Georg Winterer

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 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


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

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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

[email protected]/or

[email protected]

Documents

Georg Winterer