1 / 27

Georg Winterer

BioCog: Biomarker-based Outcome Prediction of Postoperative Cognitive Disorders. Georg Winterer. Department of Anaesthesia and Intensive Care Medicine. BioCog: New Research Program. Goals: Establish a large Biobank: Postoperative Cognitive Disorders (Neuroimaging & Molecular Biomarkers)

blade
Download Presentation

Georg Winterer

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. BioCog: Biomarker-based Outcome Prediction of Postoperative Cognitive Disorders Georg Winterer Department of Anaesthesia and Intensive Care Medicine

  2. BioCog: New Research Program Goals: Establish a large Biobank: Postoperative Cognitive Disorders (Neuroimaging & Molecular Biomarkers) Biomarker-based Outcome Prediction Understanding the Pathology • 2-Level Procedure: • Conducting a Series of (smaller) Stand-Alone Studies • In parallel, collecting Material for Building a large Biorepository

  3. Postoperative Cognitive Delirium POD DSM-IV: 293.0 Postoperative Cognitive Dysfunction POCD DSM-IV: 294.0 Postoperative Cognitive Disorders Postoperative cognitive impairment is characterized by the progressive deterioration of sensory and cognitive function following surgery with incidences of up to 30-80% Acute Chronic

  4. Postoperative Cognitive Disorders • Association of POD & POCD1 • In N = 948 non-cardiac surgical patients with cognitive assessment at 3 months follow up POCD occurred: • in 19% with no documented prior delirium • in 32% after short delirium duration (1–2 days) • in 55% after more-prolonged delirium Association of POD & Dementia2 OR = 12.52 [95% CI, 1.86-84.21] of POD and subsequent dementia after 3.2 and 5.0 years of follow-up (corrected for baseline dementia, severity of illness, age) 1 ISPOCD1 study: Rudolph et al Anaesthesia2008 63:941-47 2 Meta-analysis:Witlox et al JAMA 2010 304:443-51

  5. Postoperative Cognitive Disorders: Multimorbid Condition • Multiple Factors* associated with POD/POCD3 • age per se • inflammation • extent of surgical trauma (inflammatory response) • cholinergic parameters: (e.g. anticholinergic medication) • diabetes/life style • cardiovascular/hypovolemic shock • neuropsychiatric disorders (depression, alcoholism, dementia etc.) These factors have been implicated in the development of (Alzheimer) „dementia“ POD = Acute Model Condition of Chronic (multimorbid) Dementia * Explained variance unknown 3Deiner & Silverstein Br JAnaesth2009 103 Suppl 1:141-46

  6. Cholinergic Mechanisms • Anticholinergic (pre-)medication POD/POCD • Serum anticholinergic activity is associated with delirium • Age-related decrease of cholinergic brain function (Ncl basalis Meynert) • Alzheimer Disease (treatment: cholinergic agonists) • Inflammatory Response Mechanisms • Surgical trauma (systemic) inflammatory response POCD • Mouse model: Systemic inflammation delirium (cognitive dysfunction) • with prior decreased cholinergic brain function • Acetylcholine ( via nACHRA7) attenuates release of pro-inflammatory • cytokines, macrophage migration into hippocampus/cognitive decline Pathophysiogical/Molecular Mechanisms of Interest 4Field et al J Neurosci 2012 32:6288-94

  7. Cholinergic-Inflammatory Interface: when cytokines and acetylcholine collide

  8. Postoperative Cognitive Disorders: Biomarkers POD/POCD: Clinical Observationsandsome Experimental Animal Data but: veryfew (small) Biomarker Studies so far • Biomarkers: Tests to follow Body Processes and Diseases • Risk/Clinical Outcome Predictors • Treatment Response Predictors • Molecular Biomarkers (e.g. Genes,Proteins) • Brain Imaging Biomarkers (structural/functional) • Understand/Predict the Disease Process • Support/Speed-up Drug Development • Javitt et al Nature Rev Drug Development 2008

  9. Postoperative Cognitive Disorders: Neuroimaging vs Molecular Biomarkers • Neuroimaging Biomarkers: • Window into the brain: • allows studying abnormal brain structure and function with high • sensitivity • - In part independent of specific molecular pathology • Molecular Biomarkers: • Tracking specific molecular processes • Limited sensitvity (plasma) because of blood-brain barrier • (except CSF)

  10. Postoperative Cognitive Disorders: Structural Neuroimaging Alzheimer’s Disease Neuroimaging Initiative (ADNI) Cortical/hippocampal Volume Cognitive Performance N = 123 normal elderly (NL) vs N = 41 patients with minimal cognitive impairment (MCI) Age: 55-90 years pre- vs postsurgery (5-9 months) Postsurgical atrophy in NL and MCI but cognitive decline only in MCI Problems: Sample size/heterogeneity, lack of sensitivity of structural MRI Kline et al Anesthesiology 2012

  11. Postoperative Cognitive Disorders: Structural Neuroimaging • Study Design Improvements: • Prospective POD/POCD study design rather than retrospective study • Increase sample size • Reduce clinical variance (post-operative interval, age group etc.) • Reduce technical variance (multicenter design N > 10 inappropriate) • Add targeted high-resolution scans (e.g. Ncl. Basalis Meynert*) • Add functional Neuroimaging/Electrophysiology • with generally higher sensitivity compared to structural MRI * Ncl. Basalis Meynert = main cholinergic input to cortex

  12. Postoperative Cognitive Disorders: Electrophysiology/Functional Imaging • Arterial Spin Labeling (ASL): • Vascular perfusion imaging (without contrast agent) • In Alzheimer Disease (AD), excellent agreement with gold standard • (FDG-PET) to measure hypoperfusion • No POD/POCD studies yet • Functional Magnetic Resonance Imaging (fMRI): • Excellent spatial resolution of BOLD fMRI studies • In AD, abnormal frontoparietal/mediotemporal activation/functional • connectivity during memory tasks/resting state in AD (risk) • No POD/POCD studies yet • Altered ASL/fMRI patterns in POD/POCD (risk) are likely because two small (and older) SPECT/Xenon • perfusion studies indicated decreased perfusion in critical brain regions

  13. PharmfMRI: Ncl. Basalis Meynert Ncl. Basalis Meynert = main cholinergic input to cortex 10 never-smokers vs 13 regular smokers In smokers, higher activation in Ncl. Basalis Meynert Vossel et al. J Psychopharmacol (2010) National DFG Priority Program: Nicotine: Molecular & Physiological Effects in CNS DFG study conducted at Helmholtz Research Center Jülich

  14. PharmfMRI: Opposite Nicotine Response in High vs Low Performers Study Design: Nicotine (Nasal Spray 1mg) vs Placebo (Cross-Over) Visual Oddball Task (Selective Attention) R = 0.41 P = 0.009 R = 0.34 P = 0.03 High Activation in Poor Performer (Reaction Time/Variability) and vice versa Group Level fMRI Analysis: Increased Activation with Nicotine N = 19 Smokers, N = 22 Never-Smokers (Selected from a large Population-Based Sample N =2400) Warbrick et al Psychopharmacology (2011) National DFG Priority Program: Nicotine: Molecular & Physiological Effects in CNS DFG study conducted at Helmholtz Research Center Jülich

  15. CHRNA4 & Functional Magnetic Resonance Imaging (fMRI) - Imaging Genetics - Nicotinic CHRNA4 Exon 5 SNP: rs1044396 P = 0.042 Frontal Parietal P = 0.047 N = 47 Healthy Subjects, Visual Oddball task) Winterer et al (2007) Human Molecular Genetics National DFG Priority Program: Nicotine: Molecular & Physiological Effects in CNS

  16. Simultaneous fMRI/EEG Acquisition Employed Task Conditions: Resting, Oddball, Posner, N-Back, Verbal Memory Laser-Stimulation (Pain) EEG/ERP Continuous EEG-Recording during MR-Scan. Sampling: 5000Hz MR Volume-triggered Stimulus Presentation 32-Channel BrainCap MR fMRI EPI Sequence: 33 Slices (3mm) TR = 2000ms Helium Pump switched off! Additional Physiological /Stress Monitoring: Electrodermal Activity (EDA), ECG, RR, SO2 Siemens Magnetom Trio Partnership in Product Development

  17. Why simultaneous fMRI/EEG? With nicotine challenge, EEG-informed fMRI is more sensitive than either modality alone N = 32 (19 Smokers) (From Population-Based Sample) Warbrick et al J Cogn Neurosci (2011) National DFG Priority Program: Nicotine: Molecular & Physiological Effects in CNS DFG study conducted at Helmholtz Research Center Jülich

  18. Why simultaneous fMRI/EEG? While it is not yet entirely clear whether fMRI is abnormal in POD/POCD, EEG is heavily altered in various types of delirium/dementia incl. POD/POCD • Quantitative EEG (QEEG) predicts short-term/longterm cognitive decline in • normal elderly, MCI patients and AD • Resting QEEG predicts cognitive decline (dementia) in normal elderly with a • sensitivity of 88.9% and a specificity of 84.3% with 7-9 years follow-up • Preoperative resting QEEG slowing predicts POCD, while intraoperative EEG • slowing predicts POD Luckhaus et al Int J Geriatr Psychiat 2008 23:1148-55; Prichep et al Neurobiol Aging 2006 27:471-81; Hofsté et al Int J Clin Monit Comput 1997 14:29-36

  19. Subanesthetic Ketamine Challenge: Pharmacological Model of POD Functional Connectivity (Small World Properties) of Ketamine Effects Resting State: EEG-informed fMRI Analysis Normalized Cluster Coefficient Ketamine Delirium Reaction more frequent in Elderly NMDA-blockade: Desinhibition of GABAergic Interneurons Benzodiazepines can worsen delirium Increased „Clustering“ i.e., Communication in Visual Cortex (hallucinations?) Contrast Ketamine > Placebo: 1-70Hz, Z > 2.3, corrected Within-subject cross-over design (N = 12) Musso et al. NeuroImage 2011, Musso et al (in preparation)

  20. Postoperative Cognitive Disorders: Molecular Biomarkers Genetics: No genetic risk markers have yet been associated with POD/POCD Genomewide association studies (GWAS) currently not feasible because sufficiently large (international) samples are missing Systems Candidate Gene Approach:* Genetic Biomarker DNA: e.g. Sequencing all cholinergic genes (exons, promoters = 46.7Kb) to capture common and rare variants Genetic Biomarker RNA: e.g. Sequencing transcripts from peripheral blood (approx. 80% of genes expressed in blood cells are shared with brain tissue) * Other potential candidate genes: genes coding for proteins involved in inflammatory response

  21. Molecular Biomarkers: Specific Molecular Mechanisms Plasma/CSF Markers: Plasma markers have the advantage that they can be easily (and repeatedly), however, large samples required (blood-brain barrier etc) CSF markers* more closely reflect CNS pathology Markers that have been associated with POD/POCD: Inflammation: CRP/pro- and anti-inflammatory cytokines/TNF/interleukins (IL-8) Cholinergic: anticholinergic activity (acetylcholine esterase) Others: HbA1c//cholesterol/triglycerides/cortisol/fasting glucose/HVA/cortisol Potential candidates: Additional inflammation markers incl. migration factors/cytokine products, signature of the action of macrophage-derived pro-inflammatory cytokines Others: Oxidative stress markers, AD-markers (Phospho-Tau etc.) *Spinal anesthesia allows collecting CSF markers (incidence of POD is comparable for spinal vs general anesthesia)

  22. BioCog: Research Program - Design - Imaging Drug Challenge Studies N ~ 50-200 CSF Studies (with Imaging) Exploratory Drug Trials (with Imaging) Large Scale Small Scale Biorepository: Blood (DNA, RNA), Plasma Pre-Surgery - 1 Day Post Surgery - 4 Weeks Post Surgery Neuroimaging-Backbone (MRI, ASL, EEG/fMRI) Training Set: N = 400 Test Set: N = 1200 N = 1600 2013 2018

  23. Biomarker Establishment • Industry-standard biomarker development requires taking the technical, biometrical and organisational steps to ensure that valid biomarkers are selected • Standardized data collection/analysis - with advice from European Medicines Agency (EMA) • Training set (N = 400), test set (N = 1200) after optimization of data analysis/reduction of multivariate solution space • Deliverables: reference ranges, sensitivity and specificity with receiver operating characteristic (ROC), positive and negative predictive values (PPV, NPV), false discovery rate (FDR), reliability

  24. BioCog: Perspective BioCog is being established because of the unmet need (Outcome Prediction, Treatment) We anticipate that one group (e.g. Charité group) will not be sufficient to address this unmet need alone We suggest to give this effort an international dimension (Europe and beyond) Utrecht (Arjen Slooter) has already joined forces

  25. Biobanking POD/POCD: Establish a European Biobank Collecting a minimum of data/specimen according to a common Protocol/Standard Operating Procedure (SOP) across sites Adapted from: National DFG Priority Program: Nicotine: Molecular & Physiological Effects in CNS

  26. Thank you for your attention! Georg Winterer & COCI/PoDeCoD Group Department of Anaesthesia and Intensive Care Medicine Charité - Universitätsmedizin Berlin Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany Contact georg.winterer@charite.de and/or claudia.spies@charite.de

More Related