Biomarker Development for Postoperative Cognitive Impairment in the Elderly (BioCog)

NCT02265263 | Terminated

• 1 other identifier: BioCog
• Study Type: observational
• Target: 1,054
• Locations: 2 countries
• Sites: 2

Brief Summary

The research leading consortium to these results has received funding from the European Union Seventh Framework Programme \[FP7/2007-2013\] under grant agreement no 602461 (www.biocog.eu). The investigators will establish valid biomarkers panels (neuroimaging and molecular) for risk and clinical outcome prediction of postoperative delirium (POD)/postoperative cognitive deficit (POCD) in elective surgical patients (Age ≥ 65 years) in study centers in Berlin,Germany (data collection within 2 years after initial hospital stay) and Utrecht, The Netherlands (data collection within 1 year after initial hospital stay), thereof cerebrospinal fluid (only once on day of surgery in patients with planned spinal anesthesia/combined spinal epidural analgesia in patients, only in Berlin). A control group of ASA II/III- patients is collected for measuring the learning experience during the cognitive testings. The participants are matched on age, education, and gender to the study patients. The ASA II/III- control patients receive additionally MRI-scan (3 Tesla) at baseline, after 3 months and after 1 (Utrecht) and 2 years (Berlin). To analyze scanner variability we additionally measure at maximum 20 subjects (Age ≥ 65 years, ASA I and II) from Utrecht in the MRI scanner (3-Tesla) in Berlin and vice versa. A study group at maximum (n= 80) and is collected for measuring 7 Tesla MRI at two timepoints (Baseline and 90 days).The primary endponit of this substudy is gamma amino-butyric acid concentration in CNS after 3-months (measured by MRI). A retrospective comparison group (extracting 8000 intensive care unit patient data from the patient data management system during the BioCog study period in 2016) to analyse economic effects that are caused by the implementation of quality indicators in health care. An interim-analysis is performed on the primary endpoint after 400 included patients. The resulting (multivariate) expert system is expected: 1) to support clinical decision-making in patient care, e.g. to balance the individual POD/POCD risk against the expected overall clinical outcome of an (elective) surgical intervention, 2) to allow the design of more sophisticated and hypothesis-driven clinical studies and drug trials (translational research) in the future. The latter will be possible on the basis of biomarker-based sub-grouping of patients and a better understanding of relevant pathophysiological processes. Furthermore, a state-of-the art clinical database and biobank will be created that does not yet exist worldwide. Both the expert system and the reference database/biobank will expand the leadership of the contributing academic institutions in this particular research area. In addition, the newly created biobank will become an integral part of the European Biobanking and Biomolecular Resources Research Infrastructure (BBMRI) which allows top address specific and hypothesis-driven research questions. Most notably, the developed (multivariate) expert system also has the potential for commercialization. Possible customers are: 1) physicians and hospital departments being involved in pre-surgical decision making, 2) pharmaceutical industry intending to conduct biomarker-based drug trials in POD/POCD.

Conditions

Postoperative Delirium (POD); Postoperative Cognitive Deficit (POCD)

Outcome Measures

Primary Outcomes (2)

• Incidence of Delirium

  Postoperative delirium rate, defined according to Diagnostic and Statistical Manual of Mental Disorders (DSM-V) and/or as ≥ 2 cumulative points in the nursing Delirium Screening Scale (Nu-DESC) and/or a positive Confusion Assessment Method (CAM) and/or Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) score and/or patient chart review that shows descriptions of delirium.

  Participants will be followed for the duration of hospital stay, an expected average of 7 days

• Incidence of postoperative cognitive deficit (POCD)

  POCD will be measured by a defined Cambridge Neuropsychological Test Automated Battery (CANTAB) POCD will be measured by a defined Cambridge Neuropsychological Test Automated Battery (CANTAB) and paper pencil tests (TMT A und B, Grooved Pegboard) and the Mini - Mental State Examination (MMSE)

  Up to 3 months after the operation

Secondary Outcomes (34)

• Duration of Delirium

  Participants will be followed for the duration of hospital stay, an exspected average of 7 days

• Duration of subsyndromal postoperative delirium

  Participants will be followed for the duration of hospital stay, an exspected average of 7 days

• Incidence of subsyndromal postoperative delirium

  Participants will be followed for the duration of hospital stay, an exspected average of 7 days

• Intensive care unit length of stay

  Participants will be followed for the duration of intensive care unit stay, an expected average of 5 days

• Hospital length of stay

  Participants will be followed for the duration of hospital stay, an exspected average of 7 days

Study Arms (4)

Surgical patients - 3 Tesla MRI

A study group of at maximum n= 1200 is collected for measuring 3 Tesla MRI at two timepoints (Baseline and 90 days) in Berlin/Utrecht. They include surgical procedures within body cavity e.g. abdomen or thorax from departments of general surgery, urology, gynecology or thoracic surgery; orthopaedic operations (hip-, knee-, endoprosthesis or spine (including neurosurgical spine operations)); cardiac surgery and operation of extracranial/intracranial head and neck Data collection from study center Utrecht ist within one year after initial hospital stay. Data collection from study center Berlin is within two years after initial hospital stay.

Patients ASA II/III - 3 Tesla MRI

A control group of at maximum n= 300 ASA II/III- patients is collected for measuring the learning experience during the cognitive testings. They are matched on age, education, and gender to the study patients. The 104 ASA II/III- patients should receive additionally MRI-scan (3 Tesla) at baseline, after 3 months and after 1 year in Utrecht, after 3 months, after 1, 2 years in Berlin. Data collection from study center Utrecht ist within one year after initial hospital stay. Data collection from study center Berlin is within five years after initial hospital stay.

Volunteers ASA I/II - 3 Tesla MRI

To analyze scanner variability we additionally measure at maximum 20 subjects (Age ≥ 65 years) from Utrecht in the MRI scanner (3-Tesla) in Berlin and vice versa.

Surgical patients - 7 Tesla MRI

A study Group of at maximum n= 80 should be collected for measuring 7 Tesla MRI at two timepoints (Baseline and 90 days) in Berlin.

Eligibility Criteria

• Age: 65 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Surgical patients, 65 years or above (Berlin/Utrecht) ASA I and II patients, 65 years or above (Utrecht) ASA II and III patients, 65 years or above (Berlin/Utrecht)

You may qualify if:

• Male and female patients aged ≥ 65 years, of European descent (Caucasian)
• Elective surgery with an expected operative time ≥ 60 minutes
• Ability to give informed consent after receiving spoken and written information of the study
• Eligibility for magnetic resonance Imaging

You may not qualify if:

• Mini-Mental-State-Examination ≤ 23 points
• Homelessness or other circumstances where the patient would not be reachable by phone or postal services during follow-up.
• Participation in another prospective interventional clinical study during participation in this clinical study during hospital stay
• Accommodation in an institution due to an official or judicial order
• Missing informed consent for saving and hand out pseudonymous data
• Neuropsychiatric morbidity, which limits the conduction of the neurocognitive testing
• Anacusis or Hypoacusis, which limits the conduction of the neurocognitive testing
• Intraoperative clectroencephalography - examinations (Study Group Berlin):
• Neurological preconditions
• Proposed neurological surgery
• Control Group (Berlin/Utrecht):
• Male and female patients aged ≥ 65 years, of European descent (Caucasian)
• ASA II and III patients
• Eligibility for magnetic resonance Imaging
• Mini-Mental-State-Examination ≤ 23 Points

Sponsors & Collaborators

• Charite University, Berlin, Germany: lead
• European Union: collaborator

Study Sites (2)

Department of Anesthesiology and Intensive Care Medicine, CCM and CVK, Charité - Universitätsmedizin Berlin

Berlin, 13353, Germany

Location

Department of Intensive Care Medicine, University Medical Center Utrecht

Utrecht, 3584 CX, Netherlands

Location

Related Publications (26)

• Feinkohl I, Hadzidiakos D, Dschietzig TB, Janke J, Heinrich M, Slooter AJC, Spies C, Winterer G, Pischon T. Low-grade, systemic inflammation and the risk of perioperative neurocognitive disorders in an observational study of older adults. Sci Rep. 2025 Dec 20;15(1):44231. doi: 10.1038/s41598-025-31986-z.

  PMID: 41419753 DERIVED

• Morgeli R, Borchers F, Feinkohl I, Piper SK, Pischon T, Slooter AJC, Spies C, Wiebach J, Winterer G, Zacharias N, Lammers-Lietz F. A secondary analysis of cortical atrophy and plasma amyloid beta patterns in older patients with cognitive frailty undergoing elective surgery. BMC Geriatr. 2025 Jul 2;25(1):484. doi: 10.1186/s12877-025-05740-z.

  PMID: 40604523 DERIVED

• Starks SCE, Pohrt A, Halzl-Yurek F, Heinrich M, Muller A, Spies CD, Winterer G, Zacharias N. Long-term and pre-operative benzodiazepine use in older adults and risk for postoperative delirium: An additional analysis of the multicentre Biomarker Development for Postoperative Cognitive Impairment in the Elderly Study. Eur J Anaesthesiol. 2025 Aug 1;42(8):704-713. doi: 10.1097/EJA.0000000000002201. Epub 2025 May 16.

  PMID: 40384317 DERIVED

• Heinrich M, Spies C, Borchers F, Feinkohl I, Pischon T, Slooter AJC, von Haefen C, Zacharias N, Winterer G, Lammers-Lietz F. Perioperative Levels of IL8 and IL18, but not IL6, are Associated with Nucleus Basalis Magnocellularis Atrophy Three Months after Surgery. J Neuroimmune Pharmacol. 2024 Mar 14;19(1):10. doi: 10.1007/s11481-024-10110-4.

  PMID: 38483732 DERIVED

• Fislage M, Winzeck S, Woodrow R, Lammers-Lietz F, Stamatakis EA, Correia MM, Preller J, Feinkohl I, Hendrikse J, Pischon T, Spies CD, Slooter AJC, Winterer G, Menon DK, Zacharias N; BioCog Consortium. Structural disconnectivity in postoperative delirium: A perioperative two-center cohort study in older patients. Alzheimers Dement. 2024 Apr;20(4):2861-2872. doi: 10.1002/alz.13749. Epub 2024 Mar 7.

  PMID: 38451782 DERIVED

• Trauzeddel RF, Rothe LM, Nordine M, Dehe L, Scholtz K, Spies C, Hadzidiakos D, Winterer G, Borchers F, Kruppa J, Treskatsch S. Influence of a chronic beta-blocker therapy on perioperative opioid consumption - a post hoc secondary analysis. BMC Anesthesiol. 2024 Feb 27;24(1):80. doi: 10.1186/s12871-024-02456-2.

  PMID: 38413849 DERIVED

• Fislage M, Feinkohl I, Borchers F, Heinrich M, Pischon T, Veldhuijzen DS, Slooter AJC, Spies CD, Winterer G, Zacharias N; BioCog Consortium. Trail making test B in postoperative delirium: a replication study. BJA Open. 2023 Nov 3;8:100239. doi: 10.1016/j.bjao.2023.100239. eCollection 2023 Dec.

  PMID: 37954892 DERIVED

• Fislage M, Feinkohl I, Borchers F, Pischon T, Spies CD, Winterer G, Zacharias N; BioCog Consortium. Preoperative thalamus volume is not associated with preoperative cognitive impairment (preCI) or postoperative cognitive dysfunction (POCD). Sci Rep. 2023 Jul 20;13(1):11732. doi: 10.1038/s41598-023-38673-x.

  PMID: 37474784 DERIVED

• Feinkohl I, Janke J, Slooter AJC, Winterer G, Spies C, Pischon T; BioCog Consortium. Metabolic syndrome and the risk of postoperative delirium and postoperative cognitive dysfunction: a multi-centre cohort study. Br J Anaesth. 2023 Aug;131(2):338-347. doi: 10.1016/j.bja.2023.04.031. Epub 2023 Jun 20.

  PMID: 37344340 DERIVED

• Ditzel FL, van Montfort SJT, Vernooij LM, Kant IMJ, Aarts E, Spies CD, Hendrikse J, Slooter AJC, van Dellen E; Biomarker Development for Postoperative Cognitive Impairment in the Elderly Consortium. Functional brain network and trail making test changes following major surgery and postoperative delirium: a prospective, multicentre, observational cohort study. Br J Anaesth. 2023 Feb;130(2):e281-e288. doi: 10.1016/j.bja.2022.07.054. Epub 2022 Oct 17.

  PMID: 36261307 DERIVED

• Bosancic Z, Spies CD, Muller A, Winterer G, Piper SK, Heinrich M; BioCog Consortium. Association of cholinesterase activities and POD in older adult abdominal surgical patients. BMC Anesthesiol. 2022 Sep 16;22(1):293. doi: 10.1186/s12871-022-01826-y.

  PMID: 36114455 DERIVED

• Windmann V, Dreier JP, Major S, Spies C, Lachmann G, Koch S. Increased Direct Current-Electroencephalography Shifts During Induction of Anesthesia in Elderly Patients Developing Postoperative Delirium. Front Aging Neurosci. 2022 Jun 28;14:921139. doi: 10.3389/fnagi.2022.921139. eCollection 2022.

  PMID: 35837483 DERIVED

• Fislage M, Feinkohl I, Pischon T, Spies CD, Borchers F, Winterer G, Zacharias N; BioCog Consortium. Presurgical Thalamus Volume in Postoperative Delirium: A Longitudinal Observational Cohort Study in Older Patients. Anesth Analg. 2022 Jul 1;135(1):136-142. doi: 10.1213/ANE.0000000000005987. Epub 2022 Jun 16.

  PMID: 35442218 DERIVED

• Lammers-Lietz F, Zacharias N, Morgeli R, Spies CD, Winterer G. Functional Connectivity of the Supplementary and Presupplementary Motor Areas in Postoperative Transition Between Stages of Frailty. J Gerontol A Biol Sci Med Sci. 2022 Dec 29;77(12):2464-2473. doi: 10.1093/gerona/glac012.

  PMID: 35040961 DERIVED

• Heinrich M, Sieg M, Kruppa J, Nurnberg P, Schreier PH, Heilmann-Heimbach S, Hoffmann P, Nothen MM, Janke J, Pischon T, Slooter AJC, Winterer G, Spies CD. Association between genetic variants of the cholinergic system and postoperative delirium and cognitive dysfunction in elderly patients. BMC Med Genomics. 2021 Oct 21;14(1):248. doi: 10.1186/s12920-021-01071-1.

  PMID: 34674705 DERIVED

• Koch S, Windmann V, Chakravarty S, Kruppa J, Yurek F, Brown EN, Winterer G, Spies C; BioCog Study Group. Perioperative Electroencephalogram Spectral Dynamics Related to Postoperative Delirium in Older Patients. Anesth Analg. 2021 Dec 1;133(6):1598-1607. doi: 10.1213/ANE.0000000000005668.

  PMID: 34591807 DERIVED

• Lichtner G, Zacharias N, Spies CD, Feinkohl I, Winterer G, Pischon T, von Dincklage F; BioCog Consortium. Resting state brain network functional connectivity is not associated with inflammatory markers and blood cell counts in older adults. Clin Neurophysiol. 2021 Jul;132(7):1677-1686. doi: 10.1016/j.clinph.2021.03.042. Epub 2021 May 2.

  PMID: 34044190 DERIVED

• Heinrich M, Muller A, Cvijan A, Morgeli R, Kruppa J, Winterer G, Slooter AJC, Spies CD; BioCog Consortium. Preoperative Comparison of Three Anticholinergic Drug Scales in Older Adult Patients and Development of Postoperative Delirium: A Prospective Observational Study. Drugs Aging. 2021 Apr;38(4):347-354. doi: 10.1007/s40266-021-00839-5. Epub 2021 Mar 15.

  PMID: 33721289 DERIVED

• Kant IMJ, de Bresser J, van Montfort SJT, Mutsaerts HJMM, Witkamp TD, Buijsrogge M, Spies C, Hendrikse J, Slooter AJC. Preoperative brain MRI features and occurrence of postoperative delirium. J Psychosom Res. 2021 Jan;140:110301. doi: 10.1016/j.jpsychores.2020.110301. Epub 2020 Nov 16.

  PMID: 33260072 DERIVED

• Deffland M, Spies C, Weiss B, Keller N, Jenny M, Kruppa J, Balzer F. Effects of pain, sedation and delirium monitoring on clinical and economic outcome: A retrospective study. PLoS One. 2020 Sep 2;15(9):e0234801. doi: 10.1371/journal.pone.0234801. eCollection 2020.

  PMID: 32877411 DERIVED

• van Montfort SJT, van Dellen E, Wattel LL, Kant IMJ, Numan T, Stam CJ, Slooter AJC. Predisposition for delirium and EEG characteristics. Clin Neurophysiol. 2020 May;131(5):1051-1058. doi: 10.1016/j.clinph.2020.01.023. Epub 2020 Feb 21.

  PMID: 32199395 DERIVED

• Feinkohl I, Borchers F, Burkhardt S, Krampe H, Kraft A, Speidel S, Kant IMJ, van Montfort SJT, Aarts E, Kruppa J, Slooter A, Winterer G, Pischon T, Spies C. Stability of neuropsychological test performance in older adults serving as normative controls for a study on postoperative cognitive dysfunction. BMC Res Notes. 2020 Feb 4;13(1):55. doi: 10.1186/s13104-020-4919-3.

  PMID: 32019577 DERIVED

• Kant IMJ, Mutsaerts HJMM, van Montfort SJT, Jaarsma-Coes MG, Witkamp TD, Winterer G, Spies CD, Hendrikse J, Slooter AJC, de Bresser J; BioCog Consortium. The association between frailty and MRI features of cerebral small vessel disease. Sci Rep. 2019 Aug 5;9(1):11343. doi: 10.1038/s41598-019-47731-2.

  PMID: 31383903 DERIVED

• Windmann V, Spies C, Brown EN, Kishnan D, Lichtner G, Koch S; BioCog Study Group. Influence of midazolam premedication on intraoperative EEG signatures in elderly patients. Clin Neurophysiol. 2019 Sep;130(9):1673-1681. doi: 10.1016/j.clinph.2019.05.035. Epub 2019 Jul 10.

  PMID: 31351371 DERIVED

• Lachmann G, Kant I, Lammers F, Windmann V, Spies C, Speidel S, Borchers F, Hadzidiakos D, Hendrikse J, Winterer G, de Bresser J; BIOCOG Consortium. Cerebral microbleeds are not associated with postoperative delirium and postoperative cognitive dysfunction in older individuals. PLoS One. 2019 Jun 14;14(6):e0218411. doi: 10.1371/journal.pone.0218411. eCollection 2019.

  PMID: 31199858 DERIVED

• Feinkohl I, Janke J, Hadzidiakos D, Slooter A, Winterer G, Spies C, Pischon T. Associations of the metabolic syndrome and its components with cognitive impairment in older adults. BMC Geriatr. 2019 Mar 7;19(1):77. doi: 10.1186/s12877-019-1073-7.

  PMID: 30845934 DERIVED

Related Links

• Related Info

Biospecimen

Retention: SAMPLES WITH DNA

* Whole blood-/plasma (RNA-/DNA-Analysis) * Cerebrospinal fluid (sequencing of candidate nicotinic receptor genes and genes for acetylcholine synthesis/-catabolism: CHRNA3, CHRNA4, CHRNA5, CHRNA7, CHRNB2, CHRNB4, ACHE, CHAT) (only in Berlin).

MeSH Terms

Conditions

Emergence Delirium

Condition Hierarchy (Ancestors)

Delirium; Confusion; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Postoperative Complications; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Neurocognitive Disorders; Mental Disorders

Study Officials

• Claudia Spies, MD Prof.

  Department of Anesthesiology and Intensive Care Medicine, CVK/CCM, Charité - University Medicine Berlin

  PRINCIPAL INVESTIGATOR

• Georg Winterer (BioCog Research Program Coordinator), MD, PhD

  Department of Anesthesiology and Intensive Care Medicine, CVK/CCM, Charité - University Medicine Berlin

  STUDY CHAIR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Univ.-Prof. Dr. med. C. Spies

Study Record Dates

• First Submitted: September 23, 2014
• First Posted: October 15, 2014
• Study Start: October 1, 2014
• Primary Completion: December 1, 2017
• Study Completion: June 1, 2019
• Last Updated: September 25, 2019

Record last verified: 2019-09

Locations

DE (1); NL (1)