underwent neuroimaging. We measured cognition; Aβ, tau, p-tau levels in CSF; and resting-state intrinsic functional connectivity in six Alzheimer's disease-risk regions before and 6 weeks after surgery.There were no significant APOE4-related differences in cognition or CSF biomarkers, except APOE4 carriers had lower CSF Aβ levels than non-carriers (preoperative median CSF Aβ [median absolute deviation], APOE4 305 pg ml-1 [65] vs 378 pg ml-1 [38], respectively; P=0.001). Controlling for age, APOE4 carriers had significantly greater preoperative functional connectivity than non-carriers between several brain regions implicated in Alzheimer's disease, including between the left posterior cingulate cortex and left angular gyrus (β [95% confidence interval, CI], 0.218 [0.137-0.230]; PFWE=0.016). APOE4 carriers, but not non-carriers, experienced significant connectivity decreases from before to 6 weeks after surgery between several brain regions including between the left posterior cingulate cortex and left angular gyrus (β [95% CI], -0.196 [-0.256 to -0.136]; PFWE=0.001). Most preoperative and postoperative functional connectivity differences did not change after controlling for preoperative CSF Aβ levels.Postoperative change trajectories for cognition and CSF Aβ, tau or p-tau levels did not differ between community dwelling older APOE4 carriers and non-carriers. APOE4 carriers showed greater preoperative functional connectivity and greater postoperative decreases in functional connectivity in key Alzheimer's disease-risk regions, which occur via Aβ-independent mechanisms.

  View details for DOI 10.1016/j.bja.2021.08.012

  View details for Web of Science ID 000720819400027

  View details for PubMedID 34535274

  View details for PubMedCentralID PMC8693648

• Electroencephalogram-Based Complexity Measures as Predictors of Post-operative Neurocognitive Dysfunction FRONTIERS IN SYSTEMS NEUROSCIENCE Acker, L., Ha, C., Zhou, J., Manor, B., Giattino, C. M., Roberts, K., Berger, M., Wright, M., Colon-Emeric, C., Devinney, M., Au, S., Woldorff, M. G., Lipsitz, L. A., Whitson, H. E. 2021; 15: 718769

  Abstract

  Physiologic signals such as the electroencephalogram (EEG) demonstrate irregular behaviors due to the interaction of multiple control processes operating over different time scales. The complexity of this behavior can be quantified using multi-scale entropy (MSE). High physiologic complexity denotes health, and a loss of complexity can predict adverse outcomes. Since postoperative delirium is particularly hard to predict, we investigated whether the complexity of preoperative and intraoperative frontal EEG signals could predict postoperative delirium and its endophenotype, inattention. To calculate MSE, the sample entropy of EEG recordings was computed at different time scales, then plotted against scale; complexity is the total area under the curve. MSE of frontal EEG recordings was computed in 50 patients ≥ age 60 before and during surgery. Average MSE was higher intra-operatively than pre-operatively (p = 0.0003). However, intraoperative EEG MSE was lower than preoperative MSE at smaller scales, but higher at larger scales (interaction p < 0.001), creating a crossover point where, by definition, preoperative, and intraoperative MSE curves met. Overall, EEG complexity was not associated with delirium or attention. In 42/50 patients with single crossover points, the scale at which the intraoperative and preoperative entropy curves crossed showed an inverse relationship with delirium-severity score change (Spearman ρ = -0.31, p = 0.054). Thus, average EEG complexity increases intra-operatively in older adults, but is scale dependent. The scale at which preoperative and intraoperative complexity is equal (i.e., the crossover point) may predict delirium. Future studies should assess whether the crossover point represents changes in neural control mechanisms that predispose patients to postoperative delirium.

  View details for DOI 10.3389/fnsys.2021.718769

  View details for Web of Science ID 000733787200001

  View details for PubMedID 34858144

  View details for PubMedCentralID PMC8631543

• Locoregional Anesthesia for Major Surgery in Frail Adults May Reduce Postoperative Morbidity and Mortality Meier, J., Stevens, A. R., Berger, M., Cullum, M., Brown, C. J., Balentine, C. ELSEVIER SCIENCE INC. 2021: E62

  View details for Web of Science ID 000718306700150

• A template for physical resilience research in older adults: Methods of the PRIME-KNEE study JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Whitson, H. E., Crabtree, D., Pieper, C. F., Ha, C., Au, S., Berger, M., Cohen, H. J., Feld, J., Smith, P., Hall, K., Parker, D., Kraus, V., Kraus, W. E., Schmader, K., Colon-Emeric, C. 2021; 69 (11): 3232-3241

  Abstract

  Older adults with similar health conditions often experience widely divergent outcomes following health stressors. Variable recovery after a health stressor may be due in part to differences in biological mechanisms at the molecular, cellular, or system level, that are elicited in response to stressors. We describe the PRIME-KNEE study as an example of ongoing research to validate provocative clinical tests and biomarkers that predict resilience to specific health stressors.PRIME-KNEE is an ongoing, prospective cohort study that will enroll 250 adults ≥60 years undergoing total knee arthroplasty. Data are collected at baseline (pre-surgery), during surgery, daily for 7 days after surgery, and at 1, 2, 4, and 6 months post-surgery. Provocative tests include a cognition-motor dual-task walking test, cerebrovascular reactivity assessed by functional near-infrared spectroscopy, peripheral blood mononuclear cell reactivity ex vivo to lipopolysaccharide toxin and influenza vaccine, and heart rate variability during surgery. Cognitive, psychological, and physical performance batteries are collected at baseline to estimate prestressor reserve. Demographics, medications, comorbidities, and stressor characteristics are abstracted from the electronic medical record and via participant interview. Blood-based biomarkers are collected at baseline and postoperative day 1. Repeated measures after surgery include items from a delirium assessment tool and pain scales administered daily by telephone for 7 days and cognitive change index (participant and informant), lower extremity activities of daily living, pain scales, and step counts assessed by Garmin actigraphy at 1, 2, 4, and 6 months after surgery. Statistical models use these measures to characterize resilience phenotypes and evaluate prestressor clinical indicators associated with poststressor resilience.If PRIME-KNEE validates feasible clinical tests and biomarkers that predict recovery trajectories in older surgical patients, these tools may inform surgical decision-making, guide pre-habilitation efforts, and elucidate mechanisms underlying resilience. This study design could motivate future geriatric research on resilience.

  View details for DOI 10.1111/jgs.17384

  View details for Web of Science ID 000718004100031

  View details for PubMedID 34325481

  View details for PubMedCentralID PMC8595699

• Using local rather than general anesthesia for inguinal hernia repair may significantly reduce complications for frail Veterans AMERICAN JOURNAL OF SURGERY Meier, J., Berger, M., Hogan, T., Reisch, J., Zeh, H., Cullum, C., Lee, S. C., Skinner, C., Brown, C. J., Balentine, C. J. 2021; 222 (3): 619-624

  Abstract

  Frailty predisposes patients to poor postoperative outcomes. We evaluated whether using local rather than general anesthesia for hernia repair could mitigate effects of frailty.We used the Risk Analysis Index (RAI) to identify 8,038 frail patients in the 1998-2018 Veterans Affairs Surgical Quality Improvement Program database who underwent elective, open unilateral inguinal hernia repair under local or general anesthesia. Our outcome of interest was the incidence of postoperative complications.In total, 5,188 (65%) patients received general anesthesia and 2,850 (35%) received local. Local anesthesia was associated with a 48% reduction in complications (OR 0.52, 95%CI 0.38-0.72). Among the frailest patients (RAI≥70), predicted probability of a postoperative complication ranged from 22 to 33% with general anesthesia, compared to 13-21% with local.Local anesthesia was associated with a ∼50% reduction in postoperative complications in frail Veterans. Given the paucity of interventions for frail patients, there is an urgent need for a randomized trial comparing effects of anesthesia modality on postoperative complications in this vulnerable population.

  View details for DOI 10.1016/j.amjsurg.2021.01.026

  View details for Web of Science ID 000685555800031

  View details for PubMedID 33504434

  View details for PubMedCentralID PMC8295403

• Racial and Ethnic Disparities in Access to Local Anesthesia for Inguinal Hernia Repair JOURNAL OF SURGICAL RESEARCH Meier, J., Stevens, A., Berger, M., Hogan, T. P., Reisch, J., Cullum, C., Lee, S. C., Skinner, C., Zeh, H., Brown, C. J., Balentine, C. J. 2021; 266: 366-372

  Abstract

  Many studies have identified racial disparities in healthcare, but few have described disparities in the use of anesthesia modalities. We examined racial disparities in the use of local versus general anesthesia for inguinal hernia repair. We hypothesized that African American and Hispanic patients would be less likely than Caucasians to receive local anesthesia for inguinal hernia repair.We included 78,766 patients aged ≥ 18 years in the Veterans Affairs Surgical Quality Improvement Program database who underwent elective, unilateral, open inguinal hernia repair under general or local anesthesia from 1998-2018. We used multiple logistic regression to compare use of local versus general anesthesia and 30-day postoperative complications by race/ethnicity.In total, 17,892 (23%) patients received local anesthesia. Caucasian patients more frequently received local anesthesia (15,009; 24%), compared to African Americans (2353; 17%) and Hispanics (530; 19%), P < 0.05. After adjusting for covariates, we found that African Americans (OR 0.82, 95% CI 0.77-0.86) and Hispanics (OR 0.77, 95% CI 0.69-0.87) were significantly less likely to have hernia surgery under local anesthesia compared to Caucasians. Additionally, local anesthesia was associated with fewer postoperative complications for African American patients (OR 0.46, 95% CI 0.27-0.77).Although local anesthesia was associated with enhanced recovery for African American patients, they were less likely to have inguinal hernias repaired under local than Caucasians. Addressing this disparity requires a better understanding of how surgeons, anesthesiologists, and patient-related factors may affect the choice of anesthesia modality for hernia repair.

  View details for DOI 10.1016/j.jss.2021.04.026

  View details for Web of Science ID 000680279900046

  View details for PubMedID 34087620

  View details for PubMedCentralID PMC8489739

• Local Anesthesia is Associated with Fewer Complications in Umbilical Hernia Repair in Frail Veterans JOURNAL OF SURGICAL RESEARCH Meier, J., Berger, M., Hogan, T. P., Reisch, J., Cullum, C., Lee, S. C., Skinner, C., Zeh, H., Brown, C. J., Balentine, C. J. 2021; 266: 88-95

  Abstract

  The optimal anesthesia modality for umbilical hernia repair is unclear. We hypothesized that using local rather than general anesthesia would be associated with improved outcomes, especially for frail patients.We utilized the 1998-2018 Veterans Affairs Surgical Quality Improvement Program to identify patients who underwent elective, open umbilical hernia repair under general or local anesthesia. We used the Risk Analysis Index to measure frailty. Outcomes included complications and operative time.There were 4958 Veterans (13%) whose hernias were repaired under local anesthesia. Compared to general anesthesia, local was associated with a 12%-24% faster operative time for all patients, and an 86% lower (OR 0.14, 95%CI 0.03-0.72) complication rate for frail patients.Local anesthesia may reduce the operative time for all patients and complications for frail patients having umbilical hernia repair.

  View details for DOI 10.1016/j.jss.2021.04.006

  View details for Web of Science ID 000680279900013

  View details for PubMedID 33989892

  View details for PubMedCentralID PMC8338808

• Goldilocks and propofol dosage in older adults: Too much, too little, or just right? JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Devinney, M. J., Berger, M. 2021; 69 (8): 2106-2109

  View details for DOI 10.1111/jgs.17221

  View details for Web of Science ID 000648344700001

  View details for PubMedID 33964173

  View details for PubMedCentralID PMC8373744

• Using local rather than general anesthesia for inguinal hernia repair is associated with shorter operative time and enhanced postoperative recovery AMERICAN JOURNAL OF SURGERY Balentine, C. J., Meier, J., Berger, M., Hogan, T. P., Reisch, J., Cullum, M., Zeh, H., Lee, S. C., Skinner, C., Brown, C. J. 2021; 221 (5): 902-907

  Abstract

  Inguinal hernia repair is the most common general surgery procedure and can be performed under local or general anesthesia. We hypothesized that using local rather than general anesthesia would improve outcomes, especially for older adults.This is a retrospective review of 97,437 patients in the Veterans Affairs Surgical Quality Improvement Program who had open inguinal hernia surgery under local or general anesthesia. Outcomes included 30-day postoperative complications, operative time, and recovery time.Our cohort included 22,333 (23%) Veterans who received local and 75,104 (77%) who received general anesthesia. Mean age was 62 years. Local anesthesia was associated with a 37% decrease in the odds of postoperative complications (95% CI 0.54-0.73), a 13% decrease in operative time (95% CI 17.5-7.5), and a 27% shorter recovery room stay (95% CI 27.5-25.5), regardless of age.Using local rather than general anesthesia is associated with a profound decrease in complications (equivalent to "de-aging" patients by 30 years) and could significantly reduce costs for this common procedure.

  View details for DOI 10.1016/j.amjsurg.2020.08.024

  View details for Web of Science ID 000647273800011

  View details for PubMedID 32896372

  View details for PubMedCentralID PMC7953586

• Perioperative neurocognitive and neuroimaging trajectories in older APOE4 carriers vs non-carriers: A prospective cohort study Yang, R. O., Browndyke, J. N., Cooter, M., Berger, M. LIPPINCOTT WILLIAMS & WILKINS. 2021: 545-546

  View details for Web of Science ID 000752526600232

• Risk of Spinal Hematoma After Lumbar Puncture JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Nobuhara, C., Berger, M. 2021; 325 (8): 787-+

  View details for DOI 10.1001/jama.2020.24601

  View details for Web of Science ID 000621957400030

  View details for PubMedID 33620394

• Immunomodulatory lipid mediator profiling of cerebrospinal fluid following surgery in older adults SCIENTIFIC REPORTS Terrando, N., Park, J. J., Devinney, M., Chan, C., Cooter, M., Avasarala, P., Mathew, J. P., Quinones, Q. J., Maddipati, K., Berger, M., MADCO-PC Study Team 2021; 11 (1): 3047

  Abstract

  Arachidonic acid (AA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) derived lipids play key roles in initiating and resolving inflammation. Neuro-inflammation is thought to play a causal role in perioperative neurocognitive disorders, yet the role of these lipids in the human central nervous system in such disorders is unclear. Here we used liquid chromatography-mass spectrometry to quantify AA, DHA, and EPA derived lipid levels in non-centrifuged cerebrospinal fluid (CSF), centrifuged CSF pellets, and centrifuged CSF supernatants of older adults obtained before, 24 h and 6 weeks after surgery. GAGE analysis was used to determine AA, DHA and EPA metabolite pathway changes over time. Lipid mediators derived from AA, DHA and EPA were detected in all sample types. Postoperative lipid mediator changes were not significant in non-centrifuged CSF (p > 0.05 for all three pathways). The AA metabolite pathway showed significant changes in centrifuged CSF pellets and supernatants from before to 24 h after surgery (p = 0.0000247, p = 0.0155 respectively), from before to 6 weeks after surgery (p = 0.0000497, p = 0.0155, respectively), and from 24 h to 6 weeks after surgery (p = 0.0000499, p = 0.00363, respectively). These findings indicate that AA, DHA, and EPA derived lipids are detectable in human CSF, and the AA metabolite pathway shows postoperative changes in centrifuged CSF pellets and supernatants.

  View details for DOI 10.1038/s41598-021-82606-5

  View details for Web of Science ID 000618049600005

  View details for PubMedID 33542362

  View details for PubMedCentralID PMC7862598

• Using Local Anesthesia for Inguinal Hernia Repair Reduces Complications in Older Patients JOURNAL OF SURGICAL RESEARCH Balentine, C. J., Meier, J., Berger, M., Reisch, J., Cullum, M., Lee, S. C., Skinner, C., Brown, C. J. 2021; 258: 64-72

  Abstract

  Inguinal hernia repair is the most common general surgery operation in the United States. Nearly 80% of inguinal hernia operations are performed under general anesthesia versus 15%-20% using local anesthesia, despite the absence of evidence for the superiority of the former. Although patients aged 65 y and older are expected to benefit from avoiding general anesthesia, this presumed benefit has not been adequately studied. We hypothesized that the benefits of local over general anesthesia for inguinal hernia repair would increase with age.We analyzed 87,794 patients in the American College of Surgeons National Surgical Quality Improvement Project who had elective inguinal hernia repair under local or general anesthesia from 2014 to 2018, and we used propensity scores to adjust for known confounding. We compared postoperative complications, 30-day readmissions, and operative time for patients aged <55 y, 55-64 y, 65-74 y, and ≥75 y.Using local rather than general anesthesia was associated with a 0.6% reduction in postoperative complications in patients aged 75+ y (95% CI -0.11 to -1.13) but not in younger patients. Local anesthesia was associated with faster operative time (2.5 min - 4.7 min) in patients <75 y but not in patients aged 75+ y. Readmissions did not differ by anesthesia modality in any age group. Projected national cost savings for greater use of local anesthesia ranged from $9 million to $45 million annually.Surgeons should strongly consider using local anesthesia for inguinal hernia repair in older patients and in younger patients because it is associated with significantly reduced complications and substantial cost savings.

  View details for DOI 10.1016/j.jss.2020.08.054

  View details for Web of Science ID 000600487500009

  View details for PubMedID 33002663

  View details for PubMedCentralID PMC7968932

• Cerebrospinal Fluid Proteome Changes in Older Non-Cardiac Surgical Patients with Postoperative Cognitive Dysfunction JOURNAL OF ALZHEIMERS DISEASE VanDusen, K. W., Li, Y., Cai, V., Hall, A., Hiles, S., Thompson, J., Moseley, M., Cooter, M., Acker, L., Levy, J. H., Ghadimi, K., Quinones, Q. J., Devinney, M. J., Chung, S., Terrando, N., Moretti, E. W., Browndyke, J. N., Mathew, J. P., Berger, M., MADCO-PC Investigators 2021; 80 (3): 1281-1297

  Abstract

  Postoperative cognitive dysfunction (POCD), a syndrome of cognitive deficits occurring 1-12 months after surgery primarily in older patients, is associated with poor postoperative outcomes. POCD is hypothesized to result from neuroinflammation; however, the pathways involved remain unclear. Unbiased proteomic analyses have been used to identify neuroinflammatory pathways in multiple neurologic diseases and syndromes but have not yet been applied to POCD.To utilize unbiased mass spectrometry-based proteomics to identify potential neuroinflammatory pathways underlying POCD.Unbiased LC-MS/MS proteomics was performed on immunodepleted cerebrospinal fluid (CSF) samples obtained before, 24 hours after, and 6 weeks after major non-cardiac surgery in older adults who did (n = 8) or did not develop POCD (n = 6). Linear mixed models were used to select peptides and proteins with intensity differences for pathway analysis.Mass spectrometry quantified 8,258 peptides from 1,222 proteins in > 50%of patient samples at all three time points. Twelve peptides from 11 proteins showed differences in expression over time between patients with versus withoutPOCD (q < 0.05), including proteins previously implicated in neurodegenerative disease pathophysiology. Additionally, 283 peptides from 182 proteins were identified with trend-level differences (q < 0.25) in expression over time between these groups. Among these, pathway analysis revealed that 50 were from 17 proteins mapping to complement and coagulation pathways (q = 2.44*10-13).These data demonstrate the feasibility of performing unbiased mass spectrometry on perioperative CSF samples to identify pathways associated with POCD. Additionally, they provide hypothesis-generating evidence for CSF complement and coagulation pathway changes in patients with POCD.

  View details for DOI 10.3233/JAD-201544

  View details for Web of Science ID 000637899200032

  View details for PubMedID 33682719

  View details for PubMedCentralID PMC8052629

• <i>APOE4</i> Copy Number-Dependent Proteomic Changes in the Cerebrospinal Fluid JOURNAL OF ALZHEIMERS DISEASE Berger, M., Cooter, M., Roesler, A. S., Chung, S., Park, J., Modliszewski, J. L., VanDusen, K. W., Thompson, J., Moseley, A., Devinney, M. J., Smani, S., Hall, A., Cai, V., Browndyke, J. N., Lutz, M. W., Corcoran, D. L., Alzheimers Dis Neuroimaging Initia 2021; 79 (2): 511-530

  Abstract

  APOE4 has been hypothesized to increase Alzheimer's disease risk by increasing neuroinflammation, though the specific neuroinflammatory pathways involved are unclear.Characterize cerebrospinal fluid (CSF) proteomic changes related to APOE4 copy number.We analyzed targeted proteomic data from ADNI CSF samples using a linear regression model adjusting for age, sex, and APOE4 copy number, and additional linear models also adjusting for AD clinical status or for CSF Aβ, tau, or p-tau levels. False discovery rate was used to correct for multiple comparisons correction.Increasing APOE4 copy number was associated with a significant decrease in a CRP peptide level across all five models (q < 0.05 for each), and with significant increases in ALDOA, CH3L1 (YKL-40), and FABPH peptide levels (q < 0.05 for each) except when controlling for AD clinical status or neurodegeneration biomarkers (i.e., CSF tau or p-tau). In all models except the one controlling for CSF Aβ levels, though not statistically significant, there was a consistent inverse direction of association between APOE4 copy number and the levels of all 24 peptides from all 8 different complement proteins measured. The odds of this happening by chance for 24 unrelated peptides would be less than 1 in 16 million.Increasing APOE4 copy number was associated with decreased CSF CRP levels across all models, and increased CSF ALDOA, CH3L1, and FABH levels when controlling for CSF Aβ levels. Increased APOE4 copy number may also be associated with decreased CSF complement pathway protein levels, a hypothesis for investigation in future studies.

  View details for DOI 10.3233/JAD-200747

  View details for Web of Science ID 000611560100005

  View details for PubMedID 33337362

  View details for PubMedCentralID PMC7902966

• Relationship Between Depression/Anxiety and Cognitive Function Before and 6 Weeks After Major Non-Cardiac Surgery in Older Adults JOURNAL OF GERIATRIC PSYCHIATRY AND NEUROLOGY Oyeyemi, D. M., Cooter, M., Chung, S., Whitson, H. E., Browndyke, J. N., Devinney, M. J., Smith, P. J., Garrigues, G. E., Moretti, E., Moul, J. W., Cohen, H., Mathew, J. P., Berger, M., MADCO-PC Study Team Investigators 2022; 35 (1): 145-154

  Abstract

  To determine the relationship between affective measures and cognition before and after non-cardiac surgery in older adults.Observational prospective cohort study in 103 surgical patients age ≥ 60 years old. All participants underwent cognitive testing, Center for Epidemiologic Studies-Depression, and State Anxiety Inventory screening before and 6 weeks after surgery. Cognitive test scores were combined by factor analysis into 4 cognitive domains, whose mean was defined as the continuous cognitive index (CCI). Postoperative global cognitive change was defined by CCI change from before to after surgery, with negative CCI change indicating worsened postoperative global cognition and vice versa.Lower global cognition before surgery was associated with greater baseline depression severity (Spearman's r = -0.30, p = 0.002) and baseline anxiety severity (Spearman's r = -0.25, p = 0.010), and these associations were similar following surgery (r = -0.36, p < 0.001; r = -0.26, p = 0.008, respectively). Neither baseline depression or anxiety severity, nor postoperative changes in depression or anxiety severity, were associated with pre- to postoperative global cognitive change.Greater depression and anxiety severity were each associated with poorer cognitive performance both before and after surgery in older adults. Yet, neither baseline depression or anxiety symptoms, nor postoperative change in these symptoms, were associated with postoperative cognitive change.

  View details for DOI 10.1177/0891988720978791

  View details for Web of Science ID 000609705900001

  View details for PubMedID 33380241

  View details for PubMedCentralID PMC8243391

• Necessary Heroes and Ethos, from Fighting Nazis to COVID-19 ANESTHESIOLOGY Berger, M., Ghadimi, K. 2020; 133 (6): 1307-1310

  View details for DOI 10.1097/ALN.0000000000003488

  View details for Web of Science ID 000587822100022

  View details for PubMedID 32701574

  View details for PubMedCentralID PMC7386672

• Association Between Exposure to General Versus Regional Anesthesia and Risk of Dementia in Older Adults JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Velkers, C., Berger, M., Gill, S. S., Eckenhoff, R., Stuart, H., Whitehead, M., Austin, P. C., Rochon, P. A., Seitz, D. 2021; 69 (1): 58-67

  Abstract

  Cognitive changes are commonly observed in older adults following surgical procedures. There are concerns that exposure to general anesthesia (GA) may contribute to an increased risk of Alzheimer's disease. Our study examined the associations between exposure to GA compared with regional anesthesia (RA) administered for elective surgical procedures and the development of dementia.Population-based propensity matched retrospective cohort study.Linked administrative databases were accessed from ICES (formerly called the Institute for Clinical Evaluative Services) in Ontario, Canada.We included all community-dwelling individuals aged 66 and older who underwent one of five elective surgical procedures in Ontario, Canada, between April 1, 2007, and March 31, 2011. Individuals with evidence of dementia preceding cohort entry were excluded. Individuals who received GA were matched within surgical procedures to those who received RA on age, sex, cohort entry year, and a propensity score to control for potential confounders.The baseline characteristics of the study sample were compared before and after matching. Individuals were followed for up to 5 years following cohort entry for the occurrence of dementia using a validated algorithm. Cox proportional hazards analysis was used to determine the hazard ratio (HR) and 95% confidence interval (CI) for the association between anesthetic type and dementia. Subgroup and sensitivity analyses were undertaken.A total of 7,499 matched pairs were included in the final analysis. Overall, no difference was observed in the risk of being diagnosed with dementia for individuals who received GA when compared with RA (HR = 1.0; 95% CI = .8-1.2). There was also no association between anesthesia and dementia in most subgroup and sensitivity analyses.Elective surgery using GA was not associated with an overall elevated risk of dementia when compared with RA. Future studies are required to determine whether surgery is a risk factor for dementia irrespective of anesthetic technique.

  View details for DOI 10.1111/jgs.16834

  View details for Web of Science ID 000575390100001

  View details for PubMedID 33025584

  View details for PubMedCentralID PMC7942805

• Local Anesthesia Can Reduce Complications in Adults Undergoing Umbilical Hernia Repair Meier, J., Berger, M., Cullum, M., Lee, S. C., Zeh, H. J., Brown, C., Balentine, C. ELSEVIER SCIENCE INC. 2020: S100-S101

  View details for Web of Science ID 000582792300174

• A New Severity Scoring Scale for the 3-Minute Confusion Assessment Method (3D-CAM) JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Vasunilashorn, S. M., Devinney, M. J., Acker, L., Jung, Y., Ngo, L., Cooter, M., Huang, R., Marcantonio, E. R., Berger, M. 2020; 68 (8): 1874-1876

  View details for DOI 10.1111/jgs.16538

  View details for Web of Science ID 000539454100001

  View details for PubMedID 32479640

  View details for PubMedCentralID PMC7429287

• Developing a Real-time EEG-guided Anesthesia Management curriculum for Educating Residents (DREAMER): A randomized controlled trial Eleswarpu, S., Berger, M., Cooter, M., Udani, A. D., Heflin, M. T., Bengali, S., Ray, A., Wingfield, S. LIPPINCOTT WILLIAMS & WILKINS. 2020: 413

  View details for Web of Science ID 000619264500193

• Neurovascular and immune mechanisms that regulate postoperative delirium superimposed on dementia ALZHEIMERS & DEMENTIA Wang, P., Velagapudi, R., Kong, C., Rodriguiz, R. M., Wetsel, W. C., Yang, T., Berger, M., Gelbard, H. A., Colton, C. A., Terrando, N. 2020; 16 (5): 734-749

  Abstract

  The present work evaluates the relationship between postoperative immune and neurovascular changes and the pathogenesis of surgery-induced delirium superimposed on dementia.Postoperative delirium is a common complication in many older adults and in patients with dementia including Alzheimer's disease (AD). The course of delirium can be particularly debilitating, while its pathophysiology remains poorly defined.As of 2019, an estimated 5.8 million people of all ages have been diagnosed with AD, 97% of whom are >65 years of age. Each year, many of these patients require surgery. However, anesthesia and surgery can increase the risk for further cognitive decline. Surgery triggers neuroinflammation both in animal models and in humans, and a failure to resolve this inflammatory state may contribute to perioperative neurocognitive disorders as well as neurodegenerative pathology.We propose an immunovascular hypothesis whereby dysregulated innate immunity negatively affects the blood-brain interface, which triggers delirium and thereby exacerbates AD neuropathology.We have developed a translational model to study delirium superimposed on dementia in APPSwDI/mNos2-/- AD mice (CVN-AD) after orthopedic surgery. At 12 months of age, CVN-AD showed distinct neuroimmune and vascular impairments after surgery, including acute microgliosis and amyloid-β deposition. These changes correlated with attention deficits, a core feature of delirium-like behavior.Future research should determine the extent to which prevention of surgery-induced microgliosis and/or neurovascular unit dysfunction can prevent or ameliorate postoperative memory and attention deficits in animal models. Translational human studies should evaluate perioperative indices of innate immunity and neurovascular integrity and assess their potential link to perioperative neurocognitive disorders.Understanding the complex relationships between delirium and dementia will require mechanistic studies aimed at evaluating the role of postoperative neuroinflammation and blood-brain barrier changes in the setting of pre-existing neurodegenerative and/or aging-related pathology.Non-resolving inflammation with vascular disease that leads to cognitive impairments and dementia is increasingly important in risk stratification for AD in the aging population. The interdependence of these factors with surgery-induced neuroinflammation and cognitive dysfunction is also becoming apparent, providing a strong platform for assessing the relationship between postoperative delirium and longer term cognitive dysfunction in older adults.

  View details for DOI 10.1002/alz.12064

  View details for Web of Science ID 000577868700003

  View details for PubMedID 32291962

  View details for PubMedCentralID PMC7317948

• A Plague on Both Your Monitors! Are Bispectral Index and Cerebral Oximetry Useful for Reducing Postoperative Cognitive Impairment? JOURNAL OF CARDIOTHORACIC AND VASCULAR ANESTHESIA Klinger, R. Y., Bottiger, B., Berger, M. 2020; 34 (5): 1182-1183

  View details for DOI 10.1053/j.jvca.2020.01.001

  View details for Web of Science ID 000527819800009

  View details for PubMedID 32029372

• Of Parachutes, Speedometers, and EEG: What Evidence Do We Need to Use Devices and Monitors? ANESTHESIA AND ANALGESIA Berger, M., Mark, J. B., Kreuzer, M. 2020; 130 (5): 1274-1277

  View details for DOI 10.1213/ANE.0000000000004653

  View details for Web of Science ID 000528835700041

  View details for PubMedID 32287134

  View details for PubMedCentralID PMC7735682

• The SANDMAN Study: Sleep Apnea, Neuroinflammation, and Cognitive Dysfunction Manifesting After Non-cardiac surgery Devinney, M., Spector, A. R., Browndyke, J. N., Smith, P. J., Dominguez, J., Dominguez, A. M., Cooter, M., Eleswarpu, S., Bunning, T., VanDusen, K. W., Avasarala, P., Cai, V., Mathew, J. P., Berger, M. LIPPINCOTT WILLIAMS & WILKINS. 2020: 514-515

  View details for Web of Science ID 000619264500246

• Cognitive and Cerebrospinal fluid Alzheimer's Disease biomarker changes over time in older surgical patients and matched nonsurgical controls Ha, C., Cheong, V., Cooter, M., Browndyke, J. N., Moretti, E., Bullock, W. M., Colin, B. J., Devinney, M., Whittle, J., Ferrandino, M., Gadsden, J., Habib, A. S., Lemm, J., Moul, J. W., Ohlendorf, B., Quinones, Q. J., Runyon, S., Sandler, A., Young, C., Whitson, H. E., Cohen, H. J., Mathew, J. P., Berger, M. LIPPINCOTT WILLIAMS & WILKINS. 2020: 502

  View details for Web of Science ID 000619264500236

• The MARBLE Study: Modulating ApoE signaling to Reduce Brain inflammation, deLirium, and postopErative Cognitive Dysfunction VanDusen, K. W., Eleswarpu, S., Moretti, E., Devinney, M., Roberts, K., Cooter, M., Laskowitz, D. T., Rockhold, F. W., Berger, M. LIPPINCOTT WILLIAMS & WILKINS. 2020: 432-433

  View details for Web of Science ID 000619264500203

• A protocol to reduce self-reported pain scores and adverse events following lumbar punctures in older adults JOURNAL OF NEUROLOGY Nobuhara, C. K., Bullock, W., Bunning, T., Colin, B., Cooter, M., Devinney, M. J., Ferrandino, M. N., Gadsden, J., Garrigues, G., Habib, A. S., Moretti, E., Moul, J., Ohlendorf, B., Sandler, A., Scheri, R., Sharma, B., Thomas, J. P., Young, C., Mathew, J. P., Berger, M., MADCO-PC Investigator Team, INTUIT Investigator Team 2020; 267 (7): 2002-2006

  Abstract

  Lumbar punctures (LPs) are important for obtaining CSF in neurology studies but are associated with adverse events and feared by many patients. We determined adverse event rates and pain scores in patients prospectively enrolled in two cohort studies who underwent LPs using a standardized protocol and 25 g needle.Eight hundred and nine LPs performed in 262 patients age ≥ 60 years in the MADCO-PC and INTUIT studies were analyzed. Medical records were monitored for LP-related adverse events, and patients were queried about subjective complaints. We analyzed adverse event rates, including headaches and pain scores.There were 22 adverse events among 809 LPs performed, a rate of 2.72% (95% CI 1.71-4.09%). Patient hospital stay did not increase due to adverse events. Four patients (0.49%) developed a post-lumbar puncture headache (PLPH). Twelve patients (1.48%) developed nausea, vasovagal responses, or headaches that did not meet PLPH criteria. Six patients (0.74%) reported lower back pain at the LP site not associated with muscular weakness or paresthesia. The median pain score was 1 [0, 3]; the mode was 0 out of 10.The LP protocol described herein may reduce adverse event rates and improve patient comfort in future studies.

  View details for DOI 10.1007/s00415-020-09797-1

  View details for Web of Science ID 000520898400001

  View details for PubMedID 32198714

  View details for PubMedCentralID PMC7336280

• Response to 'Correlation between bispectral index and age-adjusted minimal alveolar concentration' (<i>Br J Anaesth</i> 2020; 124:e8) BRITISH JOURNAL OF ANAESTHESIA Berger, M., Cooter, M., Ni, K., Thomas, J., Gupta, D. K., Kertai, M. D. 2020; 124 (3): E38-E39

  View details for Web of Science ID 000514166800004

  View details for PubMedID 31983410

  View details for PubMedCentralID PMC7187794

• Postoperative Neurocognitive Disorders in the Geriatric Patient ESSENTIALS OF NEUROSURGICAL ANESTHESIA & CRITICAL CARE: STRATEGIES FOR PREVENTION, EARLY DETECTION, AND SUCCESSFUL MANAGEMENT OF PERIOPERATIVE COMPLICATIONS, 2ND EDITION Schenning, K. J., Berger, M., Brambrink, A. M., Kirsch 2020: 105-107

  View details for DOI 10.1007/978-3-030-17410-1_15

  View details for Web of Science ID 000582667500017

• The MARBLE Study Protocol: Modulating ApoE Signaling to Reduce Brain Inflammation, DeLirium, and PostopErative Cognitive Dysfunction JOURNAL OF ALZHEIMERS DISEASE VanDusen, K. W., Eleswarpu, S., Moretti, E. W., Devinney, M. J., Crabtree, D. M., Laskowitz, D. T., Woldorff, M. G., Roberts, K. C., Whittle, J., Browndyke, J. N., Cooter, M., Rockhold, F. W., Anakwenze, O., Bolognesi, M. P., Easley, M. E., Ferrandino, M. N., Jiraneki, W. A., Berger, M., Adams, S. B., Amundsen, C. L., Avasarala, P., Barber, M. D., Berchuck, A., Blazer, D. G., Brassard, R., Brigman, B. E., Cai, V., Christensen, S. K., Cox, M. W., Davidson, B. A., DeOrio, J. K., Erdmann, D., Erickson, M. M., Funk, B. L., Gadsden, J., Gage, M. J., Gingrich, J. R., Greenup, R. A., Ha, C., Habib, A., Hachem, R., Hall, A. E., Hartwig, M. G., Havrilesky, L. J., Heflin, M. T., Holland, C., Hollenbeck, S. T., Hopkins, T. J., Inman, B. A., Jang, D. W., Kahmke, R. R., Karikari, I., Kawasaki, A., Klapper, J. A., Klifto, C. S., Klinger, R., Knechtle, S. J., Lagoo-Deenadayalan, S. A., Lee, W. T., Levinson, H., Lewis, B. D., Lidsky, M. E., Lipkin, M. E., Mantyh, C. R., McDonald, S. R., Migaly, J., Miller, T. E., Mithani, S. K., Mosca, P. J., Moul, J. W., Novick, T. L., Olson, S. A., Pappas, T. N., Park, J. J., Peterson, A. C., Phillips, B. T., Polascik, T. J., Potash, P., Preminger, G. M., Previs, R. A., Robertson, C. N., Scales, C. D., Shah, K. N., Scheri, R. P., Siddiqui, N. Y., Smani, S., Southerland, K. W., Stang, M. T., Syed, A., Szydlowska, A., Thacker, J. M., Terrando, N., Toulgoat-DuBois, Y., Visco, A. G., Weidner, A. C., Yanamadala, M., Zani, S., MARBLE Study Investigators 2020; 75 (4): 1319-1328

  Abstract

  Perioperative neurocognitive disorders (PND) are common complications in older adults associated with increased 1-year mortality and long-term cognitive decline. One risk factor for worsened long-term postoperative cognitive trajectory is the Alzheimer's disease (AD) genetic risk factor APOE4. APOE4 is thought to elevate AD risk partly by increasing neuroinflammation, which is also a theorized mechanism for PND. Yet, it is unclear whether modulating apoE4 protein signaling in older surgical patients would reduce PND risk or severity.MARBLE is a randomized, blinded, placebo-controlled phase II sequential dose escalation trial designed to evaluate perioperative administration of an apoE mimetic peptide drug, CN-105, in older adults (age≥60 years). The primary aim is evaluating the safety of CN-105 administration, as measured by adverse event rates in CN-105 versus placebo-treated patients. Secondary aims include assessing perioperative CN-105 administration feasibility and its efficacy for reducing postoperative neuroinflammation and PND severity.201 patients undergoing non-cardiac, non-neurological surgery will be randomized to control or CN-105 treatment groups and receive placebo or drug before and every six hours after surgery, for up to three days after surgery. Chart reviews, pre- and postoperative cognitive testing, delirium screening, and blood and CSF analyses will be performed to examine effects of CN-105 on perioperative adverse event rates, cognition, and neuroinflammation. Trial results will be disseminated by presentations at conferences and peer-reviewed publications.MARBLE is a transdisciplinary study designed to measure CN-105 safety and efficacy for preventing PND in older adults and to provide insight into the pathogenesis of these geriatric syndromes.

  View details for DOI 10.3233/JAD-191185

  View details for Web of Science ID 000550022100022

  View details for PubMedID 32417770

  View details for PubMedCentralID PMC7923142

• Age-dependent decrease in minimum alveolar concentration of inhaled anaesthetics: a systematic search of published studies and meta-regression analysis BRITISH JOURNAL OF ANAESTHESIA Cooter, M., Ni, K., Thomas, J., Gupta, D. K., Hopkins, T. J., Miller, T. E., James, M. L., Kertai, M. D., Berger, M. 2020; 124 (1): E4-E7

  View details for DOI 10.1016/j.bja.2019.09.037

  View details for Web of Science ID 000503385700003

  View details for PubMedID 31679750

  View details for PubMedCentralID PMC7034808

• State of the clinical science of perioperative brain health: report from the American Society of Anesthesiologists Brain Health Initiative Summit 2018 (vol 123, pg 464, 2019) BRITISH JOURNAL OF ANAESTHESIA Mahanna-Gabrielli, E., Schenning, K. J., Eriksson, L. I., Browndyke, J. N., Wright, C. B., Culley, D. J., Evered, L., Scott, D. A., Wang, N., Brown, C. H., Oh, E., Purdon, P., Inouye, S., Berger, M., Whittington, R. A., Price, C. C., Deiner, S. 2019; 123 (6): 917

  View details for DOI 10.1016/j.bja.2019.09.014

  View details for Web of Science ID 000496915500023

  View details for PubMedID 31591017

  View details for PubMedCentralID PMC6883482

• Flow Cytometry Characterization of Cerebrospinal Fluid Monocytes in Patients With Postoperative Cognitive Dysfunction: A Pilot Study ANESTHESIA AND ANALGESIA Berger, M., Murdoch, D. M., Staats, J. S., Chan, C., Thomas, J. P., Garrigues, G. E., Browndyke, J. N., Cooter, M., Quinones, Q. J., Mathew, J. P., Weinhold, K. J., Young, C., Amundsen, C. L., Bengali, S., Brigman, B. E., Bullock, W., Carter, J., Chapman, J., Ching, V., Cohen, H. J., Colin, B., D'Amico, T. A., Devinney, M. J., DeOrio, J. K., Ellet, T., Esclamado, R. M., Ferrandino, M. N., Gadsden, J., Guercio, J., Habib, A., Harpole, D. H., Hartwig, M. G., Iboaya, E., Inman, B. A., Khan, A., Lagoo-Deenadayalan, S., Lee, P. S., Lee, W. T., Lemm, J., Levinson, H., Mantyh, C., McDonagh, D. L., Migaly, J., Mithani, S. K., Moretti, E., Moul, J. W., Newman, M. F., Ni, K., Ohlendorf, B., Perez, A., Peterson, A. C., Ponussamy, V., Preminger, G. M., Robertson, C. N., Roman, S. A., Runyon, S., Sandler, A., Scheri, R. P., Smith, S., Talbot, L., Thacker, J. M., Tong, B. C., Tu, A., Vaslef, S. N., Waldron, N., Wang, X., Whitson, H., Wickenheisser, V., MADCO-PC Study Team 2019; 129 (5): E150-E154

  Abstract

  Animal models suggest postoperative cognitive dysfunction may be caused by brain monocyte influx. To study this in humans, we developed a flow cytometry panel to profile cerebrospinal fluid (CSF) samples collected before and after major noncardiac surgery in 5 patients ≥60 years of age who developed postoperative cognitive dysfunction and 5 matched controls who did not. We detected 12,654 ± 4895 cells/10 mL of CSF sample (mean ± SD). Patients who developed postoperative cognitive dysfunction showed an increased CSF monocyte/lymphocyte ratio and monocyte chemoattractant protein 1 receptor downregulation on CSF monocytes 24 hours after surgery. These pilot data demonstrate that CSF flow cytometry can be used to study mechanisms of postoperative neurocognitive dysfunction.

  View details for DOI 10.1213/ANE.0000000000004179

  View details for Web of Science ID 000490258700003

  View details for PubMedID 31085945

  View details for PubMedCentralID PMC6800758

• State of the clinical science of perioperative brain health: report from the American Society of Anesthesiologists Brain Health Initiative Summit 2018 BRITISH JOURNAL OF ANAESTHESIA Mahanna-Gabrielli, E., Schenning, K. J., Eriksson, L., Browndyke, J. N., Wright, C. B., Evered, L., Scott, D. A., Wang, N., Brown, C. H., Oh, E., Purdon, P., Inouye, S., Berger, M., Whittington, R. A., Deiner, S. 2019; 123 (4): 464-478

  Abstract

  Cognitive recovery after anaesthesia and surgery is a concern for older adults, their families, and caregivers. Reports of patients who were 'never the same' prompted a scientific inquiry into the nature of what patients have experienced. In June 2018, the ASA Brain Health Initiative held a summit to discuss the state of the science on perioperative cognition, and to create an implementation plan for patients and providers leveraging the current evidence. This group included representatives from the AARP (formerly the American Association of Retired Persons), American College of Surgeons, American Heart Association, and Alzheimer's Association Perioperative Cognition and Delirium Professional Interest Area. This paper summarises the state of the relevant clinical science, including risk factors, identification and diagnosis, prognosis, disparities, outcomes, and treatment of perioperative neurocognitive disorders. Finally, we discuss gaps in current knowledge with suggestions for future directions and opportunities for clinical and translational projects.

  View details for DOI 10.1016/j.bja.2019.07.004

  View details for Web of Science ID 000485836200056

  View details for PubMedID 31439308

  View details for PubMedCentralID PMC6871269

• In Response. Anesthesia and analgesia Berger, M., Angst, M. S., Culley, D. J., Price, C. E., Scott, D. A., Whittington, R. A., Eckenhoff, R. G. 2019; 129 (3): e112-e113

  View details for DOI 10.1213/ANE.0000000000004300

  View details for PubMedID 31425253

• Paradox of age: older patients receive higher age-adjusted minimum alveolar concentration fractions of volatile anaesthetics yet display higher bispectral index values BRITISH JOURNAL OF ANAESTHESIA Ni, K., Cooter, M., Gupta, D. K., Thomas, J., Hopkins, T. J., Miller, T. E., James, M. L., Kertai, M. D., Berger, M. 2019; 123 (3): 288-297

  Abstract

  Minimum alveolar concentration (MAC) and MAC-awake decrease with age. We hypothesised that, in clinical practice, (i) end-tidal MAC fraction in older patients would decline by less than the predicted age-dependent MAC decrease (i.e. older patients would receive relatively excessive anaesthetic concentrations), and (ii) bispectral index (BIS) values would therefore be lower in older patients.We examined the relationship between end-tidal MAC fraction, BIS values, and age in 4699 patients > 30 yr in age at a single centre using unadjusted local regression (locally estimated scatterplot smoothing), Spearman's correlation, stratification, and robust univariable and multivariable linear regression.The end-tidal MAC fraction in older patients declined by 3.01% per decade (95% confidence interval [CI]: 2.56-3.45; P<0.001), less than the 6.47% MAC decrease per decade that we found in a meta-regression analysis of published studies of age-dependent changes in MAC (P<0.001), and less than the age-dependent decrease in MAC-awake. The BIS values correlated positively with age (ρ=0.15; 95% CI: 0.12-0.17; P<0.001), and inversely with the age-adjusted end-tidal MAC (aaMAC) fraction (ρ= -0.13; 95% CI: -0.16, -0.11; P<0.001).The age-dependent decline in end-tidal MAC fraction delivered in clinical practice at our institution was less than the age-dependent percentage decrease in MAC and MAC-awake determined from published studies. Despite receiving higher aaMAC fractions, older patients paradoxically showed higher BIS values. This most likely suggests that the BIS algorithm is inaccurate in older adults.

  View details for DOI 10.1016/j.bja.2019.05.040

  View details for Web of Science ID 000480437100038

  View details for PubMedID 31279479

  View details for PubMedCentralID PMC7104362

• Impact of Cognitive Impairment Across Specialties: Summary of a Report From the U13 Conference Series JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Carpenter, C. R., McFarland, F., Avidan, M., Berger, M., Inouye, S. K., Karlawish, J., Lin, F. R., Marcantonio, E., Morris, J. C., Reuben, D. B., Shah, R. C., Whitson, H. E., Asthana, S., Verghese, J. 2019; 67 (10): 2011-2017

  Abstract

  Although declines in cognitive capacity are assumed to be a characteristic of aging, increasing evidence shows that it is age-related disease, rather than age itself, that causes cognitive impairment. Even so, older age is a primary risk factor for cognitive decline, and with individuals living longer as a result of medical advances, cognitive impairment and dementia are increasing in prevalence. On March 26 to 27, 2018, the American Geriatrics Society convened a conference in Bethesda, MD, to explore cognitive impairment across the subspecialties. Bringing together representatives from several subspecialties, this was the third of three conferences, supported by a U13 grant from the National Institute on Aging, to aid recipients of Grants for Early Medical/Surgical Specialists' Transition to Aging Research (GEMSSTAR) in integrating geriatrics into their subspecialties. Scientific sessions focused on the impact of cognitive impairment, sensory contributors, comorbidities, links between delirium and dementia, and issues of informed consent in cognitively impaired populations. Discussions highlighted the complexity not only of cognitive health itself, but also of the bidirectional relationship between cognitive health and the health of other organ systems. Thus, conference participants noted the importance of multidisciplinary team science in future aging research. This article summarizes the full conference report, "The Impact of Cognitive Impairment Across Specialties," and notes areas where GEMSSTAR scholars can contribute to progress as they embark on their careers in aging research. J Am Geriatr Soc 67:2011-2017, 2019.

  View details for DOI 10.1111/jgs.16093

  View details for Web of Science ID 000482735300001

  View details for PubMedID 31436318

  View details for PubMedCentralID PMC6800784

• In Response. Anesthesia and analgesia Berger, M., Angst, M. S., Culley, D. J., Price, C. E., Scott, D. A., Whittington, R. A., Eckenhoff, R. G., Perioperative Neurotoxicity Working Group 2019

  View details for DOI 10.1213/ANE.0000000000004300

  View details for PubMedID 31283620

• Intravenous Lidocaine Does Not Improve Neurologic Outcomes after Cardiac Surgery A Randomized Controlled Trial ANESTHESIOLOGY Klinger, R. Y., Cooter, M., Bisanar, T., Terrando, N., Berger, M., Podgoreanu, M., Stafford-Smith, M., Newman, M. F., Mathew, J. P., Mathew, O. P., Blumenthal, J. A., Karhausen, J. A., Kertai, M. D., Krishnamoorthy, V., Newman, M., Podgorcanu, M., Swaminathan, M., Wamer, D. S., Funk, B. L., Brassard, R., Toulgoat-Dubois, Y., Waweru, P., Babyak, M. A., Browndyke, J. N., Awelsh-Bohmer, K., Sketch, M. H., Bennett, E. R., Graffagnino, C., Laskowitz, D. T., Strittmatter, W. J., Collins, K., Smigla, G., Shearer, I., D'Amico, T. A., Daneshmand, M. A., Gaca, J. G., Glower, D. D., Haney, J., Harpole, D., Hartwig, M. G., Hughes, G., Klapper, A. A., Lin, S. S., Lodge, A. J., Milano, C. A., Plichta, R. P., Schroeder, J. N., Smith, P. K., Tong, B. C., Duke Heart Ctr 2019; 130 (6): 958-970

  Abstract

  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.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.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.Intravenous lidocaine administered during and after cardiac surgery did not reduce postoperative cognitive decline at 6 weeks.

  View details for DOI 10.1097/ALN.0000000000002668

  View details for Web of Science ID 000467856100014

  View details for PubMedID 30870159

  View details for PubMedCentralID PMC6520120

• THE SANDMAN STUDY: SLEEP APNEA, NEUROINFLAMMATION, AND COGNITIVE DYSFUNCTION MANIFESTING AFTER NON-CARDIAC SURGERY Devinney, M., Spector, A. R., Browndyke, J. N., Smith, P. J., Dominguez, J., Bunning, T., Cooter, M., Mathew, J. P., Berger, M. LIPPINCOTT WILLIAMS & WILKINS. 2019: 918

  View details for Web of Science ID 000619263200429

• THE INTUIT STUDY: INVESTIGATING NEUROINFLAMMATION UNDERLYING POSTOPERATIVE NEUROCOGNITIVE DYSFUNCTION AND DELIRIUM IN OLDER ADULTS Bunning, T., Whitson, H. E., Weinhold, K., Woldorff, M. G., Moretti, E., Oyeyemi, D., Cooter, M., Chan, C., Cabeza, R., Browndyke, J. N., Murdoch, D., Devinney, M., Shaw, L., Cohen, H. J., Mathew, J. P., Berger, M. LIPPINCOTT WILLIAMS & WILKINS. 2019: 432

  View details for Web of Science ID 000619263200211

• INTRA-OPERATIVE ELECTROENCEPHALOGRAM CORRELATES OF POST-OPERATIVE NEUROCOGNITIVE RESILIENCE IN OLDER ADULTS Acker, L., Berger, M., Zhou, J., Lipsitz, L., Woldorff, M. G., Whitson, H. E. LIPPINCOTT WILLIAMS & WILKINS. 2019: 489

  View details for Web of Science ID 000619263200233

• METABOLIPIDOMIC ANALYSIS OF CEREBROSPINAL FLUID REVEALS INCREASED ARACHIDONIC ACID-DERIVED LIPIDS AND SPECIALIZED PRO-RESOLVING MEDIATORS 24 HRS AND 6-WEEKS FOLLOWING SURGERY AND ANESTHESIA Devinney, M., Maddipati, K., Chan, C., Mathew, J. P., Cooter, M., Terrando, N., Berger, M. LIPPINCOTT WILLIAMS & WILKINS. 2019: 485-486

  View details for Web of Science ID 000619263200231

• The INTUIT Study: Investigating Neuroinflammation Underlying Postoperative Cognitive Dysfunction JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Berger, M., Oyeyemi, D., Olurinde, M. O., Whitson, H. E., Weinhold, K. J., Woldorff, M. G., Lipsitz, L. A., Moretti, E., Giattino, C. M., Roberts, K. C., Zhou, J., Bunning, T., Ferrandino, M., Scheri, R. P., Cooter, M., Chan, C., Cabeza, R., Browndyke, J. N., Murdoch, D. M., Devinney, M. J., Shaw, L. M., Cohen, H., Mathew, J. P., Akinyemi, O., Amundsen, C., Avasarala, P., Barber, M., Beach, R., Berchuck, A., Blazer, D. G., Bolognesi, M., Brassard, R., Bullock, W., Burke, A., Cai, V., Cheong, V., Christensen, S., Cox, M., Crabtree, D., D'Amico, T., Davidson, B., DeOrio, J. K., Easley, M. E., Ehieli, E., Enzor, J. H., Erdmann, D., Funk, B., Gadsden, J., Garrigues, G. E., Greenup, R., Habib, A., Harpole, D., Hartwig, M., Havrilesky, L., Henley, T., Holland, C., Hollenbeck, S., Huang, R., Iboaya, E., Kawasaki, A., Klapper, J., Knechtle, S. J., Lagoo-Deenadayalan, S., Lee, W. T., Lewis, B. D., Lipkin, M., Litchfield, H., Marlor, E., Maxwell, C., Migaly, J., Moul, J., Olson, S., Pappas, T., Pellom, G., Peterson, A., Podgoreanu, A., Polascik, T., Preminger, G., Previs, R., Rampersaud, E., Renne, A., Roman, S., Sanders, E., Sandler, A., Scales, C. D., Seymour, K., Shah, K. N., Stang, J., Stanley, S., Sweeney, K., Szydlowska, A., Terrando, N., Thacker, J., Thomas, J., Tong, B. C., Toulgoat-DuBois, Y., Wellman, S., Williams, D., Zani, S., INTUIT Investigators 2019; 67 (4): 794-798

  Abstract

  Every year, up to 40% of the more than 16 million older Americans who undergo anesthesia/surgery develop postoperative cognitive dysfunction (POCD) or delirium. Each of these distinct syndromes is associated with decreased quality of life, increased mortality, and a possible increased risk of Alzheimer's disease. One pathologic process hypothesized to underlie both delirium and POCD is neuroinflammation. The INTUIT study described here will determine the extent to which postoperative increases in cerebrospinal fluid (CSF) monocyte chemoattractant protein 1 (MCP-1) levels and monocyte numbers are associated with delirium and/or POCD and their underlying brain connectivity changes.Observational prospective cohort.Duke University Medical Center, Duke Regional Hospital, and Duke Raleigh Hospital.Patients 60 years of age or older (N = 200) undergoing noncardiac/nonneurologic surgery.Participants will undergo cognitive testing before, 6 weeks, and 1 year after surgery. Delirium screening will be performed on postoperative days 1 to 5. Blood and CSF samples are obtained before surgery, and 24 hours, 6 weeks, and 1 year after surgery. CSF MCP-1 levels are measured by enzyme-linked immunosorbent assay, and CSF monocytes are assessed by flow cytometry. Half the patients will also undergo pre- and postoperative functional magnetic resonance imaging scans. 32-channel intraoperative electroencephalogram (EEG) recordings will be performed to identify intraoperative EEG correlates of neuroinflammation and/or postoperative cognitive resilience. Eighty patients will also undergo home sleep apnea testing to determine the relationships between sleep apnea severity, neuroinflammation, and impaired postoperative cognition. Additional assessments will help evaluate relationships between delirium, POCD, and other geriatric syndromes.INTUIT will use a transdisciplinary approach to study the role of neuroinflammation in postoperative delirium and cognitive dysfunction and their associated functional brain connectivity changes, and it may identify novel targets for treating and/or preventing delirium and POCD and their sequelae. J Am Geriatr Soc 67:794-798, 2019.

  View details for DOI 10.1111/jgs.15770

  View details for Web of Science ID 000464350900023

  View details for PubMedID 30674067

  View details for PubMedCentralID PMC6688749

• Workshop on Synergies Between Alzheimers Research and Clinical Gerontology and Geriatrics: Current Status and Future Directions (vol 10, pg 1229, 2018) JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES Brinkley, T. E., Berger, M., Callahan, K. E., Fieo, R. A., Jennings, L. A., Morris, J. K., Wilkins, H. M., Kritchevsky, S. B. 2019; 74 (3): 432

  View details for DOI 10.1093/gerona/gly156

  View details for Web of Science ID 000462192600020

  View details for PubMedID 30137213

  View details for PubMedCentralID PMC6784264

• Longitudinal Changes in Regional Cerebral Perfusion and Cognition After Cardiac Operation ANNALS OF THORACIC SURGERY Smith, P. J., Browndyke, J. N., Monge, Z. A., Harshbarger, T. B., James, M. L., Gaca, J. G., Alexander, J. H., Berger, M. M., Newman, M. F., Milano, C. A., Mathew, J. P., Neurologic Outcomes Res Grp NORG 2019; 107 (1): 112-118

  Abstract

  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.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.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 (β = 0.35, p = 0.016), whereas no important differences were found between the groups in vascular territory perfusion and cognition at 1 year.Cardiac operation is associated with important short-term increases in MCA perfusion with associated improvements in psychomotor speed.

  View details for DOI 10.1016/j.athoracsur.2018.07.056

  View details for Web of Science ID 000453013400047

  View details for PubMedID 30253158

  View details for PubMedCentralID PMC7087447

• Recommendations for the nomenclature of cognitive change associated with anaesthesia and surgery-2018 BRITISH JOURNAL OF ANAESTHESIA Evered, L., Silbert, B., Knopman, D. S., Scott, D. A., DeKosky, S. T., Rasmussen, L. S., Oh, E. S., Crosby, G., Berger, M., Eckenhoff, R. G., Nomenclature Consensus Working Grp 2018; 121 (5): 1005-1012

  Abstract

  Cognitive change affecting patients after anaesthesia and surgery has been recognised for more than 100 yr. Research into cognitive change after anaesthesia and surgery accelerated in the 1980s when multiple studies utilised detailed neuropsychological testing for assessment of cognitive change after cardiac surgery. This body of work consistently documented decline in cognitive function in elderly patients after anaesthesia and surgery, and cognitive changes have been identified up to 7.5 yr afterwards. Importantly, other studies have identified that the incidence of cognitive change is similar after non-cardiac surgery. Other than the inclusion of non-surgical control groups to calculate postoperative cognitive dysfunction, research into these cognitive changes in the perioperative period has been undertaken in isolation from cognitive studies in the general population. The aim of this work is to develop similar terminology to that used in cognitive classifications of the general population for use in investigations of cognitive changes after anaesthesia and surgery. A multispecialty working group followed a modified Delphi procedure with no prespecified number of rounds comprised of three face-to-face meetings followed by online editing of draft versions. Two major classification guidelines [Diagnostic and Statistical Manual for Mental Disorders, fifth edition (DSM-5) and National Institute for Aging and the Alzheimer Association (NIA-AA)] are used outside of anaesthesia and surgery, and may be useful for inclusion of biomarkers in research. For clinical purposes, it is recommended to use the DSM-5 nomenclature. The working group recommends that 'perioperative neurocognitive disorders' be used as an overarching term for cognitive impairment identified in the preoperative or postoperative period. This includes cognitive decline diagnosed before operation (described as neurocognitive disorder); any form of acute event (postoperative delirium) and cognitive decline diagnosed up to 30 days after the procedure (delayed neurocognitive recovery) and up to 12 months (postoperative neurocognitive disorder).

  View details for DOI 10.1016/j.bja.2017.11.087

  View details for Web of Science ID 000447406000006

  View details for PubMedID 30336844

  View details for PubMedCentralID PMC7069032

• Recommendations for the nomenclature of cognitive change associated with anaesthesia and surgery-2018 ACTA ANAESTHESIOLOGICA SCANDINAVICA Evered, L., Silbert, B., Knopman, D. S., Scott, D. A., DeKosky, S. T., Rasmussen, L. S., Oh, E. S., Crosby, G., Berger, M., Eckenhoff, R. G., Nomenclature Consensus Working Grp 2018; 62 (10): 1473-1480

  Abstract

  Cognitive change affecting patients after anaesthesia and surgery has been recognised for more than 100 yr. Research into cognitive change after anaesthesia and surgery accelerated in the 1980s when multiple studies utilised detailed neuropsychological testing for assessment of cognitive change after cardiac surgery. This body of work consistently documented decline in cognitive function in elderly patients after anaesthesia and surgery, and cognitive changes have been identified up to 7.5 yr afterwards. Importantly, other studies have identified that the incidence of cognitive change is similar after non-cardiac surgery. Other than the inclusion of non-surgical control groups to calculate postoperative cognitive dysfunction, research into these cognitive changes in the perioperative period has been undertaken in isolation from cognitive studies in the general population. The aim of this work is to develop similar terminology to that used in cognitive classifications of the general population for use in investigations of cognitive changes after anaesthesia and surgery. A multispecialty working group followed a modified Delphi procedure with no prespecified number of rounds comprised of three face-to-face meetings followed by online editing of draft versions. Two major classification guidelines [Diagnostic and Statistical Manual for Mental Disorders, fifth edition (DSM-5) and National Institute for Aging and the Alzheimer Association (NIA-AA)] are used outside of anaesthesia and surgery, and may be useful for inclusion of biomarkers in research. For clinical purposes, it is recommended to use the DSM-5 nomenclature. The working group recommends that 'perioperative neurocognitive disorders' be used as an overarching term for cognitive impairment identified in the preoperative or postoperative period. This includes cognitive decline diagnosed before operation (described as neurocognitive disorder); any form of acute event (postoperative delirium) and cognitive decline diagnosed up to 30 days after the procedure (delayed neurocognitive recovery) and up to 12 months (postoperative neurocognitive disorder).

  View details for DOI 10.1111/aas.13250

  View details for Web of Science ID 000447364900017

  View details for PubMedID 30325016

• Neurocognitive Function after Cardiac Surgery <i>From Phenotypes to Mechanisms</i> ANESTHESIOLOGY Berger, M., Terrando, N., Smith, S., Browndyke, J. N., Newman, M. F., Mathew, J. P. 2018; 129 (4): 829-851

  Abstract

  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.

  View details for DOI 10.1097/ALN.0000000000002194

  View details for Web of Science ID 000444808500032

  View details for PubMedID 29621031

  View details for PubMedCentralID PMC6148379

• Workshop on Synergies Between Alzheimer's Research and Clinical Gerontology and Geriatrics: Current Status and Future Directions JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES Brinkley, T. E., Berger, M., Callahan, K. E., Fieo, R. A., Jennings, L. A., Morris, J. K., Wilkins, H. M., Kritchevsky, S. B. 2018; 73 (9): 1229-1237

  Abstract

  Age is the strongest risk factor for physical disability and Alzheimer's disease (AD) and related dementias. As such, other aging-related risk factors are also shared by these two health conditions. However, clinical geriatrics and gerontology research has included cognition and depression in models of physical disability, with less attention to the pathophysiology of neurodegenerative disease. Similarly, AD research generally incorporates limited, if any, measures of physical function and mobility, and therefore often fails to consider the relevance of functional limitations in neurodegeneration. Accumulating evidence suggests that common pathways lead to physical disability and cognitive impairment, which jointly contribute to the aging phenotype. Collaborations between researchers focusing on the brain or body will be critical to developing, refining, and testing research paradigms emerging from a better understanding of the aging process and the interacting pathways contributing to both physical and cognitive disability. The National Institute of Aging sponsored a workshop to bring together the Claude D. Pepper Older Americans Independence Center and AD Center programs to explore areas of synergies between the research concerns of the two programs. This article summarizes the proceedings of the workshop and presents key gaps and research priorities at the intersection of AD and clinical aging research identified by the workshop participants.

  View details for DOI 10.1093/gerona/gly041

  View details for Web of Science ID 000441747200012

  View details for PubMedID 29982466

  View details for PubMedCentralID PMC6454460

• Postoperative Delirium and Postoperative Cognitive Dysfunction <i>Two Sides of the Same Coin</i>? ANESTHESIOLOGY Devinney, M. J., Mathew, J. P., Berger, M. 2018; 129 (3): 389-391

  View details for DOI 10.1097/ALN.0000000000002338

  View details for Web of Science ID 000441864900001

  View details for PubMedID 29965817

  View details for PubMedCentralID PMC6092234

• F-18-florbetapir Positron Emission Tomography-determined Cerebral -Amyloid Deposition and Neurocognitive Performance after Cardiac Surgery ANESTHESIOLOGY Klinger, R. Y., James, O. G., Borges-Neto, S., Bisanar, T., Li, Y., Qi, W., Berger, M., Terrando, N., Newman, M. F., Doraiswamy, P., Mathew, J. P., Alzheimers Dis Neuroimaging, NORG 2018; 128 (4): 728–44

  Abstract

  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.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.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.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.

  View details for PubMedID 29389750

  View details for PubMedCentralID PMC5849499

• Transnasal Transsphenoidal Elevation of Optic Chiasm in Secondary Empty Sella Syndrome Following Prolactinoma Treatment WORLD NEUROSURGERY Cobb, M., Crowson, M., Mintz-Cole, R., Husain, A. M., Berger, M., Jang, D., Codd, P. 2018; 112: 250-253

  Abstract

  Prolactinomas are typically treated nonsurgically with a dopamine agonist. Once the tumor shrinks, adjacent eloquent structures, such as the optic apparatus, can become skeletonized and herniate into the dilated parasellar space.A 48-year-old man with a prolactin-secreting macroadenoma treated with cabergoline presented with progressive bitemporal hemianopsia. Magnetic resonance imaging showed no recurrence of disease and a stretched optic chiasm herniating into an empty sella. Elevation of the optic chiasm via a transnasal transsphenoidal approach with ALLODERM graft and septal cartilage strut was performed. The patient was discharged home the next day with significant improvement in vision; magnetic resonance imaging showed interval elevation of the optic chiasm.We review secondary empty sella syndrome and discuss surgical strategies for optic chiasmapexy.

  View details for DOI 10.1016/j.wneu.2018.01.202

  View details for Web of Science ID 000432932700149

  View details for PubMedID 29421446

• IS OBSTRUCTIVE SLEEP APNEA ASSOCIATED WITH POSTOPERATIVE DELIRIUM AND COGNITIVE DECLINE? Devinney, M., Cheong, Y., Wickenheisser, V., Cooter, M., Dominguez, J., Berger, M. LIPPINCOTT WILLIAMS & WILKINS. 2018: 704-705

  View details for Web of Science ID 000460106500386

• PERIOPERATIVE TRAJECTORY OF ALZHEIMER'S DISEASE BIOMARKERS IN SURGICAL PATIENTS AND MATCHED NON-SURGICAL CONTROLS Cheong, Y., Cooter, M., Huang, R. L., Whitson, H. E., Cohen, H. J., Mathew, J. P., Berger, M. LIPPINCOTT WILLIAMS & WILKINS. 2018: 353-356

  View details for Web of Science ID 000460106500206

• Task-related changes in degree centrality and local coherence of the posterior cingulate cortex after major cardiac surgery in older adults HUMAN BRAIN MAPPING Browndyke, J. N., Berger, M., Smith, P. J., Harshbarger, T. B., Monge, Z. A., Panchal, V., Bisanar, T. L., Glower, D. D., Alexander, J. H., Cabeza, R., Welsh-Bohmer, K., Newman, M. F., Mathew, J. P., Duke Neurologic Outcomes Res Grp 2018; 39 (2): 985-1003

  Abstract

  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.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.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.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.

  View details for DOI 10.1002/hbm.23898

  View details for Web of Science ID 000419856200028

  View details for PubMedID 29164774

  View details for PubMedCentralID PMC5764802

• Best Practices for Postoperative Brain Health: Recommendations From the Fifth International Perioperative Neurotoxicity Working Group. Anesthesia and analgesia Berger, M. n., Schenning, K. J., Brown, C. H., Deiner, S. G., Whittington, R. A., Eckenhoff, R. G., Angst, M. S., Avramescu, S. n., Bekker, A. n., Brzezinski, M. n., Crosby, G. n., Culley, D. J., Eckenhoff, M. n., Eriksson, L. I., Evered, L. n., Ibinson, J. n., Kline, R. P., Kofke, A. n., Ma, D. n., Mathew, J. P., Maze, M. n., Orser, B. A., Price, C. C., Scott, D. A., Silbert, B. n., Su, D. n., Terrando, N. n., Wang, D. S., Wei, H. n., Xie, Z. n., Zuo, Z. n. 2018

  Abstract

  As part of the American Society of Anesthesiology Brain Health Initiative goal of improving perioperative brain health for older patients, over 30 experts met at the fifth International Perioperative Neurotoxicity Workshop in San Francisco, CA, in May 2016, to discuss best practices for optimizing perioperative brain health in older adults (ie, >65 years of age). The objective of this workshop was to discuss and develop consensus solutions to improve patient management and outcomes and to discuss what older adults should be told (and by whom) about postoperative brain health risks. Thus, the workshop was provider and patient oriented as well as solution focused rather than etiology focused. For those areas in which we determined that there were limited evidence-based recommendations, we identified knowledge gaps and the types of scientific knowledge and investigations needed to direct future best practice. Because concerns about perioperative neurocognitive injury in pediatric patients are already being addressed by the SmartTots initiative, our workshop discussion (and thus this article) focuses specifically on perioperative cognition in older adults. The 2 main perioperative cognitive disorders that have been studied to date are postoperative delirium and cognitive dysfunction. Postoperative delirium is a syndrome of fluctuating changes in attention and level of consciousness that occurs in 20%-40% of patients >60 years of age after major surgery and inpatient hospitalization. Many older surgical patients also develop postoperative cognitive deficits that typically last for weeks to months, thus referred to as postoperative cognitive dysfunction. Because of the heterogeneity of different tools and thresholds used to assess and define these disorders at varying points in time after anesthesia and surgery, a recent article has proposed a new recommended nomenclature for these perioperative neurocognitive disorders. Our discussion about this topic was organized around 4 key issues: preprocedure consent, preoperative cognitive assessment, intraoperative management, and postoperative follow-up. These 4 issues also form the structure of this document. Multiple viewpoints were presented by participants and discussed at this in-person meeting, and the overall group consensus from these discussions was then drafted by a smaller writing group (the 6 primary authors of this article) into this manuscript. Of course, further studies have appeared since the workshop, which the writing group has incorporated where appropriate. All participants from this in-person meeting then had the opportunity to review, edit, and approve this final manuscript; 1 participant did not approve the final manuscript and asked for his/her name to be removed.

  View details for PubMedID 30303868

• The Effect of Propofol vs. isoflurane anesthesia on Postoperative Changes in Cerebrospinal Fluid Cytokine levels: results from a randomized Trial FRONTIERS IN IMMUNOLOGY Berger, M., Ponnusamy, V., Greene, N., Cooter, M., Nadler, J. W., Friedman, A., McDonagh, D. L., Laskowitz, D. T., Newman, M. F., Shaw, L. M., Warner, D. S., Mathew, J. P., James, M. L., MAD-PIA Investigators 2017; 8: 1528

  Abstract

  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.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-1β, and TNF-α before and 24 h after intracranial surgery in these study patients.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-1β, 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.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.

  View details for DOI 10.3389/fimmu.2017.01528

  View details for Web of Science ID 000414908100001

  View details for PubMedID 29181002

  View details for PubMedCentralID PMC5694037

• Orbitocerebral Impalement: Case Discussion and Management Algorithm CRANIOMAXILLOFACIAL TRAUMA & RECONSTRUCTION Crowson, M., Berger, M., McCarthy, G. C., Powers, D. B. 2017; 10 (3): 225-229

  Abstract

  Orbitocerebral impalement by inanimate objects is a relatively uncommon event. If orbitocerebral impalement is suspected, management entails prompt referral to a trauma facility with neurosurgical, neuroanesthesiological, craniomaxillofacial, and ophthalmological expertise. The aim of this report is to describe the unique mechanism and perioperative considerations of a remarkable, deep orbitocerebral impalement from a walker brake lever through the orbital roof after a fall from standing. We discuss clinical vignette, evaluation, anesthetic approach, and considerations and review the literature on the epidemiology, pathophysiology, surgical and anesthetic management, and prognosis of this traumatic mechanism. We also offer a management algorithm that aims to streamline management.

  View details for DOI 10.1055/s-0036-1592098

  View details for Web of Science ID 000406508600010

  View details for PubMedID 28751948

  View details for PubMedCentralID PMC5526688

• Intraoperative Frontal Alpha-Band Power Correlates with Preoperative Neurocognitive Function in Older Adults FRONTIERS IN SYSTEMS NEUROSCIENCE Giattino, C. M., Gardner, J. E., Sbahi, F. M., Roberts, K. C., Cooter, M., Moretti, E., Browndyke, J. N., Mathew, J. P., Woldorff, M. G., Berger, M., MADCO-PC Investigators 2017; 11: 24

  Abstract

  Each year over 16 million older Americans undergo general anesthesia for surgery, and up to 40% develop postoperative delirium and/or cognitive dysfunction (POCD). Delirium and POCD are each associated with decreased quality of life, early retirement, increased 1-year mortality, and long-term cognitive decline. Multiple investigators have thus suggested that anesthesia and surgery place severe stress on the aging brain, and that patients with less ability to withstand this stress will be at increased risk for developing postoperative delirium and POCD. Delirium and POCD risk are increased in patients with lower preoperative cognitive function, yet preoperative cognitive function is not routinely assessed, and no intraoperative physiological predictors have been found that correlate with lower preoperative cognitive function. Since general anesthesia causes alpha-band (8-12 Hz) electroencephalogram (EEG) power to decrease occipitally and increase frontally (known as "anteriorization"), and anesthetic-induced frontal alpha power is reduced in older adults, we hypothesized that lower intraoperative frontal alpha power might correlate with lower preoperative cognitive function. Here, we provide evidence that such a correlation exists, suggesting that lower intraoperative frontal alpha power could be used as a physiological marker to identify older adults with lower preoperative cognitive function. Lower intraoperative frontal alpha power could thus be used to target these at-risk patients for possible therapeutic interventions to help prevent postoperative delirium and POCD, or for increased postoperative monitoring and follow-up. More generally, these results suggest that understanding interindividual differences in how the brain responds to anesthetic drugs can be used as a probe of neurocognitive function (and dysfunction), and might be a useful measure of neurocognitive function in older adults.

  View details for DOI 10.3389/fnsys.2017.00024

  View details for Web of Science ID 000401656200001

  View details for PubMedID 28533746

  View details for PubMedCentralID PMC5420579

• Resting-State Functional Connectivity and Cognition After Major Cardiac Surgery in Older Adults without Preoperative Cognitive Impairment: Preliminary Findings JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Browndyke, J. N., Berger, M., Harshbarger, T. B., Smith, P. J., White, W., Bisanar, T. L., Alexander, J. H., Gaca, J. G., Welsh-Bohmer, K., Newman, M. F., Mathew, J. P. 2017; 65 (1): E6-E12

  Abstract

  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.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.Academic medical center.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).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).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.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.

  View details for DOI 10.1111/jgs.14534

  View details for Web of Science ID 000394551300001

  View details for PubMedID 27858963

  View details for PubMedCentralID PMC5258858

• Effect of intravenous lidocaine on the transcerebral inflammatory response during cardiac surgery: a randomized-controlled trial CANADIAN JOURNAL OF ANESTHESIA-JOURNAL CANADIEN D ANESTHESIE Klinger, R. Y., Cooter, M., Berger, M., Podgoreanu, M. V., Stafford-Smith, M., Ortel, T. L., Welsby, I. J., Levy, J. H., Rinder, H. M., Newman, M. F., Mathew, J. P., Neurologic Outcomes Res Grp NORG, Duke Heart Ctr 2016; 63 (11): 1223-1232

  Abstract

  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.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.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.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).

  View details for DOI 10.1007/s12630-016-0704-0

  View details for Web of Science ID 000387504800003

  View details for PubMedID 27470233

  View details for PubMedCentralID PMC7097969

• Anesthetic Suppression of Thalamic High-Frequency Oscillations: Evidence that the Thalamus Is More Than Just a Gateway to Consciousness? ANESTHESIA AND ANALGESIA Berger, M., Garcia, P. S. 2016; 122 (6): 1737-1739

  View details for DOI 10.1213/ANE.0000000000001207

  View details for Web of Science ID 000376463000003

  View details for PubMedID 27195617

  View details for PubMedCentralID PMC4874518

• The Effect of Propofol Versus Isoflurane Anesthesia on Human Cerebrospinal Fluid Markers of Alzheimer's Disease: Results of a Randomized Trial JOURNAL OF ALZHEIMERS DISEASE Berger, M., Nadler, J. W., Friedman, A., McDonagh, D. L., Bennett, E. R., Cooter, M., Qi, W., Laskowitz, D. T., Ponnusamy, V., Newman, M. F., Shaw, L. M., Warner, D. S., Mathew, J. P., James, M. L., MAD-PIA Investigators 2016; 52 (4): 1299-1310

  Abstract

  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-β (Aβ).We asked whether isoflurane and propofol have differential effects on the tau/Aβ ratio (the primary outcome), and individual AD biomarkers. We also examined whether genetic/intraoperative factors influenced perioperative changes in AD biomarkers.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.The CSF tau/Aβ ratio did not differ between isoflurane- versus propofol-treated patients (p = 1.000). CSF tau/Aβ 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 Aβ 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).Neurosurgery/otolaryngology procedures are associated with an increase in the CSF tau/Aβ ratio, and this increase was not influenced by anesthetic type. The increased CSF tau/Aβ ratio was largely driven by increases in tau levels. Future work should determine the functional/prognostic significance of these perioperative CSF tau elevations.

  View details for DOI 10.3233/JAD-151190

  View details for Web of Science ID 000378792100013

  View details for PubMedID 27079717

  View details for PubMedCentralID PMC5938737

• Postoperative Cognitive Dysfunction: Minding the Gaps in Our Knowledge of a Common Postoperative Complication in the Elderly. Anesthesiology clinics Berger, M., Nadler, J. W., Browndyke, J., Terrando, N., Ponnusamy, V., Cohen, H. J., Whitson, H. E., Mathew, J. P. 2015; 33 (3): 517-50

  Abstract

  Postoperative cognitive dysfunction (POCD) is a common complication associated with significant morbidity and mortality in elderly patients. There is much interest in and controversy about POCD, reflected partly in the increasing number of articles published on POCD recently. Recent work suggests surgery may also be associated with cognitive improvement in some patients, termed postoperative cognitive improvement (POCI). As the number of surgeries performed worldwide approaches 250 million per year, optimizing postoperative cognitive function and preventing/treating POCD are major public health issues. In this article, we review the literature on POCD and POCI, and discuss current research challenges in this area.

  View details for DOI 10.1016/j.anclin.2015.05.008

  View details for PubMedID 26315636

• Intraoperative Glycemic Control to Prevent Delirium after Cardiac Surgery <i>Steering a Course between Scylla and Charybdis</i> ANESTHESIOLOGY Berger, M., Browndyke, J., Mathew, J. P. 2015; 122 (6): 1186-1188

  View details for DOI 10.1097/ALN.0000000000000670

  View details for Web of Science ID 000363534400002

  View details for PubMedID 25844843

• G alpha(i/o)-coupled receptor signaling restricts pancreatic beta-cell expansion PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Berger, M., Scheel, D. W., Macias, H., Miyatsuka, T., Kim, H., Hoang, P., Ku, G. M., Honig, G., Liou, A., Tang, Y., Regard, J. B., Sharifnia, P., Yu, L., Wang, J., Coughlin, S. R., Conklin, B. R., Deneris, E. S., Tecott, L. H., German, M. S. 2015; 112 (9): 2888–93

  Abstract

  Gi-GPCRs, G protein-coupled receptors that signal via Gα proteins of the i/o class (Gαi/o), acutely regulate cellular behaviors widely in mammalian tissues, but their impact on the development and growth of these tissues is less clear. For example, Gi-GPCRs acutely regulate insulin release from pancreatic β cells, and variants in genes encoding several Gi-GPCRs--including the α-2a adrenergic receptor, ADRA2A--increase the risk of type 2 diabetes mellitus. However, type 2 diabetes also is associated with reduced total β-cell mass, and the role of Gi-GPCRs in establishing β-cell mass is unknown. Therefore, we asked whether Gi-GPCR signaling regulates β-cell mass. Here we show that Gi-GPCRs limit the proliferation of the insulin-producing pancreatic β cells and especially their expansion during the critical perinatal period. Increased Gi-GPCR activity in perinatal β cells decreased β-cell proliferation, reduced adult β-cell mass, and impaired glucose homeostasis. In contrast, Gi-GPCR inhibition enhanced perinatal β-cell proliferation, increased adult β-cell mass, and improved glucose homeostasis. Transcriptome analysis detected the expression of multiple Gi-GPCRs in developing and adult β cells, and gene-deletion experiments identified ADRA2A as a key Gi-GPCR regulator of β-cell replication. These studies link Gi-GPCR signaling to β-cell mass and diabetes risk and identify it as a potential target for therapies to protect and increase β-cell mass in patients with diabetes.

  View details for DOI 10.1073/pnas.1319378112

  View details for Web of Science ID 000350224900071

  View details for PubMedID 25695968

  View details for PubMedCentralID PMC4352814

• Alzheimer's Disease, Anesthesia, and Surgery: A Clinically Focused Review JOURNAL OF CARDIOTHORACIC AND VASCULAR ANESTHESIA Berger, M., Burke, J., Eckenhoff, R., Mathew, J. 2014; 28 (6): 1609-1623

  View details for DOI 10.1053/j.jvca.2014.04.014

  View details for Web of Science ID 000346758800030

  View details for PubMedID 25267693

• Neurological complications of cardiac surgery LANCET NEUROLOGY McDonagh, D. L., Berger, M., Mathew, J. P., Graffagnino, C., Milano, C. A., Newman, M. F. 2014; 13 (5): 490-502

  Abstract

  As increasing numbers of elderly people undergo cardiac surgery, neurologists are frequently called upon to assess patients with neurological complications from the procedure. Some complications mandate acute intervention, whereas others need longer term observation and management. A large amount of published literature exists about these complications and guidance on best practice is constantly changing. Similarly, despite technological advances in surgical intervention and modifications in surgical technique to make cardiac procedures safer, these advances often create new avenues for neurological injury. Accordingly, rapid and precise neurological assessment and therapeutic intervention rests on a solid understanding of the evidence base and procedural variables.

  View details for DOI 10.1016/S1474-4422(14)70004-3

  View details for Web of Science ID 000335108100015

  View details for PubMedID 24703207

  View details for PubMedCentralID PMC5928518

• Preventing Delirium After Cardiothoracic Surgery: Provocative but Preliminary Evidence for Bispectral Index Monitoring ANESTHESIA AND ANALGESIA Berger, M., Nadler, J., Mathew, J. P. 2014; 118 (4): 706-707

  View details for DOI 10.1213/ANE.0000000000000130

  View details for Web of Science ID 000335396500005

  View details for PubMedID 24651223

• A novel application for bolus remifentanil: blunting the hemodynamic response to Mayfield skull clamp placement CURRENT MEDICAL RESEARCH AND OPINION Berger, M., Philips-Bute, B., Guercio, J., Hopkins, T. J., James, M. L., Borel, C. O., Warner, D. S., McDonagh, D. L. 2014; 30 (2): 243-250

  Abstract

  Neurosurgery often requires skull immobilization with a Mayfield clamp, which often causes brief intense nociceptive stimulation, hypertension and tachycardia. Blunting this response may help prevent increased intracranial pressure, cerebral aneurysm or vascular malformation rupture, and/or myocardial stress. While various interventions have been described to blunt this response, no reports have compared administration of a propofol versus a remifentanil bolus.We retrospectively analyzed the hemodynamic response to Mayfield placement in over 800 patients who received a prior propofol or remifentanil bolus from 2004 to 2010.Patients who received remifentanil experienced a 55% smaller increase in heart rate (p < 0.0001) and a 40% smaller increase in systolic blood pressure (p < 0.0001) after Mayfield placement than patients who received propofol. These data were retrospectively obtained from patients who were not randomized to receive remifentanil versus propofol, and hence these data could be subject to possible confounding. Nonetheless, these differences remained significant after multivariate analysis for possible confounding variables.Thus, a remifentanil bolus is more effective than a propofol bolus in blunting hemodynamic responses to Mayfield placement, and possibly for other short, intense nociceptive stimuli.

  View details for DOI 10.1185/03007995.2013.855190

  View details for Web of Science ID 000330848200012

  View details for PubMedID 24161010

• Volatile Anesthetic Sedation During Therapeutic Hypothermia After Cardiac Arrest in the ICU: A Journey of a Thousand Miles Begins With a Single Step CRITICAL CARE MEDICINE Berger, M., Warner, D. S., McDonagh, D. L. 2014; 42 (2): 494-495

  View details for DOI 10.1097/01.ccm.0000435689.93091.d0

  View details for Web of Science ID 000329863400070

  View details for PubMedID 24434469

• General anesthetic and the risk of dementia in elderly patients: current insights CLINICAL INTERVENTIONS IN AGING Hussain, M., Berger, M., Eckenhoff, R. G., Seitz, D. P. 2014; 9: 1619-1628

  Abstract

  In this review, we aim to provide clinical insights into the relationship between surgery, general anesthesia (GA), and dementia, particularly Alzheimer's disease (AD). The pathogenesis of AD is complex, involving specific disease-linked proteins (amyloid-beta [Aβ] and tau), inflammation, and neurotransmitter dysregulation. Many points in this complex pathogenesis can potentially be influenced by both surgery and anesthetics. It has been demonstrated in some in vitro, animal, and human studies that some anesthetics are associated with increased aggregation and oligomerization of Aβ peptide and enhanced accumulation and hyperphosphorylation of tau protein. Two neurocognitive syndromes that have been studied in relation to surgery and anesthesia are postoperative delirium and postoperative cognitive dysfunction, both of which occur more commonly in older adults after surgery and anesthesia. Neither the route of anesthesia nor the type of anesthetic appears to be significantly associated with the development of postoperative delirium or postoperative cognitive dysfunction. A meta-analysis of case-control studies found no association between prior exposure to surgery utilizing GA and incident AD (pooled odds ratio =1.05, P=0.43). The few cohort studies on this topic have shown varying associations between surgery, GA, and AD, with one showing an increased risk, and another demonstrating a decreased risk. A recent randomized trial has shown that patients who received sevoflurane during spinal surgery were more likely to have progression of preexisting mild cognitive impairment compared to controls and to patients who received propofol or epidural anesthesia. Given the inconsistent evidence on the association between surgery, anesthetic type, and AD, well-designed and adequately powered studies with longer follow-up periods are required to establish a clear causal association between surgery, GA, and AD.

  View details for DOI 10.2147/CIA.S49680

  View details for Web of Science ID 000342057200002

  View details for PubMedID 25284995

  View details for PubMedCentralID PMC4181446

• Rapid ventricular pacing assisted hypotension in the management of sudden intraoperative hemorrhage during cerebral aneurysm clipping. Asian journal of neurosurgery Khan, S. A., Berger, M., Agrawal, A., Huang, M., Karikari, I., Nimjee, S. M., Zomorodi, A. R., McDonagh, D. L. 2014; 9 (1): 33-5

  Abstract

  Sudden intraoperative hemorrhage during intracranial aneurysm surgery from vascular injury or aneurysmal rupture has been known to dramatically increase the associated morbidity and mortality. We describe the first reported use of rapid ventricular pacing (RVP) assisted hypotension to control sudden intraoperative hemorrhage during intracranial aneurysm surgery where temporary arterial occlusion was not achievable.

  View details for DOI 10.4103/1793-5482.131066

  View details for PubMedID 24891888

• Anesthetic Neuroprotection: Antecedents and An Appraisal of Preclinical and Clinical Data Quality CURRENT PHARMACEUTICAL DESIGN Ishida, K., Berger, M., Nadler, J., Warner, D. S. 2014; 20 (36): 5751-5765

  Abstract

  Anesthetics have been studied for nearly fifty years as potential neuroprotective compounds in both perioperative and resuscitation medicine. Although anesthetics present pharmacologic properties consistent with preservation of brain viability in the context of an ischemic insult, no anesthetic has been proven efficacious for neuroprotection in humans. After such effort, it could be concluded that anesthetics are simply not neuroprotective in humans. Moreover, pharmacologic neuroprotection with non-anesthetic drugs has also repeatedly failed to be demonstrated in human acute brain injury. Recent focus has been on rectification of promising preclinical neuroprotection data and subsequent failed clinical trials. This has led to consensus guidelines for the process of transferring purported therapeutics from bench to bedside. In this review we first examined the history of anesthetic neuroprotection research. Then, a systematic review was performed to identify major clinical trials of anesthetic neuroprotection. Both the preclinical neuroprotection portfolio cited to justify a clinical trial and the design and conduct of that clinical trial were evaluated using modern standards that include the Stroke Therapy Academic Industry Roundtable (STAIR) and Consolidated Standards of Reporting Trials (CONSORT) guidelines. In publications intended to define anesthetic neuroprotection, we found overall poor quality of both preclinical efficacy analysis portfolios and clinical trial designs and conduct. Hence, using current translational research standards, it was not possible to conclude from existing data whether anesthetics ameliorate perioperative ischemic brain injury. Incorporation of advances in translational neuroprotection research conduct may provide a basis for more definitive and potentially successful clinical trials of anesthetics as neuroprotectants.

  View details for DOI 10.2174/1381612820666140204111701

  View details for Web of Science ID 000342006100010

  View details for PubMedID 24502575

• Intraoperative Magnesium Administration Does Not Improve Neurocognitive Function After Cardiac Surgery STROKE Mathew, J. P., White, W. D., Schinderle, D. B., Podgoreanu, M. V., Berger, M., Milano, C. A., Laskowitz, D. T., Stafford-Smith, M., Blumenthal, J. A., Newman, M. F., Duke Heart Ctr 2013; 44 (12): 3407-3413

  Abstract

  Neurocognitive decline occurs frequently after cardiac surgery and persists in a significant number of patients. Magnesium is thought to provide neuroprotection by preservation of cellular energy metabolism, blockade of the N-methyl-D-aspartate receptor, diminution of the inflammatory response, and inhibition of platelet activation. We therefore hypothesized that intraoperative magnesium administration would decrease postoperative cognitive impairment.After approval by the Duke University Health System Institutional Review Board, 389 patients undergoing cardiac surgery were enrolled in this prospective, randomized, double-blind, placebo-controlled clinical trial. Subjects were randomized to receive magnesium as a 50 mg/kg bolus followed by another 50 mg/kg infusion for 3 hours or placebo bolus and infusion. Cognitive function was assessed preoperatively and again at 6 weeks postoperatively using a standardized test battery. Mean CD11b fluorescence and percentage of platelets expressing CD62P, which are markers of leukocyte and platelet activation, respectively, were assessed by flow cytometry as a secondary outcome. The effect of magnesium on postoperative cognition was tested using multivariable regression modeling, adjusting for age, years of education, baseline cognition, sex, race, and weight.Among the 389 allocated subjects (magnesium: n=198; placebo: n=191), the incidence of cognitive deficit in the magnesium group was 44.4% compared with 44.9% in the placebo group (P=0.93). The cognitive change score and platelet and leukocyte activation were also not different between the groups. Multivariable analysis revealed a marginal interaction between treatment group and weight such that heavier subjects receiving magnesium were less likely to have cognitive deficit (P=0.06).Magnesium administered intravenously during cardiac surgery does not reduce postoperative cognitive dysfunction.http://www.clinicaltrials.gov. Unique identifier: NCT00041392.

  View details for DOI 10.1161/STROKEAHA.113.002703

  View details for Web of Science ID 000327386300312

  View details for PubMedID 24105697

  View details for PubMedCentralID PMC3891363

• Precise pattern of recombination in serotonergic and hypothalamic neurons in a Pdx1-cre transgenic mouse line JOURNAL OF BIOMEDICAL SCIENCE Honig, G., Liou, A., Berger, M., German, M. S., Tecott, L. H. 2010; 17: 82

  Abstract

  Multicellular organisms are characterized by a remarkable diversity of morphologically distinct and functionally specialized cell types. Transgenic techniques for the manipulation of gene expression in specific cellular populations are highly useful for elucidating the development and function of these cellular populations. Given notable similarities in developmental gene expression between pancreatic β-cells and serotonergic neurons, we examined the pattern of Cre-mediated recombination in the nervous system of a widely used mouse line, Pdx1-cre (formal designation, Tg(Ipf1-cre)89.1Dam), in which the expression of Cre recombinase is driven by regulatory elements upstream of the pdx1 (pancreatic-duodenal homeobox 1) gene.Single (hemizygous) transgenic mice of the pdx1-creCre/0 genotype were bred to single (hemizygous) transgenic reporter mice (Z/EG and rosa26R lines). Recombination pattern was examined in offspring using whole-mount and sectioned histological preparations at e9.5, e10.5, e11.5, e16.5 and adult developmental stages.In addition to the previously reported pancreatic recombination, recombination in the developing nervous system and inner ear formation was observed. In the central nervous system, we observed a highly specific pattern of recombination in neuronal progenitors in the ventral brainstem and diencephalon. In the rostral brainstem (r1-r2), recombination occurred in newborn serotonergic neurons. In the caudal brainstem, recombination occurred in non-serotonergic cells. In the adult, this resulted in reporter expression in the vast majority of forebrain-projecting serotonergic neurons (located in the dorsal and median raphe nuclei) but in none of the spinal cord-projecting serotonergic neurons of the caudal raphe nuclei. In the adult caudal brainstem, reporter expression was widespread in the inferior olive nucleus. In the adult hypothalamus, recombination was observed in the arcuate nucleus and dorsomedial hypothalamus. Recombination was not observed in any other region of the central nervous system. Neuronal expression of endogenous pdx1 was not observed.The Pdx1-cre mouse line, and the regulatory elements contained in the corresponding transgene, could be a valuable tool for targeted genetic manipulation of developing forebrain-projecting serotonergic neurons and several other unique neuronal sub-populations. These results suggest that investigators employing this mouse line for studies of pancreatic function should consider the possible contributions of central nervous system effects towards resulting phenotypes.

  View details for DOI 10.1186/1423-0127-17-82

  View details for Web of Science ID 000283724600001

  View details for PubMedID 20950489

  View details for PubMedCentralID PMC2966455

• The Expanded Biology of Serotonin ANNUAL REVIEW OF MEDICINE Berger, M., Gray, J. A., Roth, B. L. 2009; 60: 355-366

  Abstract

  Serotonin is perhaps best known as a neurotransmitter that modulates neural activity and a wide range of neuropsychological processes, and drugs that target serotonin receptors are used widely in psychiatry and neurology. However, most serotonin is found outside the central nervous system, and virtually all of the 15 serotonin receptors are expressed outside as well as within the brain. Serotonin regulates numerous biological processes including cardiovascular function, bowel motility, ejaculatory latency, and bladder control. Additionally, new work suggests that serotonin may regulate some processes, including platelet aggregation, by receptor-independent, transglutaminase-dependent covalent linkage to cellular proteins. We review this new "expanded serotonin biology" and discuss how drugs targeting specific serotonin receptors are beginning to help treat a wide range of diseases.

  View details for DOI 10.1146/annurev.med.60.042307.110802

  View details for Web of Science ID 000268071100026

  View details for PubMedID 19630576

  View details for PubMedCentralID PMC5864293

• Molecular determinants in the second intracellular loop of the 5-hydroxytryptamine-1A receptor for G-protein coupling MOLECULAR PHARMACOLOGY Kushwaha, N., Harwood, S. C., Wilson, A. M., Berger, M., Tecott, L. H., Roth, B. L., Albert, P. R. 2006; 69 (5): 1518-1526

  Abstract

  This study provides the first comprehensive evidence that the second intracellular loop C-terminal domain (Ci2) is critical for receptor-G protein coupling to multiple responses. Although Ci2 is weakly conserved, its role in 5-hydroxytryptamine-1A (5-HT1A) receptor function was suggested by the selective loss of Gbetagamma-mediated signaling in the T149A-5-HT1A receptor mutant. More than 60 point mutant 5-HT1A receptors in the alpha-helical Ci2 sequence (143DYVNKRTPRR152) were generated. Most mutants retained agonist binding and were tested for Gbetagamma signaling to adenylyl cyclase II or phospholipase C and Galphai coupling to detect constitutive and agonist-induced Gi/Go coupling. Remarkably, most point mutations markedly attenuated 5-HT1A signaling, indicating that the entire Ci2 domain is critical for receptor G-protein coupling. Six signaling phenotypes were observed: wild-type-like, Galphai-coupled/weak Gbetagamma-coupled, Gbetagamma-uncoupled, Gbetagamma-selective coupled, uncoupled, and inverse coupling. Our data elucidate specific roles of Ci2 residues consistent with predictions based on rhodopsin crystal structure. The absolute coupling requirement for lysine, arginine, and proline residues is consistent with a predicted amphipathic alpha-helical Ci2 domain that is kinked at Pro150. Polar residues (Thr149, Asn146) located in the externally oriented positively charged face were required for Gbetagamma but not Galphai coupling, suggesting a direct interface with Gbetagamma subunits. The hydrophobic face includes the critical Tyr144 that directs the specificity of coupling to both Gbetagamma and Galphai pathways. The key coupling residues Tyr144/Lys147 (Ci2) are predicted to orient internally, forming hydrogen and ionic bonds with Asp133/Arg134 (Ni2 DRY motif) and Glu340 (Ci3) to stabilize the Gprotein coupling domain. Thus, the 5-HT1A receptor Ci2 domain determines Gbetagamma specificity and stabilizes Galphai-mediated signaling.

  View details for DOI 10.1124/mol.105.019844

  View details for Web of Science ID 000236874100004

  View details for PubMedID 16410407

• Different G_i-coupled chemoattractant receptors signal qualitatively different functions in human neutrophils JOURNAL OF LEUKOCYTE BIOLOGY Berger, M., Budhu, S., Lu, E., Li, Y. M., Loike, D., Silverstein, S. C., Loike, J. D. 2002; 71 (5): 798-806

  Abstract

  fMLP- or TNF-alpha-stimulated neutrophils produced H(2)O(2) when they adhered to fibrinogen-coated surfaces but not when they adhered to collagen I-, collagen IV-, or Matrigel-coated surfaces. In contrast, LTB4- or IL-8-stimulated neutrophils did not produce H(2)O(2) when they adhered to any of these surfaces. fMLP and TNF-alpha were much more potent than LTB4 and IL-8 in stimulating neutrophils to up-regulate and to activate their alpha(M)beta(2) integrins, as measured by the binding of specific monoclonal antibodies. Pretreatment of neutrophils with pertussis toxin completely blocked their production of H(2)O(2) on fibrinogen-coated surfaces in response to fMLP and their migration through Matrigel in response to fMLP, LTB4, and IL-8. These data show that although the fMLP, LTB4, and IL-8 receptors are coupled to pertussis toxin-sensitive Galpha proteins, they signal neutrophils to initiate qualitatively different effector functions. We propose that the qualitative differences in effector functions signaled by different chemoattractants reflect qualitative differences in using G-protein beta and/or gamma subunits or other factors by their cognate receptors.

  View details for Web of Science ID 000175489000008

  View details for PubMedID 11994504