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)
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
Postoperative
Cognitive
Dysfunction
POCD
DSM-IV: 293.0
DSM-IV: 294.0
Acute
Chronic
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 Anaesthesia 2008 63:941-47
et al JAMA 2010 304:443-51
2 Meta-analysis: Witlox
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 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
4Field
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
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
Cognitive Performance
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)
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!
Siemens Magnetom Trio
Additional Physiological /Stress Monitoring: Electrodermal Activity (EDA), ECG, RR, SO2
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)
Small Scale
BioCog: Research Program
- Design Imaging Drug Challenge Studies
CSF Studies (with Imaging)
N ~ 50-200
Large Scale
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)
• 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
Contact
georg.winterer@charite.de
and/or
claudia.spies@charite.de