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

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.

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 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

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.

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.

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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.