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Figure.  pTau181 and Neurofilament Light Chain (NfL) Plasma Concentrations Increase Significantly During the Perioperative Period
pTau181 and Neurofilament Light Chain (NfL) Plasma Concentrations Increase Significantly During the Perioperative Period

A, In patients undergoing cardiac surgery, pTau181 concentrations peak during surgery and remain elevated on postoperative days 1 (POD1) and 2 (POD2). Lines are color coded to distinguish individual patients. B, A similar but less pronounced temporal pattern was observed in patients undergoing hip replacement surgery. C, In patients undergoing cardiac surgery, NfL levels remain flat on the day of surgery, but peak on POD1 and POD2. D, In contrast, no significant elevation of NfL was detected in patients undergoing hip replacement surgery. Data are analyzed by repeated-measures analysis of variance with Tukey post hoc multiple comparisons test. CPB indicates cardiopulmonary bypass.

aP < .05.

bP < .01.

cP < .001.

Table.  Demographic and Surgical Patient Details
Demographic and Surgical Patient Details
1.
Newman  MF, Kirchner  JL, Phillips-Bute  B,  et al; Neurological Outcome Research Group and the Cardiothoracic Anesthesiology Research Endeavors Investigators.  Longitudinal assessment of neurocognitive function after coronary-artery bypass surgery.   N Engl J Med. 2001;344(6):395-402. doi:10.1056/NEJM200102083440601PubMedGoogle ScholarCrossref
2.
Kapila  AK, Watts  HR, Wang  T, Ma  D.  The impact of surgery and anesthesia on post-operative cognitive decline and Alzheimer’s disease development: biomarkers and preventive strategies.   J Alzheimers Dis. 2014;41(1):1-13. doi:10.3233/JAD-132258PubMedGoogle ScholarCrossref
3.
Evered  L, Silbert  B, Scott  DA, Zetterberg  H, Blennow  K.  Association of changes in plasma neurofilament light and tau levels with anesthesia and surgery: results from the CAPACITY and ARCADIAN studies.   JAMA Neurol. 2018;75(5):542-547. doi:10.1001/jamaneurol.2017.4913PubMedGoogle ScholarCrossref
4.
Janelidze  S, Mattsson  N, Palmqvist  S,  et al.  Plasma P-tau181 in Alzheimer’s disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer’s dementia.   Nat Med. 2020;26(3):379-386. doi:10.1038/s41591-020-0755-1PubMedGoogle ScholarCrossref
5.
Hesse  C, Rosengren  L, Andreasen  N,  et al.  Transient increase in total tau but not phospho-tau in human cerebrospinal fluid after acute stroke.   Neurosci Lett. 2001;297(3):187-190. doi:10.1016/S0304-3940(00)01697-9PubMedGoogle ScholarCrossref
6.
Neselius  S, Brisby  H, Theodorsson  A, Blennow  K, Zetterberg  H, Marcusson  J.  CSF-biomarkers in Olympic boxing: diagnosis and effects of repetitive head trauma.   PLoS One. 2012;7(4):e33606. doi:10.1371/journal.pone.0033606PubMedGoogle Scholar
Research Letter
September 20, 2021

Plasma Biomarkers of Tau and Neurodegeneration During Major Cardiac and Noncardiac Surgery

Author Affiliations
  • 1Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, California
  • 2Department of Neurology and Neurological Sciences, Stanford University, Stanford, California
JAMA Neurol. 2021;78(11):1407-1409. doi:10.1001/jamaneurol.2021.2823

Major surgery is often complicated by postoperative neurocognitive disorder. Affected patients exhibit problems with memory and executive function, similar to deficits seen in Alzheimer disease (AD).1,2 A critical question is whether surgery can exacerbate or unmask latent pathophysiology underlying the development of AD.2

Plasma biomarkers of neuronal damage including total tau and neurofilament light chain (NfL) suggest that surgery can trigger injury.3 Unlike total tau and NfL levels that increase in different brain disorders, the plasma level of tau protein phosphorylated at threonine residue 181 (pTau181) is relatively specific and predictive of AD.4 Whether major surgery triggers increases in plasma pTau181 is unknown.

Methods

The study was approved by Stanford University’s Institutional Review Board. All participants gave written informed consent. Patients undergoing cardiac surgery (n = 6) requiring cardiopulmonary bypass and patients undergoing hip replacement surgery (n = 8) were studied. In patients undergoing cardiac surgery, blood was collected before and after induction of anesthesia, after incision, while undergoing cardiopulmonary bypass, after cardiopulmonary bypass, and on postoperative day (POD) 1 and POD2 (only 4 of 6 samples were collected before induction and on POD2). In patients undergoing hip replacement surgery, blood was collected before and 1 hour after surgery and on POD1 and POD2. pTau181, total tau, and NfL plasma concentrations were analyzed for each sample (eMethods in the Supplement). Repeated-measures analysis of variances and the Tukey post hoc test examined temporal changes (adjusted P < .05).

Results

Five men and 1 woman underwent cardiac surgery with a median age of 65 years (range, 53-83 years). Five men and 3 women underwent hip replacement surgery with a median age of 76 years (range, 33-84 years). Further patient and procedural characteristics are in the Table. In patients undergoing cardiac surgery, median plasma pTau181 concentrations before incision were 1.40 pg/mL (range, 1.10-1.66) and below the threshold (1.81 pg/mL), associated with progression to AD.4 Intraoperatively, pTau181 levels increased 5.1-fold to 6.75 pg/mL (range, 2.90-17.20) (Figure, A). Plasma total tau levels increased 26.1-fold, from 2.44 pg/mL (range, 1.58-4.12) to 58.74 pg/mL (range, 3.43-92.60) (data available on request from I.F.). pTau181 and total tau levels remained elevated on POD1 and POD2, although not significantly. In patients undergoing hip replacement surgery, pTau181 levels increased 2.5-fold from 1.25 pg/mL (range, 1.10-2.60) to 3.45 pg/mL (range, 1.80-6.50) immediately after surgery (Figure, B). Total tau levels increased 3.8-fold, from 2.05 pg/mL (range, 0.90-3.66) to 9.47 pg/mL (range, 2.24-16.1) (data available on request from I.F.). pTau181 and total tau levels remained elevated on POD1 and POD2, although not significantly.

In patients undergoing cardiac surgery, plasma NfL remained unchanged through surgery but rose 2.4-fold on POD1 from 13.69 pg/mL (range, 5.02-33.90) to 39.40 pg/mL (range, 19.10-71.40) and remained elevated on POD2 (Figure, C). In patients undergoing hip replacement surgery, NfL levels were also unchanged through surgery but rose 1.4-fold on POD1 from 13.5 pg/mL (range, 7.45-42.40) to 21.0 pg/mL (range, 10.10-99.60) and remained elevated on POD2, although not significantly (Figure, D).

Discussion

Results corroborate prior reports showing increased total tau and NfL levels in patients undergoing major surgery3 and added novelty by demonstrating parallel increases of plasma pTau181. Tau hyperphosphorylation is associated with its accelerated separation from microtubules and aggregation into neurofibrillary tangles, although how these changes relate to neuronal dysfunction and death is under active investigation. Elevated plasma levels of phosphorylated isoforms of tau, including pTau181, discriminate AD from other neurodegenerative disorders.4 A growing body of evidence also suggests that this specificity extends to acute brain injury. For example, acute stroke and traumatic injuries are associated with increased total tau and NfL levels, while pTau181 levels remain unchanged.5,6 Our results provide novel insights into a pathogenic process potentially linking surgery to the subsequent development of AD in vulnerable patients. Importantly, given the small sample size and limited follow-up period of this study, larger-scale longitudinal investigations are needed to further explore this potential link.

Biomarker increases were accentuated in cardiac surgery, which entails a higher risk of postoperative neurocognitive disorder than noncardiac surgery.1 Cardiac surgery–specific parameters, including extracorporeal circulation and the potential need for circulatory arrest and hypothermia, may increase the risk of neuronal injury and subsequent cognitive decline. Plasma biomarkers may help identify patient and procedure-based risks of postoperative neurocognitive disorder and assist the development of protocols to minimize risk. However, studies extending beyond the perioperative period and concurrently assessing cognition are required to link perioperative biomarker profiles to long-term cognitive outcomes.

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Article Information

Accepted for Publication: July 2, 2021.

Published Online: September 20, 2021. doi:10.1001/jamaneurol.2021.2823

Corresponding Author: Igor Feinstein, MD, PhD, Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, 300 Pasteur Dr, Room H3580, Stanford, CA 94305 (ifeinste@stanford.edu).

Author Contributions: Drs Angst and Greicius had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Angst and Greicius contributed equally as co–senior authors.

Concept and design: Feinstein, Wilson, Angst, Greicius.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Feinstein, Wilson, Angst, Greicius.

Critical revision of the manuscript for important intellectual content: Feinstein, Wilson, Swarovski, Andreasson, Greicius.

Statistical analysis: Wilson, Andreasson, Greicius.

Obtained funding: Angst, Greicius.

Administrative, technical, or material support: Feinstein, Wilson, Swarovski, Andreasson, Angst.

Supervision: Andreasson, Angst.

Conflict of Interest Disclosures: None were reported.

Funding/Support: Dr Wilson is the recipient of the Stanford University Dean of Medicine’s Postdoctoral Fellowship. This work was also supported by the Iqbal Farrukh & Asad Jamal Fund and the National Institutes of Health (grant AG066515).

Role of the Funder/Sponsor: The Iqbal Farrukh & Asad Jamal Fund and the National Institutes of Health had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

References
1.
Newman  MF, Kirchner  JL, Phillips-Bute  B,  et al; Neurological Outcome Research Group and the Cardiothoracic Anesthesiology Research Endeavors Investigators.  Longitudinal assessment of neurocognitive function after coronary-artery bypass surgery.   N Engl J Med. 2001;344(6):395-402. doi:10.1056/NEJM200102083440601PubMedGoogle ScholarCrossref
2.
Kapila  AK, Watts  HR, Wang  T, Ma  D.  The impact of surgery and anesthesia on post-operative cognitive decline and Alzheimer’s disease development: biomarkers and preventive strategies.   J Alzheimers Dis. 2014;41(1):1-13. doi:10.3233/JAD-132258PubMedGoogle ScholarCrossref
3.
Evered  L, Silbert  B, Scott  DA, Zetterberg  H, Blennow  K.  Association of changes in plasma neurofilament light and tau levels with anesthesia and surgery: results from the CAPACITY and ARCADIAN studies.   JAMA Neurol. 2018;75(5):542-547. doi:10.1001/jamaneurol.2017.4913PubMedGoogle ScholarCrossref
4.
Janelidze  S, Mattsson  N, Palmqvist  S,  et al.  Plasma P-tau181 in Alzheimer’s disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer’s dementia.   Nat Med. 2020;26(3):379-386. doi:10.1038/s41591-020-0755-1PubMedGoogle ScholarCrossref
5.
Hesse  C, Rosengren  L, Andreasen  N,  et al.  Transient increase in total tau but not phospho-tau in human cerebrospinal fluid after acute stroke.   Neurosci Lett. 2001;297(3):187-190. doi:10.1016/S0304-3940(00)01697-9PubMedGoogle ScholarCrossref
6.
Neselius  S, Brisby  H, Theodorsson  A, Blennow  K, Zetterberg  H, Marcusson  J.  CSF-biomarkers in Olympic boxing: diagnosis and effects of repetitive head trauma.   PLoS One. 2012;7(4):e33606. doi:10.1371/journal.pone.0033606PubMedGoogle Scholar
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