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Perioperative Medicine  |   April 2018
18F-florbetapir Positron Emission Tomography–determined Cerebral β-Amyloid Deposition and Neurocognitive Performance after Cardiac Surgery
Author Notes
  • From the Department of Anesthesiology (R.Y.K., T.B., M.B., N.T., M.F.N., J.P.M.), Department of Radiology (O.G.J., S.B.-N.), Department of Biostatistics and Bioinformatics (Y.-J.L., W.Q.), and the Department of Psychiatry and Behavioral Science (P.M.D.), Duke University, Durham, North Carolina.
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  • This article is featured in “This Month in Anesthesiology,” page 1A.
    This article is featured in “This Month in Anesthesiology,” page 1A.×
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • *Members of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) Study Group are listed in appendix 1. Data used in preparation of this article were obtained from the ADNI database (https://adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ANDI and/or provided data but did not participate in the analysis or writing of this report. A complete listing of ADNI investigators can be found at https://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf and in appendix 1.
    Members of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) Study Group are listed in appendix 1. Data used in preparation of this article were obtained from the ADNI database (https://adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ANDI and/or provided data but did not participate in the analysis or writing of this report. A complete listing of ADNI investigators can be found at https://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf and in appendix 1.×
  • Members of the Neurologic Outcomes Research Group (NORG) are listed in appendix 2.
    Members of the Neurologic Outcomes Research Group (NORG) are listed in appendix 2.×
  • Submitted for publication June 19, 2017. Accepted for publication December 27, 2017.
    Submitted for publication June 19, 2017. Accepted for publication December 27, 2017.×
  • Address correspondence to Dr. Klinger: Department of Anesthesiology, Duke University Box 3094, 2301 Erwin Road, Durham, North Carolina 27710. kling004@mc.duke.edu. This article may be accessed for personal use at no charge through the Journal Web site, www.anesthesiology.org.
Article Information
Perioperative Medicine / Clinical Science / Central and Peripheral Nervous Systems / Geriatric Anesthesia
Perioperative Medicine   |   April 2018
18F-florbetapir Positron Emission Tomography–determined Cerebral β-Amyloid Deposition and Neurocognitive Performance after Cardiac Surgery
Anesthesiology 4 2018, Vol.128, 728-744. doi:10.1097/ALN.0000000000002103
Anesthesiology 4 2018, Vol.128, 728-744. doi:10.1097/ALN.0000000000002103
Abstract

Background: Amyloid deposition is a potential contributor to postoperative cognitive dysfunction. The authors hypothesized that 6-week global cortical amyloid burden, determined by 18F-florbetapir positron emission tomography, would be greater in those patients manifesting cognitive dysfunction at 6 weeks postoperatively.

Methods: Amyloid deposition was evaluated in cardiac surgical patients at 6 weeks (n = 40) and 1 yr (n = 12); neurocognitive function was assessed at baseline (n = 40), 6 weeks (n = 37), 1 yr (n = 13), and 3 yr (n = 9). The association of 6-week amyloid deposition with cognitive dysfunction was assessed by multivariable regression, accounting for age, years of education, and baseline cognition. Differences between the surgical cohort with cognitive deficit and the Alzheimer’s Disease Neuroimaging Initiative cohorts (normal and early/late mild cognitive impairment) was assessed, adjusting for age, education, and apolipoprotein E4 genotype.

Results: The authors found that 6-week abnormal global cortical amyloid deposition was not associated with cognitive dysfunction (13 of 37, 35%) at 6 weeks postoperatively (median standard uptake value ratio [interquartile range]: cognitive dysfunction 0.92 [0.89 to 1.07] vs. 0.98 [0.93 to 1.05]; P = 0.455). In post hoc analyses, global cortical amyloid was also not associated with cognitive dysfunction at 1 or 3 yr postoperatively. Amyloid deposition at 6 weeks in the surgical cohort was not different from that in normal Alzheimer’s Disease Neuroimaging Initiative subjects, but increased over 1 yr in many areas at a rate greater than in controls.

Conclusions: In this study, postoperative cognitive dysfunction was not associated with 6-week cortical amyloid deposition. The relationship between cognitive dysfunction and regional amyloid burden and the rate of postoperative amyloid deposition merit further investigation.

What We Already Know about This Topic
  • Cardiac surgery and anesthesia are associated with long-term cognitive deficits

  • β-Amyloid deposition is associated with Alzheimer disease

  • Anesthesia in animals has been associated with increases in brain β-amyloid

  • It is unclear whether cardiac surgery and anesthesia are associated with changes in β-amyloid in humans

What This Article Tells Us That Is New
  • In this prospective clinical study involving 40 patients undergoing cardiopulmonary bypass, there were no differences in global β-amyloid deposition between patients with or without cognitive impairment 6 weeks after cardiac surgery

  • On secondary analysis, β-amyloid deposition in the hippocampus was increased 6 weeks after cardiac surgery in patients with postoperative cognitive deficits when compared to those without cognitive deficits, although these changes were not significant after adjustment

  • A larger prospective study will be needed to determine whether surgery and anesthesia increase global or hippocampal β-amyloid

UP to 50% of patients undergoing cardiac surgery may experience postoperative cognitive dysfunction at the time of hospital discharge.1  While there appears to be an initial improvement in the months after surgery, cognitive dysfunction persists in up to 42% at 5 yr after surgery,1  resulting in a diminished quality of life and loss of functional independence.2 
The mechanisms underlying postoperative cognitive dysfunction remain elusive, although several contributing factors have been proposed: preoperative cognitive impairment, genetic predisposition, transcerebral platelet activation, cerebral microembolism or hypoperfusion during cardiopulmonary bypass (CPB), central nervous and systemic inflammatory responses to surgery, hemodilution, hyperglycemia, hyperthermia, and the unmasking of Alzheimer disease and acceleration of amyloid deposition associated with inhalational anesthetics (reviewed elsewhere3 ). Because cardiac surgery generally takes place in older adults, the possibility exists that cognitive dysfunction after cardiac surgery represents a form of mild cognitive impairment, which also affects older adults. Mild cognitive impairment has been suggested to be a transitional phase between normal aging and dementia and a precursor to Alzheimer disease.4  Both mild cognitive impairment and Alzheimer disease involve the accumulation of β-amyloid in the central nervous system. Laboratory studies have shown that inhalational anesthetics increase β-amyloid generation5  and promote β-amyloid oligomerization in cultured cells.6  Thus, anesthesia itself may influence β-amyloid processing and play a role in the evolution of cognitive dysfunction in the aging, in common with mild cognitive impairment/Alzheimer disease. However, human studies have provided conflicting results about whether cerebrospinal fluid (CSF) β-amyloid levels rise, fall, or remain unchanged after anesthesia and surgery.7,8  Thus, we attempted to directly measure amyloid deposition in the brain after surgery using the positron emission tomography tracer 18F-florbetapir.
Positron emission tomography agents have shown great promise in mapping fibrillar amyloid deposition in the brain. 18F-florbetapir [(E)-4-(2-(6-(2-(2-(2-18F-fluoroethoxy)ethoxy)ethoxy)pyridin-3-yl)vinyl)-N-methylbenzamine] is a novel imaging agent that binds with high affinity (Kd 3.1 nM+0.7) to β-amyloid peptide fibrils in brain amyloid plaques.9,10  In a multicenter study, 18F-florbetapir was shown to have the highest cortical retention in Alzheimer subjects, the lowest in cognitively normal subjects, and intermediate retention in those with mild cognitive impairment.11 18F-florbetapir has been used in an increasing number of investigations of Alzheimer disease and has demonstrated comparable, or better, sensitivity and specificity for diagnosing Alzheimer disease compared to clinical criteria.12  Furthermore, 18F-florbetapir imaging is the modality used in the longitudinal Alzheimer’s Disease Neuroimaging Initiative (ADNI)—a multicenter investigation of subjects with normal cognition, varying degrees of mild cognitive impairment, and Alzheimer disease.13 
In this study, we utilized 18F-florbetapir imaging to assess the relationship between global cortical and regional amyloid deposition and cognitive dysfunction in patients at 6 weeks after cardiac surgery with CPB. We also conducted follow-up cognitive testing and imaging at 1 and 3 yr postsurgery for post hoc analyses. We hypothesized that 6-week 18F-florbetapir cortical amyloid burden would be greater in those patients manifesting postoperative cognitive dysfunction at 6 weeks, and that the amyloid deposition pattern in patients with cognitive dysfunction would be similar to that seen in individuals from the Alzheimer’s Disease Neuroimaging Initiative cohort with mild cognitive impairment.
Materials and Methods
Study Population
Following approval by the Duke University Health Systems Institutional Review Board (Durham, North Carolina) and informed consent, 40 patients age 60 yr or older and undergoing cardiac surgery (coronary artery bypass grafting [CABG], CABG + valve, or valve only) with CPB were prospectively enrolled between July 2011 and November 2013. Patients were excluded if they had a history of symptomatic cerebrovascular disease (e.g., previous stroke) with residual deficits, alcoholism (more than two drinks/day), psychiatric illness (any clinical diagnoses requiring therapy), drug abuse (any illicit drug use in the preceding 3 months before surgery), hepatic insufficiency (liver function tests greater than 1.5 times the upper limit of normal), severe pulmonary insufficiency (requiring home oxygen), or renal failure (serum creatinine greater than 2.0 mg/dl). Pregnant or premenopausal women and patients who were unable to read and thus complete the cognitive testing or who scored lower than 24 on a baseline Mini Mental State examination or higher than 27 on the baseline Center for Epidemiological Studies Depression scale were similarly excluded. Patients who received any antiamyloid therapies or had any radiopharmaceutical imaging in the 7 days before the surgery were also excluded.
Elderly control patients and patients with early mild cognitive impairment and late mild cognitive impairment (early vs. late defined by specific cutoffs on the Logical Memory II subscale of the Wechsler Memory Scale–Revised, as defined by ADNI-2),14  who had been previously enrolled and imaged with 18F-florbetapir positron emission tomography through the ADNI (https://adni.loni.usc.edu)15,16  were utilized to compare regional patterns of amyloid deposition to our surgical cohort. The ADNI was launched in 2003 as a public-private partnership, led by Principal Investigator Michael W. Weiner, M.D. The primary goal of the ADNI has been to assess whether serial magnetic resonance imaging, positron emission tomography, biologic markers, and clinical and neuropsychologic assessment can be combined to measure the progression of mild cognitive impairment and early Alzheimer disease. 18F-florbetapir imaging was included in the ADNI-GO and ADNI-2 protocols. All participants gave written informed consent that was approved by the institutional review board of each participating institution.
Surgical Patient Management
Anesthesia was induced with propofol, midazolam, fentanyl, and neuromuscular blocking agents, and isoflurane was used for maintenance. All patients underwent nonpulsatile, hypothermic (30° to 32°C) CPB with a membrane oxygenator and arterial line filter by a pump primed with crystalloid. Serial hematocrit levels were maintained at 0.21 or greater. Before initiating CPB, heparinization (300 to 400 U/kg) was performed to a target activated coagulation time greater than 480 s. Perfusion was maintained at flow rates of 2 to 2.4 l · min–1 · m–2 throughout CPB to maintain a mean arterial pressure of 50 to 80 mmHg. Arterial blood gases were measured every 15 to 30 min to maintain the PaCO2 at 35 to 40 mmHg, unadjusted for temperature (α-stat) and the PAO2 at 150 to 250 mmHg.
Neuroimaging
Cardiac surgical study participants underwent 18F-florbetapir positron emission tomography/computerized tomography imaging at the Duke Positron Emission Tomography Center (Durham, North Carolina) at 6 weeks after surgery. Given funding constraints, imaging was performed at 6 weeks after surgery, since amyloid burden is not expected to change significantly over a 6-week period.17  At approximately the midpoint of the study, imaging was added at the 1-yr postoperative time point to provide pilot data on the change in amyloid burden over this time interval. A 10 mCi (370 MBq) dose of 18F-florbetapir (Avid Radiopharmaceuticals, USA) was assayed with a dose calibrator and administered via bolus injection through a peripheral vein. Once 50 min had elapsed after 18F-florbetapir injection, patients underwent 10 min of continuous brain positron emission tomography imaging. A low-dose computerized tomography scan was also performed for attenuation-correction of the positron emission tomography images. Positron emission tomography images were immediately reconstructed after the scan, and if any motion was detected, another 10-min continuous scan was performed.
For quantitative evaluation, 18F-florbetapir images were spatially normalized to the stereotactic Montreal Neurologic Institute brain atlas space.18  A standard uptake value ratio was calculated using an average of six target regions (medial orbital frontal, anterior cingulate, parietal, posterior cingulate, precuneus, and lateral temporal) with respect to the whole cerebellum as a reference region. 18F-florbetapir signal was also measured in the hippocampus, pons, centrum, putamen, and caudate, and the standard uptake value ratio for each region was calculated with respect to the cerebellum. Amyloid burden, as previously described,19  was identified based on standard uptake value ratio values (greater than or equal to 1.10 is β-amyloid-positive [abnormal amyloid deposition] and less than 1.10 is β-amyloid-negative).
Neurocognitive Testing
Neurocognitive testing was performed at baseline (preoperatively) and at 6 weeks. Post hoc, 1-yr, and 3-yr follow-up points were added to provide pilot data on the relationship between baseline amyloid burden and long-term neurocognitive function. In accordance with the consensus statement on assessment of neurobehavioral outcomes after cardiac surgery,20  the following tests were included in the assessment battery: (1) Hopkins Verbal Learning Test,21  (2) Randt Short Story Memory Test,22  (3) Modified Visual Reproduction Test from the Wechsler Memory Scale,23  (4) Digit Span and Digit Symbol and Vocabulary subtests from the Wechsler Adult Intelligence Scale-Revised,23  and (5) Trail Making Test, Parts A and B.24 
Blood Sample and Apolipoprotein E Genotyping
One 10-ml sample of peripheral blood was obtained from each patient and stored at 4°C. Genomic DNA were extracted for each sample and stored at the Duke Molecular Physiology Institute (Durham, North Carolina) at –20°C. Genotyping for apolipoprotein E was performed at the Molecular Genetics Core at the Duke Molecular Physiology Institute following previously described protocols.25 
Statistical Analyses
To characterize cognitive function over time while minimizing potential redundancy in the cognitive measures, a factor analysis with oblique rotation (a linear transformation of the data, which allows for correlated factors) was performed on the 14 cognitive test scores from baseline. Scoring coefficients (weights) of each test on each factor were determined using the rotated factor solution from the factor analysis conducted on 508 eligible cardiac patients in our ongoing prospective post-CABG cognitive testing database. Factors of each subject in our cohort were computed for all time points using the same scoring coefficients, so that the cognitive domain structure remained consistent and comparable over time. Factor analysis suggested a five-factor solution, which accounts for 80% of the variability in the original test scores, and represents five cognitive domains: (1) structured verbal memory (i.e., the ability to recall from a list); (2) unstructured verbal memory (i.e., the ability to remember from a narrative); (3) visual memory; (4) executive function; and (5) attention and concentration. Two outcome measures were calculated to represent postoperative cognitive dysfunction: (1) continuous outcome—the change in cognitive score calculated by subtracting the baseline cognitive index (the five-domain mean) from the follow-up cognitive index (a change score of 0 indicates no change from baseline, while a negative score indicates cognitive decline, and a positive score indicates cognitive improvement); and (2) binary outcome (cognitive deficit), defined as a decline of greater than 1 SD in at least one domain.
The relationship between 6-week global cortical amyloid burden (standard uptake value ratio 1.1 or greater) and cognition at 6 weeks after surgery was prespecified as the primary outcome. Secondary outcomes included the relationship between regional amyloid burden and cognition at 6 weeks postoperatively, and the relationship between global amyloid burden and cognition at 1 yr. We used the chi-square test, Fisher exact test, or Wilcoxon rank sum test, as appropriate, to examine differences between patients with and without cognitive deficit. We then computed Pearson’s correlation coefficients of amyloid burden with age, years of education, baseline cognitive score, 6-week cognitive score, and change in cognitive score. Finally, multivariable regression was used to test the association of cognitive deficit and mean 6-week cognitive score change with abnormal amyloid deposition (standard uptake value ratio 1.1 or greater), accounting for age, years of education, and baseline cognition. Subject demographics and amyloid burden in our surgical cohort was compared to age- and sex-matched normal, early mild cognitive impairment, and late mild cognitive impairment subsets in the ADNI database using the two-sample t test, Wilcoxon rank sum test, chi-square test, or Fisher exact test, as appropriate.
Apolipoprotein E4 genotype was categorized by the presence (homozygous or heterozygous) or absence of the apolipoprotein E-ε4 allele. The association of apolipoprotein E4 status with amyloid burden at 6 weeks was assessed using the two-sample t test, Wilcoxon rank sum test, chi-square test, or Fisher exact test, as appropriate. An analysis of covariance model was then used to test differences among four cognitive categories: cognitive deficit at 6 weeks in our surgical cohort and normal, early mild cognitive impairment, and late mild cognitive impairment in the ADNI cohort (adjusting for age, years of education, and apolipoprotein E4 genotype).
In the absence of any published data on amyloid deposition in surgical patients, we relied upon preliminary data from a study conducted by a coinvestigator (P.M.D.) evaluating amyloid deposition in healthy, mild cognitive impairment, and Alzheimer disease subjects, where the estimated mean and SD of the healthy and mild cognitive impairment groups were used for power calculation. Based on these data, we assessed the statistical power for detecting the correlation between cognitive score changes and amyloid burden. Under a linear regression model with the SD of amyloid burden at 0.25 from preliminary data, we estimated that 40 patients in the cardiac surgical group would provide 80% power to detect a correlation between cognitive score changes and amyloid burden at an R-square of 0.171.
All analyses were performed with SAS version 9.4 (SAS Institute Inc., USA). P < 0.05 was considered significant. Post hoc analyses of regional amyloid deposition were adjusted for multiple comparisons by computing a false discovery rate.
Results
Neurocognitive Outcomes
Of the 40 patients initially enrolled, 37 had complete baseline and 6-week cognitive and neuroimaging data; at 1 yr after surgery, 28 patients had complete baseline and 1-yr cognitive data and 12 had neuroimaging; and at 3 yr after surgery, 18 patients completed cognitive testing. The mean (SD) cognitive change score (from baseline) was 0.10 (0.29) at 6 weeks, 0.13 (0.31) at 1 yr after surgery, and 0.08 (0.51) at 3 yr after surgery. Cognitive deficit, defined as a 1 or greater SD decline in at least one cognitive domain, was present in 35% (13 of 37) of the cardiac surgical patients at 6 weeks after surgery, 57% (16 of 28) at 1 yr, and 44% (8 of 18) at 3 yr. Interestingly, several patients without deficit at 6 weeks went on to develop deficit at 1 yr postoperatively, while others recovered (Supplemental Digital Content 1, http://links.lww.com/ALN/B616, and Supplemental Digital Content 2, http://links.lww.com/ALN/B617). Table 1 lists the demographic and surgical characteristics of the enrolled patients.
Table 1.
Characteristics of the Cardiac Surgical Cohort
Characteristics of the Cardiac Surgical Cohort×
Characteristics of the Cardiac Surgical Cohort
Table 1.
Characteristics of the Cardiac Surgical Cohort
Characteristics of the Cardiac Surgical Cohort×
×
Global Cortical Amyloid Deposition and Postoperative Cognitive Dysfunction at 6 Weeks and 1 Yr.
Representative images from our study cohort of normal (A) and abnormal (B) amyloid deposition as measured by 18F-florbetapir imaging are shown in figure 1. Global cortical amyloid deposition was measured as standard uptake value ratio 1.03 (0.17) in the 40 patients imaged at 6 weeks and 1.04 (0.20) in the 12 patients imaged at 1 yr. Cortical amyloid deposition was considered abnormal (standard uptake value ratio greater than or equal to 1.1) in seven patients (17.5%) imaged at 6 weeks and in two patients (16.7%) imaged at 1 yr. The cognitive change score at 6 weeks and 1 yr after surgery in patients with and without 6-week abnormal global cortical amyloid deposition was 0.108 (0.186) versus 0.095 (0.311), P = 0.92; and 0.193 (0.266) versus –0.121 (0.325), P = 0.62, respectively.
Fig. 1.
Images of patients with normal (A) and abnormal (B) amyloid deposition by 18F-florbetapir positron emission tomography imaging. The brighter orange to yellow colors indicate greater amyloid deposition.
Images of patients with normal (A) and abnormal (B) amyloid deposition by 18F-florbetapir positron emission tomography imaging. The brighter orange to yellow colors indicate greater amyloid deposition.
Fig. 1.
Images of patients with normal (A) and abnormal (B) amyloid deposition by 18F-florbetapir positron emission tomography imaging. The brighter orange to yellow colors indicate greater amyloid deposition.
×
With regard to our primary outcome, 6-week global cortical amyloid deposition was not different in patients with and without cognitive deficit at 6 weeks (median standard uptake value ratio (interquartile range, 0.92 [0.89 to 1.07] vs. 0.98 [0.93 to 1.05], P = 0.455; table 2), nor was there a difference in the proportion of patients with and without postoperative cognitive dysfunction who had abnormal amyloid deposition (proportion difference, 0.106). Similar patterns were seen at 1 yr after surgery (median standard uptake value ratio [interquartile range], 0.96 [0.89 to 1.02] vs. 1.02 [0.97 to 1.06]). Abnormal 6-week amyloid deposition was seen in three patients with cognitive deficit and in three patients without deficit at 6 weeks postoperatively (P = 0.644; table 3). Similarly, one patient with cognitive deficit at 1 yr had abnormal global cortical amyloid deposition at 1 yr, while one patient without deficit had abnormal deposition. There were no significant correlations of global cortical amyloid deposition at 6 weeks with baseline, 6-week, 1-yr, or 3-yr cognitive scores or change scores. In multivariable regression analyses, we found no significant association between 6-week abnormal global cortical amyloid burden and cognitive change scores (β, 0.09; model R2, 0.12) or with the occurrence of postoperative cognitive dysfunction at 6 weeks (odds ratio, 0.47; 95% CI, 0.07 to 3.43; model R2, 0.09) when controlling for age, years of education, and baseline cognition. There were also no significant associations of 6-week amyloid burden with cognitive outcomes at 1 or 3 yr after surgery.
Table 2.
Global Cortical and Regional SUVr Values in Patients with and without Cognitive Deficit at 6 Weeks
Global Cortical and Regional SUVr Values in Patients with and without Cognitive Deficit at 6 Weeks×
Global Cortical and Regional SUVr Values in Patients with and without Cognitive Deficit at 6 Weeks
Table 2.
Global Cortical and Regional SUVr Values in Patients with and without Cognitive Deficit at 6 Weeks
Global Cortical and Regional SUVr Values in Patients with and without Cognitive Deficit at 6 Weeks×
×
Table 3.
Frequency of Abnormal Global Cortical and Regional Amyloid Deposition at 6 Weeks in Patients with and without Cognitive Deficit
Frequency of Abnormal Global Cortical and Regional Amyloid Deposition at 6 Weeks in Patients with and without Cognitive Deficit×
Frequency of Abnormal Global Cortical and Regional Amyloid Deposition at 6 Weeks in Patients with and without Cognitive Deficit
Table 3.
Frequency of Abnormal Global Cortical and Regional Amyloid Deposition at 6 Weeks in Patients with and without Cognitive Deficit
Frequency of Abnormal Global Cortical and Regional Amyloid Deposition at 6 Weeks in Patients with and without Cognitive Deficit×
×
Regional Amyloid Deposition and Postoperative Cognitive Dysfunction.
In post hoc analyses we found that the frequency of abnormal amyloid deposition (standard uptake value ratio greater than or equal to 1.1) in the hippocampus was significantly different between patients with and without postoperative cognitive dysfunction at 6 weeks postoperatively, although this difference was no longer significant after adjustment for multiple comparisons (P = 0.041, false discovery rate = 0.429; table 3). Patients who had abnormal 6-week amyloid in the hippocampus showed significantly greater decline in the structured verbal memory domain (median change score [interquartile range], –1.08 [–2.05 to –0.69] in patients with standard uptake value ratio greater than or equal to 1.1 vs. –0.075 [–0.82 to 0.46] for patients with standard uptake value ratio less than 1.1; P = 0.019). Total hippocampal standard uptake value ratio (continuous variable), although higher, was not statistically different between patients with and without deficit (table 2). The caudate standard uptake value ratio was also greater in patients who had a cognitive deficit at 6 weeks, but this difference was no longer significant after adjustment for multiple comparisons (median [interquartile range], deficit 0.96 [0.85 to 1.03] vs. no deficit 0.81 [0.70 to 0.94]; P = 0.047, false discovery rate = 0.561). Furthermore, the standard uptake value ratios in the caudate failed to meet the greater than or equal to 1.1 threshold for defining abnormal amyloid deposition.
Trajectory of Amyloid Deposition.
While cognitive deficit and the cognitive change score were not associated with abnormal global cortical amyloid deposition in the smaller cohort of 12 patients with 1-yr neuroimaging, amyloid deposition increased in many brain regions over time. In these 12 patients, global cortical amyloid deposition increased significantly from 6 weeks to 1 yr (mean standard uptake value ratio change, 0.02 ± 0.02; P = 0.011). Statistically significant increases in standard value uptake ration from 6 weeks to 1 yr postoperatively were observed in the hippocampus, posterior cingulate, caudate, and occipital regions (fig. 2).
Fig. 2.
Box plots showing median (interquartile range) change in standard uptake value ratio relative to cerebellum (SUVr) in each imaged brain region from 6 weeks to 1 yr postoperatively. Positive values represent increase in SUVr, while negative values represent decrease in SUVr. N = 12.
Box plots showing median (interquartile range) change in standard uptake value ratio relative to cerebellum (SUVr) in each imaged brain region from 6 weeks to 1 yr postoperatively. Positive values represent increase in SUVr, while negative values represent decrease in SUVr. N = 12.
Fig. 2.
Box plots showing median (interquartile range) change in standard uptake value ratio relative to cerebellum (SUVr) in each imaged brain region from 6 weeks to 1 yr postoperatively. Positive values represent increase in SUVr, while negative values represent decrease in SUVr. N = 12.
×
Comparison to ADNI Cohort.
Overall, our cardiac surgical cohort was more similar to the ADNI subjects with normal cognition than the age- and sex-matched early or late mild cognitive impairment cohorts, with regard to education and apolipoprotein E4 carrier status (Supplemental Digital Content 3, http://links.lww.com/ALN/B618) and global and regional amyloid deposition (Supplemental Digital Content 4, http://links.lww.com/ALN/B619, and Supplemental Digital Content 5, http://links.lww.com/ALN/B620).
Abnormal Amyloid Deposition and Cognitive Deficit in Apolipoprotein E4 Carriers.
Apolipoprotein E genotype was available for 37 patients in our cohort. Eight patients were found to be apolipoprotein E4 carriers (seven heterozygous, one homozygous), and 29 were noncarriers. Of the eight apolipoprotein E4 carriers, seven had complete 6-week cognitive testing data; of the 29 noncarriers, 27 had complete 6-week cognitive testing data. Of the seven apolipoprotein E4 carriers with complete 6-week cognitive testing, four (57%) demonstrated cognitive deficit at 6 weeks. This was not statistically different from the deficit rate in the non-apolipoprotein E4 carriers (7 of 27, 26%; P = 0.178). Apolipoprotein E4 genotype was, however, significantly associated with worse baseline cognitive score (mean [SD], –0.631 [0.382] vs. 0.001 [0.555] in noncarriers; P = 0.005), but there was no difference at 6 weeks or in the change score from baseline to 6 weeks between apolipoprotein E4 carriers and noncarriers. Global and regional standard uptake value ratios in apolipoprotein E4 carriers versus noncarriers are shown in Supplemental Digital Content 6 (http://links.lww.com/ALN/B621). An analysis of covariance model, incorporating the ADNI cohort, revealed a significant association of global cortical amyloid deposition at 6 weeks with apolipoprotein E4 genotype (P < 0.001) and age (P = 0.001), and that the surgical cohort with cognitive deficit at 6 weeks had smaller global cortical amyloid deposition at 6 weeks than the late mild cognitive impairment subjects (P = 0.001) in the ADNI cohort, but not the normal (P = 0.68) or early mild cognitive impairment patients (P = 0.07).
When evaluating regional standard uptake value ratio greater than or equal to 1.1 in apolipoprotein E4 carriers, only the parietal region was different between the carriers and noncarriers before adjustment for multiple comparisons (38% [3 of 8] in carriers vs. 3% [1 of 29] in noncarriers; P = 0.02; false discovery rate = 0.282).
Discussion
We did not find an association between 6-week global cortical amyloid burden and cognitive dysfunction at 6 weeks after cardiac surgery. Cognitive dysfunction after cardiac surgery remains a significant problem without a clear etiology. Given that cardiac surgery predominantly takes place in the aged, the possibility exists that the cognitive decline seen in some patients is similar to mild cognitive impairment, which in many will eventually progress to Alzheimer disease. Both diseases are believed to involve the accumulation of β-amyloid and τ proteins in the brain. While the role of β-amyloid oligomers in the pathogenesis of Alzheimer disease remains controversial,26  there is evidence that β-amyloid can lead to synaptic dysfunction and memory deficits in animals.27  CPB is known to disrupt the blood-brain barrier,28  and blood-brain barrier dysfunction is associated with increased entry of amyloid into the brain.29  Alzheimer-type neurodegeneration is accelerated by neuroinflammation,30  raising the possibility that perioperative inflammation could stimulate/accelerate β–amyloid-mediated neurologic degeneration, which could contribute to postoperative cognitive dysfunction. Finally, cardiac surgical patients share many of the risk factors for Alzheimer disease,31  and there is a known intersection between Alzheimer and cardiovascular/cerebrovascular disease.32  While there is no evidence that cardiovascular disease severity directly affects amyloid burden,33  it is plausible that some component of postoperative cognitive dysfunction may be related to cardiovascular risk factors that accelerate the progression toward Alzheimer-type cognitive decline.
To investigate the relationship between postoperative cognitive dysfunction and β-amyloid protein deposition in patients undergoing cardiac surgery, we utilized the novel positron emission tomography tracer, 18F-florbetapir, which binds with high affinity to β-amyloid fibrils and has been shown to differentiate cerebral β-amyloid deposition between both cognitively normal and deficient subjects.34  With regard to our primary outcome, we did not find a significant association between 6-week global cortical amyloid burden and cognitive dysfunction at 6 weeks. Six-week amyloid burden was also not associated with cognitive dysfunction at 1 or 3 yr postoperatively, although our sample size at these time points was very small.
In post hoc analyses of regional amyloid deposition, we found an increased proportion of patients with cognitive dysfunction at 6 weeks with abnormal 6-week amyloid deposition in the hippocampus, which was associated with a verbal memory deficit. While these results were not significant after adjustment for multiple comparisons, the unadjusted findings may point to regions that deserve closer scrutiny in future studies. The hippocampus is an intriguing region because it plays an important role in the acquisition and storage of episodic memories35 —those related to unique personal experiences—and has been linked with postsurgical cognitive changes in animals.36  Hippocampal synapse loss occurs early in Alzheimer and, to a greater extent than in other brain regions, in advanced Alzheimer. Furthermore, hippocampal damage correlates better with cognitive impairment in Alzheimer disease than the presence/quantity of β-amyloid plaques or neurofibrillary tangles.37  Finally, Badgaiya et al. previously showed significant decreases in memory-related regional cerebral blood flow within the hippocampus and parahippocampus after cardiac surgery,38  which may indicate regions of the brain that are more vulnerable to ischemic blood-brain barrier dysfunction and consequent cerebral deposition of circulating amyloid after cardiac surgery.29 
We also observed that amyloid deposition significantly increased from 6 weeks to 1 yr after surgery in many regions of the brain and that this rate of increase was greater than that reported elsewhere. In a study by Palmqvist et al.,39  the mean global standard uptake value ratio change/year in nondemented subjects with normal positron emission tomography scans was 0.0024 (95% CI, 0.0010 to 0.0039), while that for subjects with abnormal CSF and scan results was 0.011 (95% CI, 0.0083 to 0.013). Similarly, in the longitudinal ADNI cohort, the mean standard uptake value ratio change in 154 control subjects with a normal baseline scan was 0.0027 (0.0100), but was 0.0160 (0.0161) in 61 controls with abnormal baseline scans (Susan Landau, Ph.D., Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, California; email communication, October 2017). In comparison, the mean (SD) global cortical standard uptake value ratio change in our surgical patients was 0.02 (0.02), nearly tenfold than seen in scan-negative nonsurgical patients, and just slightly higher than that in scan-positive nonsurgical patients. When we removed patients with abnormal 6-week amyloid deposition (N = 2) from our analyses, the rate of change in our surgical cohort remained higher at 0.014 (0.018). Percent standard uptake value ratio change, which discounts variation in reference regions, may be more informative; in the Palmqvist et al. study,39  the percent global standard uptake value ratio change/year was 0.35% (95% CI, 0.14 to 0.56%), compared to 1.9 ± 2.0% in our surgical cohort. However, our study sample is limited, and changes over the course of a year are small.
This trajectory of amyloid at 1 yr after surgery raises the question of how surgery and/or anesthesia may impact cerebral amyloid deposition and longer-term cognitive outcomes. Several in vitro and animal studies have established a link between anesthetic agents and enhanced β-amyloid formation, aggregation, and β-amyloid-induced cytotoxicity.5,6  Human studies have demonstrated that low preoperative ratios of β-amyloid/τ proteins in the CSF are associated with postoperative delirium and cognitive decline, although this is thought to predict a predisposition to cognitive dysfunction due to preclinical Alzheimer disease, rather than a direct anesthetic effect.40  Surgery may also have an independent effect on the risk of Alzheimer development in the postoperative setting.41  Tang et al.7  and Berger et al.8  both demonstrated a CSF change in the ratio of β-amyloid/τ proteins in patients undergoing surgery consistent with that seen in Alzheimer and correlated with perioperative neuroinflammatory mediator release. The association of perioperative inflammatory changes and Alzheimer-like cognitive decline may be particularly relevant in the highly inflammatory milieu of cardiac surgery. Cardiac surgery with CPB has been shown to produce an intense cerebral inflammatory response in conjunction with Alzheimer-like changes in CSF β amyloid.42  Vascular dysfunction and inflammation, both hallmarks of cardiac surgery, have also been associated with amyloid deposition.43  Thus, one concern has been whether cardiac surgery itself could increase the rate of amyloid deposition as a consequence of blood-brain barrier disruption.28 
Our finding that some patients experienced cognitive decline over time, while others improved also merits further study and correlation with observed changes in the trajectory of global and regional cortical amyloid deposition. Cognitive improvement over time after surgery is certainly a recognized phenomenon and can been seen either globally or in select cognitive domains.44  However, no mechanistic explanation has yet been uncovered as to why some patients improve while others continue to decline/recover more slowly.
It is important to interpret our findings in the context of our sample size limitations. Without any previous studies on amyloid burden in surgical patients, our initial sample size estimation was based on the hypothesis that patients with postoperative cognitive dysfunction would have amyloid deposition to individuals with mild cognitive impairment. For our primary outcome, comparison of the binary variables of abnormal amyloid deposition and postoperative cognitive dysfunction demonstrated a proportion difference of 0.106; we are only powered to detect a proportion difference of 0.5, thus we cannot conclusively exclude an association between 6-week abnormal amyloid deposition and a clinically meaningful decline in cognitive function after cardiac surgery. Furthermore, we estimate that we have 80% power to detect a mean standard uptake value ratio difference of 0.16 between patients with and without postoperative cognitive at 6 weeks postoperatively; thus, our detected standard uptake value ratio difference of 0.06 falls below this threshold. Based on these data, we estimate that 117 patients would be needed to achieve 80% power in a future study (Supplemental Digital Content 7, http://links.lww.com/ALN/B622).
The lack of baseline imaging and longer-term (more than 3 yr) follow-up are further limitations of our study. While the existing literature indicates a longer time course for change in amyloid,17  we cannot say with certainty that surgery does not produce changes in amyloid deposition in the immediate postoperative period. Future studies should include a baseline assessment of brain amyloid before surgery as well as longer duration of follow-up. Based on the existing literature in mild cognitive impairment subjects, the time course of clinically significant β-amyloid deposition needed to produce cognitive decline may be significantly longer.45,46  Finally, we are limited by the relatively younger and male-dominated nature of our surgical cohort. Older age has been shown to increase the risk for postoperative cognitive dysfunction47  and Alzheimer disease, and multiple studies have indicated that females have a higher prevalence and incidence of Alzheimer disease48  and mild cognitive impairment progression over time than men.49  Future studies should include an older surgical group that more closely matches the ADNI mild cognitive impairment cohort.
In conclusion, this study employed amyloid imaging using 18F-florbetapir to investigate 6-week and evolving brain amyloid burden in patients undergoing cardiac surgery with CPB. We observed that postoperative cognitive dysfunction was not associated with 6-week global cortical amyloid deposition, but the rate of amyloid deposition after surgery was greater than what has been reported in normal elderly subjects. The findings from this study support further investigation of: (1) the relationship between hippocampal amyloid deposition and early postoperative cognitive dysfunction; and (2) the significance of amyloid deposition increases within 1 yr of cardiac surgery.
Acknowledgments
The authors thank Abhinay Joshi, M.S., from Avid Radiopharmaceuticals for assistance with image analytics in a blinded fashion. The authors also thank Avid Radiopharmaceuticals (Philadelphia, Pennsylvania) for their support of this study through the provision of 18F-florbetapir.
Regarding the ADNI data used in this study: data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI; National Institutes of Health [Bethesda, Maryland] grant No. U01 AG024904) and Department of Defense ADNI (grant No. W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai, Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd. and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development LLC; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer, Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (http://www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. This study is supported in part by grant Nos. HL108280, HL096978, and HL109971 from the National Institutes of Health. 18F-florbetapir is provided courtesy of Avid Radiopharmaceuticals, but Avid had no input into the clinical study design or decision to publish this report.
Competing Interests
Dr. Doraiswamy has received research grants (through Duke University) from Avid (Philadelphia, Pennsylvania), Lilly (Indianapolis, Indiana), Neuronetrix (Louisville, Kentucky), Avanir (Aliso Viejo, California), Alzheimer’s Drug Discovery Foundation (New York, New York), Forum (Waltham, Massachusetts), and has received speaking or advisory fees from Anthrotronix (Silver Spring, Maryland), Cognoptix (Acton, Massachusetts), Takeda (Deerfield, Illinois), Genomind (King of Prussia, Pennsylvania), Sonexa (San Diego, California), Targacept (Winston-Salem, North Carolina), Neurocog Trials (Durham, North Carolina), Forum (Waltham, Massachusetts), T3D Therapeutics (Research Triangle Park, North Carolina), Alzheimer’s Association (Chicago, Illinois), Hintsa (Zurich, Switzerland), MindLink (London, England), Global Alzheimer’s Platform (Washington, D.C.), and University of Miami (Miami, Florida). Dr. Doraiswamy owns shares in Maxwell Health (Boston, Massachusetts), Muses Labs (Raleigh, North Carolina), Anthrotronix, Evidation Health (San Mateo, California), Turtle Shell Technologies (Karnataka, India), and Advera Health Analytics (Santa Rosa, California). Dr. Doraiswamy is a coinventor on patents relating to dementia biomarkers that are unlicensed. The other authors declare no competing interests.
References
Newman, MF, Kirchner, JL, Phillips-Bute, B, Gaver, V, Grocott, H, Jones, RH, Mark, DB, Reves, JG, Blumenthal, JA ; Neurological Outcome Research Group and the Cardiothoracic Anesthesiology Research Endeavors Investigators: Longitudinal assessment of neurocognitive function after coronary-artery bypass surgery. N Engl J Med 2001; 344:395–402 [Article] [PubMed]
Phillips-Bute, B, Mathew, JP, Blumenthal, JA, Grocott, HP, Laskowitz, DT, Jones, RH, Mark, DB, Newman, MF . Association of neurocognitive function and quality of life 1 year after coronary artery bypass graft (CABG) surgery. Psychosom Med 2006; 68:369–75 [Article] [PubMed]
Berger, M, Burke, J, Eckenhoff, R, Mathew, J . Alzheimer’s disease, anesthesia, and surgery: A clinically focused review. J Cardiothorac Vasc Anesth 2014; 28:1609–23 [Article] [PubMed]
Grundman, M, Petersen, RC, Ferris, SH, Thomas, RG, Aisen, PS, Bennett, DA, Foster, NL, Jack, CRJr, Galasko, DR, Doody, R, Kaye, J, Sano, M, Mohs, R, Gauthier, S, Kim, HT, Jin, S, Schultz, AN, Schafer, K, Mulnard, R, van Dyck, CH, Mintzer, J, Zamrini, EY, Cahn-Weiner, D, Thal, LJ ; Alzheimer’s Disease Cooperative Study: Mild cognitive impairment can be distinguished from Alzheimer disease and normal aging for clinical trials. Arch Neurol 2004; 61:59–66 [Article] [PubMed]
Xie, Z, Culley, DJ, Dong, Y, Zhang, G, Zhang, B, Moir, RD, Frosch, MP, Crosby, G, Tanzi, RE . The common inhalation anesthetic isoflurane induces caspase activation and increases amyloid beta-protein level in vivo. Ann Neurol 2008; 64:618–27 [Article] [PubMed]
Eckenhoff, RG, Johansson, JS, Wei, H, Carnini, A, Kang, B, Wei, W, Pidikiti, R, Keller, JM, Eckenhoff, MF . Inhaled anesthetic enhancement of amyloid-beta oligomerization and cytotoxicity. Anesthesiology 2004; 101:703–9 [Article] [PubMed]
Tang, JX, Baranov, D, Hammond, M, Shaw, LM, Eckenhoff, MF, Eckenhoff, RG . Human Alzheimer and inflammation biomarkers after anesthesia and surgery. Anesthesiology 2011; 115:727–32 [Article] [PubMed]
Berger, M, Nadler, JW, Friedman, A, McDonagh, DL, Bennett, ER, Cooter, M, Qi, W, Laskowitz, DT, Ponnusamy, V, Newman, MF, Shaw, LM, Warner, DS, Mathew, JP, James, ML ; MAD-PIA trial team: The effect of propofol versus isoflurane anesthesia on human cerebrospinal fluid markers of Alzheimer’s disease: Results of a randomized trial. J Alzheimers Dis 2016; 52:1299–310 [Article] [PubMed]
Carpenter, APJr, Pontecorvo, MJ, Hefti, FF, Skovronsky, DM . The use of the exploratory IND in the evaluation and development of 18F-PET radiopharmaceuticals for amyloid imaging in the brain: A review of one company’s experience. Q J Nucl Med Mol Imaging 2009; 53:387–93 [PubMed]
Choi, SR, Schneider, JA, Bennett, DA, Beach, TG, Bedell, BJ, Zehntner, SP, Krautkramer, MJ, Kung, HF, Skovronsky, DM, Hefti, F, Clark, CM . Correlation of amyloid PET ligand florbetapir F 18 binding with Aβ aggregation and neuritic plaque deposition in postmortem brain tissue. Alzheimer Dis Assoc Disord 2012; 26:8–16 [Article] [PubMed]
Johnson, KA, Sperling, RA, Gidicsin, CM, Carmasin, JS, Maye, JE, Coleman, RE, Reiman, EM, Sabbagh, MN, Sadowsky, CH, Fleisher, AS, Murali Doraiswamy, P, Carpenter, AP, Clark, CM, Joshi, AD, Lu, M, Grundman, M, Mintun, MA, Pontecorvo, MJ, Skovronsky, DM ; AV45-A11 study group: Florbetapir (F18-AV-45) PET to assess amyloid burden in Alzheimer’s disease dementia, mild cognitive impairment, and normal aging. Alzheimers Dement 2013; 9(5 Suppl):S72–83 [Article] [PubMed]
Yeo, JM, Waddell, B, Khan, Z, Pal, S . A systematic review and meta-analysis of (18)F-labeled amyloid imaging in Alzheimer’s disease. Alzheimers Dement (Amst) 2015; 1:5–13 [PubMed]
Jagust, WJ, Landau, SM, Koeppe, RA, Reiman, EM, Chen, K, Mathis, CA, Price, JC, Foster, NL, Wang, AY . The Alzheimer’s Disease Neuroimaging Initiative 2 PET Core: 2015. Alzheimers Dement 2015; 11:757–71 [Article] [PubMed]
Aisen, PS, Petersen, RC, Donohue, MC, Gamst, A, Raman, R, Thomas, RG, Walter, S, Trojanowski, JQ, Shaw, LM, Beckett, LA, Jack, CRJr, Jagust, W, Toga, AW, Saykin, AJ, Morris, JC, Green, RC, Weiner, MW ; Alzheimer’s Disease Neuroimaging Initiative: Clinical Core of the Alzheimer’s Disease Neuroimaging Initiative: Progress and plans. Alzheimers Dement 2010; 6:239–46 [Article] [PubMed]
Weiner, MW, Aisen, PS, Jack, CRJr, Jagust, WJ, Trojanowski, JQ, Shaw, L, Saykin, AJ, Morris, JC, Cairns, N, Beckett, LA, Toga, A, Green, R, Walter, S, Soares, H, Snyder, P, Siemers, E, Potter, W, Cole, PE, Schmidt, M ; Alzheimer’s Disease Neuroimaging Initiative: The Alzheimer’s disease neuroimaging initiative: Progress report and future plans. Alzheimers Dement 2010; 6:202–11.e7 [Article] [PubMed]
Murphy, KR, Landau, SM, Choudhury, KR, Hostage, CA, Shpanskaya, KS, Sair, HI, Petrella, JR, Wong, TZ, Doraiswamy, PM ; Alzheimer’s Disease Neuroimaging Initiative: Mapping the effects of ApoE4, age and cognitive status on 18F-florbetapir PET measured regional cortical patterns of beta-amyloid density and growth. Neuroimage 2013; 78:474–80 [Article] [PubMed]
Landau, SM, Fero, A, Baker, SL, Koeppe, R, Mintun, M, Chen, K, Reiman, EM, Jagust, WJ . Measurement of longitudinal β-amyloid change with 18F-florbetapir PET and standardized uptake value ratios. J Nucl Med 2015; 56:567–74 [Article] [PubMed]
Joshi, AD, Pontecorvo, MJ, Lu, M, Skovronsky, DM, Mintun, MA, Devous, MDSr . A semiautomated method for quantification of F 18 florbetapir PET images. J Nucl Med 2015; 56:1736–41 [Article] [PubMed]
Joshi, AD, Pontecorvo, MJ, Clark, CM, Carpenter, AP, Jennings, DL, Sadowsky, CH, Adler, LP, Kovnat, KD, Seibyl, JP, Arora, A, Saha, K, Burns, JD, Lowrey, MJ, Mintun, MA, Skovronsky, DM ; Florbetapir F 18 Study Investigators: Performance characteristics of amyloid PET with florbetapir F 18 in patients with Alzheimer’s disease and cognitively normal subjects. J Nucl Med 2012; 53:378–84 [Article] [PubMed]
Murkin, JM, Newman, SP, Stump, DA, Blumenthal, JA . Statement of consensus on assessment of neurobehavioral outcomes after cardiac surgery. Ann Thorac Surg 1995; 59:1289–95 [Article] [PubMed]
Rasmusson, DX, Bylsma, FW, Brandt, J . Stability of performance on the Hopkins Verbal Learning Test. Arch Clin Neuropsychol 1995; 10:21–6 [Article] [PubMed]
Randt, C, Brown, E . Adminstration manual: Randt memory test. 1983 New York, Life Sciences Associates.
Wechsler, D. The Wechsler Adult Intelligence Scale-Revised (Manual), 1981Psychological Corporation.
Reitan, R . Validity of the trail making test as an indicator of organic brain damage. Percept Mot Skills 1958; 8:271–6 [Article]
Tupler, LA, Krishnan, KR, Greenberg, DL, Marcovina, SM, Payne, ME, MacFall, JR, Charles, HC, Doraiswamy, PM . Predicting memory decline in normal elderly: genetics, MRI, and cognitive reserve. Neurobiol Aging 2007; 28:1644–56 [Article] [PubMed]
Morris, GP, Clark, IA, Vissel, B . Inconsistencies and controversies surrounding the amyloid hypothesis of Alzheimer’s disease. Acta Neuropathol Commun 2014; 2:135 [PubMed]
Shankar, GM, Li, S, Mehta, TH, Garcia-Munoz, A, Shepardson, NE, Smith, I, Brett, FM, Farrell, MA, Rowan, MJ, Lemere, CA, Regan, CM, Walsh, DM, Sabatini, BL, Selkoe, DJ . Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 2008; 14:837–42 [Article] [PubMed]
Merino, JG, Latour, LL, Tso, A, Lee, KY, Kang, DW, Davis, LA, Lazar, RM, Horvath, KA, Corso, PJ, Warach, S . Blood-brain barrier disruption after cardiac surgery. AJNR Am J Neuroradiol 2013; 34:518–23 [Article] [PubMed]
Pluta, R, Amek, MU . Brain ischemia and ischemic blood-brain barrier as etiological factors in sporadic Alzheimer’s disease. Neuropsychiatr Dis Treat 2008; 4:855–64 [Article] [PubMed]
Agostinho, P, Cunha, RA, Oliveira, C . Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer’s disease. Curr Pharm Des 2010; 16:2766–78 [Article] [PubMed]
Gorelick, PB, Scuteri, A, Black, SE, Decarli, C, Greenberg, SM, Iadecola, C, Launer, LJ, Laurent, S, Lopez, OL, Nyenhuis, D, Petersen, RC, Schneider, JA, Tzourio, C, Arnett, DK, Bennett, DA, Chui, HC, Higashida, RT, Lindquist, R, Nilsson, PM, Roman, GC, Sellke, FW, Seshadri, S ; American Heart Association Stroke Council, Council on Epidemiology and Prevention, Council on Cardiovascular Nursing, Council on Cardiovascular Radiology and Intervention, and Council on Cardiovascular Surgery and Anesthesia: Vascular contributions to cognitive impairment and dementia: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011; 42:2672–713 [Article] [PubMed]
Santos, CY, Snyder, PJ, Wu, WC, Zhang, M, Echeverria, A, Alber, J . Pathophysiologic relationship between Alzheimer’s disease, cerebrovascular disease, and cardiovascular risk: A review and synthesis. Alzheimers Dement (Amst) 2017; 7:69–87 [PubMed]
Irina, A, Seppo, H, Arto, M, Paavo, RSr, Hilkka, S . Beta-amyloid load is not influenced by the severity of cardiovascular disease in aged and demented patients. Stroke 1999; 30:613–8 [Article] [PubMed]
Wong, DF, Rosenberg, PB, Zhou, Y, Kumar, A, Raymont, V, Ravert, HT, Dannals, RF, Nandi, A, Brasić, JR, Ye, W, Hilton, J, Lyketsos, C, Kung, HF, Joshi, AD, Skovronsky, DM, Pontecorvo, MJ . In vivo imaging of amyloid deposition in Alzheimer disease using the radioligand 18F-AV-45 (florbetapir [corrected] F 18). J Nucl Med 2010; 51:913–20 [Article] [PubMed]
Hornberger, M, Piguet, O . Episodic memory in frontotemporal dementia: A critical review. Brain 2012; 135(Pt 3):678–92 [Article] [PubMed]
Zhang, MD, Barde, S, Yang, T, Lei, B, Eriksson, LI, Mathew, JP, Andreska, T, Akassoglou, K, Harkany, T, Hökfelt, TG, Terrando, N . Orthopedic surgery modulates neuropeptides and BDNF expression at the spinal and hippocampal levels. Proc Natl Acad Sci USA 2016; 113:E6686–95 [Article] [PubMed]
Terry, RD, Masliah, E, Salmon, DP, Butters, N, DeTeresa, R, Hill, R, Hansen, LA, Katzman, R . Physical basis of cognitive alterations in Alzheimer’s disease: Synapse loss is the major correlate of cognitive impairment. Ann Neurol 1991; 30:572–80 [Article] [PubMed]
Badgaiyan, RD, Weise, S, Wack, DS, Vidal Melo, MF . Attenuation of regional cerebral blood flow during memory processing after coronary artery bypass surgery. Anesth Analg 2014; 119:550–3 [Article] [PubMed]
Palmqvist, S, Mattsson, N, Hansson, O ; Alzheimer’s Disease Neuroimaging Initiative: Cerebrospinal fluid analysis detects cerebral amyloid-β accumulation earlier than positron emission tomography. Brain 2016; 139(Pt 4):1226–36 [Article] [PubMed]
Evered, L, Silbert, B, Scott, DA, Ames, D, Maruff, P, Blennow, K . Cerebrospinal fluid biomarker for Alzheimer disease predicts postoperative cognitive dysfunction. Anesthesiology 2016; 124:353–61 [Article] [PubMed]
Wan, Y, Xu, J, Meng, F, Bao, Y, Ge, Y, Lobo, N, Vizcaychipi, MP, Zhang, D, Gentleman, SM, Maze, M, Ma, D . Cognitive decline following major surgery is associated with gliosis, β-amyloid accumulation, and τ phosphorylation in old mice. Crit Care Med 2010; 38:2190–8 [Article] [PubMed]
Lee, TA, Wolozin, B, Weiss, KB, Bednar, MM . Assessment of the emergence of Alzheimer’s disease following coronary artery bypass graft surgery or percutaneous transluminal coronary angioplasty. J Alzheimers Dis 2005; 7:319–24 [Article] [PubMed]
Salminen, A, Kauppinen, A, Kaarniranta, K . Hypoxia/ischemia activate processing of Amyloid Precursor Protein: Impact of vascular dysfunction in the pathogenesis of Alzheimer’s disease. J Neurochem 2017; 140:536–49 [Article] [PubMed]
Berger, M, Nadler, JW, Browndyke, J, Terrando, N, Ponnusamy, V, Cohen, HJ, Whitson, HE, Mathew, JP . Postoperative cognitive dysfunction: Minding the gaps in our knowledge of a common postoperative complication in the elderly. Anesthesiol Clin 2015; 33:517–50 [Article] [PubMed]
Condello, C, Schain, A, Grutzendler, J . Multicolor time-stamp reveals the dynamics and toxicity of amyloid deposition. Sci Rep 2011; 1:19 [Article] [PubMed]
Klunk, WE, Mathis, CA, Price, JC, Lopresti, BJ, DeKosky, ST . Two-year follow-up of amyloid deposition in patients with Alzheimer’s disease. Brain 2006; 129(Pt 11):2805–7 [Article] [PubMed]
Moller, JT, Cluitmans, P, Rasmussen, LS, Houx, P, Rasmussen, H, Canet, J, Rabbitt, P, Jolles, J, Larsen, K, Hanning, CD, Langeron, O, Johnson, T, Lauven, PM, Kristensen, PA, Biedler, A, van Beem, H, Fraidakis, O, Silverstein, JH, Beneken, JE, Gravenstein, JS . Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators. International Study of Post-Operative Cognitive Dysfunction. Lancet 1998; 351:857–61 [Article] [PubMed]
Ruitenberg, A, Ott, A, van Swieten, JC, Hofman, A, Breteler, MM . Incidence of dementia: Does gender make a difference? Neurobiol Aging 2001; 22:575–80 [Article] [PubMed]
Lin, KA, Choudhury, KR, Rathakrishnan, BG, Marks, DM, Petrella, JR, Doraiswamy, PM ; Alzheimer’s Disease Neuroimaging Initiative: Marked gender differences in progression of mild cognitive impairment over 8 years. Alzheimers Dement (N Y) 2015; 1:103–10 [PubMed]
Appendix 1. Members of the Alzheimer’s Disease Neuroimaging Initiative (ADNI)
I. ADNI I, GO, and II
Part A: Leadership and Infrastructure
Principal Investigator
Michael W. Weiner, M.D., University of California, San Francisco
ADCS Principal Investigator and Director of Coordinating Center Clinical Core
Paul Aisen, M.D., University of Southern California
Executive Committee
Michael Weiner, M.D., University of California, San Francisco
Paul Aisen, M.D., University of Southern California
Ronald Petersen, M.D., Ph.D., Mayo Clinic, Rochester
Clifford R. Jack, Jr., M.D., Mayo Clinic, Rochester
William Jagust, M.D., University of California, Berkeley
John Q. Trojanowki, M.D., Ph.D., University of Pennsylvania
Arthur W. Toga, Ph.D., University of Southern California
Laurel Beckett, Ph.D., University of California, Davis
Robert C. Green, M.D., M.P.H., Brigham and Women’s Hospital/Harvard Medical School
Andrew J. Saykin, Psy.D., Indiana University
John Morris, M.D., Washington University St. Louis
Leslie M. Shaw, University of Pennsylvania
ADNI External Advisory Board (ESAB)
Zaven Khachaturian, Ph.D., Prevent Alzheimer’s Disease 2020 (Chair)
Greg Sorensen, M.D., Siemens
Maria Carrillo, Ph.D., Alzheimer’s Association
Lew Kuller, M.D., University of Pittsburgh
Marc Raichle, M.D., Washington University St. Louis
Steven Paul, M.D., Cornell University
Peter Davies, M.D., Albert Einstein College of Medicine of Yeshiva University
Howard Fillit, M.D., AD Drug Discovery Foundation
Franz Hefti, Ph.D., Acumen Pharmaceuticals
David Holtzman, M.D., Washington University St. Louis
M. Marcel Mesulam, M.D., Northwestern University
William Potter, M.D., National Institute of Mental Health
Peter Snyder, Ph.D., Brown University
ADNI 2 Private Partner Scientific Board (PPSB)
Adam Schwartz, M.D., Eli Lilly (Chair)
Data and Publications Committee
Robert C. Green, M.D., M.P.H., BWH/HMS (Chair)
Resource Allocation Review Committee
Tom Montine, M.D., Ph.D., University of Washington (Chair)
Clinical Core Leaders
Ronald Petersen, M.D., Ph.D., Mayo Clinic, Rochester (Core Principal Investigator)
Paul Aisen, M.D., University of Southern California
Clinical Informatics and Operations
Ronald G. Thomas, Ph.D., University of California, San Diego
Michael Donohue, Ph.D., University of California, San Diego
Sarah Walter, M.Sc., University of California, San Diego
Devon Gessert, University of California, San Diego
Tamie Sather, M.A., University of California, San Diego
Gus Jiminez, M.B.S., University of California, San Diego
Archana B. Balasubramanian, Ph.D., University of California, San Diego
Jennifer Mason, M.P.H., University of California, San Diego
Iris Sim, University of California, San Diego
Biostatistics Core Leaders and Key Personnel
Laurel Beckett, Ph.D., University of California, Davis (Core Principal Investigator)
Danielle Harvey, Ph.D., University of California, Davis
Michael Donohue, Ph.D., University of California, San Diego
Magnetic Resonance Imaging Core Leaders and Key Personnel
Clifford R. Jack, Jr., M.D., Mayo Clinic, Rochester (Core Principal Investigator)
Matthew Bernstein, Ph.D., Mayo Clinic, Rochester
Nick Fox, M.D., University of London
Paul Thompson, Ph.D., University of California, Los Angeles School of Medicine
Norbert Schuff, Ph.D., University of California, San Francisco Magnetic Resonance Imaging
Charles DeCArli, M.D., University of California, Davis
Bret Borowski, R.T., Mayo Clinic
Jeff Gunter, Ph.D., Mayo Clinic
Matt Senjem, M.S., Mayo Clinic
Prashanthi Vemuri, Ph.D., Mayo Clinic
David Jones, M.D., Mayo Clinic
Kejal Kantarci, Mayo Clinic
Chad Ward, Mayo Clinic
PET Core Leaders and Key Personnel
William Jagust, M.D., University of California, Berkeley (Core Principal Investigator)
Robert A. Koeppe, Ph.D., University of Michigan
Norm Foster, M.D., University of Utah
Eric M. Reiman, M.D., Banner Alzheimer’s Institute
Kewei Chen, Ph.D., Banner Alzheimer’s Institute
Chet Mathis, M.D., University of Pittsburgh
Susan Landau, Ph.D., University of California, Berkeley
Neuropathology Core Leaders
John C. Morris, M.D., Washington University, St. Louis
Nigel J. Cairns, Ph.D., F.R.C.Path., Washington University, St. Louis
Erin Franklin, M.S., C.C.R.P., Washington University, St. Louis
Lisa Taylor-Reinwald, B.A., H.T.L., Washington University, St. Louis (ASCP) – Past Investigator
Biomarkers Core Leaders and Key Personnel
Leslie M. Shaw, Ph.D., University of Pennsylvania School of Medicine
John Q. Trojanowki, M.D., Ph.D., University of Pennsylvania School of Medicine
Virginia Lee, Ph.D., M.B.A., University of Pennsylvania School of Medicine
Magdalena Korecka, Ph.D., University of Pennsylvania School of Medicine
Michal Figurski, Ph.D., University of Pennsylvania School of Medicine
Informatics Core Leaders and Key Personnel
Arthur W. Toga, Ph.D., University of Southern California (Core Principal Investigator)
Karen Crawford, University of Southern California
Scott Neu, Ph.D., University of Southern California
Genetics Core Leaders and Key Personnel
Andrew J. Saykin, Psy.D., Indiana University
Tatiana M. Foroud, Ph.D., Indiana University
Steven Potkin, M.D., University of California, Irvine
Li Shen, Ph.D., Indiana University
Kelley Faber, M.S., C.C.R.C., Indiana University
Sungeun Kim, Ph.D., Indiana University
Kwangsik Nho, Ph.D., Indiana University
Initial Concept Planning and Development
Michael W. Weiner, M.D., University of California, San Francisco
Lean Thal, M.D., University of California, San Diego
Zaven Khachaturian, Ph.D., Prevent Alzheimer’s Disease 2020
Early Project Proposal Development
Leon Thal, M.D., University of California, San Diego
Neil Buckholtz, National Institute on Aging
Michael W. Weiner, M.D., University of California, San Francisco
Peter J. Snyder, Ph.D., Brown University
William Potter, M.D., National Institute of Mental Health
Steven Paul, M.D., Cornell University
Marilyn Albert, Ph.D., Johns Hopkins University
Richard Frank, M.D., Ph.D., Richard Frank Consulting
Zaven Khachaturian, Ph.D., Prevent Alzheimer’s Disease 2020
NIA
John Hsiao, M.D., National Institute on Aging
Part B: Investigators by Site
Oregon Health & Science University
Jeffrey Kaye, M.D.
Joseph Quinn, M.D.
Lisa Silbert, M.D.
Betty Lind, B.S.
Raina Carter, B.A. – Past Investigator
Sara Dolen, B.S. – Past Investigator
University of Southern California
Lon S. Schneider, M.D.
Sonia Pawluczyk, M.D.
Mauricio Becerra, B.S.
Liberty Teodoro, R.N.
Bryan M. Spann, D.O., Ph.D. – Past Investigator
University of California, San Diego
James Brewer, M.D., Ph.D.
Helen Vanderswag, R.N.
Adam Fleisher, M.D. – Past Investigator
University of Michigan
Judith L. Heidebrink, M.D., M.S.
Joanne L. Lord, L.P.N., B.A., C.C.R.C. – Past Investigator
Mayo Clinic, Rochester
Ronald Petersen, M.D., Ph.D.
Sara S. Mason, R.N.
Colleen S. Albers, R.N.
David Knopman, M.D.
Kris Johnson, R.N. – Past Investigator
Baylor College of Medicine
Rachelle S. Doody, M.D., Ph.D.
Javier Villanueva-Meyer, M.D.
Valory Pavlik, Ph.D.
Victoria Shibley, M.S.
Munir Chowdhury, M.B.B.S., M.S. – Past Investigator
Susan Rountree, M.D. – Past Investigator
Mimi Dang, M.D. – Past Investigator
Columbia University Medical Center
Yaakov Stern, Ph.D.
Lawrence S. Honig, M.D., Ph.D.
Karen L. Bell, M.D.
Washington University, St. Louis
Beau Ances, M.D.
John C. Morris, M.D.
Maria Carroll, R.N., M.S.N.
Mary L. Creech, R.N., M.S.W.
Erin Franklin, M.S., C.C.R.P.
Mark A. Mintun, M.D. – Past Investigator
Stacy Schneider, A.P.R.N., B.C., G.N.P. – Past Investigator
Angela Oliver, R.N., B.S.N., M.S.G. – Past Investigator
University of Alabama - Birmingham
Daniel Marson, J.D., Ph.D.
David Geldmacher, M.D.
Marissa Natelson Love, M.D.
Randall Griffith, Ph.D., A.B.P.P. – Past Investigator
David Clark, M.D. – Past Investigator
John Brockington, M.D. – Past Investigator
Erik Roberson, M.D. – Past Investigator
Mount Sinai School of Medicine
Hillel Grossman, M.D.
Effie Mitsis, Ph.D.
Rush University Medical Center
Raj C. Shah, M.D.
Leyla deToledo-Morrell, Ph.D. – Past Investigator
Wien Center
Ranjan Duara, M.D.
Maria T. Greig-Custo, M.D.
Warren Barker, M.A., M.S.
Johns Hopkins University
Marilyn Albert, Ph.D.
Chiadi Onyike, M.D.
Daniel D’Agostino II, B.S.
Stephanie Kielb, B.S. – Past Investigator
New York University
Martin Sadowski, M.D., Ph.D.
Mohammed O. Sheikh, M.D.
Anaztasia Ulysse
Mrunalini Gaikwad
Duke University Medical Center
P. Murali Doraiswamy, M.B.B.S., F.R.C.P.
Jeffrey R. Petrella, M.D.
Salvador Borges-Neto, M.D.
Terence Z. Wong, M.D. – Past Investigator
Edward Coleman – Past Investigator
University of Pennsylvania
Steven E. Arnold, M.D.
Jason H. Karlawish, M.D.
David A. Wolk, M.D.
Christopher M. Clark, M.D.
University of Kentucky
Charles D. Smith, M.D.
Greg Jicha, M.D.
Peter Hardy, Ph.D.
Partha Sinha, Ph.D.
Elizabeth Oates, M.D.
Gary Conrad, M.D.
University of Pittsburgh
Oscar L. Lopez, M.D.
MaryAnn Oakley, M.A.
Donna M. Simpson, C.R.N.P., M.P.H.
University of Rochester Medical Center
Anton P. Porsteinsson, M.D.
Bonnie S. Goldstein, M.S., N.P.
Kim Martin, R.N.
Kelly M. Makino, B.S. – Past Investigator
M. Saleem Ismail, M.D. – Past Investigator
Connie Brand, R.N. – Past Investigator
University of California, Irvine
Steven G. Potkin, M.D.
Adrian Preda, M.D.
Dana Nguyen, Ph.D.
University of Texas Southwestern Medical School
Kyle Womack, M.D.
Dana Mathews, M.D., Ph.D.
Mary Quiceno, M.D.
Emory University
Allan I. Levey, M.D., Ph.D.
James J. Lah, M.D., Ph.D.
Janet S. Cellar, D.N.P., P.M.H.C.N.S.-B.C.
University of Kansas, Medical Center
Jeffrey M. Burns, M.D.
Russell H. Swerdlow, M.D.
William M. Brooks, Ph.D.
University of California, Los Angeles
Liana Apostolova, M.D.
Kathleen Tingus, Ph.D.
Ellen Woo, Ph.D.
Daniel H.S. Silverman, M.D., Ph.D.
Po H. Lu, Psy.D. – Past Investigator
George Bartzokis, M.D. – Past Investigator
Mayo Clinic, Jacksonville
Neill R Graff-Radford, M.B.B.C.H., F.R.C.P. (London)
Francine Parfitt, M.S.H., C.C.R.C.
Kim Poki-Walker, B.A.
Indiana University
Martin R. Farlow, M.D.
Ann Marie Hake, M.D.
Brandy R. Matthews, M.D. – Past Investigator
Jared R. Brosch, M.D.
Scott Herring, R.N., C.C.R.C.
Yale University School of Medicine
Christopher H. van Dyck, M.D.
Richard E. Carson, Ph.D.
Martha G. MacAvoy, Ph.D.
Pradeep Varma, M.D.
McGill Univ., Montreal-Jewish General Hospital
Howard Chertkow, M.D.
Howard Bergman, M.D.
Chris Hosein, M.Ed.
Sunnybrook Health Sciences, Ontario
Sandra Black, M.D., F.R.C.P.C.
Bojana Stefanovic, Ph.D.
Curtis Caldwell, Ph.D.
UBC Clinic for AD & Related Disorders
Ging-Yuek
Robin Hsiung, M.D., M.H.Sc., F.R.C.P.C.
Benita Mudge, B.S.
Vesna Sossi, Ph.D.
Howard Feldman, M.D., F.R.C.P.C. – Past Investigator
Michele Assaly, M.A. – Past Investigator
Cognitive Neurology - St. Joseph’s, Ontario
Elizabeth Finger, M.D.
Stephen Pasternack, M.D., Ph.D.
Irina Rachisky, M.D.
Dick Trost, Ph.D. – Past Investigator
Andrew Kertesz, M.D. – Past Investigator
Cleveland Clinic Lou Ruvo Center for Brain Health
Charles Bernick, M.D., M.P.H.
Donna Munic, Ph.D.
Northwestern University
Marek-Marsel Mesulam, M.D.
Emily Rogalski, Ph.D.
Kristine Lipowski, M.A.
Sandra Weintraub, Ph.D.
Borna Bonakdarpour, M.D.
Diana Kerwin, M.D. – Past Investigator
Chuang-Kuo Wu, M.D., Ph.D. – Past Investigator
Nancy Johnson, Ph.D. – Past Investigator
Premiere Research Inst (Palm Beach Neurology)
Carl Sadowsky, M.D.
Teresa Villena, M.D.
Georgetown University Medical Center
Raymond Scott Turner, M.D., Ph.D.
Kathleen Johnson, N.P.
Brigid Reynolds, N.P.
Brigham and Women’s Hospital
Reisa A. Sperling, M.D.
Keith A. Johnson, M.D.
Gad Marshall, M.D.
Stanford University
Jerome Yesavage, M.D.
Joy L. Taylor, Ph.D.
Barton Lane, M.D.
Allyson Rosen, Ph.D. – Past Investigator
Jared Tinklenberg, M.D. – Past Investigator
Banner Sun Health Research Institute
Marwan N. Sabbagh, M.D.
Christine M. Belden, Psy.D.
Sandra A. Jacobson, M.D.
Sherye A. Sirrel, C.C.R.C.
Boston University
Neil Kowall, M.D.
Ronald Killiany, Ph.D.
Andrew E. Budson, M.D.
Alexander Norbash, M.D. – Past Investigator
Patricia Lynn Johnson, B.A. – Past Investigator
Howard University
Thomas O. Obisesan, M.D., M.P.H.
Saba Wolday, M.Sc.
Joanne Allard, Ph.D.
Case Western Reserve University
Alan Lerner, M.D.
Paula Ogrocki, Ph.D.
Curtis Tatsuoka, Ph.D.
Parianne Fatica, B.A., C.C.R.C.
University of California, Davis – Sacramento
Evan Fletcher, Ph.D.
Pauline Maillard, Ph.D.
John Olichney, M.D.
Charles DeCarli, M.D. – Past Investigator
Owen Carmichael, Ph.D. – Past Investigator
Neurological Care of CNY
Smita Kittur, M.D. – Past Investigator
Parkwood Hospital
Michael Borrie, M.B.Ch.B.
T-Y Lee, Ph.D.
Dr Rob Bartha, Ph.D.
University of Wisconsin
Sterling Johnson, Ph.D.
Sanjay Asthana, M.D.
Cynthia M. Carlsson, M.D., M.S.
University of California, Irvine - BIC
Steven G. Potkin, M.D.
Adrian Preda, M.D.
Dana Nguyen, Ph.D.
Banner Alzheimer’s Institute
Pierre Tariot, M.D.
Anna Burke, M.D.
Ann Marie Milliken, N.M.D.
Nadira Trncic, M.D., Ph.D., C.C.R.C. – Past Investigator
Adam Fleisher, M.D. – Past Investigator
Stephanie Reeder, B.A. – Past Investigator
Dent Neurologic Institute
Vernice Bates, M.D.
Horacio Capote, M.D.
Michelle Rainka, Pharm.D., C.C.R.P.
Ohio State University
Douglas W. Scharre, M.D.
Maria Kataki, M.D., Ph.D.
Brendan Kelley, M.D.
Albany Medical College
Earl A. Zimmerman, M.D.
Dzintra Celmins, M.D.
Alice D. Brown, F.N.P.
Hartford Hospital, Olin Neuropsychiatry Research Center
Godfrey D. Pearlson, M.D.
Karen Blank, M.D.
Karen Anderson, R.N.
Dartmouth-Hitchcock Medical Center
Laura A. Flashman, Ph.D.
Marc Seltzer, M.D.
Mary L. Hynes, R.N., M.P.H.
Robert B. Santulli, M.D. – Past Investigator
Wake Forest University Health Sciences
Kaycee M. Sink, M.D., M.A.S.
Leslie Gordineer
Jeff D. Williamson, M.D., M.H.S. – Past Investigator
Pradeep Garg, Ph.D. – Past Investigator
Franklin Watkins, M.D. – Past Investigator
Rhode Island Hospital
Brian R. Ott, M.D.
Geoffrey Tremont, Ph.D.
Lori A. Daiello, Pharm.D, Sc.M.
Butler Hospital
Stephen Salloway, M.D., M.S.
Paul Malloy, Ph.D.
Stephen Correia, Ph.D.
UC San Francisco
Howard J. Rosen, M.D.
Bruce L. Miller, M.D.
David Perry, M.D.
Medical University South Carolina
Jacobo Mintzer, M.D., M.B.A.
Kenneth Spicer, M.D., Ph.D.
David Bachman, M.D.
St. Joseph’s Health Care
Elizabeth Finger, M.D.
Stephen Pasternak, M.D.
Irina Rachinsky, M.D.
John Rogers, M.D.
Andrew Kertesz, M.D. – Past Investigator
Dick Drost, M.D. – Past Investigator
Nathan Kline Institute
Nunzio Pomara, M.D.
Raymundo Hernando, M.D.
Antero Sarrael, M.D.
University of Iowa College of Medicine
Susan K. Schultz, M.D.
Karen Ekstam Smith, R.N.
Hristina Koleva, M.D.
Ki Won Nam, M.D.
Hyungsub Shim, M.D.– Past Investigator
Cornell University
Norman Relkin, M.D., Ph.D.
Gloria Chiang, M.D.
Michael Lin, M.D.
Lisa Ravdin, Ph.D.
University of South Florida: USF Health Byrd Alzheimer’s Institute
Amanda Smith, M.D.
Balebail Ashok Raj, M.D.
Kristin Fargher, M.D.– Past Investigator
Department of Defense ADNI
Part A: Leadership and Infrastructure
Principal Investigator
Michael W. Weiner, M.D., University of California, San Francisco
ADCS Principal Investigator and Director of Coordinating Center Clinical Core
Paul Aisen, M.D., University of Southern California
Executive Committee
Michael Weiner, M.D., University of California, San Francisco
Paul Aisen, M.D., University of Southern California
Ronald Petersen, M.D., Ph.D., Mayo Clinic, Rochester
Robert C. Green, M.D., M.P.H., Brigham and Women’s Hospital/ Harvard Medical School
Danielle Harvey, Ph.D., University of California, Davis
Clifford R. Jack, Jr., M.D., Mayo Clinic, Rochester
William Jagust, M.D., University of California, Berkeley
John C. Morris, M.D., Washington University, St. Louis
Andrew J. Saykin, Psy.D., Indiana University
Leslie M. Shaw, Ph.D., Perelman School of Medicine, University of Pennsylvania
Arthur W. Toga, Ph.D., University of Southern California
John Q. Trojanowki, M.D., Ph.D., Perelman School of Medicine, University of Pennsylvania
Psychological Evaluation/Posttraumatic Stress Disorder Core
Thomas Neylan, M.D., University of California, San Francisco
Traumatic Brain Injury/TBI Core
Jordan Grafman, Ph.D.
Jordan Grafman, Ph.D., Rehabilitation Institute of Chicago, Feinberg School of Medicine, Northwestern University
Data and Publication Committee (DPC)
Robert C. Green, M.D., M.P.H., B.W.H./H.M.S. (Chair)
Resource Allocation Review Committee
Tom Montine, M.D., Ph.D., University of Washington (Chair)
Clinical Core Leaders
Michael Weiner, M.D., Core Principal Investigator
Ronald Petersen, M.D., Ph.D., Mayo Clinic, Rochester (Core Principal Investigator)
Paul Aisen, M.D., University of Southern California
Clinical Informatics and Operations
Ronald G. Thomas, Ph.D., University of California, San Diego
Michael Donohue, Ph.D., University of California, San Diego
Devon Gessert, University of California, San Diego
Tamie Sather, M.A., University of California, San Diego
Melissa Davis, University of California, San Diego
Rosemary Morrison, M.P.H., University of California, San Diego
Gus Jiminez, M.B.S., University of California, San Diego
Thomas Neylan, M.D., University of California, San Francisco
Jacqueline Hayes, University of California, San Francisco
Shannon Finely, University of California, San Francisco
Biostatistics Core Leaders and Key Personnel
Danielle Harvey, Ph.D., Neylan Davis (Core Principal Investigator)
Michael Donohue, Ph.D., Neylan San Diego
MRI Core Leaders and Key Personnel
Clifford R. Jack, Jr., M.D., Mayo Clinic, Rochester (Core Principal Investigator)
Matthew Bernstein, Ph.D., Mayo Clinic, Rochester
Bret Borowski, R.T., Mayo Clinic
Jeff Gunter, Ph.D., Mayo Clinic
Matt Senjem, M.S., Mayo Clinic
Kejal Kantarci, Mayo Clinic
Chad Ward, Mayo Clinic
PET Core Leaders and Key Personnel
William Jagust, M.D., Senjem Berkeley (Core Principal Investigator)
Robert A. Koeppe, Ph.D., University of Michigan
Norm Foster, M.D., University of Utah
Eric M. Reiman, M.D., Banner Alzheimer’s Institute
Kewei Chen, Ph.D., Banner Alzheimer’s Institute
Susan Landau, Ph.D., Senjem Berkeley
Neuropathology Core Leaders
John C. Morris, M.D., Washington University, St. Louis
Nigel J. Cairns, Ph.D., F.R.C.Path., Washington University, St. Louis
Erin Householder, M.S., Washington University, St. Louis
Biomarkers Core Leaders and Key Personnel
Leslie M. Shaw, Ph.D., Perelman School of Medicine, University of Pennsylvania
John Q. Trojanowki, M.D., Ph.D., Perelman School of Medicine, University of Pennsylvania
Virginia Lee, Ph.D., M.B.A., Perelman School of Medicine, University of Pennsylvania
Magdalena Korecka, Ph.D., Perelman School of Medicine, University of Pennsylvania
Michal Figurski, Ph.D., Perelman School of Medicine, University of Pennsylvania
Informatics Core Leaders and Key Personnel
Arthur W. Toga, Ph.D., University of Southern California (Core Principal Investigator)
Karen Crawford, University of Southern California
Scott Neu, Ph.D., University of Southern California
Genetics Core Leaders and Key Personnel
Andrew J. Saykin, Psy.D., Indiana University
Tatiana M. Foroud, Ph.D., Indiana University
Steven Potkin, M.D., University of California, Irvine
Li Shen, Ph.D., Indiana University
Kelley Faber, M.S., C.C.R.C., Indiana University
Sungeun Kim, Ph.D., Indiana University
Kwangsik Nho, Ph.D., Indiana University
Initial Concept Planning and Development
Michael W. Weiner, M.D., University of California, San Francisco
Karl Friedl, Department of Defense (retired)
Part B: Investigators by Site
University of Southern California
Lon S. Schneider, M.D., M.S.
Sonia Pawluczyk, M.D.
Mauricio Becerra
University of California, San Diego
James Brewer, M.D., Ph.D.
Helen Vanderswag, R.N.
Columbia University Medical Center
Yaakov Stern, Ph.D.
Lawrence S. Honig, M.D., Ph.D.
Karen L. Bell, M.D.
Rush University Medical Center
Debra Fleischman, Ph.D.
Konstantinos Arfanakis, Ph.D.
Raj C. Shah, M.D.
Wien Center
Ranjan Duara, M.D., Principal Investigator
Daniel Varon, M.D., Co-Principal Investigator
Maria T Greig, HP Coordinator
Duke University Medical Center
P. Murali Doraiswamy, M.B.B.S.
Jeffrey R. Petrella, M.D.
Olga James, M.D.
University of Rochester Medical Center
Anton P. Porsteinsson, M.D., Director
Bonnie Goldstein, M.S., N.P., Coordinator
Kimberly S. Martin, R.N.
University of California, Irvine
Steven G. Potkin, M.D.
Adrian Preda, M.D.
Dana Nguyen, Ph.D.
Medical University South Carolina
Jacobo Mintzer, M.D., M.B.A.
Dino Massoglia, M.D., Ph.D.
Olga Brawman-Mintzer, M.D.
Premiere Research Institute (Palm Beach Neurology)
Carl Sadowsky, M.D.
Walter Martinez, M.D.
Teresa Villena, M.D.
University of California, San Francisco
William Jagust, M.D.
Susan Landau, Ph.D.
Howard Rosen, M.D.
David Perry
Georgetown University Medical Center
Raymond Scott Turner, M.D., Ph.D.
Kelly Behan
Brigid Reynolds, N.P.
Brigham and Women’s Hospital
Reisa A. Sperling, M.D.
Keith A. Johnson, M.D.
Gad Marshall, M.D.
Banner Sun Health Research Institute
Marwan N. Sabbagh, M.D.
Sandra A. Jacobson, M.D.
Sherye A. Sirrel, M.S., C.C.R.C.
Howard University
Thomas O. Obisesan, M.D., M.P.H.
Saba Wolday, M.Sc.
Joanne Allard, Ph.D.
University of Wisconsin
Sterling C. Johnson, Ph.D.
J. Jay Fruehling, M.A.
Sandra Harding, M.S.
University of Washington
Elaine R. Peskind, M.D.
Eric C. Petrie, M.D., MS
Gail Li, M.D., Ph.D.
Stanford University
Jerome A. Yesavage, M.D.
Joy L. Taylor, Ph.D.
Ansgar J. Furst, Ph.D.
Steven Chao, M.D.
Cornell University
Norman Relkin, M.D., Ph.D.
Gloria Chiang, M.D.
Lisa Ravdin, Ph.D.
Appendix 2. Members of the Neurologic Outcome Research Group (NORG)
Director: Joseph P. Mathew, M.D., Co-Director: James A. Blumenthal, Ph.D.
Anesthesiology: Miles Berger, M.D., Ph.D., Jorn A. Karhausen, M.D., Miklos D. Kertai, M.D., Rebecca Y. Klinger, M.D., M.S., Yi-Ju Li, Ph.D., Joseph P. Mathew, M.D., Mark F. Newman, M.D, Mihai V. Podgoreanu, M.D., Mark Stafford-Smith, M.D., Madhav Swaminathan, M.D., Niccolo Terrando, Ph.D., David S. Warner, M.D., Bonita L. Funk, R.N., C.C.R.P., Narai Balajonda, M.D., Rachele Brassard, B.S.W., Tiffany Bisanar, R.N., B.S.N., Mary Cooter, M.S., Yanne Toulgoat-Dubois, B.A., Peter Waweru, C.C.R.P.
Behavioral Medicine: Michael A. Babyak, Ph.D., James A. Blumenthal, Ph.D., Jeffrey N. Browndyke, Ph.D., Kathleen A. Welsh-Bohmer, Ph.D.
Cardiology: Michael H. Sketch, Jr., M.D.
Neurology: Ellen R. Bennett, Ph.D., Carmelo Graffagnino, M.D., Daniel T. Laskowitz, M.D., Warren J. Strittmatter, M.D.
Perfusion Services: Kevin Collins, B.S., C.C.P., Greg Smigla, B.S., C.C.P., Ian Shearer, B.S., C.C.P.
Surgery: Thomas A. D’Amico, M.D., Mani A. Daneshmand, M.D., R. Jeffrey G. Gaca, M.D., Donald D. Glower, M.D., Jack Haney, M.D., R. David Harpole, M.D., Mathew G. Hartwig, M.D., G. Chad Hughes, M.D., Jacob A. Klapper, M.D., Shu S. Lin, M.D., Andrew J. Lodge, M.D., Carmelo A. Milano, M.D., Ryan P. Plichta, M.D., Jacob N. Schroeder, M.D., Peter K. Smith, M.D., Betty C. Tong, M.D.
Fig. 1.
Images of patients with normal (A) and abnormal (B) amyloid deposition by 18F-florbetapir positron emission tomography imaging. The brighter orange to yellow colors indicate greater amyloid deposition.
Images of patients with normal (A) and abnormal (B) amyloid deposition by 18F-florbetapir positron emission tomography imaging. The brighter orange to yellow colors indicate greater amyloid deposition.
Fig. 1.
Images of patients with normal (A) and abnormal (B) amyloid deposition by 18F-florbetapir positron emission tomography imaging. The brighter orange to yellow colors indicate greater amyloid deposition.
×
Fig. 2.
Box plots showing median (interquartile range) change in standard uptake value ratio relative to cerebellum (SUVr) in each imaged brain region from 6 weeks to 1 yr postoperatively. Positive values represent increase in SUVr, while negative values represent decrease in SUVr. N = 12.
Box plots showing median (interquartile range) change in standard uptake value ratio relative to cerebellum (SUVr) in each imaged brain region from 6 weeks to 1 yr postoperatively. Positive values represent increase in SUVr, while negative values represent decrease in SUVr. N = 12.
Fig. 2.
Box plots showing median (interquartile range) change in standard uptake value ratio relative to cerebellum (SUVr) in each imaged brain region from 6 weeks to 1 yr postoperatively. Positive values represent increase in SUVr, while negative values represent decrease in SUVr. N = 12.
×
Table 1.
Characteristics of the Cardiac Surgical Cohort
Characteristics of the Cardiac Surgical Cohort×
Characteristics of the Cardiac Surgical Cohort
Table 1.
Characteristics of the Cardiac Surgical Cohort
Characteristics of the Cardiac Surgical Cohort×
×
Table 2.
Global Cortical and Regional SUVr Values in Patients with and without Cognitive Deficit at 6 Weeks
Global Cortical and Regional SUVr Values in Patients with and without Cognitive Deficit at 6 Weeks×
Global Cortical and Regional SUVr Values in Patients with and without Cognitive Deficit at 6 Weeks
Table 2.
Global Cortical and Regional SUVr Values in Patients with and without Cognitive Deficit at 6 Weeks
Global Cortical and Regional SUVr Values in Patients with and without Cognitive Deficit at 6 Weeks×
×
Table 3.
Frequency of Abnormal Global Cortical and Regional Amyloid Deposition at 6 Weeks in Patients with and without Cognitive Deficit
Frequency of Abnormal Global Cortical and Regional Amyloid Deposition at 6 Weeks in Patients with and without Cognitive Deficit×
Frequency of Abnormal Global Cortical and Regional Amyloid Deposition at 6 Weeks in Patients with and without Cognitive Deficit
Table 3.
Frequency of Abnormal Global Cortical and Regional Amyloid Deposition at 6 Weeks in Patients with and without Cognitive Deficit
Frequency of Abnormal Global Cortical and Regional Amyloid Deposition at 6 Weeks in Patients with and without Cognitive Deficit×
×