Browsing by Author "Devinney, Michael J"

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    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 Investigators

    Background

    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.
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    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 Investigators
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    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 Investigators

    Objective

    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).
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    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 Investigators
    BACKGROUND/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.
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    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 Investigators
    BACKGROUND: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.
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    The potential link between obstructive sleep apnea and postoperative neurocognitive disorders: current knowledge and possible mechanisms.
    (Canadian journal of anaesthesia = Journal canadien d'anesthesie, 2022-08-18) Devinney, Michael J; VanDusen, Keith W; Kfouri, Jad M; Avasarala, Pallavi; Spector, Andrew R; Mathew, Joseph P; Berger, Miles

    Purpose

    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.

    Source

    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.

    Principal findings

    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.

    Conclusion

    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.