Browsing by Author "Browndyke, Jeffrey N"
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Item Open Access Aerobic exercise and neurocognitive performance: a meta-analytic review of randomized controlled trials.(Psychosom Med, 2010-04) Smith, Patrick J; Blumenthal, James A; Hoffman, Benson M; Cooper, Harris; Strauman, Timothy A; Welsh-Bohmer, Kathleen; Browndyke, Jeffrey N; Sherwood, AndrewOBJECTIVES: To assess the effects of aerobic exercise training on neurocognitive performance. Although the effects of exercise on neurocognition have been the subject of several previous reviews and meta-analyses, they have been hampered by methodological shortcomings and are now outdated as a result of the recent publication of several large-scale, randomized, controlled trials (RCTs). METHODS: We conducted a systematic literature review of RCTs examining the association between aerobic exercise training on neurocognitive performance between January 1966 and July 2009. Suitable studies were selected for inclusion according to the following criteria: randomized treatment allocation; mean age > or =18 years of age; duration of treatment >1 month; incorporated aerobic exercise components; supervised exercise training; the presence of a nonaerobic-exercise control group; and sufficient information to derive effect size data. RESULTS: Twenty-nine studies met inclusion criteria and were included in our analyses, representing data from 2049 participants and 234 effect sizes. Individuals randomly assigned to receive aerobic exercise training demonstrated modest improvements in attention and processing speed (g = 0.158; 95% confidence interval [CI]; 0.055-0.260; p = .003), executive function (g = 0.123; 95% CI, 0.021-0.225; p = .018), and memory (g = 0.128; 95% CI, 0.015-0.241; p = .026). CONCLUSIONS: Aerobic exercise training is associated with modest improvements in attention and processing speed, executive function, and memory, although the effects of exercise on working memory are less consistent. Rigorous RCTs are needed with larger samples, appropriate controls, and longer follow-up periods.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 Changes in Brain Resting-state Functional Connectivity Associated with Peripheral Nerve Block: A Pilot Study.(Anesthesiology, 2016-08) Melton, M Stephen; Browndyke, Jeffrey N; Harshbarger, Todd B; Madden, David J; Nielsen, Karen C; Klein, Stephen MBACKGROUND: Limited information exists on the effects of temporary functional deafferentation (TFD) on brain activity after peripheral nerve block (PNB) in healthy humans. Increasingly, resting-state functional connectivity (RSFC) is being used to study brain activity and organization. The purpose of this study was to test the hypothesis that TFD through PNB will influence changes in RSFC plasticity in central sensorimotor functional brain networks in healthy human participants. METHODS: The authors achieved TFD using a supraclavicular PNB model with 10 healthy human participants undergoing functional connectivity magnetic resonance imaging before PNB, during active PNB, and during PNB recovery. RSFC differences among study conditions were determined by multiple-comparison-corrected (false discovery rate-corrected P value less than 0.05) random-effects, between-condition, and seed-to-voxel analyses using the left and right manual motor regions. RESULTS: The results of this pilot study demonstrated disruption of interhemispheric left-to-right manual motor region RSFC (e.g., mean Fisher-transformed z [effect size] at pre-PNB 1.05 vs. 0.55 during PNB) but preservation of intrahemispheric RSFC of these regions during PNB. Additionally, there was increased RSFC between the left motor region of interest (PNB-affected area) and bilateral higher order visual cortex regions after clinical PNB resolution (e.g., Fisher z between left motor region of interest and right and left lingual gyrus regions during PNB, -0.1 and -0.6 vs. 0.22 and 0.18 after PNB resolution, respectively). CONCLUSIONS: This pilot study provides evidence that PNB has features consistent with other models of deafferentation, making it a potentially useful approach to investigate brain plasticity. The findings provide insight into RSFC of sensorimotor functional brain networks during PNB and PNB recovery and support modulation of the sensory-motor integration feedback loop as a mechanism for explaining the behavioral correlates of peripherally induced TFD through PNB.Item Open Access Cognition and brain changes associated with high-dose atorvastatin: A BOLD proposition?(American Heart Journal, 2018-01-01) Browndyke, Jeffrey N; Heflin, Mitchell TItem Open Access Effects of the dietary approaches to stop hypertension diet, exercise, and caloric restriction on neurocognition in overweight adults with high blood pressure.(Hypertension, 2010-06) Smith, Patrick J; Blumenthal, James A; Babyak, Michael A; Craighead, Linda; Welsh-Bohmer, Kathleen A; Browndyke, Jeffrey N; Strauman, Timothy A; Sherwood, AndrewHigh blood pressure increases the risks of stroke, dementia, and neurocognitive dysfunction. Although aerobic exercise and dietary modifications have been shown to reduce blood pressure, no randomized trials have examined the effects of aerobic exercise combined with dietary modification on neurocognitive functioning in individuals with high blood pressure (ie, prehypertension and stage 1 hypertension). As part of a larger investigation, 124 participants with elevated blood pressure (systolic blood pressure 130 to 159 mm Hg or diastolic blood pressure 85 to 99 mm Hg) who were sedentary and overweight or obese (body mass index: 25 to 40 kg/m(2)) were randomized to the Dietary Approaches to Stop Hypertension (DASH) diet alone, DASH combined with a behavioral weight management program including exercise and caloric restriction, or a usual diet control group. Participants completed a battery of neurocognitive tests of executive function-memory-learning and psychomotor speed at baseline and again after the 4-month intervention. Participants on the DASH diet combined with a behavioral weight management program exhibited greater improvements in executive function-memory-learning (Cohen's D=0.562; P=0.008) and psychomotor speed (Cohen's D=0.480; P=0.023), and DASH diet alone participants exhibited better psychomotor speed (Cohen's D=0.440; P=0.036) compared with the usual diet control. Neurocognitive improvements appeared to be mediated by increased aerobic fitness and weight loss. Also, participants with greater intima-medial thickness and higher systolic blood pressure showed greater improvements in executive function-memory-learning in the group on the DASH diet combined with a behavioral weight management program. In conclusion, combining aerobic exercise with the DASH diet and caloric restriction improves neurocognitive function among sedentary and overweight/obese individuals with prehypertension and hypertension.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 Infarct‐related structural disconnection and delirium in surgical aortic valve replacement patients(Annals of Clinical and Translational Neurology) Browndyke, Jeffrey N; Tomalin, Lewis E; Erus, Guray; Overbey, Jessica R; Kuceyeski, Amy; Moskowitz, Alan J; Bagiella, Emilia; Iribarne, Alexander; Acker, Michael; Mack, Michael; Mathew, Joseph; O'Gara, Patrick; Gelijns, Annetine C; Suarez-Farinas, Mayte; Messé, Steven R; Cardiothoracic Surgical Trials Network (CTSN) InvestigatorsAbstractObjectiveAlthough acute brain infarcts are common after surgical aortic valve replacement (SAVR), they are often unassociated with clinical stroke symptoms. The relationship between clinically “silent” infarcts and in‐hospital delirium remains uncertain; obscured, in part, by how infarcts have been traditionally summarized as global metrics, independent of location or structural consequence. We sought to determine if infarct location and related structural connectivity changes were associated with postoperative delirium after SAVR.MethodsA secondary analysis of a randomized multicenter SAVR trial of embolic protection devices (NCT02389894) was conducted, excluding participants with clinical stroke or incomplete neuroimaging (N = 298; 39% female, 7% non‐White, 74 ± 7 years). Delirium during in‐hospital recovery was serially screened using the Confusion Assessment Method. Parcellation and tractography atlas‐based neuroimaging methods were used to determine infarct locations and cortical connectivity effects. Mixed‐effect, zero‐inflated gaussian modeling analyses, accounting for brain region‐specific infarct characteristics, were conducted to examine for differences within and between groups by delirium status and perioperative neuroprotection device strategy.Results23.5% participants experienced postoperative delirium. Delirium was associated with significantly increased lesion volumes in the right cerebellum and temporal lobe white matter, while diffusion weighted imaging infarct‐related structural disconnection (DWI‐ISD) was observed in frontal and temporal lobe regions (p‐FDR < 0.05). Fewer brain regions demonstrated DWI‐ISD loss in the suction‐based neuroprotection device group, relative to filtration‐based device or standard aortic cannula.InterpretationStructural disconnection from acute infarcts was greater in patients who experienced postoperative delirium, suggesting that the impact from covert perioperative infarcts may not be as clinically “silent” as commonly assumed.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 Longitudinal Changes in Regional Cerebral Perfusion and Cognition Following Cardiac Surgery.(The Annals of thoracic surgery, 2018-09-22) Smith, Patrick J; Browndyke, Jeffrey N; Monge, Zachary A; Harshbarger, Todd B; James, Michael L; Gaca, Jeffrey G; Alexander, John H; Berger, Miles M; Newman, Mark F; Milano, Carmelo A; Mathew, Joseph P; Neurologic Outcomes Research Group (NORG)Cardiac surgery 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 / repair surgery 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 surgery and 27 matched controls. Arterial spin labeling (ASL) magnetic resonance perfusion imaging was used to quantify cerebral blood flow within the anterior communicating artery (ACA), middle cerebral artery (MCA), and posterior communicating artery (PCA) vascular territories prior to surgery and postoperatively at 6-weeks and 1-year. Cognitive performance was examined during the same intervals using a battery of tests tapping 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 following cardiac surgery (P = .035 for interaction). Perfusion changes were most notable in distal territories of the MCA and PCA 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 = .016); whereas, no significant differences were found between groups in vascular territory perfusion and cognition at 1-year.Cardiac surgery is associated with significant short-term increases in MCA perfusion with associated improvements in psychomotor speed.Item Open Access Neural activation for actual and imagined movement following unilateral hand transplantation: a case study.(Neurocase, 2019-09-24) Madden, David J; Melton, M Stephen; Jain, Shivangi; Cook, Angela D; Browndyke, Jeffrey N; Harshbarger, Todd B; Cendales, Linda CTransplantation of a donor hand has been successful as a surgical treatment following amputation, but little is known regarding the brain mechanisms contributing to the recovery of motor function. We report functional magnetic resonance imaging (fMRI) findings for neural activation related to actual and imagined movement, for a 54-year-old male patient, who had received a donor hand transplant 50 years following amputation. Two assessments, conducted 3 months and 6 months post-operatively, demonstrate engagement of motor-control related brain regions for the transplanted hand, during both actual and imagined movement of the fingers. The intact hand exhibited a more intense and focused pattern of activation for actual movement relative to imagined movement, whereas activation for the transplanted hand was more widely distributed and did not clearly differentiate actual and imagined movement. However, the spatial overlap of actual-movement and imagined-movement voxels, for the transplanted hand, did increase over time to a level comparable to that of the intact hand. At these relatively early post-operative assessments, brain regions outside of the canonical motor-control networks appear to be supporting movement of the transplanted hand.Item Open Access Neurological injury after transcatheter aortic valve implantation: are the trees falling silently or is our hearing impaired?(Circ Cardiovasc Interv, 2013-12) Browndyke, Jeffrey N; Mathew, Joseph PItem 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 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 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 Devil Is in the Details: Comparison of Postoperative Delirium and Neurocognitive Dysfunction.(Anesthesiology, 2019-05-24) Browndyke, Jeffrey N; Devinney, Michael; Mathew, Joseph PItem 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.