Browsing by Author "Berger, Miles"
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Item Open Access Anesthetic Suppression of Thalamic High-Frequency Oscillations: Evidence that the Thalamus Is More Than Just a Gateway to Consciousness?(Anesth Analg, 2016-06) Berger, Miles; García, Paul SItem Open Access Awake spinal anesthesia facilitates spine surgery in poor surgical candidates: A case series.(Neuro-Chirurgie, 2023-05) Sykes, David AW; Tabarestani, Troy Q; Salven, David S; Chaudhry, Nauman S; Wang, Timothy Y; Gottfried, Oren N; Shaffrey, Christopher I; Guinn, Nicole R; Gadsden, Jeffrey; Ayoub, Chakib M; Bullock, W Michael; Berger, Miles; Abd-El-Barr, Muhammad MBackground
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.Methods
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.Results
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.Conclusion
For patients with symptomatic, refractory DSD and relative contraindications to GA, SA may facilitate safe surgical intervention with excellent outcomes.Item Open Access 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, 2023-05) Sykes, David AW; Tabarestani, Troy Q; Chaudhry, Nauman S; Salven, David S; Shaffrey, Christopher I; Bullock, W Michael; Guinn, Nicole R; Gadsden, Jeffrey; Berger, Miles; Abd-El-Barr, Muhammad MObjective
There is increasing interest in 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 vs general anesthesia (GA) for spinal fusion procedures on length of stay (LOS), opioid use, time to ambulation (TTA), and procedure duration.Methods
The authors performed a retrospective review of a single surgeon's patients who underwent lumbar fusions under SA vs 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 (MME), TTA, and LOS.Results
10 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 vs GA patients (12.87 vs 50.79 hours, p=0.001). Opioid utilization was reduced in SA vs GA patients (10.76 vs 31.43 MME, p=0.006). TTA was reduced in SA vs 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).Conclusion
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.Item Open Access Cerebrospinal Fluid Proteome Changes in Older Non-Cardiac Surgical Patients with Postoperative Cognitive Dysfunction.(Journal of Alzheimer's disease : JAD, 2021-02-26) VanDusen, Keith W; Li, Yi-Ju; Cai, Victor; Hall, Ashley; Hiles, Sarah; Thompson, J Will; Moseley, M Arthur; Cooter, Mary; Acker, Leah; Levy, Jerrold H; Ghadimi, Kamrouz; Quiñones, Quintin J; Devinney, Michael J; Chung, Stacey; Terrando, Niccolò; Moretti, Eugene W; Browndyke, Jeffrey N; Mathew, Joseph P; Berger, Miles; MADCO-PC InvestigatorsBackground
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.Objective
To utilize unbiased mass spectrometry-based proteomics to identify potential neuroinflammatory pathways underlying POCD.Methods
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.Results
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).Conclusion
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.Item Open Access Flow Cytometry Characterization of Cerebrospinal Fluid Monocytes in Patients With Postoperative Cognitive Dysfunction: A Pilot Study.(Anesthesia and analgesia, 2019-05-03) Berger, Miles; Murdoch, David M; Staats, Janet S; Chan, Cliburn; Thomas, Jake P; Garrigues, Grant E; Browndyke, Jeffrey N; Cooter, Mary; Quinones, Quintin J; Mathew, Joseph P; Weinhold, Kent J; MADCO-PC Study TeamAnimal 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.Item Open Access Immunomodulatory lipid mediator profiling of cerebrospinal fluid following surgery in older adults.(Scientific reports, 2021-02-04) Terrando, Niccolò; Park, John J; Devinney, Michael; Chan, Cliburn; Cooter, Mary; Avasarala, Pallavi; Mathew, Joseph P; Quinones, Quintin J; Maddipati, Krishna Rao; Berger, Miles; MADCO-PC Study TeamArachidonic 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.Item Open Access Intraoperative Frontal Alpha-Band Power Correlates with Preoperative Neurocognitive Function in Older Adults.(Front Syst Neurosci, 2017) Giattino, Charles M; Gardner, Jacob E; Sbahi, Faris M; Roberts, Kenneth C; Cooter, Mary; Moretti, Eugene; Browndyke, Jeffrey N; Mathew, Joseph P; Woldorff, Marty G; Berger, Miles; MADCO-PC InvestigatorsEach 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.Item Open Access Intravenous Lidocaine Does Not Improve Neurologic Outcomes after Cardiac Surgery: A Randomized Controlled Trial.(Anesthesiology, 2019-06) Klinger, Rebecca Y; Cooter, Mary; Bisanar, Tiffany; Terrando, Niccolò; Berger, Miles; Podgoreanu, Mihai V; Stafford-Smith, Mark; Newman, Mark F; Mathew, Joseph P; Neurologic Outcomes Research Group of the Duke Heart CenterBackground
Cognitive decline after cardiac surgery occurs frequently and persists in a significant proportion of patients. Preclinical studies and human trials suggest that intravenous lidocaine may confer protection in the setting of neurologic injury. It was hypothesized that lidocaine administration would reduce cognitive decline after cardiac surgery compared to placebo.Methods
After institutional review board approval, 478 patients undergoing cardiac surgery were enrolled into this multicenter, prospective, randomized, double-blinded, placebo-controlled, parallel group trial. Subjects were randomized to lidocaine 1 mg/kg bolus after the induction of anesthesia followed by a continuous infusion (48 μg · kg · min for the first hour, 24 μg · kg · min for the second hour, and 10 μg · kg · min for the next 46 h) or saline with identical volume and rate changes to preserve blinding. Cognitive function was assessed preoperatively and at 6 weeks and 1 yr postoperatively using a standard neurocognitive test battery. The primary outcome was change in cognitive function between baseline and 6 weeks postoperatively, adjusting for age, years of education, baseline cognition, race, and procedure type.Results
Among the 420 allocated subjects who returned for 6-week follow-up (lidocaine: N = 211; placebo: N = 209), there was no difference in the continuous cognitive score change (adjusted mean difference [95% CI], 0.02 (-0.05, 0.08); P = 0.626). Cognitive deficit (greater than 1 SD decline in at least one cognitive domain) at 6 weeks occurred in 41% (87 of 211) in the lidocaine group versus 40% (83 of 209) in the placebo group (adjusted odds ratio [95% CI], 0.94 [0.63, 1.41]; P = 0.766). There were no differences in any quality of life outcomes between treatment groups. At the 1-yr follow-up, there continued to be no difference in cognitive score change, cognitive deficit, or quality of life.Conclusions
Intravenous lidocaine administered during and after cardiac surgery did not reduce postoperative cognitive decline at 6 weeks.Item Open Access Necessary Heroes and Ethos, from Fighting Nazis to COVID-19.(Anesthesiology, 2020-12) Berger, Miles; Ghadimi, KamrouzItem Open Access Perioperative neurocognitive and functional neuroimaging trajectories in older APOE4 carriers compared with non-carriers: secondary analysis of a prospective cohort study(British Journal of Anaesthesia, 2021-09) Browndyke, Jeffrey N; Wright, Mary C; Yang, Rosa; Syed, Ayesha; Park, John; Hall, Ashley; Martucci, Katherine; Devinney, Michael J; Shaw, Leslie; Waligorska, Teresa; Moretti, Eugene W; Whitson, Heather E; Cohen, Harvey J; Mathew, Joseph P; Berger, Miles; MADCO-PC InvestigatorsItem Open Access Postoperative changes in cognition and cerebrospinal fluid neurodegenerative disease biomarkers.(Annals of clinical and translational neurology, 2022-02) Berger, Miles; Browndyke, Jeffrey N; Cooter Wright, Mary; Nobuhara, Chloe; Reese, Melody; Acker, Leah; Bullock, W Michael; Colin, Brian J; Devinney, Michael J; Moretti, Eugene W; Moul, Judd W; Ohlendorf, Brian; Laskowitz, Daniel T; Waligorska, Teresa; Shaw, Leslie M; Whitson, Heather E; Cohen, Harvey J; Mathew, Joseph P; MADCO-PC InvestigatorsObjective
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.Methods
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.Results
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).Interpretation
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).Trial registration
clinicaltrials.gov (NCT01993836).Item Open Access Precise pattern of recombination in serotonergic and hypothalamic neurons in a Pdx1-cre transgenic mouse line(2010) Honig, Gerard; Liou, Angela; Berger, Miles; German, Michael S; Tecott, Laurence HBackground: 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 beta 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. Methods: Single (hemizygous) transgenic mice of the pdx1-cre(Cre/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. Results: 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. Conclusions: 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.Item Open Access Resting-State Functional Connectivity and Cognition After Major Cardiac Surgery in Older Adults without Preoperative Cognitive Impairment: Preliminary Findings.(J Am Geriatr Soc, 2017-01) Browndyke, Jeffrey N; Berger, Miles; Harshbarger, Todd B; Smith, Patrick J; White, William; Bisanar, Tiffany L; Alexander, John H; Gaca, Jeffrey G; Welsh-Bohmer, Kathleen; Newman, Mark F; Mathew, Joseph POBJECTIVES: To look for changes in intrinsic functional brain connectivity associated with postoperative changes in cognition, a common complication in seniors undergoing major surgery, using resting-state functional magnetic resonance imaging. DESIGN: Objective cognitive testing and functional brain imaging were prospectively performed at preoperative baseline and 6 weeks after surgery and at the same time intervals in nonsurgical controls. SETTING: Academic medical center. PARTICIPANTS: Older adults undergoing cardiac surgery (n = 12) and nonsurgical older adult controls with a history of coronary artery disease (n = 12); no participants had cognitive impairment at preoperative baseline (Mini-Mental State Examination score >27). MEASUREMENTS: Differences in resting-state functional connectivity (RSFC) and global cognitive change relationships were assessed using a voxel-wise intrinsic connectivity method, controlling for demographic factors and pre- and perioperative cerebral white matter disease volume. Analyses were corrected for multiple comparisons (false discovery rate P < .01). RESULTS: Global cognitive change after cardiac surgery was significantly associated with intrinsic RSFC changes in regions of the posterior cingulate cortex and right superior frontal gyrus-anatomical and functional locations of the brain's default mode network (DMN). No statistically significant relationships were found between global cognitive change and RSFC change in nonsurgical controls. CONCLUSION: Clinicians have long known that some older adults develop postoperative cognitive dysfunction (POCD) after anesthesia and surgery, yet the neurobiological correlates of POCD are not well defined. The current results suggest that altered RSFC in specific DMN regions is positively correlated with global cognitive change 6 weeks after cardiac surgery, suggesting that DMN activity and connectivity could be important diagnostic markers of POCD or intervention targets for potential POCD treatment efforts.Item Open Access Risk of Spinal Hematoma After Lumbar Puncture.(JAMA, 2021-02) Nobuhara, Chloe Kimi; Berger, MilesItem Open Access Sparcl1/Hevin drives pathological pain through spinal cord astrocyte and NMDA receptor signaling.(JCI insight, 2022-10) Chen, Gang; Xu, Jing; Luo, Hao; Luo, Xin; Singh, Sandeep K; Ramirez, Juan J; James, Michael L; Mathew, Joseph P; Berger, Miles; Eroglu, Cagla; Ji, Ru-RongHevin/Sparcl1 is an astrocyte-secreted protein and regulates synapse formation. Here we show that astrocytic hevin signaling plays a critical role in maintaining chronic pain. Compared to wild-type mice, hevin-null mice exhibited normal mechanical and heat sensitivity but reduced inflammatory pain. Interestingly, hevin-null mice have faster recovery than wild-type mice from neuropathic pain after nerve injury. Intrathecal injection of wild-type hevin was sufficient to induce persistent mechanical allodynia in naïve mice. In hevin-null mice with nerve injury, AAV-mediated re-expression of hevin in GFAP-expressing spinal cord astrocytes could reinstate neuropathic pain. Mechanistically, hevin is crucial for spinal cord NMDA receptor (NMDAR) signaling. Hevin potentiated NMDA currents mediated by the GluN2B-containing NMDARs. Furthermore, intrathecal injection of a neutralizing antibody against hevin alleviated acute and persistent inflammatory pain, postoperative pain, and neuropathic pain. Secreted hevin 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 antibody may provide a new therapeutic strategy for treating acute and chronic pain and NMDAR-medicated neurodegeneration.Item Open Access 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, 2019-08) Mahanna-Gabrielli, Elizabeth; Schenning, Katie J; Eriksson, Lars I; Browndyke, Jeffrey N; Wright, Clinton B; Culley, Deborah J; Evered, Lis; Scott, David A; Wang, Nae Yah; Brown, Charles H; Oh, Esther; Purdon, Patrick; Inouye, Sharon; Berger, Miles; Whittington, Robert A; Price, Catherine C; Deiner, StacieItem Open Access Task-related changes in degree centrality and local coherence of the posterior cingulate cortex after major cardiac surgery in older adults.(Hum Brain Mapp, 2017-11-21) Browndyke, Jeffrey N; Berger, Miles; Smith, Patrick J; Harshbarger, Todd B; Monge, Zachary A; Panchal, Viral; Bisanar, Tiffany L; Glower, Donald D; Alexander, John H; Cabeza, Roberto; Welsh-Bohmer, Kathleen; Newman, Mark F; Mathew, Joseph P; Duke Neurologic Outcomes Research Group (NORG)OBJECTIVES: Older adults often display postoperative cognitive decline (POCD) after surgery, yet it is unclear to what extent functional connectivity (FC) alterations may underlie these deficits. We examined for postoperative voxel-wise FC changes in response to increased working memory load demands in cardiac surgery patients and nonsurgical controls. EXPERIMENTAL DESIGN: Older cardiac surgery patients (n = 25) completed a verbal N-back working memory task during MRI scanning and cognitive testing before and 6 weeks after surgery; nonsurgical controls with cardiac disease (n = 26) underwent these assessments at identical time intervals. We measured postoperative changes in degree centrality, the number of edges attached to a brain node, and local coherence, the temporal homogeneity of regional functional correlations, using voxel-wise graph theory-based FC metrics. Group × time differences were evaluated in these FC metrics associated with increased N-back working memory load (2-back > 1-back), using a two-stage partitioned variance, mixed ANCOVA. PRINCIPAL OBSERVATIONS: Cardiac surgery patients demonstrated postoperative working memory load-related degree centrality increases in the left dorsal posterior cingulate cortex (dPCC; p < .001, cluster p-FWE < .05). The dPCC also showed a postoperative increase in working memory load-associated local coherence (p < .001, cluster p-FWE < .05). dPCC degree centrality and local coherence increases were inversely associated with global cognitive change in surgery patients (p < .01), but not in controls. CONCLUSIONS: Cardiac surgery patients showed postoperative increases in working memory load-associated degree centrality and local coherence of the dPCC that were inversely associated with postoperative global cognitive outcomes and independent of perioperative cerebrovascular damage.Item Open Access The Effect of Propofol Versus Isoflurane Anesthesia on Human Cerebrospinal Fluid Markers of Alzheimer's Disease: Results of a Randomized Trial.(J Alzheimers Dis, 2016-04-15) Berger, Miles; Nadler, Jacob W; Friedman, Allan; McDonagh, David L; Bennett, Ellen R; Cooter, Mary; Qi, Wenjing; Laskowitz, Daniel T; Ponnusamy, Vikram; Newman, Mark F; Shaw, Leslie M; Warner, David S; Mathew, Joseph P; James, Michael L; MAD-PIA trial teamBACKGROUND: 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). OBJECTIVE: 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. METHODS: Patients undergoing neurosurgical/otolaryngology procedures requiring lumbar cerebrospinal fluid (CSF) drain placement were prospectively randomized to receive isoflurane (n = 21) or propofol (n = 18) for anesthetic maintenance. We measured perioperative CSF sample AD markers, performed genotyping assays, and examined intraoperative data from the electronic anesthesia record. A repeated measures ANOVA was used to examine changes in AD markers by anesthetic type over time. RESULTS: The CSF tau/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). CONCLUSION: 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.Item Open Access The INTUIT Study: Investigating Neuroinflammation Underlying Postoperative Cognitive Dysfunction.(Journal of the American Geriatrics Society, 2019-01-23) Berger, Miles; Oyeyemi, Deborah; Olurinde, Mobolaji O; Whitson, Heather E; Weinhold, Kent J; Woldorff, Marty G; Lipsitz, Lewis A; Moretti, Eugene; Giattino, Charles M; Roberts, Kenneth C; Zhou, Junhong; Bunning, Thomas; Ferrandino, Michael; Scheri, Randall P; Cooter, Mary; Chan, Cliburn; Cabeza, Roberto; Browndyke, Jeffrey N; Murdoch, David M; Devinney, Michael J; Shaw, Leslie M; Cohen, Harvey Jay; Mathew, Joseph P; INTUIT InvestigatorsBACKGROUND/OBJECTIVES: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. DESIGN:Observational prospective cohort. SETTING:Duke University Medical Center, Duke Regional Hospital, and Duke Raleigh Hospital. PARTICIPANTS:Patients 60 years of age or older (N = 200) undergoing noncardiac/nonneurologic surgery. MEASUREMENTS: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. CONCLUSION: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.Item Open Access The MARBLE Study Protocol: Modulating ApoE Signaling to Reduce Brain Inflammation, DeLirium, and PostopErative Cognitive Dysfunction.(Journal of Alzheimer's disease : JAD, 2020-01) VanDusen, Keith W; Eleswarpu, Sarada; Moretti, Eugene W; Devinney, Michael J; Crabtree, Donna M; Laskowitz, Daniel T; Woldorff, Marty G; Roberts, Kenneth C; Whittle, John; Browndyke, Jeffrey N; Cooter, Mary; Rockhold, Frank W; Anakwenze, Oke; Bolognesi, Michael P; Easley, Mark E; Ferrandino, Michael N; Jiranek, William A; Berger, Miles; MARBLE Study InvestigatorsBACKGROUND: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. OBJECTIVE: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. METHODS: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. CONCLUSION: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.