Conditions: Alzheimers Disease Postoperative Delirium Post Operative Cognitive Dysfunction
Keywords: isoflurane propofol total intravenous anesthesia inhaled anesthetic volatile anesthetic anesthesia delirium Post Operative Cognitive Dysfunction Alzheimer's Disease Mild Cognitive Impairment
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 191
Healthy volunteers: no

Brief summary:
This study will examine the hypothesis that changes in the cognition (i.e. thinking and memory) after anesthesia and surgery are correlated with changes in markers of Alzheimers Disease in the fluid around the brain and spinal cord (i.e. cerebrospinal fluid, or CSF), and/or changes in brain connectivity. The investigators will also examine whether different types of anesthesia have different effects on these CSF markers of Alzheimers disease, or different effects on thinking and memory after anesthesia and surgery, or differential effects on the correlation between cognitive changes and CSF marker changes.

Detailed description:

Arms:
arm 1: Patients in this arm will receive general anesthesia with propofol as the primary amnestic agent. arm 2: Patients in this arm will undergo general anesthesia with isoflurane as the primary amnestic agent.

Interventions: intervention 1: Total intravenous anesthesia with propofol intervention 2: General anesthesia with isoflurane
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
SAP_002.pdf: 
 
 
 
 
 Project: MADCO-PC Study (Markers of Alzheimer’s Disease and Cognitive Outcomes 
after Perioperative Care  
Clinicaltrials.gov registration Number: NCT01993836  
Date: September 5, 2017 
Document: SAP_2405_Berger_v5 
 
 


 
 
 
 
 
Statistical Analysis Plan  
ACTIVATE: CSF trajectories 
SAP Version: 5.0 
SAP Date: 9/5/17 
Author: Mary Cooter  
Primary Investigator: Miles Berger 
Revisions/Notes: 
V2.0 5/20/17: Revised SAP structure to highlight hypotheses of interest, 
added data flow diagram and table shell 
V3.0 6/5/17: Made primary and secondary hypotheses to match order in 
ct.gov listing. Added in current table 1 
V4.0 7/28/17: There are 2 patients whose CSF data has yet to be analyzed, 
currently analyzed with imputation but if results returned from the lab 
will want to incorporate that data into the analysis.


 
 
 Study Objective: AD biomarker change in CSF and relationship with cognitive change. 
Animal studies have shown that inhaled anesthetic agents increase the levels of Alzheimer’s disease 
related neural markers (such as amyloid beta and tau). Several studies have measured blood serum 
markers indirectly related to Alzheimer’s disease in patients randomized to inhaled versus intravenous 
anesthesia, no randomized controlled trial has ever examined these markers in the cerebrospinal fluid 
of patients given inhaled versus intravenous anesthesia. No randomized controlled study to date has 
ever examined whether inhaled anesthetics (versus intravenous anesthetics) alter brain levels of 
Alzheimer’s associated markers in humans, and/or whether such changes (if they occur) correlate with 
POCD or other cognitive changes, or changes in brain structure or activity after surgery and anesthesia. 
 
Here, we propose to measure Alzheimer’s disease-related neural markers in the cerebrospinal fluid 
(CSF) of patients exposed to anesthesia during surgery, as well as in non-surgical controls (age matched 
community dwelling individuals age 60 and over). These studies should clarify the effect of common 
anesthetic agents on Alzheimer’s disease related neural markers and cognitive outcomes. 
 
1. Hypotheses:   
i. 
The degree of increase in AD marker CSF levels will be associated with cognitive outcomes. 
ii. 
AD biomarkers will increase from baseline to the 24 hours postop time point.  
2. Outcomes:  
Outcome 
Description 
Specifications 
Variables and Source  
Cognitive Change 
from baseline to 6 
weeks 
As a numeric variable 
(continuous cognitive change) 
or as binary outcome (POCD 
w/>1 or 2 SD drop) 
Derive factor weights within 
sample and compare to that 
of historical non-cardiac 
population 
Use bluecap database 
for cognitive data 
3. Study population and datasets:  
 
Inclusion Criteria: Patients undergoing urologic, general or other surgical procedures, aged 60 
and above, English speaking [Per PI will include all patients with BL and 6 week cognitive data 
available and run imputations to fill in missing CSF data in primary analysis] 
 
Exclusion Criteria: inmate of a correctional facility (i.e. prisoners), documented or suspected 
family or personal history of malignant hyperthermia, unable to receive either propofol and/or 
isoflurane due to allergy or other specific contraindication, receiving systemic chemotherapy 
after the first cognitive testing session and before the 6 wk or 1 year follow up cognitive testing 
sessions, major head trauma that occurs after the first cognitive testing session and before the 
6 wk or 1 year follow up cognitive testing sessions. 
Data Set Sources 
Penn AD CSF data— Contains baseline, 24hr, and 6 week AD biomarker analysis (tau, abeta, p-tau) 
Patient characteristics data—IT pull ticket 2494 
Cognitive Data--Use BlueCap database and data entry from CRC groupAD Biomarkers (Primary Variable 
of Interest) 
 


 
 
Variable names 
Description  
Specifications (e.g. formula) 
CSF A beta 
Measured BL, 24 hr, 6 
weeks 
 
Look at individual time points, trajectory, 
and change BL to 24 hr, and BL to 6 
weeks 
CSF tau 
CSF phospho-tau 
CSF tau/a beta 
Quotient of tau and a-beta at 
each time point 
CSF p-tau/a beta 
Quotient of p-tau and a-beta 
at each time point 
 
4. Adjustment Variables 
Candidate Covariates 
Description 
Anesthetic Type (randomized) 
Propofol vs. Isoflurane group 
Demographics 
age,  
BMI, 
race,  
sex,  
years of education 
Baseline Cognitive Status 
MMSE score (raw and categorical [≥25, 20-24, <20]),  
mean cognitive index,  
domain scores 
Clinical Factors 
ASA status,  
surgical type (urology, orthopedics, plastics, thoracic surgery, 
general/abdominal, gynecologic etc), 
 open incision vs laparoscopic approach,  
epidural block, regional block, vs no block,  
surgery duration (from incision to end surgery time stamps),  
IO BIS (mean of median filtered),  
ET aaMAC (mean of medians filtered),  
propofol dose,  
ketamine use,  
dexmedetomidine use,  
admitted to ICU by POD1 
6. Statistical Methods and results  
0.   Merge, clean summarize data and check missing-ness patterns and tabulate data  
 
i. Merge demographic data from IT pull, the Penn CSF data, and bluecap cognitive data 
 
ii. Summarize numeric (mean (SD), median [Q1, Q3]) and categorical (N (%)) patient Characteristics.  
a. Will look across anesthetic type and compare characteristics between types 
b. Will use standardized differences to assess group differences (if required will add p-
values from univariable tests of association (t-tests, WRS, chi-square, or Fisher’s 
Exact) 
 


 
 
ii. Calculate degree of missingness (expected to be 10% or less) 
a. Determine if missingness is sufficiently random or if highly correlated with specific 
values 
b. Develop imputation strategy for CSF and cognition—SRCWare 
i. Used the following variables for imputation: age weight height years education, 
gender, race, ASA, surgical service, iso vs prop group, surgery duration, baseline 
MMSE, and available baseline, 24hr and 6 week CSF and nptest data 
iii. Determine how cognitive factors will be calculated 
a. Using same sample for derivation of factor loadings and analysis 
i. Performed factor analysis and wrote code to evaluate stability of the solution 
(code factorsolutionchecking.sas) 
ii. Determined that solution from ACTIVATE cohort is too unstable to use 
iii. Emailed with PI and per emails on 7/27 will proceed with using historical weights 
b. Using historical sample weights 
a. Re-ran factor analysis on ND sample (N=389) to get oblique solution 
b. Code applied in impute_data.sas, based on McDonagh et al datasets 
 
Hypothesis 1: The degree of increase in AD marker CSF levels will be associated with cognitive outcomes. 
1. Data visualization of  
a. differences in 24 hour and six-week CSF change and numeric/binary cognitive outcomes 
(figure 2)—ACTIVATE _ResultsSummary_0727 sheet CSFTraj_byPOCD and CSFchange 
b. Added 7/28/17: Spaghetti plots of individual change over time 
c. Added 7/28/17: Use of Les Shaw cut points for MCI/AD, and four quadrant plot of observed 
Tau by AB---—Based on Miles’ personal correspondence (7/28) with Les he recommended 
the same threshold for Tau (93), but an increased Abeta cutoff of 250. 
2. Univariate Analysis  
a. Association of CSF change with numeric cognitive outcome via correlation coefficient 
(Pearson/spearman)--- ACTIVATE _ResultsSummary_0727 sheet CSFchange 
b. Association of CSF change with binary cognitive outcome via t-tests or Wilcoxon rank sum 
tests. 
i. Summary statistics on ACTIVATE _ResultsSummary_0727 sheet CSFchange 
ii. Still need to determine how to run non-parametric test on MI datasets (as of 7/28) 
c. Added 7/27/17: Association of baseline CSF with numeric baseline cognition and cognitive 
change via spearman correlation 
3. Multivariate Analysis 
a. Use linear and logistic regression to study association of CSF with cognition adjusting for 
patient characteristics 
b. Candidate variables for model: age, ASA status, years of education, baseline cognitive index, 
baseline MMSE score, baseline CSF AD biomarker measures, CSF AD biomarker changes 
from before to after surgery (from before to 24 hrs postop, and from before to 6 weeks 
postop), DARS, mean of median end tidal MAC fraction (age adjusted), surgery type, surgery 
length, MAC-hours, cumulative propofol dosage 
c. Adjustment variables added as indicated via univariate association with outcome and as 
allowed by sample size restrictions in model 


 
 
d. Model assumptions will be evaluated and performance measured 
i. Numeric cognitive change: assess residual Q-Q plot, mse, R2 
ii. Binary cognitive change: C-index, R2, GOF 
4. Investigate CSF associations with individual cognitive domains in exploratory analysis (figure 3). This 
would help evaluate for the possibility that pre to post op changes in CSF AD biomarkers may be 
particularly related to changes in one particular cognitive domain (such as memory) rather than 
global cognition. 
Hypothesis 2: AD biomarkers will increase from baseline to the 24 hours postop time point. 
1. Data visualization of CSF change over time (BL, 24hrs, 6wk)—Figure 1 
2. Calculate change from baseline to 
a. 24 hrs—assess if change is significant via t-test or Wilcox Signed Rank Test 
b. 6 week—assess if change is significant via t-test or Wilcox Signed Rank Test 
3. CSF trajectory analysis (BL, 24hr, 6 week)—repeated measures mixed model 
 
 
7. Proposed Tables and Figures 
1. Table 1 describing baseline characteristics of the study cohort   
a. Demographics: age, BMI, race, sex, years of education 
b. Baseline Cognitive status: MMSE score (raw and categorical [≥25, 20-24, <20]), mean cognitive 
index, domain scores 
c. Baseline CSF measures 
d. Clinical factors: ASA status, surgical type (urology, orthopedics, plastics, thoracic surgery, 
general/abdominal, gynecologic etc), open incision vs laparoscopic approach, epidural block, 
regional block, vs no block, surgery duration (from incision to end surgery time stamps), IO BIS 
(mean of median filtered), ET MAC (mean of medians filtered), propofol dose, ketamine use, 
dexmedetomidine use, admitted to ICU by POD1 
 
2. Figure 1  
a. CSF A beta as a function of time- preop, 24 hr postop, 6 weeks postop 
b. CSF tau as a function of time- preop, 24 hr postop, 6 weeks postop 
c. CSF phospho-tau as a function of time- preop, 24 hr postop, 6 weeks postop 
d. CSF tau/a beta ratio as a function of time- preop, 24 hr postop, 6 weeks postop 
e. CSF p-tau/a beta ratio as a function of time- preop, 24 hr postop, 6 weeks postop 
f. (Could also consider making stratified plots for 2A-2D with two lines for each graph, one line 
for patients with POCD by either a 1 or 2 SD drop in any cognitive domain rule, and one line 
for patients without POCD) 
3. Figure 2 
a. Dot plot- CSF tau change from preop to 24 hrs on Y axis, Continuous Cognitive index change 
from before to 6 weeks on X axis, each patient is one dot on the graph  
b. Dot plot- CSF tau change from preop to 6 weeks on Y axis, Continuous Cognitive index 
change from before to 6 weeks on X axis, each patient is one dot on the graph;  


 
 
c. (or could combine plots 3A and 3B by just plotting maximal increase in CSF tau from preop 
to either 24 hrs or 6 weeks on Y axis- whichever is larger- and cognitive change index from 
preop to 6 weeks postop on X axis) 
d. C, D- equivalent of 2a,2b, but with amyloid beta instead of tau 
e. E, F- equivalent of 2a,2b, but with p-tau instead of tau 
f. G Dot plot- CSF tau/abeta ratio change from preop to 24 hrs on Y axis, Continuous Cognitive 
index change from before to 6 weeks on X axis, each patient is one dot on the graph;  
g. H Dot plot- CSF/Abeta tau ratio change from preop to 6 hrs on Y axis, Continuous Cognitive 
index change from before to 6 weeks on X axis, each patient is one dot on the graph;  
 
4. Repeating Figure 2 A-D with the X axis representing change in each of the 4 individual cognitive 
domain scores rather than the overall cognitive index score.  
 

Prot_001.pdf: 
Project: MADCO-PC Study (Markers of Alzheimer’s Disease and Cognitive Outcomes after Perioperative 
Care  
Clinicaltrials.gov registration Number: NCT01993836  
Date: July 15, 2016
Document: MADCO-PC Protocol Brief Summary 7-12-2016 


MADCO-PC Protocol Summary 
 
Purpose:  
This study will examine the hypothesis that changes in the cognition (i.e. thinking and memory) 
after anesthesia and surgery are correlated with changes in markers of Alzheimers Disease in 
the fluid around the brain and spinal cord (i.e. cerebrospinal fluid, or CSF), and/or changes in 
brain connectivity. The investigators will also examine whether different types of anesthesia 
have different effects on these CSF markers of Alzheimers disease, or different effects on 
thinking and memory after anesthesia and surgery, or differential effects on the correlation 
between cognitive changes and CSF marker changes. 
 
Outcome Measures: 
Primary Outcome Measure: Assess the correlation between perioperative change in CSF 
Markers of Alzheimers Disease and perioperative cognitive change. [Time Frame: up to 6 
weeks ] 
We will assess the magnitude of the Spearman correlation coefficient for the relationship 
between perioperative change in CSF Markers of Alzheimers Disease and the perioperative 
change in the continuous cognitive index score. 
 
Secondary Outcome Measures:  
1. Continuous cognitive index score change [Time Frame: 1 year]  
We will examine the difference in the continuous cognitive index score over time in the subjects 
treated with propofol versus those treated with isoflurane, and versus such changes seen in 
non-surgical controls. We will also assess the correlation between perioperative change in CSF 
Markers of Alzheimers Disease and perioperative cognitive change in patients randomized to 
receive isoflurane vs propofol. 
 
2. Assess CSF Markers of Alzheimers Disease [Time Frame: up to 6 weeks ]  
We will examine CSF Markers of Alzheimer's Disease over time in the subjects treated with 
propofol versus those treated with isoflurane, and versus any such changes seen in non-
surgical controls.  
 
3. Acute Perioperative CSF Tau/Abeta ratio change [Time Frame: 24 hours ]  
We will measure the perioperative change in the CSF tau/Abeta ratio from the start of 
anesthesia/surgery to 24 hours later, and compare this to changes seen in the non-surgical 
controls at the cognate time points.  
 
4. Chronic Perioperative CSF Tau/Abeta ratio change [Time Frame: 1 year]  
We will measure the stability of any acute 24 hour postoperative changes in the CSF tau/Abeta 
ratio out to 6 weeks and 1 year later in surgical patients, and compare these changes to any 
changes seen over time in the non-surgical controls.  
 
 
Enrollment Numbers, Inclusion and exclusion criteria 
 
Targeted enrollment is 108 surgical patients who complete the 6 week follow up visit, which 
provides >80% power to detect a spearman correlation coefficient of 0.3 or greater (a low-


moderate correlation) for the aforementioned primary outcome measure. 54 non-surgical 
controls will also be enrolled as described below.  
Ages Eligible for Study:   
60 Years and older  
Genders Eligible for Study:   
Both 
 
Inclusion Criteria: 
 
Age 60 year or older 
 
Surgery scheduled to last at least 2 hours (including time for anesthesia induction, etc) 
 
English speaking ability. 
 
 Exclusion Criteria: 
 
Inmate of a correctional facility (i.e. prisoners). 
 
Pregnancy 
 
Documented or suspected family or personal history of malignant hyperthermia. 
 
Patient unable to receive either propofol or isoflurane due to allergy or other specific 
contraindication. 
 
Inclusion criteria for the non-surgical controls are the same as those described above, with the 
exception of the second inclusion criteria (surgery scheduled to last at least 2 hours). Non-
surgical controls (i.e. community dwelling older adults) will be recruited from several Duke 
research subject registries, and will be matched to surgical patients on a 2:1 basis (2 surgical 
patients for each non-surgical control) based on age, sex, and educational status. Non-surgical 
controls will undergo the same study procedures as surgical patients at the same cognate time 
intervals.  
 
 
Study Procedures: 
 
Cognition: Our full POCD cognitive test battery (as described in Newman MF et al, NEJM, 2001) 
is performed on study patients within one month (typically one week) prior to anesthesia and 
surgery, and then again six weeks and one year after anesthesia and surgery.  
All patients are screened for delirium on postoperative days one through seven by our 
experienced neurocognitive testing team. 
 
Biochemical Studies/Samples:  CSF and peripheral blood samples are obtained immediately 
prior to anesthesia and surgery, 24 hours later, six weeks later, and one year later. These 
samples will be assayed for Alzheimer’s disease biomarkers (including amyloid beta, tau and 
phospho-tau) as well as inflammatory markers and other biomarkers of interest.  
 
Brain imaging: Functional MRI scans are performed within one month prior to Anesthesia and 
surgery, and then again six weeks after anesthesia and surgery. Multiple scan sequences are 
used to evaluate anatomic and functional Brain connectivity. 


 
 
For more information, please see: 
https://clinicaltrials.gov/ct2/show/NCT01993836?term=Miles+Berger&rank=1 
 
Newman MF et al, NEJM, 2001.  
Berger M et al, Anesthesiology Clinics, 2015.  
Berger M et al, JCTVA, 2014.