georg winterer
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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) - PowerPoint PPT PresentationTRANSCRIPT
Georg Winterer
BioCog: Biomarker-based Outcome Prediction of
Postoperative Cognitive Disorders
Department of Anaesthesia and Intensive Care Medicine
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:
A. Conducting a Series of (smaller) Stand-Alone Studies
B. In parallel, collecting Material for Building a large Biorepository
Postoperative Cognitive Disorders
Postoperative Cognitive Delirium
PODDSM-IV: 293.0
Postoperative Cognitive
DysfunctionPOCD
DSM-IV: 294.0
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
Postoperative Cognitive Disorders
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)
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
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
These factors have been implicated in the development of (Alzheimer) „dementia“
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.)
* Explained variance unknown3Deiner & Silverstein Br JAnaesth 2009 103 Suppl 1:141-46
POD = Acute Model Condition of Chronic (multimorbid) Dementia
Pathophysiogical/Molecular Mechanisms of Interest
4Field et al J Neurosci 2012 32:6288-94
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
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 DiseaseNeuroimaging Initiative (ADNI)
Cortical/hippocampal Volume Cognitive Performance
N = 123 normal elderly (NL)vsN = 41 patients with minimal cognitive impairment (MCI)
Age: 55-90 yearspre- 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
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 CNSDFG study conducted at Helmholtz Research Center Jülich
Ncl. Basalis Meynert = main cholinergic input to cortex
PharmfMRI: Opposite Nicotine Response in High vs Low Performers
Study Design: Nicotine (Nasal Spray 1mg) vs Placebo (Cross-Over)Visual Oddball Task (Selective Attention)
Group Level fMRI Analysis: Increased Activation with Nicotine
High Activation in Poor Performer (Reaction Time/Variability) and vice versa
R = 0.41 P = 0.009 R = 0.34 P = 0.03
Warbrick et al Psychopharmacology (2011)National DFG Priority Program: Nicotine: Molecular & Physiological Effects in CNSDFG study conducted at Helmholtz Research Center Jülich
N = 19 Smokers, N = 22 Never-Smokers(Selected from a large Population-Based Sample N =2400)
Winterer et al (2007) Human Molecular Genetics
N = 47 Healthy Subjects, Visual Oddball task)
P = 0.042
P = 0.047
Frontal
Parietal
Nicotinic CHRNA4 Exon 5 SNP: rs1044396
CHRNA4 & Functional Magnetic Resonance Imaging (fMRI)
- Imaging Genetics -
National DFG Priority Program: Nicotine: Molecular & Physiological Effects in CNS
Simultaneous fMRI/EEG Acquisition
32-ChannelBrainCap MR
EEG/ERP
Employed Task Conditions:
Resting, Oddball, Posner, N-Back, Verbal MemoryLaser-Stimulation (Pain)
Partnership in Product Development
Continuous EEG-Recording
during MR-Scan. Sampling: 5000Hz
Siemens Magnetom Trio
EPI Sequence:
33 Slices (3mm) TR = 2000ms
Helium Pump switched off!
fMRI
MR Volume-triggered Stimulus Presentation
Additional Physiological /Stress Monitoring: Electrodermal Activity (EDA), ECG, RR, SO2
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 CNSDFG 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
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
• 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
Functional Connectivity (Small World Properties) of Ketamine EffectsResting State: EEG-informed fMRI Analysis
Normalized Cluster Coefficient
Contrast Ketamine > Placebo: 1-70Hz, Z > 2.3, correctedWithin-subject cross-over design (N = 12)
Musso et al. NeuroImage 2011, Musso et al (in preparation)
Subanesthetic Ketamine Challenge: Pharmacological Model of POD
Ketamine Delirium Reactionmore frequent in Elderly
NMDA-blockade: Desinhibition of GABAergic Interneurons
Benzodiazepines can worsen delirium
Increased „Clustering“ i.e., Communication in Visual Cortex (hallucinations?)
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 -
Biorepository: Blood (DNA, RNA), Plasma
Pre-Surgery - 1 Day Post Surgery - 4 Weeks Post Surgery
Neuroimaging-Backbone (MRI, ASL, EEG/fMRI)
Imaging Drug Challenge Studies
La
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Sc
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S
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N = 1600
Training Set: N = 400 Test Set: N = 1200
CSF Studies (with Imaging)
Exploratory Drug Trials (with Imaging)
2013 2018
N ~ 50-200
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
Biomarker Establishment
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
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