Beispiel Titelfolie - Headline

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

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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
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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 (12 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
63941-47 2 Meta-analysis Witlox et al JAMA
2010 304443-51
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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 1141-46
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Pathophysiogical/Molecular Mechanisms of Interest

4Field et al J Neurosci 2012 326288-94
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Cholinergic-Inflammatory Interface when
cytokines and acetylcholine collide
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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

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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)

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Postoperative Cognitive Disorders Structural
Neuroimaging
Alzheimers 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
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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
  gt 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
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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

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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
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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
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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
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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
Additional Physiological /Stress Monitoring
Electrodermal Activity (EDA), ECG, RR, SO2
Partnership in Product Development
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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) Nationa
l DFG Priority Program Nicotine Molecular
Physiological Effects in CNS DFG study conducted
at Helmholtz Research Center Jülich
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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
231148-55 Prichep et al Neurobiol Aging 2006
27471-81 Hofsté et al Int J Clin Monit Comput
1997 1429-36
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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 gt Placebo 1-70Hz,
Z gt 2.3, corrected Within-subject cross-over
design (N 12)
Musso et al. NeuroImage 2011, Musso et al (in
preparation)
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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

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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/inter
leukins (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)
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BioCog Research Program - Design -
N 50-200
2013 2018
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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

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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
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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
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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_at_charite.de and/or claudia.s
pies_at_charite.de
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