MADCO-PC: Markers of Alzheimers Disease and Cognitive Outcomes After Perioperative Care

• Sponsor: Duke University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01993836
• Collaborator: (none)
• Enrollment: 191
• Location: 1
• Arms: 2
• Actual Duration (Months): 62.3
• Patients Per Site Per Month: 3.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Alzheimers Disease; Postoperative Delirium; Post Operative Cognitive Dysfunction	Drug: Total intravenous anesthesia with propofol; Drug: General anesthesia with isoflurane	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 191 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Outcomes Assessor)
• Primary Purpose: Diagnostic
• Official Title: Markers of Alzheimers Disease and Cognitive Outcomes After Perioperative Care
• Actual Study Start Date: Nov 1, 2013
• Actual Primary Completion Date: Jan 10, 2019
• Actual Study Completion Date: Jan 10, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Total Intravenous Anesthesia with Propofol Patients in this arm will receive general anesthesia with propofol as the primary amnestic agent.	Drug: Total intravenous anesthesia with propofol
Active Comparator: General anesthesia with Isoflurane Patients in this arm will undergo general anesthesia with isoflurane as the primary amnestic agent.	Drug: General anesthesia with isoflurane

Outcome Measures

Primary Outcome Measures

1. Correlation Between Perioperative Change in Cerebrospinal Fluid (CSF) Markers of Alzheimers Disease and Perioperative Cognitive Change [Baseline to 6 weeks]

   Spearman correlation was used here as the CSF markers follow a skewed distribution. Spearman correlation describes the strength of the monotonic relationship between two measures and is bounded between -1 and 1. Negative values indicate an inverse relationship while positive values mean that the variables move in tandem.

2. Correlation Between Perioperative Change in Ratios of Cerebrospinal Fluid (CSF) Markers of Alzheimers Disease and Perioperative Cognitive Change [Baseline to 6 weeks]

   Spearman correlation was used here as the ratio of CSF markers follow a skewed distribution. Spearman correlation describes the strength of the monotonic relationship between two measures and is bounded between -1 and 1. Negative values indicate an inverse relationship while positive values mean that the variables move in tandem.

Secondary Outcome Measures

1. Continuous Cognitive Index Score Change Difference Between Anesthetic Agent Groups [Baseline to 6 weeks]

   To characterize cognitive function over time, while minimizing potential redundancy in the cognitive measures, a factor analysis was performed on the 10 cognitive test scores from baseline. To quantify overall cognitive function, a baseline cognitive index was first calculated as the mean of the preoperative domain scores. The cognitive index score has a mean of zero, thus any positive score is above the mean, any negative score is below the mean. A continuous change score was then calculated by subtracting the baseline from the 6-week cognitive index. A negative change score indicating decline and a positive score indicating improvement. The resulting outcome measure is unbounded with a standard deviation of 0.31 in the full surgical cohort.

2. Change in CSF Markers of Alzheimers Disease by Anesthetic Agent Group [Baseline to 6 weeks]

   CSF Markers of Alzheimer's Disease over time in the subjects treated with propofol versus those treated with isoflurane.

3. Change in Ratio of CSF Markers of Alzheimers Disease by Anesthetic Agent Group [baseline to 6-weeks]

   Change in ratio of CSF Markers of Alzheimer's Disease over time in the subjects treated with propofol versus those treated with isoflurane.

4. Perioperative CSF Tau/Abeta Ratio Change [Baseline to 24 hours]

   The perioperative change in the CSF tau/Abeta ratio from the start of anesthesia/surgery to 24 hours later.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 60 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Surgical patients 60 years of age or older

• Surgery scheduled to last at least 2 hours (including time for anesthesia induction, etc)

• English speaking ability.

• Ability to give informed consent

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Duke University Medical Center	Durham	North Carolina	United States	27710

Sponsors and Collaborators

• Duke University

Investigators

• Principal Investigator: Miles Berger, MD, PhD, Duke University Medical Center, Anesthesiology Department, Neuroanesthesia Division

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 16, 2019

More Information

Publications

None provided.

• Responsible Party: Duke University
• ClinicalTrials.gov Identifier: NCT01993836
• Other Study ID Numbers: Pro00045180
• First Posted: Nov 25, 2013
• Last Update Posted: May 5, 2020
• Last Verified: May 1, 2020

• Keywords provided by Duke University: isoflurane; propofol; total intravenous anesthesia; inhaled anesthetic; volatile anesthetic; anesthesia; delirium; Post Operative Cognitive Dysfunction; Alzheimer's Disease; Mild Cognitive Impairment
• Additional relevant MeSH terms: Alzheimer Disease; Delirium; Postoperative Cognitive Complications; Cognitive Dysfunction; Anesthetics; Propofol; Isoflurane

Study Results

Participant Flow

Arm/Group Title	General Anesthesia With Isoflurane	Total Intravenous Anesthesia With Propofol	Non-Surgical Controls
Arm/Group Description	Surgical patients randomized to receive inhalational anesthesia with isoflurane during surgery	Surgical patients randomized to receive intravenous anesthesia with propofol during surgery	Cohort of community dwelling healthy controls for tertiary comparison
Period Title: Overall Study
STARTED	72	68	51
COMPLETED	55	55	46
NOT COMPLETED	17	13	5

Baseline Characteristics

Arm/Group Title	General Anesthesia With Isoflurane	Total Intravenous Anesthesia With Propofol	Non-Surgical Controls	Total
Arm/Group Description	Surgical patients randomized to receive inhalational anesthesia with isoflurane during surgery	Surgical patients randomized to receive iintravenous anesthesia with propofol during surgery	Cohort of community dwelling healthy controls for tertiary comparison	Total of all reporting groups
Overall Participants	55	55	46	156
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	68.6 (6.1)	69.7 (6.9)	69.6 (7.6)	69.3 (6.8)
Sex: Female, Male (Count of Participants)
Female	17 30.9%	24 43.6%	18 39.1%	59 37.8%
Male	38 69.1%	31 56.4%	28 60.9%	97 62.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	1 2.2%	1 0.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	2 3.6%	8 14.5%	9 19.6%	19 12.2%
White	52 94.5%	47 85.5%	36 78.3%	135 86.5%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	1 1.8%	0 0%	0 0%	1 0.6%
Region of Enrollment (participants) [Number]
United States	55 100%	55 100%	46 100%	156 100%
Baseline CSF levels (pg/ml) [Median (Full Range) ]
Tau	47	50	58.5	49
Abeta	369	352	330.5	347
P-Tau	26	28	21.0	25
Baseline CSF ratio levels (ratio) [Median (Full Range) ]
Tau/Abeta Ratio	0.13	0.14	0.16	0.14
P-Tau/Abeta Ratio	0.08	0.08	0.06	0.07

Outcome Measures

1. Primary Outcome

Title	Correlation Between Perioperative Change in Cerebrospinal Fluid (CSF) Markers of Alzheimers Disease and Perioperative Cognitive Change
Description	Spearman correlation was used here as the CSF markers follow a skewed distribution. Spearman correlation describes the strength of the monotonic relationship between two measures and is bounded between -1 and 1. Negative values indicate an inverse relationship while positive values mean that the variables move in tandem.
Time Frame	Baseline to 6 weeks

Outcome Measure Data

Analysis Population Description

Analysis for the primary and secondary outcome 6 use the combination of both randomized treatment groups. The treatment groups are separated and compared in secondary analysis of outcomes 3-5, and the control group is only used in tertiary analyses. To be included in the outcome analysis patients must have returned for six-week follow-up visit.

Arm/Group Title	Combined Surgical Cohort
Arm/Group Description	The combination of both surgical randomized treatment groups.
Measure Participants	110
Tau	-1.21
Abeta	-5.09
P-Tau	-0.44

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Surgical Cohort
	Comments	Correlation between 6-week change in Tau and continuous cognitive index
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Spearman Correlation
	Estimated Value	-0.03
	Confidence Interval	(2-Sided) 95%; -0.23 to 0.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Surgical Cohort
	Comments	Correlation between 6-week change in Abeta and continuous cognitive index
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Spearman Correlation
	Estimated Value	-0.08
	Confidence Interval	(2-Sided) 95%; -0.29 to 0.13
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Surgical Cohort
	Comments	Correlation between 6-week change in P-Tau and continuous cognitive index
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Spearman Correlation
	Estimated Value	0.12
	Confidence Interval	(2-Sided) 95%; -0.08 to 0.32
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Correlation Between Perioperative Change in Ratios of Cerebrospinal Fluid (CSF) Markers of Alzheimers Disease and Perioperative Cognitive Change
Description	Spearman correlation was used here as the ratio of CSF markers follow a skewed distribution. Spearman correlation describes the strength of the monotonic relationship between two measures and is bounded between -1 and 1. Negative values indicate an inverse relationship while positive values mean that the variables move in tandem.
Time Frame	Baseline to 6 weeks

Outcome Measure Data

Analysis Population Description

Analysis for the primary and secondary outcome 6 use the combination of both randomized treatment groups. The treatment groups are separated and compared in secondary analysis of outcomes 3-5, and the control group is only used in tertiary analyses. To be included in the outcome analysis patients must have returned for six-week follow-up visit.

Arm/Group Title	Combined Surgical Cohort
Arm/Group Description	The combination of both surgical randomized treatment groups.
Measure Participants	110
Tau/Abeta Ratio	0.001
P-Tau/Abeta Ratio	0.002

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Surgical Cohort
	Comments	Correlation between 6-week change in Tau/Abeta ratio and continuous cognitive index
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Spearman Correlation
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -0.19 to 0.22
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Surgical Cohort
	Comments	Correlation between 6-week change in P-Tau/Abeta ratio and continuous cognitive index
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Spearman Correlation
	Estimated Value	0.16
	Confidence Interval	(2-Sided) 95%; -0.05 to 0.34
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Continuous Cognitive Index Score Change Difference Between Anesthetic Agent Groups
Description	To characterize cognitive function over time, while minimizing potential redundancy in the cognitive measures, a factor analysis was performed on the 10 cognitive test scores from baseline. To quantify overall cognitive function, a baseline cognitive index was first calculated as the mean of the preoperative domain scores. The cognitive index score has a mean of zero, thus any positive score is above the mean, any negative score is below the mean. A continuous change score was then calculated by subtracting the baseline from the 6-week cognitive index. A negative change score indicating decline and a positive score indicating improvement. The resulting outcome measure is unbounded with a standard deviation of 0.31 in the full surgical cohort.
Time Frame	Baseline to 6 weeks

Outcome Measure Data

Analysis Population Description

Analysis for the primary and secondary outcome 6 use the combination of both randomized treatment groups. The treatment groups are separated and compared in secondary analysis of outcomes 3-5, and the control group is only used in tertiary analyses. To be included in the outcome analysis patients must have returned for six-week follow-up visit.

Arm/Group Title	Total Intravenous Anesthesia With Propofol	General Anesthesia With Isoflurane
Arm/Group Description	Patients in this arm will receive general anesthesia with propofol as the primary amnestic agent. Total intravenous anesthesia with propofol	Patients in this arm will undergo general anesthesia with isoflurane as the primary amnestic agent. General anesthesia with isoflurane
Measure Participants	55	55
Mean (Standard Error) [units on a scale]	0.019 (0.05)	0.061 (0.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Surgical Cohort, General Anesthesia With Isoflurane
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.360
	Comments
	Method	t-test, 2 sided
	Comments

4. Secondary Outcome

Title	Change in CSF Markers of Alzheimers Disease by Anesthetic Agent Group
Description	CSF Markers of Alzheimer's Disease over time in the subjects treated with propofol versus those treated with isoflurane.
Time Frame	Baseline to 6 weeks

Outcome Measure Data

Analysis Population Description

Analysis for the primary and secondary outcome 6 use the combination of both randomized treatment groups. The treatment groups are separated and compared in secondary analysis of outcomes 3-5, and the control group is only used in tertiary analyses. To be included in the outcome analysis patients must have returned for six-week follow-up visit.

Arm/Group Title	Total Intravenous Anesthesia With Propofol	General Anesthesia With Isoflurane
Arm/Group Description	Patients in this arm will receive general anesthesia with propofol as the primary amnestic agent. Total intravenous anesthesia with propofol	Patients in this arm will undergo general anesthesia with isoflurane as the primary amnestic agent. General anesthesia with isoflurane
Measure Participants	55	55
Tau	-0.80	-1.67
Abeta	-2.10	-9.50
P-Tau	-2.25	1.10

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Surgical Cohort, General Anesthesia With Isoflurane
	Comments	Difference in 6-week Tau Change between anesthetic groups
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.532
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Surgical Cohort, General Anesthesia With Isoflurane
	Comments	Difference in 6-week Abeta Change between anesthetic groups
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.565
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Surgical Cohort, General Anesthesia With Isoflurane
	Comments	Difference in 6-week P-Tau Change between anesthetic groups
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.110
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

5. Secondary Outcome

Title	Change in Ratio of CSF Markers of Alzheimers Disease by Anesthetic Agent Group
Description	Change in ratio of CSF Markers of Alzheimer's Disease over time in the subjects treated with propofol versus those treated with isoflurane.
Time Frame	baseline to 6-weeks

Outcome Measure Data

Analysis Population Description

Analysis for the primary and secondary outcome 6 use the combination of both randomized treatment groups. The treatment groups are separated and compared in secondary analysis of outcomes 3-5, and the control group is only used in tertiary analyses. To be included in the outcome analysis patients must have returned for six-week follow-up visit.

Arm/Group Title	Total Intravenous Anesthesia With Propofol	General Anesthesia With Isoflurane
Arm/Group Description	Patients in this arm will receive general anesthesia with propofol as the primary amnestic agent. Total intravenous anesthesia with propofol	Patients in this arm will undergo general anesthesia with isoflurane as the primary amnestic agent. General anesthesia with isoflurane
Measure Participants	55	55
Tau/Abeta Ratio	0.00	-0.00
P-Tau/Abeta Ratio	-0.00	0.01

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Surgical Cohort, General Anesthesia With Isoflurane
	Comments	Difference in 6-week Tau/Abeta ratio Change between anesthetic groups
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.439
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Surgical Cohort, General Anesthesia With Isoflurane
	Comments	Difference in 6-week P-Tau/Abeta Change between anesthetic groups
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.082
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

6. Secondary Outcome

Title	Perioperative CSF Tau/Abeta Ratio Change
Description	The perioperative change in the CSF tau/Abeta ratio from the start of anesthesia/surgery to 24 hours later.
Time Frame	Baseline to 24 hours

Outcome Measure Data

Analysis Population Description

Analysis for the primary and secondary outcome 6 use the combination of both randomized treatment groups. The treatment groups are separated and compared in secondary analysis of outcomes 3-5, and the control group is only used in tertiary analyses. To be included in the outcome analysis patients must have returned for six-week follow-up visit.

Arm/Group Title	Combined Surgical Cohort
Arm/Group Description	The combination of both surgical randomized treatment groups.
Measure Participants	110
Median (Full Range) [ratio]	-0.001

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Surgical Cohort
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.801
	Comments
	Method	Wilcoxon Signed Rank
	Comments

Adverse Events

Time Frame	6 weeks
Arm/Group Title	General Anesthesia With Isoflurane		Total Intravenous Anesthesia With Propofol		Non-Surgical Controls
Arm/Group Description	Surgical patients randomized to receive inhalational anesthesia with isoflurane during surgery		Surgical patients randomized to receive iintravenous anesthesia with propofol during surgery		Cohort of community dwelling healthy controls for comparison
All Cause Mortality
	General Anesthesia With Isoflurane		Total Intravenous Anesthesia With Propofol		Non-Surgical Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/72 (0%)		2/68 (2.9%)		0/51 (0%)
Serious Adverse Events
	General Anesthesia With Isoflurane		Total Intravenous Anesthesia With Propofol		Non-Surgical Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/72 (0%)		0/68 (0%)		0/51 (0%)
Other (Not Including Serious) Adverse Events
	General Anesthesia With Isoflurane		Total Intravenous Anesthesia With Propofol		Non-Surgical Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/72 (2.8%)		8/68 (11.8%)		7/51 (13.7%)
Blood and lymphatic system disorders
Elevated PTT	0/72 (0%)	0	1/68 (1.5%)	1	0/51 (0%)	0
Cardiac disorders
Vagal Event	1/72 (1.4%)	1	3/68 (4.4%)	3	2/51 (3.9%)	2
General disorders
Fever	0/72 (0%)	0	1/68 (1.5%)	1	0/51 (0%)	0
Leg Pain and Swelling	1/72 (1.4%)	1	0/68 (0%)	0	0/51 (0%)	0
Back Pain	0/72 (0%)	0	1/68 (1.5%)	1	3/51 (5.9%)	5
Neck Stiffness	0/72 (0%)	0	1/68 (1.5%)	1	0/51 (0%)	0
Nervous system disorders
Headache	0/72 (0%)	0	1/68 (1.5%)	1	0/51 (0%)	0
Post-dural puncture headache	0/72 (0%)	0	1/68 (1.5%)	1	2/51 (3.9%)	2
Respiratory, thoracic and mediastinal disorders
Shortness of Breath	0/72 (0%)	0	1/68 (1.5%)	1	0/51 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.