Transcript Biomarker-based Outcome Prediction of Postoperative Cognitive
BioCog: Biomarker-based Outcome Prediction of Postoperative Cognitive Disorders
Georg Winterer
Department of Anaesthesia and Intensive Care Medicine
Goals:
BioCog: New Research Program
Establish a large Biobank: Postoperative Cognitive Disorders (Neuroimaging & Molecular Biomarkers) Biomarker-based Outcome Prediction Understanding the Pathology
2-Level Procedure: A. Conducting a Series of (smaller) Stand-Alone Studies B. In parallel, collecting Material for Building a large Biorepository
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%
Postoperative Cognitive Delirium POD DSM-IV: 293.0
Acute
Postoperative Cognitive Dysfunction POCD DSM-IV: 294.0
Chronic
Postoperative Cognitive Disorders
Association of POD & POCD 1 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 & Dementia 2 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
Anaesthesia
2008
63
:941-47 2 Meta-analysis: Witlox et al
JAMA
2010
304
:443-51
-
Postoperative Cognitive Disorders: Multimorbid Condition
Multiple Factors* associated with POD/POCD 3 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 3 Deiner & Silverstein
Br JAnaesth
2009
103 Suppl 1
:141-46
Pathophysiogical/Molecular Mechanisms of Interest
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 4 Field et al
J Neurosci
2012
32
:6288-94
Cholinergic-Inflammatory Interface: when cytokines and acetylcholine collide
Postoperative Cognitive Disorders: Biomarkers
POD/POCD: Clinical Observations and some Experimental Animal Data but: very few (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
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)
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
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
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
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
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
CHRNA4 & Functional Magnetic Resonance Imaging (fMRI) - Imaging Genetics Nicotinic CHRNA4 Exon 5 SNP: rs1044396
P = 0.042
Frontal P = 0.047
Parietal N = 47 Healthy Subjects, Visual Oddball task)
Winterer et al (2007)
Human Molecular Genetics
National DFG Priority Program: Nicotine: Molecular & Physiological Effects in CNS
Simultaneous fMRI/EEG Acquisition
Employed Task Conditions: Resting, Oddball, Posner, N-Back, Verbal Memory Laser-Stimulation (Pain)
Continuous EEG-Recording during MR-Scan. Sampling: 5000Hz MR Volume-triggered Stimulus Presentation
fMRI EEG/ERP
EPI Sequence: 33 Slices (3mm) TR = 2000ms
Helium Pump switched off!
Siemens Magnetom Trio Additional Physiological /Stress Monitoring: Electrodermal Activity (EDA), ECG, RR, S O2 32-Channel BrainCap MR
Partnership in Product Development
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
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
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)
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
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)
BioCog: Research Program
- Design -
Imaging Drug Challenge Studies CSF Studies (with Imaging)
N ~ 50-200
Exploratory Drug Trials (with Imaging) 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
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
BioCog: Perspective
•
BioCog is being established because of the unmet need (Outcome Prediction, Treatment)
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We anticipate that one group (e.g. Charit é group) will not be sufficient to address this unmet need alone
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We suggest to give this effort an international dimension (Europe and beyond) Utrecht (Arjen Slooter) has already joined forces
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
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
and/or [email protected]