Neuroinflammation in Obesity
Phase: NA
Conditions: Obesity
Sponsor: Washington University School of Medicine

 
Protocol  
Version 6: August 25, 2020 
 
 
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Neuroinflammation in Obesity 
 
 
 
Principal Investigator: Sarah Eisenstein 
Washington University 
660 Euclid Ave. 
Campus Box 8134 
St. Louis, MO 63110 
Phone: 314.362.7107  
E-mail: seisens@wustl.edu 
ClinicalTrials.gov NCT#: 04116229 
Document date: August 25, 2020 
 
 

 
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SCHEMA 
 
Title: Neuroinflammation in Obesity 
 
Total N = 20 (10 non-obese and 10 obese), nondiabetic male and female adults 
 
Screening 
 
Medical history 
 
Current psychiatric disorders as assessed by Structured Clinical Interview for DSM-IV1 
 
Current binge eating disorder as assessed by Binge Eating Scale2 
 
Inclusion criteria:  
 
Non-obese (BMI = 18 -25 kg/m2) or Obese (BMI ≥ 30 kg/m2) 
 
Age 18-75 years  
 
Any race or ethnicity 
 
Male or Female 
 
Native English Speaker 
 
Exclusion criteria:  
 
Current or past diabetes 
 
Psychotropic medications  
 
Previous or current neurologic illness including but not limited to stroke, seizure, 
generalized dystonia, parkinsonism 
 
History of or current drug abuse 
 
Current mental illness 
 
Binge eating disorder 
 
Non-native speaker of English 
 
MRI contraindications 
 
Pregnancy (confirmed with negative urine pregnancy test unless postmenopausal or 
surgically sterilized) 
 
Currently lactating 
 
Tobacco use within the past month 
 
>350 lb 
 
 
 
 
 

 
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Title: Neuroinflammation in Obesity 
 
 
TABLE OF CONTENTS 
 
 
Section 
 
 
 
 
 
 
 
 
 
Page 
 
 
 
 
SCHEMA 
 
 
 
 
 
 
 
2 
 
 
1.0 
 
BACKGROUND AND RATIONALE  
 
 
 
4 
                                  
            2.0 
 
OBJECTIVES  
 
 
 
 
 
 
4 
 
 
3.0 
 
METHODS 
 
 
 
 
 
 
 
4 
 
 
    
 
3.1. Research Subjects 
 
 
 
 
 
4 
 
3.2. Experimental Design 
 
 
 
 
 
5 
 
3.3. Statistical Analysis 
 
 
 
 
 
7 
 
                                 
 
4.0 
 
DATA SAFETY MONITORING 
 
 
 
 
7 
 
                                  4.1. Human Subjects Education Certification 
 
 
7 
  
                                  4.2. Procedures for Maintaining Confidentiality and                    8 
Data Security  
 
 
 
           4.3. Risks and Benefit 
 
 
 
 
 
8 
                                                                        
            5.0                   REFERENCES 
 
 
 
 
 
 
10 
 
 
 
 
 

 
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1.0 BACKGROUND AND RATIONALE 
 
 
More than a third of individuals in the United States are obese3. Obesity has recently 
been associated with increased risk for cognitive impairment and dementia such as Alzheimer’s 
disease (AD)4-10. In young and middle-aged people, higher BMI relates to diminished learning, 
memory, and executive function11-14. Cournot et al. found that higher BMI during middle age is 
associated with impaired delayed recall at baseline and at several years follow-up11. Long-term 
obesity (from age 25 through late midlife,mean age = 61 yrs) predicts lower Mini-Mental State 
Examination (MMSE) scores and impairments in memory and executive function in late midlife 
independent of age and education, according to the Whitehall II Cohort Study15. Although 
previous human studies have investigated structural and functional differences between obese 
and non-obese individuals, strong relationships between these differences and cognitive 
performance have not been found16. It is likely that a key specific component to obesity-related 
brain effects on cognition has yet to be studied. 
     Obesity is a disease characterized by chronic low-grade systemic inflammation17. We 
propose that neuroinflammation is a major mechanism by which young and mid-life 
overweight or obesity contributes to cognitive impairment. Reduced blood brain barrier integrity 
induced by chronic high fat diet is thought to be a major way in which pro-inflammatory 
elements cross over into the brain and induce neuroinflammation18.  Indeed, recent studies in 
rodents show that diet-induced obesity induces neuroinflammation19-23 accompanied by 
cognitive impairment19,23. However, only a few studies have addressed these questions in obese 
humans22,24.  
     The current proposal investigates whether indicators of neuroinflammation are present in 
obese humans and whether these indicators are associated with cognitive performance. We 
will use MR-based DBSI, an extension of diffusion weighted imaging (DWI) developed at 
Washington University School of Medicine (WUSM) by Dr. Sheng-Kwei Song that differentiates 
between axon/myelin integrity, axonal density, and extra-fiber components including 
inflammation and edema in white matter25. In addition, we will  use a complimentary MR-based 
multimodal approach that includes functional connectivity MRI (fcMRI) and quantitative gradient 
recalled echo (qGRE, GEPCI, SMART), which distinguishes neuronal, synaptic and glial 
components of the MR signal26.  
 
2.0   OBJECTIVES  
 
The objective of this proposal is to use MRI imaging to identify indicators of neuroinflammation in 
obese individuals. Further, greater neuroinflammation should correlate with greater cognitive 
impairment in obese individuals. 
 
Aim 1: To determine if obesity is associated with increased cellularity and glial levels in the 
brain using MR-based Diffusion Basis Spectrum Imaging (DBSI) and qGRE (GEPCI/SMART). 
Aim 2: To determine if indicators of neuroinflammation, including cellularity and glial levels are 
associated with cognitive performance in obesity. 
 
3.0 METHODS 
 
3.1.1  Research Subjects:  
 
We will study 10 non-obese and 10 obese adults, both male and female, who are non-diabetic, 
aged 18-75 years. 

 
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Inclusion criteria:  Non-obese (18-25 kg/m2) or obese (BMI ≥ 30 kg/m2), male or female, any race 
or ethnicity, aged 18-75 years.  
 
Exclusion criteria: Exclusion criteria include the following: history of diabetes, >350 lb (scanner 
weight limit), binge eating disorder, history of or current serious neurological illness, current 
mental illness, not a native speaker of English, history of drug abuse or currently taking 
psychotropic medication, MRI contraindications. Additionally, participants will be excluded if they 
are currently pregnant (positive urine pregnancy test) or breastfeeding. Finally, any participant 
with tobacco use in the past month will also be excluded.  
 
Sample size justification: We received funding to study 20 individuals. This is a pilot and 
feasibility study. 
 
3.1.2. Recruitment: 
 
We will call or email previous participants from a previous study of obesity (IRB#201104109; PI: 
Hershey). Subjects will be screened on a private line in a private suite using the phone script. 
They will be informed of the nature of the experiment and, if interested, will be questioned about 
inclusion and exclusion criteria. Those subjects meeting these criteria, and expressing further 
interest after this screening will be scheduled for study visits.  
 
We will also recruit through Volunteers for Health and make use of their services including 
Facebook, Centerwatch, and Twitter posts, and flyers (for email blasts and posting at various 
sites).  
 
Upon arrival into the laboratory for the first session, if the investigators are satisfied that the 
subject meets all of the inclusion and exclusion criteria, and the subject agrees to participate, the 
Human Research Protection Office (HRPO) approved informed consent will be signed.  
 
3.2. Experimental Design:  
 
3.2.1. Facilities.   
 
The MRIs will take place in a Siemens 3T scanner in the Center for Clinical Imaging Research 
(CCIR) at Barnes-Jewish Hospital or in the East Building at WUSM. Screening and cognitive 
testing will take place in a private testing room. Oral glucose tolerance tests (OGTTs) will take 
place at the Clinical Research Unit (CTRU) at WUSM.  
 
3.2.2. Overview of Procedures.  
 
Initially, potential subjects will be screened by a phone interview that assesses medical history. 
In addition, subjects will be screened for psychiatric disorders and Binge Eating Disorder using 
the SCID for DSM-IV1. If they remain eligible for the study, they will be emailed a link to a REDCap 
survey on binge eating habits (https://redcap.wustl.edu/redcap/surveys/?s=8WWXCWFLJR; 
adapted from the Binge Eating Scale2). If their score is below the threshold for binge eating, they 
will remain eligible for the study.  An informed consent document will be emailed to eligible 
volunteers. Obtainment of informed consent will occur via email prior to the on-site study visit day. 
The OGTT, 90 min MRI scan and cognitive testing will occur during one on-site study visit day.  

 
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3.2.3. Imaging Methods: 
  
 
3.2.3.2 MRI 
 
MRI-based scans will be performed in the Siemens 3T Prisma in the Center for Clinical Imaging 
Research (CCIR) at Barnes-Jewish Hospital or in the East Building at WUSM. Scans will be 
performed over 1.5 hr. 
 
High-resolution structural images will be acquired using a sagittal MP-RAGE 3D T1-weighted 
sequence (sagittal orientation, TR=2500 ms, TE=2.9 ms, TI=1070 ms, voxel res=1x1x1mm, 
frames=176, Flip=8, Time=6:09-8:42 min.) and T2-weighted anatomical images (sagittal 
orientation, TR=3200 ms, TE=564 ms, voxel res=1x1x1mm, frames=176, Flip=120, Time=4:42-
6:51 min). These structural images will be used for between-subject registration and anatomic 
localization.  
 
We will acquire a DWI sequence optimized for DBSI analyses with 2 echo planar sequences with 
a multiband factor of 3 and 102 volumes each, one with b-values ranging from 0-1500 and the 
other 0-3000 s/mm2 (transverse orientation, TR=3500 ms, TE=83 ms, voxel res=2x2x2 mm, 
Time=6:14 min).  
 
Three 6 min blood oxygenation level dependent (BOLD) functional MRI (fMRI) scans will be 
acquired for analyses of functional connectivity of networks at rest.  Sequence parameters: 64 
slices; transverse orientation; TR=1230 ms; TE=33 ms; FA=63 degrees; FOV=216 x 216; voxel 
resolution=2.4 x 2.4 x 2.4 mm. 
 
Gradient Echo Plural Contrast Imaging (GEPCI)/SMART. Used to quantify tissue alterations that 
reflect integrity of cellular brain structure. (1) GEPCI: TR=50 ms, 10 echo times equally spaced 
from 4-40ms, voxel res=1x1x2mm, FA=30 deg, Time=6:05 min. (2) SMART: TR=20 ms, TE 
1,2,3=3,7,11 ms, voxel res=1x1x2mm, Time=2:01 min x 5 variations of flip angle (5, 10, 20, 40, 
60 deg). This novel technique, which includes the more advanced GEPCI-based sequences 
qGRE and SMART, should provide quantitative in vivo high-resolution 3D measurements of 
several brain-tissue-specific relaxation properties (GEPCI metrics) of the gradient recalled echo 
(GRE) MRI signal. Since GEPCI metrics depend on the molecular constituents present in the 
brain, the GEPCI metrics can serve as surrogate markers of tissue alterations that reflect the 
integrity of brain cellular structure and disease-related tissue damage. These techniques are 
based on a standard Siemens GRE-based sequence and do not require contrast. 
 
3.2.4 Oral Glucose Tolerance Test (OGTT) 
 
For the OGTT patients will be admitted to the CTRU in the a.m. after at least 8 hours of fasting. 
An IV will be put in place for blood draws. Patient will be asked to drink 75 grams of glucola after 
drawing time 0’ sample of OGTT. Samples for blood glucose levels by glucose oxidase method 
and insulin levels and C- peptide by immulite will be measured at -5, 0, 10, 20, 30, 60 and 120 
min. Insulin secretion and sensitivity will be calculated from the OGTT glucose, insulin and C-
peptide levels using the homeostasis model assessment (HOMA), quantitative insulin sensitivity 
check index (QUICKI) and modeling of insulin secretion. Blood samples will be saved and sent 
to the Core Lab for Clinical Studies for measuring of peripheral immune function.  

 
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3.2.5 Hemoglobin A1c testing 
Approximately 2 tsp of blood will be drawn from your arm to conduct blood tests that 
include blood glucose levels and hemoglobin Alc 
 
3.2.6 Cognitive testing.  
  
Participants will be assessed for cognitive function using well-validated computer-based tests 
available from the NIH Toolbox27. Episodic memory28, executive function, and processing 
speed29 test scores are expected to be lower in obese relative to non-obese individuals. The 
testing should take approximately 30 min.   
 
3.2.7. Study Visit 
 
3.2.7.1 Anticipated duration of entire research activity per patient    
 
Participant involvement will last for approximately 6 hours over the span of 1-3 days including 
phone screening and electronic survey completion.  If there is a technical problem with the MR 
data collection, participants may be asked to repeat the MR session.  In this case, total 
participation would last up to 8 hours. Participants will be provided with lunch after the OGTT. 
 
3.3. Statistical Analysis:   
 
 
Aim 1: To determine if obesity is associated with increased cellularity and glial levels in 
the brain using MR-based Diffusion Basis Spectrum Imaging (DBSI) and qGRE 
(GEPCI/SMART).  We will use analyses of covariance (ANCOVA) to compare MRI-based 
metrics between obese and non-obese controlling for age, sex, gender, and insulin resistance . 
Aim 2: To determine if indicators of neuroinflammation, including cellularity and glial 
levels are associated with cognitive performance in obesity. We will use Pearson’s r 
correlational analyses to determine whether MRI metrics relate to impaired cognition in obesity.  
 
 
4.0. DATA SAFETY MONITORING 
 
 
These are not clinical trials as defined by NIH. The independent data and safety monitor 
is Dr. Ana Maria Arbelaez, M.D. She will monitor the study for unanticipated problems, life-
threatening events or deaths.  
 
 
The Data and Safety Monitoring Plan (DSMP) for this project includes monitoring any 
adverse events and reporting by Dr. Arbelaez and the PI for this protocol.  Dr. Arbelaez will 
meet quarterly with the PI and other study personnel to discuss the study. Any serious adverse 
events or other adverse events are reported to the Washington University’s Human Research 
Protection Office (HRPO) and to the Radioactive Drug Research Committee (RDRC). 
  
 
Serious adverse events (SAEs) will be reported to HRPO within 7 calendar days using 
the eIRB Notification System. In the case of an SAE, the study is not resumed until authorized 
by HRPO. Stopping criteria for an individual participant, in addition to the participant’s wish to 

 
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stop for any reason, include evidence of harmful side-effects of the research procedures. In the 
absence of adverse events, summary reports are provided annually to HRPO.  
 
4.1. Human Subjects Education Certification 
 
All key personnel involved in the design or conduct of research involving human subjects will 
receive the required education on the protection of human research participants prior to the 
performance of these studies. 
 
 
4.2. Procedures for Maintaining Confidentiality and Data Security 
 
All staff present will be HIPAA certified and essential to conduct the study.  Any potential 
observers for educational purposes will be allowed only at the discretion of the subject.  After 
consent, we will assure the subjects that no information regarding third parties will be asked or 
recorded.  We will collect information as described in the protocol but if subjects decide that they 
no longer want to participate, we will not collect any more information.  We will assure all 
subjects that their participation in this study will be held in the strictest of confidence. 
 
Paper data will be stored in a locked file drawer in the East Building, which is a secured 
building. All data will be de-identified utilizing a code number. The material obtained from the 
research participants is specifically for research purposes and will only be shared among the 
study team members.  Electronic data is stored in a private, firewall protected, password 
protected manner on a drive specified for research data.  All research data will only be available 
to members of the research team. 
 
Saliva obtained for genotyping purposes will not be saved. Blood obtained for OGTT and 
peripheral immune measures will not be saved after analyses are complete. 
 
The following privacy protections will be enacted for all e-mail communications involving PHI: 
1) a test e-mail will be sent to the participant to verify their identity (confirm correct recipient) and 
that this e-mail will be sent in a secure manner (i.e., [secure] in subject line); 
2) the body of the e-mail will instruct the participant to send all information as a response to this 
thread and to not remove the “[secure]” from the subject line; 
3) We will document in our research records the participant’s agreement to provide information 
over e-mail. 
 
4.3. Risks and Benefits 
 
We see no psychosocial, social or legal risks beyond those of participating in non-therapeutic 
research per se. The physical risks are those associated with intravenous lines (bruising and 
very low risk of infection), discomfort from lying flat (including lying flat for 1.5 hour for the MRI), 
and possible risk of claustrophobia.  All research carries some risk of loss of confidentiality. 
4.3.1. Likely Risks:  
There are no known physical risks to subjects receiving MRI scans who meet our inclusion and 
exclusion criteria.  
 
4.3.2. Less Likely Risks:  
 

 
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Risks of i.v. placement, including pain, bleeding, bruising, and infection. 
 
Participants may develop mild muscle aches and pains due to immobility and exposure to the 
acoustic noise of the MRI scanner. The development of muscle aches and pains is minimized 
by providing appropriate cushions at pressure points and beneath the knees as desired by the 
subject. Ear phones or earplugs will be used to dampen the sound of the MRI procedure. 
Participants may feel anxious when in the MR scanner. However, participants will be able to 
communicate with us throughout the scan and can tell us whenever they want the scan to be 
stopped or interrupted. Subjects may experience claustrophobia when placed in a MRI scanner. 
This can occur without a prior history or claustrophobia. 
 
The risk of having IVs placed and blood samples taken include soreness or slight bruising at the 
site of the blood draw.  Further risks of the OGTT are nausea and lightheadedness. 
 
The risks of performing cognitive testing include frustration when tasks are difficult and fatigue.   
 
4.3.3. Rare Risks:  
 
Loss of confidentiality. 
 
There is a potential risk of heart rhythm disturbances in individuals who have previous rhythm 
abnormalities or in patients with certain types of heart pacemakers. Because individuals with heart 
rhythm disturbances or pacemakers might be harmed by being in the MRI scanner, they should 
not participate in the study. There is a substantial risk to individuals who have metallic objects 
inside their bodies because the MRI scanner uses a high strength magnet. This risk involves the 
metallic objects being pulled by the magnetic field, which would cause physical harm. The 
following items may interfere with the MRI scans and some can potentially be hazardous: Cardiac 
pacemaker, aneurysm clip(s), implanted insulin/drug pump, neurostimulator (TENS unit), 
biostimulator/bone growth stimulator, hearing aid/cochlear implant, Gianturco coil (embolus coil), 
vascular clip(s), surgical clip or staple(s), heart valve prosthesis, Greenfield vena cava filter, 
middle ear implant, penile prosthesis, shrapnel or bullet, wire sutures, tattooed eye liner, any type 
of dental item held in place by a magnet, any other implanted item not mentioned, diaphragm/IUD, 
intraventricular shunt, wire mesh, artificial limb or joint, any orthopedic item (i.e., pins, rods, 
screws, nails, clips, plates, wire, etc.), dentures, dental braces, any type of removable dental 
items, or pregnancy. Participants complete an MR screening form to screen for these items and 
will not be consented if they meet any of the above rare risk factors. Thus, if participants have any 
of the above, they will be excluded from the study. 
 
 
 
4.3.4. Benefits: 
  
Direct benefits to the participating subjects are not anticipated. To the extent of societal benefit, it 
leads to a better understanding of the occurrence of neuroinflammation in obesity and whether it 
contributes to cognitive impairment in obesity. Given these potential benefits and our efforts to 
minimize risks, the risks of this study are reasonable in relation to the benefits. 
 
 

 
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5.0  REFERENCES 
 
1 
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8 
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20 
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21 
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22 
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23 
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24 
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25 
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26 
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27 
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28 
Cheke, L. G., Simons, J. S. & Clayton, N. S. Higher body mass index is associated with 
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29 
Ihle, A. et al. The Relation of Obesity to Performance in Verbal Abilities, Processing 
Speed, and Cognitive Flexibility in Old Age: The Role of Cognitive Reserve. Dement 
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