Postoperative changes in cognition and cerebrospinal fluid neurodegenerative disease biomarkers

Miles Berger, Jeffrey N Browndyke, Mary Cooter Wright, Chloe Nobuhara, Melody Reese, Leah Acker, W Michael Bullock, Brian J Colin, Michael J Devinney, Eugene W Moretti, Judd W Moul, Brian Ohlendorf, Daniel T Laskowitz, Teresa Waligorska, Leslie M Shaw, Heather E Whitson, Harvey J Cohen, Joseph P Mathew, MADCO-PC Investigators, C L Amundsen, E Bennett, D G Blazer, M P Bolognesi, R Brassard, B E Brigman, J Carter, J Chapman, V Cheong, T A D'Amico, J K DeOrio, D Erdmann, R M Esclamado, M N Ferrandino, B Funk, J C Gadsden, S Grant, G E Garrigues, J R Guercio, A S Habib, R K Hallows, D H Harpole, M G Hartwig, S T Hollenbeck, J Hu, E Iboaya, B A Inman, D W Jang, J Kaisen, A Khan, S Lagoo-Deenadayalan, P S Lee, W T Lee, J Lemm, H Levinson, M E Lipkin, C R Mantyh, K T Martucci, D L McDonagh, J Migaly, S K Mithani, P Mosca, M F Newman, K Ni, T Novick, T N Pappas, A N Perez, A C Peterson, T J Polascik, A Podgoreanu, G M Preminger, Q J Quinones, E N Rampersaud, K Roberts, C N Robertson, S Roman, S Runyon, A Sandler, C D Scales, R P Scheri, S K Smith, L Talbot, J K M Thacker, J Thomas, B C Tong, Y Toulgoat-Dubois, A Tu, S N Vaslef, N Waldron, D S Warner, X Wang, S S Wellman, T Wickenheisser, M Woldorff, C Young, S Zani, Miles Berger, Jeffrey N Browndyke, Mary Cooter Wright, Chloe Nobuhara, Melody Reese, Leah Acker, W Michael Bullock, Brian J Colin, Michael J Devinney, Eugene W Moretti, Judd W Moul, Brian Ohlendorf, Daniel T Laskowitz, Teresa Waligorska, Leslie M Shaw, Heather E Whitson, Harvey J Cohen, Joseph P Mathew, MADCO-PC Investigators, C L Amundsen, E Bennett, D G Blazer, M P Bolognesi, R Brassard, B E Brigman, J Carter, J Chapman, V Cheong, T A D'Amico, J K DeOrio, D Erdmann, R M Esclamado, M N Ferrandino, B Funk, J C Gadsden, S Grant, G E Garrigues, J R Guercio, A S Habib, R K Hallows, D H Harpole, M G Hartwig, S T Hollenbeck, J Hu, E Iboaya, B A Inman, D W Jang, J Kaisen, A Khan, S Lagoo-Deenadayalan, P S Lee, W T Lee, J Lemm, H Levinson, M E Lipkin, C R Mantyh, K T Martucci, D L McDonagh, J Migaly, S K Mithani, P Mosca, M F Newman, K Ni, T Novick, T N Pappas, A N Perez, A C Peterson, T J Polascik, A Podgoreanu, G M Preminger, Q J Quinones, E N Rampersaud, K Roberts, C N Robertson, S Roman, S Runyon, A Sandler, C D Scales, R P Scheri, S K Smith, L Talbot, J K M Thacker, J Thomas, B C Tong, Y Toulgoat-Dubois, A Tu, S N Vaslef, N Waldron, D S Warner, X Wang, S S Wellman, T Wickenheisser, M Woldorff, C Young, S Zani

Abstract

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).

Conflict of interest statement

M. B. has received material support (i.e., EEG monitor loan) for a postoperative recovery study in older adults from Masimo, and legal consulting fees related to postoperative neurocognitive function in older adults. J. N. B. acknowledges funding from Claret Medical, Inc. D. T. L. is an officer of AegisCN, which is developing the ApoE mimetic peptide CN‐105 for clinical use. The other authors have no other conflicts of interest to disclose related to this manuscript.

© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

Figures

Figure 1
Figure 1
MADCO‐PC study flow diagram. Out of 140 patients who consented to and enrolled in the study and underwent baseline testing, 110 patients returned for cognitive testing at 6 weeks after surgery. These 110 patients were used in the final data analysis.
Figure 2
Figure 2
CSF biomarkers in MADCO‐PC surgical patients before, 24 h after, and 6 weeks after anesthesia and surgery. In (A–F) black lines represent the group medians, error bars represent MADs. Colored lines in (A–E) represent biomarker trajectories for individual patients who had values >1.5 the interquartile range from the median (a standard statistical definition for outliers 75 ) at any time point. (A) CSF Aβ levels. CSF Aβ42 levels were within 1.5 times the IQR from the group median at all three time points in all patients. (B) CSF tau levels. Six patients had CSF tau levels >1.5 times the IQR from the group median at one or more time points. (C) CSF p‐tau‐181p levels. Nine patients had CSF p‐tau‐181p levels >1.5 times the IQR from the group median at one or more time points. In one of the two patients with p‐tau‐181p levels >90 at the 6‐week time point, CSF samples were unavailable at the preoperative and 24 h time points, so these values were imputed (see Methods section). (D) CSF tau/Aβ ratio. Sixteen patients had CSF tau/Aβ42 ratios >1.5 times the IQR from the group median at one or more time points. (E) CSF p‐tau‐181p/Aβ ratio. 14 patients had CSF p‐tau‐181p/Aβ42 ratios >1.5 times the IQR from the group median at one or more time points. In one of the two patients with a p‐tau‐181p/Aβ ratio >0.5 at the 6‐week time point, CSF samples were unavailable at the preoperative and 24 h time points, so these values were imputed (see Methods section). (F) CSF tau versus Aβ plot in MADCO‐PC patients, with dashed lines representing the cutoffs for pathological Aβ and tau levels. [Colour figure can be viewed at wileyonlinelibrary.com]
Figure 3
Figure 3
Cognitive results before and 6 weeks after surgery. (A) overall cognitive index; (B) verbal memory; (C) visual memory; (D) executive function; (E) attention/concentration. A positive score on the y‐axis represents an improvement in cognitive score from before to after surgery, and vice versa. * indicates a significant difference between the preoperative and 6‐week timepoints at p < 0.05.
Figure 4
Figure 4
Correlation between changes in CSF biomarkers and overall cognitive index change from before to 6 weeks after surgery and anesthesia. (A) CSF Aβ; (B) CSF tau; (C) CSF p‐tau‐181p; (D) tau/Aβ ratio; (E) p‐tau‐181p/Aβ ratio. A positive score on the x‐ or y‐axis represents an improvement in cognitive score or an increase in the indicated biomarker from before to after surgery, respectively, and vice versa.

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