FDDNP-PET Imaging in Persons at Risk for Chronic Traumatic Encephalopathy
Conditions: CTE, TBI (Traumatic Brain Injury)
Sponsor: University of California, Los Angeles

UCLA IRB# 11-001077 
PI: Gary W. Small, M.D.                                                                                     P a g e  | 1 
 
 
 
Study Protocol and Statistical Analysis Plan 
 
 
Study Title: FDDNP-PET Imaging in Persons at risk for Chronic Traumatic 
Encephalopathy 
 
PI: Gary W. Small M.D. 
NCT #:  
 
Date of Document: 05/17/2011  (original approval) 
                                 12/03/2018  (most recent approval) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

UCLA IRB# 11-001077 
PI: Gary W. Small, M.D.                                                                                     P a g e  | 2 
 
FDDNP-PET Imaging in Persons at risk for Chronic Traumatic Encephalopathy 
Protocol 
 
Specific Aims:  
The proposed project will focus on application of small molecule radiolabeled probes of 
tau neurofibrillary tangles (NFTs) for in vivo positron emission tomography (PET) 
imaging of brain pathology for early detection and treatment monitoring of Chronic 
Traumatic Encephalopathy (CTE) and related neurodegenerative diseases (dementias 
and cognitive impairment).  
 
We plan to test the following hypothesis: PET imaging with small molecule probes, in the 
form of novel fluorescent dyes with radioactive labels, will demonstrate distinct cerebral 
patterns of binding in subjects with CTE. These cerebral patterns will differentiate from 
those of age-matched persons who are cognitively intact or from the patients with other 
neurodegenerative diseases.  
 
The binding patterns will match the disease specific pattern of brain pathology 
characteristic for CTE (or other dementias, when studied). CTE distinguishes itself from 
other dementias by its clear tauopathy: NFTs and neuritic threads. In addition, brains of 
CTE subjects show white matter changes and inflammation. 
 
In order to assess in vivo deposition of CTE’s tauopathy, we propose to use PET 
imaging with [F-18]FDDNP, a molecular imaging probe for PET, with high in vitro binding 
affinity to NFTs and of the fibrillar tau deposits as shown with fluorescent microscopy 
with non-radioactive FDDNP. The analysis of [F-18]FDDNP will allow us to evaluate the 
specificity and sensitivity of this imaging probe for detection of the brain pathology and 
utilization of these methods for detection of early deposition and for monitoring of any 
therapeutic intervention aimed at stopping or reducing the deposition of neuropathologic 
aggregates. 
 
Simple blood-based biomarkers that correlate biochemical changes to clinical or 
cognitive status, when used in conjunction with genetic risk status, may increase the 
power of predicting who will decline in an asymptomatic population. An additional aspect 
of this protocol is to obtain blood based biomarker information to identify differences in 
markers of CTE sufferers. Better characterizing the relationship between various 
biochemical markers and disease status may allow us to improve our understanding of 
CTE causes, enhance our ability to diagnose early, and may lead to more effective 
treatments in the future. We propose investigating several blood-based biomarkers 
related to inflammation, (Interleukin (IL)-1, I-309, IL-6, IL-13, and superoxide dismutase 
3; SOD3) in diseased (clinical diagnosis of AD) and healthy APOE e3 and APOE e4 
carrying individuals to better characterize inflammation levels in these genetic groups. 
 
In addition to the above hypotheses, neuropathological data from autopsy follow-up will 
be used to determine correlations between regional plaque and tangle deposition 
patterns and PET signals. We will create PET cortical surface maps for [F-18]FDDNP-
PET between subjects with Traumatic Brain Injury and controls compared with region of 
interest analysis in transaxial PET images. MRI scans will be available for diffusion 
tensor imaging (DTI), and we will use these DTI measures to confirm our anticipated 
findings of greater white matter integrity in controls compared with AD patients.  
 

UCLA IRB# 11-001077 
PI: Gary W. Small, M.D.                                                                                     P a g e  | 3 
 
Background and Significance:  
Emerging evidence indicates that repetitive, mild traumatic brain injury (MTBI) may have 
long lasting effects following exposure during contact sports or military activities. As a 
result of the recent military conflicts, 95% of U.S. veterans have returned from the war 
returning from the war in Iraq and Afghanistan with head injuries resulting from non-
penetrating mechanisms.  
 
The syndrome of Chronic Traumatic Encephalopathy (CTE) has been established by 
WVU researchers in 25 contact-sport athletes, including one military veteran previously 
diagnosed as having Post Traumatic Stress Disorder. CTE was first diagnosed in 2005 
by the neuropathologist Bennet Omalu, M.D. (Raghupathi, Graham & McIntosh, 2000; 
Omalu et al. 2005; 2006). In addition, studies of retired NFL players have found a high 
incidence of dementia, Alzheimer’s disease, mild cognitive impairment, and depression 
in these patients. The only correlative risk factor was the presence of three or more 
significant concussions or MTBI’s during their NFL playing career (Guskiewicz et al., 
2005; 2007).  
 
Chronic Traumatic Encephalopathy consists of a characteristic neurobehavioral 
syndrome manifested by failed relationships, marriages, and businesses, emotional 
disturbances, depression, alcohol and substance abuse, and suicide attempts and 
completions. It typically begins after a latency period of several years following single or 
repeated Traumatic Brain Injuries (TBIs). A history of cerebral concussion may or may 
not be present. The clinical syndrome usually terminates in suicide (Bailes & Cantu, 
2001; Omalu et al., 2010; 2010b).  The neuroanatomical correlate consists of a 
tauopathy, the abnormal staining indicative of tau protein deposition in neuronal cell 
bodies and their axonal and dendritic connections. These representative changes of 
neurofibrillary tangles (NFTs) and neuritic threads (NTs) are characteristic of CTE, and 
distinguish it from other forms of dementia.  In addition, white matter changes and 
inflammation are also seen in these brain specimens (Omalu et al., 2010b).  
 
Chronic Traumatic Encephalopathy has a classical distribution that differs than other 
forms of dementia, and sub-typing based on location and distribution is reflected in the 
recent Omalu-Bailes classification (Omalu et al., 2010b).  The areas of involvement are 
the temporal and frontal cortices, in addition to the mesencephalon and upper pons, 
locus cereuleus, and substantia nigra. This distribution, along with the history of multiple 
exposures to MTBI, the age distribution, and anatomical patterns further distinguishes 
this condition from Alzheimer’s disease and other forms of dementia.  In addition, 70% of 
athletes diagnosed postmortem with CTE are positive for apolipoprotein A3 (Omalu et 
al., 2010b ).  
 
Currently, the only method to diagnose CTE is through post-mortem brain examination, 
utilizing special immuno-staining techniques for tau protein deposits in NFTs and NTs.  
The ability to image tau protein collections in vivo in the form of NFTs would provide 
tremendous benefit for clinical management, treatment, and possibly prevention if a pre-
morbid diagnosis could be confirmed.  The implications for the sports communities, 
military organizations, and the general population, all of whom have potential exposure 
to MTBI, are tremendous. 
 
UCLA scientists have developed the only currently available in vivo method to measure 
NFTs and of the fibrillar tau deposits in the brain. This discovery was led by Dr. Jorge 

UCLA IRB# 11-001077 
PI: Gary W. Small, M.D.                                                                                     P a g e  | 4 
 
Barrio (Molecular and Medical Pharmacology), Dr. Gary Small (UCLA Center on Aging, 
Aging and Memory Research Center at the Semel Institute at UCLA), and others, 
working in the UCLA PET scan program.  They sought a way to directly measure the 
physical evidence of Alzheimer’s disease – the abnormal amyloid brain protein deposits 
including amyloid plaques and tau NFTs– in the living patient.  A key to the discovery 
was the realization that the internal environments of these abnormal proteins were 
hydrophobic, that is, less friendly to water than to fat.  Dr. Jorge Barrio synthesized a 
new group of compounds that thrived in these hydrophobic environments, and these 
molecules passed easily from the blood stream to brain tissues.  
 
In initial autopsy studies, the UCLA group found that one of these new compounds 
(called FDDNP – UCLA Patent Ref. No. 1998-507-1) clearly displayed the well-defined 
amyloid proteins characteristic of the disease.  They then injected a radioactive form of 
the compound into the veins of living Alzheimer’s patients, and the PET scan accurately 
measured the concentration of the compound in the patient’s brain.  This allowed them 
to see for the first time, increased signals coming from living human brains in areas that 
contained dense collections of the abnormal proteins.  . 
 
The chemical marker essentially seeks out and temporarily attaches itself to the 
abnormal amyloid, thus providing a clear PET scan signal in the areas of the brain where 
Alzheimer’s strikes.  In healthy people without Alzheimer’s, these brain regions produce 
little or no signal.  However, in people with the disease, the signal is so strong and 
accurate that it actually correlates with each individual’s degree of memory impairment.  
The UCLA group has also found that people who are at risk for Alzheimer’s disease 
(mild cognitive impairment) have an amyloid-PET pattern intermediate between normal 
people and patients with Alzheimer’s and that [F-18]FDDNP binding is influenced by 
APOE-4 status (Small et al., 2009; 2010).  Therefore, this technology will likely assist in 
early detection of the disease so that prevention treatments might be used prior to 
significant cognitive decline.  It will also be useful in detecting and developing treatments 
for other conditions.  Patients with dementias that have different treatment approaches 
(e.g., frontotemporal) have an [F-18]FDDNP-PET pattern distinct from Alzheimer’s, as 
do patients with cognitive impairment associated with prion disease(Kepe et al., 2010). 
 
Research Design and Methods:  
Subjects in all portions of the study will have the procedures outlined below.  
The following procedures are performed solely for research purposes. 
Potential subjects will be recruited from a variety of sources including: 
1. Referrals from our co-investigators, and other colleagues; 
2. Referral from previously enrolled research subjects; 
3. Self-referral from word of mouth in the community or from media 
surrounding our pilot study (Small et al., 2013); 
4. Referrals from healthcare providers, the NFL Network, NFL Player’s 
Association and other sports associations and leagues. 
5. Referrals from TauMark, licensee of the FDDNP tracer.  
 
Potential participants will be screened via telephone by a staff member to determine 
eligibility. Subjects who meet eligibility criteria will be enrolled. Oral consent will be 
required to perform the telephone screen.  

UCLA IRB# 11-001077 
PI: Gary W. Small, M.D.                                                                                     P a g e  | 5 
 
Study Procedures 
A. Screening and Clinical Evaluation (1 hr) 
B. Informed Consent (30 min) 
C. Routine Laboratory Blood Draw, DNA Blood Sample and EKG (1 hr) 
D. [F-18]FDDNP-PET/CT scan (1 hr) 
E. Neuropsychological Evaluation (3 hrs) 
F. MRI or Computed Tomography (CT) Scan (1 hr)  
a. Only subjects who are not eligible for MRI scans will undergo CT 
scanning. 
 
A. Screening and Clinical Evaluation: The screening and evaluation are performed in 
a private office on the UCLA medical campus. The medical evaluation includes a 
psychosocial history and medical record review by one of the study physicians, as well 
as a neuropsychiatric evaluation. If there is doubt that a player’s diagnosis is consistent 
with CTE, one of the study neurologists will provide a second opinion and conduct a 
neurological evaluation. Other measures recorded are as follows: 
 
1. Hachinski Ischemic Scale - completed by physician  
2. Clinical Dementia Rating Scale - completed by physician 
3. Blessed Dementia Scale - completed by SRA under physician’s supervision 
4. Cornell Scale for Depression in Dementia - completed by SRA under physician’s 
supervision 
5. Katz Scale - completed by SRA under physician’s supervision 
6. Family History Questionnaire - completed by SRA 
7. Framingham Stroke Risk Factor Prediction Chart - completed by SRA 
8. STOP-BANG Questionnaire for Sleep Apnea - completed by SRA 
9. Pittsburg Sleep Quality Index - completed by SRA 
  
B. Informed Consent:  
 
If the potential subject meets inclusion criteria following screening and clinical 
evaluation, the subject will be consented and enrolled into the study.  
 
Autopsy Consent: 
Patients seen as part of the study may choose (or their families may choose for them) to 
sign UCLA form #30903 (rev 5/07), “UCLA Healthcare Report of Death and Permission 
for Postmortem Examination” authorizing a clinical autopsy to be conducted at UCLA. 
The autopsy program is administered through the UCLA Decedent Affairs office.  
 
C. Laboratory Assessment (Blood Draw): Subjects are taken to the Clinical and 
Translational Research Center (CTRC) or to the Clinical Translational Research 
Laboratory (CTRL) for routine lab work and collection of a DNA blood sample. Subjects 
must be fasting 8-9 hours priori to the labs, for accuracy on the cholesterol lab test. The 
following tests are performed: 
1. CBC & PLT & DIFF 
2. Free T4 Index 
3. Vitamin B12 Serum  
4. Chem Panel  
5. Uric Acid  
6. TSH  
7. Cholesterol  

UCLA IRB# 11-001077 
PI: Gary W. Small, M.D.                                                                                     P a g e  | 6 
 
8. RPR with FTA Confirmation 
9. Blood collection for DNA Analysis 
10. Vital Signs, Height and Weight, and an Electrocardiogram 
 
D. [F-18]FDDNP-PET Scan or PET/CT Scan: Subjects will undergo the [F-18]FDDNP-
PET/CT scan at the UCLA Nuclear Medicine Clinic, the Ronald Reagan Medical Center 
Neurosurgery Center (6th Floor), or the UCLA Brain Mapping Center. While in the 
scanner in a dimmed room, all subjects receive a 10 mCi intravenous injection of F-
18]FDDNP. During the scanning, each subject is asked to lie still. The procedure will 
take 1 hour of the subject's time. 
 
Scanning is performed on a CTI/Siemens 831-08 tomograph (Siemens Corp, Hoffman 
Estates, 111) in three-dimensional acquisition mode (inter-plane septa removed), using 
double the previous standard axial sampling (Cherry et al, 1991, 1992). Imaging 
commences immediately after administration of the radiolabeled dye and lasts for 65 
minutes, with > 2 million counts per plane.  
 
Female subjects of child-bearing age will be required to provide a urine sample prior to 
undergoing the FDDNP PET scan. The urine pregnancy test will be done at the Nuclear 
Medicine Clinic, the Ronald Reagan Medical Center Neurosurgery Center (6th Floor), or 
the UCLA Brain Mapping Center. Pregnant women will be withdrawn from the study.  
 
E. Neuropsychological Evaluation: The neuropsychological test battery includes: 
 
A. INTERVIEW 
B. MOOD SCREENING 
 
Hamilton Rating Scale Depression (17 item)  
 
Hamilton Anxiety Scale  
 
Suicide Behavior Questionnaire - Revised  
 
Pfeffer Functional Activities Questionnaire (FAQ)  
 
Geriatric Depression Scale (GDS)  
 
Mini-mental Status Exam (MMSE) (10 min) 
C. NEUROPSYCHOLOGICAL MEASURES 
 
Test of Premorbid Functioning (i.e. revised version of Wechsler Test of Adult 
Reading)  
 
WAIS-IV Digit Span 
 
Boston Naming Test 
 
WMS-IV Logical Memory—Immediate 
 
WAIS-IV Block Design 
 
Benton Facial Recognition Test (short form)  
 
WAIS-IV Similarities 
 
Buschke Selective Reminding Test 
 
Trails A 
 
Trails B  
 
Rey-Osterrieth Complex Figure Test 
 
Verbal Fluency—CFL  or FAS (4 min) 
 
Animal Naming (2 min) 
 
Baron-Cohen Emotional Recognition Tests 
 
Advanced Clinical solutions Social Perception Subtests 

UCLA IRB# 11-001077 
PI: Gary W. Small, M.D.                                                                                     P a g e  | 7 
 
 
Malingering test: Nonverbal Medical Symptom Validity Test  
 
Patients are tested in a private office. Healthy and motivated subjects can generally 
complete the battery in a three-hour period, including time for periodic rest breaks. 
 
F. MRI Scan or CT Scan:  
A 3 Tesla Siemens Trio with a 12 channel receive head array will be used. 2-fold parallel 
acceleration will be used for all image acquisitions. Specific image acquisitions will be as 
follows:  
 
3-D T1-weighted Anatomic Imaging (8 min):  MP-RAGE imaging will be obtained at a 
spatial resolution of 1x1x1 mm3 using ADNI compliant image acquisition parameters. 
 
DTI (14 min):  High angular resolution diffusion imaging (HARDI) will be obtained using a 
vendor supplied single-shot spin-echo echo-planar imaging (SE-EPI) pulse sequence 
that incorporates a twice-refocused spin echo acquisition to reduce eddy current induced 
spatial distortions.  Sixty-four diffusion weighted image (DWI) volumes will be collected 
using a b-factor of 1000 sec mm-2 and uniform directional sampling. Ten image volumes 
will be collected with a near zero b-factor with all other acquisition parameters held 
identical to those used for the b = 1000 DWIs. Each 3D DWI volume will consist of 75 
contiguous 2-mm thick axial slices having 2.0 x 2.0 mm2 in-plane resolution. 
 
SWI (5 min): Susceptibility Weighted Imaging will be performed using the vendor 
supplied pulse sequence (gradient recalled echo imaging with TR/TE/FA = 30/20/15, 1.0 
x 1.0 x 2.0 mm3 spatial resolution). 
 
FLAIR (4 min): Fluid attenuated inversion recovery imaging will be performed using a 
vendor supplied turbo spin-echo pulse sequence with TR/TE/TI = 9000/80/2500 and 
spatial resolution = 1.0 x 1.0 x 2.0 mm3. 
 
Image Quality Review: FLAIR images will be reviewed for incidental findings such as 
mass lesions or brain infection that are unrelated to the study goals. Subjects showing 
such findings will be replaced by new recruitments. All other images will be reviewed for 
incidental findings and/or artifacts, such as head motion during the DTI image 
acquisition. If artifacts are present, the subject will be invited to return for a replacement 
study or be replaced by a new recruitment. 
 
Image Preprocessing: For each set of individual subject images the following procedures 
will be performed. MP-RAGE images will be intensity-normalized, skull stripped and 
segmented for tissue type (GM, WM, CSF and background (BG)) using standard 
automated procedures (e.g. FSL, SPM, MIPAV software). Any head injury related white 
matter lesions (i.e. DAI, microhemorrhage etc) that are misassigned by the segmentation 
procedure will be manually corrected. FDDNP labeled GM regions are sometimes also 
mislabeled by automatic segmentation programs. These segmentation errors will also be 
checked for and manually corrected if necessary. MP-RAGE, FLAIR, and SWI image 
volumes will be aligned to the DTI image volumes by reading spatial parameters stored 
in the DICOM headers for each image type and then calculating and applying the 
optimal re-alignment matrix that will align these images with the DTI-related images. 
Alignments done in this way are very accurate but can be adversely affected by scan 
subject movement. If evidence of movement is present, hard body intensity-based 

UCLA IRB# 11-001077 
PI: Gary W. Small, M.D.                                                                                     P a g e  | 8 
 
alignment will be used to correct the alignment. FDDNP images will be aligned to the 
skull stripped MP-RAGE intensity images using hard body intensity-based alignment 
after spatial rescale to match voxel size. Then FDDNP images will then be aligned to the 
DTI space using the same realignment matrix that is used for the MP-RAGE images. 
Tissue segment images will be aligned to the DTI space using this same procedure 
(e.g., Fig. 1 shows alignment of DTI and FDDNP images). This approach to within-study 
alignment reduces the possibility of alignment errors that result from EPI-related surface 
distortions in the DTI images and makes optimal use of the DTI resolution. Eddy current 
distortions will be corrected for each DWI and B0 image individually using software that 
corrects for distortion in the phase encode direction only. Principal diffusivities (λ1, λ2, λ3 
(eigenvalues)), mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD), fiber 
orientation (eigenvector) images, and fractional anisotropy (FA) images will be computed 
using the standard approach (Basser, 1995). Automated streamline tractography will 
then be used to identify all detectable WM tracts (DTIStudio or FSL software). This 
process will result in the following aligned 3D images for each subject: MP-RAGE 
intensity, GM, WM, CSF, FDDNP, SWI magnitude, SWI phase, FLAIR, λ1, λ2, λ3, MD, 
FA, and an array of Streamline Tract (ST) images.  
 
 
 
 
 
 
 
 
 
 
Fig. 1. Example of alignment of FDDNP 
and DTI images on a patient with MCI 
with basal ganglia and thalamus FDDNP 
labeling. The top panel shows 8 slices 
from a 3D FDDNP image volume that 
has been aligned to the DTI target 
space.  The bottom panel shows the DTI 
color map data for this subject overlaid 
onto the same FDDNP images. 
 
 
Location of scanner and procedure for research subjects: 
Subjects will undergo a structural/functional scans using the 3-Tesla MRI scanner in the 
Staglin IMHRO Center for Cognitive Neuroscience at UCLA. Alternatively, subjects may 
undergo scanning at the UCLA Department of Radiology or at the UCLA Brain Mapping 
Center, using a 1.5 or 3 Tesla MRI scanner. Subject will lie on a narrow bed in a closed 
screened room. The sound of the MRI scanner can be loud and special earplugs will be 
given to subjects to minimize the noise. During the MRI, subjects may be asked to 
perform sensory, mental or movement tasks. Subjects will need to remain motionless for 
periods of up to 30 minutes (although most procedures will be much shorter). The MRI 
scan will take approximately one hour. 
 

UCLA IRB# 11-001077 
PI: Gary W. Small, M.D.                                                                                     P a g e  | 9 
 
Subjects who cannot undergo MRI scanning will undergo one Diagnostic Brain 
Computed Tomography scan in the UCLA Department of Nuclear Medicine or the 
Department Radiology. 
 
G. Benzodiazepine Medication for Anxiety 
Subjects who anticipate becoming anxious or claustrophobic during brain imaging 
procedures may request benzodiazepine medication during the PET/CT, MRI and CT 
scans. One of the study physicians will evaluate requests individually and if warranted, 
prescribe one of the following medications:    
 
Alprazolam 0.5-2 mg 
 
Lorazepam 0.5-4 mg 
 
Clonazepam 0.25-2 mg 
 
Diazepam 5-20 mg 
  
Data Analysis of Records from Database IRB# 12-001391 
Research records from control subjects will be retrieved from the Longevity Center 
Research Database and compared to TBI participants’ research records.  
 
Data is stored in an MS Access table-based relational database, which resides 
on a 64-bit SSL encrypted server to provide security for transmission of any 
sensitive or confidential data. The computerized database will be protected 
through the use of entry codes available only to authorized personnel. An 
identification (ID) number is assigned to each subject; only the ID numbers and 
not subjects' names are used in data files. The key that matches the participant 
names and ID numbers remains in a file cabinet accessible only to authorized 
personnel. Subjects' identities are not disclosed by publication or any other 
means. Comparison subjects will be identified only through their subject ID. Data 
used in this study will not contain comparison subjects’ identifying information 
other than age.  
 
Between-group analyses have been described in section 6.0 “Statistics and Data 
Analysis.” 
 
Data Collection and Analysis 
Time required of subjects, per visit or contact, and in total for the study: 
The study duration is 4-6 weeks. The total time per subject will not exceed twelve hours. 
 
Statistics and Data Analysis:  
The study examines FDDNP binding signals at baseline in persons with a history of 
Traumatic Brain Injury with and without signs of cognitive and mood changes congruent 
with Chronic Traumatic Encephalopathy (CTE) presentation. We expect to show greater 
FDDNP binding in the regions of interest with age-matched controls. Data for age-
matched controls will be obtained through previously collected data from Database IRB# 
12-00391. The study’s hypotheses will be examined by using nonparametric Wilcoxon 
tests, with global, frontal and medial temporal FDDNP signals as the dependent 
variables and group (CTE vs. control) as the classification variable.  We will also 
estimate regression models within the CTE group and examine whether more impaired 
neurocognitive performance is associated with greater FDDNP binding signals, 
especially in the medial temporal region. Again, rank-based analyses will be conducted 

UCLA IRB# 11-001077 
PI: Gary W. Small, M.D.                                                                                     P a g e  | 10 
 
due to the small sample size. Data will also be compared to neuropathological data 
obtained at autopsy.  
Inclusion and Exclusion Criteria 
Inclusion Criteria: 
1. Agreement to participate in study  
2. A history of Traumatic Brain Injury resulting from, but not limited to, any of 
the following: sports, accidents, violence, and military combat.  
3. Age 18 or older 
4. No significant cerebrovascular disease – modified Ischemic Score of ≤ 8 
(Rosen et al, 1980) 
5. Adequate visual and auditory acuity to allow neuropsychological testing. 
 
Exclusion Criteria: 
1. Preexisting major neurologic or other physical illness that could confound 
results (e.g., multiple sclerosis, diabetes, cancer)  
2. Unstable cardiac disease 
3. Uncontrolled hypertension (systolic BP > 170 or diastolic BP > 100) 
4. Current major psychiatric disorders such as mania or schizophrenia, 
which might interfere with completing study procedures (APA, 2000) 
5. Subjects taking ibuprofen or naproxen will be asked to stop taking the 
medication for five days before the PET scan since these medicines may 
affect FDDNP-PET scan results.  Other anti-inflammatory medicines, 
such as diclofenac or aspirin, can be substituted during that period. If the 
subject cannot temporarily discontinue the medicine, that subject will be 
excluded from the study. 
6. Use of any investigational drugs within the previous month or longer 
(depending on drug half-life)  
7. Pregnant and nursing subjects will be excluded. 
 
 
POTENTIAL RISKS AND DISCOMFORTS (as described to subjects) 
1. SCREENING  
You may feel uncomfortable answering some of the screening questions.  You do not 
have to answer any questions you do not wish to answer and you may stop at any time. 
Your participation in the screening is voluntary. A decision whether or not to participate 
in the screening will not affect your relationship with UCLA. You will not directly benefit 
from the screening.  
Your answers will be confidential. No one will know the answers except for the research 
team.  If you decide to answer the questions of the screening interview, it will determine 
your eligibility for the research.  If you qualify for the study, you will be asked to read 
through and sign an informed consent. Your answers will be kept with your other 
research generated records.  If you do not qualify for the study, your answers will be 
destroyed.  
2. BLOOD DRAW FOR ROUTINE BLOOD ANALYSIS AND DNA SAMPLE 
The risks include problems associated with blood drawing. This is a routine procedure 
performed under standard and sterile medical conditions. The potential side effects of 

UCLA IRB# 11-001077 
PI: Gary W. Small, M.D.                                                                                     P a g e  | 11 
 
removing blood may include momentary discomfort during the puncture, 
lightheadedness, faintness, and soreness and discoloration of the area for several days. 
In very rare instances, either bleeding or infection can develop at the venipuncture site. 
There is no more discomfort encountered than when blood samples are taken during 
periodic medical examinations or when blood is donated at a blood bank. 
 
3. BLOOD DRAW FOR GENETIC ANALYSIS 
The data collected for genetic analysis will not be kept in your medical record and will 
remain strictly confidential. The potential side effects of genetic analysis of blood may, 
however, involve certain psychological and social risks in the advent of inadvertent 
disclosure. These risks include:  
a. Broad sharing of phenotype and genomic data (e.g. genotype, DNA sequence, 
expression profiles, etc.); 
b. Computer security breaches; 
c. Other unanticipated distributions arising from maintaining data in an electronic 
format; 
d. Privacy breaches (both those known and those unforeseen at this time); 
e. Uncertainty of findings related to genetic risk for a given disease or trait; 
f. Risks to relatives or identifiable populations or groups; 
g. Physical risks (such as those associated with collecting blood or other tissues 
samples). 
 
Effective November 2009, federal legislation (The Genetic Information Nondiscrimination 
Act, or GINA) was passed to provide baseline protection against discrimination in 
employment and health insurances decisions across the nation.  
 
4. NEUROPSYCHOLOGICAL EVALUATION 
You may experience feelings of failure, frustration, or anxiety induced by 
neuropsychological testing.  The psychologist administering the tests is experienced in 
assessing persons and will convey a relaxed and confident attitude. You have the right 
to refuse to answer any questions that you may not wish to answer. If you do have the 
above reaction to the evaluation, it should go away at the completion of the test.  If you 
finish the test and feel anxious, then you can talk to the psychologist who administered 
the test.   
In the event that you tell the research staff that you are thinking about killing yourself or 
you answer yes to a question about having thoughts about suicide, the investigator will 
ask you more questions about these thoughts.  Depending on your answers to these 
questions, the research staff may: 
a. Provide you with referrals for treatment; 
b. Work with you to contact your personal physician, trusted family member, or 
therapist to discuss your thoughts of harming yourself; 
c. Work with you on a plan that may include getting you to a hospital for safety. 
 
5. PET/CT SCAN and CT SCAN SRADIATION EXPOSURE   
You are exposed to radiation on a daily basis, both from natural (sun and earth) and 
manmade sources. The estimated radiation dose that you will receive as a volunteer for 
this type of research has been compared to the limits allowed for a radiation worker. This 

UCLA IRB# 11-001077 
PI: Gary W. Small, M.D.                                                                                     P a g e  | 12 
 
limit is low and is not expected to be harmful. The person obtaining your consent can 
answer any questions you have, and provide detailed written information about the 
amount of radiation resulting from this study. 
 
PARTICIPATING IN OTHER RESEARCH STUDIES INVOLVING RADIATION: 
If within one year, you have participated, are participating, or are considering 
participating in another research study that involves radiation (PET scan, SPEC scan, 
DEXA scan, CT scan, radiation therapy, chemotherapy, etc.), please let a member of the 
research personnel know immediately.  
Research personnel may ask you to sign a medical release form to access your medical 
history in order to determine whether it is safe for you to partake in the study. The 
investigator/or associates will ensure through accurate record keeping, that the total 
amount of radioactivity administered for research purposes will remain small and is not 
expected to cause any adverse effects.  
Estimated Radiation Doses for One FDDNP-PET/CT Scan: 
If the PET/CT scan is performed, the total estimated radiation dose to the whole body 
would be 153 millirem, or 3% of the 5,000 millirem annual whole body limit allowed adult 
radiation workers. The total estimated radiation dose to the primary critical organ 
(gallbladder) would be 544 millirem, or 1% of the 50,000 millirem annual limit radiation 
workers. The total estimated radiation dose to the secondary critical organ (liver) would 
be 497 millirem, or 1% of the 50,000 millirem annual limit allowed radiation workers. 
 
Estimated Radiation Dose for One Helical CT Scan of the Head: 
If the CT scan is performed, the total estimated radiation dose to the whole body would 
be 220 millirem, or 4% of the 5,000 millirem annual whole body limit allowed adult 
radiation workers. 
 
6. MAGNETIC RESONANCE IMAGING (MRI)  
You may experience anxiety and/or claustrophobia from being in an enclosed space. 
You can ask to be taken out of the scanner at any time. Earplugs will be given during the 
MRI procedure. 
The magnetism of the machine attracts certain metals; therefore, people with these 
metals within their bodies (such as pacemakers, infusion pumps, aneurysm clips, metal 
prostheses, joints, rods, or plates) will be excluded from the study. The “metal” in dental 
fillings is less responsive to magnetism and is therefore allowed. The MRI technician will 
ask you if you have any metals within your body. You will be expected to notify the 
investigator conducting the study of any metal in your body, other than dental 
fillings.  
There are no other known side effects resulting from exposure to the MRI scan. 
However, there may be risks that are currently unforeseeable. In the studies performed 
so far, there have been no significant risks reported in animals or humans for similar 
exposures. 
7. BENZODIAZEPINE MEDICATION FOR ANXIETY (This section may not apply to 
you) 

UCLA IRB# 11-001077 
PI: Gary W. Small, M.D.                                                                                     P a g e  | 13 
 
Benzodiazepines in general tend to be very well tolerated. Some common side effects 
include temporary drowsiness, dizziness and increased saliva production. The doctor will 
make sure to go over your medical history to make sure that this medication is safe for 
you.  
This study may include unforeseen risks. 

UCLA IRB# 11-001077 
PI: Gary W. Small, M.D.                                                                                     P a g e  | 14 
 
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PI: Gary W. Small, M.D.                                                                                     P a g e  | 15 
 
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PI: Gary W. Small, M.D.                                                                                     P a g e  | 16 
 
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PI: Gary W. Small, M.D.                                                                                     P a g e  | 19 
 
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PI: Gary W. Small, M.D.                                                                                     P a g e  | 20 
 
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PI: Gary W. Small, M.D.                                                                                     P a g e  | 21 
 
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PI: Gary W. Small, M.D.                                                                                     P a g e  | 22 
 
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PI: Gary W. Small, M.D.                                                                                     P a g e  | 23 
 
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PI: Gary W. Small, M.D.                                                                                     P a g e  | 26 
 
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