Clinical trial NCT03958630
Conditions: Dementia
Keywords: Fronto Temporal Dementia Amyloid Neuroinflammation
Sponsor: National Institute of Mental Health (NIMH)
Start date: 2019-07-03; Completion date: 2023-12-04
Enrollment: 13 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Background:

Aging-related progressive neurological disorders include frontotemporal dementia, Lou Gehrig s disease, and Alzheimer s disease. Little is known about what causes these disorders. Brain inflammation may be involved. Researchers want to see if scans using radioactive drugs can show brain inflammation.

Objective:

To see if the drug \[11C\]ER176 can show inflammation in the brain in people with certain progressive neurological disorders compared to healthy adults. Also to find genes that might be associated with or cause these disorders.

Eligibility:

People ages 18 and older with an aging-related neurological disorder, and healthy adults

Design:

Participants will be screened with a medical history, physical exam, neurological exam, psychiatric history, and blood tests.

Participants will have 2-5 visits for the first session. They will have 2 PET scans and 1 MRI scan. They may have 3 more sessions: 6 months to about 18 months later, 1 year after that, and about 30 months to 5 years after the first visit. There may be up to 20 total visits.

For the scans, participants will lie on a bed that slides into the scanners. For the PET scans, a strap will fix their head in place. A radioactive drug will be injected through a catheter. A needle will guide a thin plastic tube into an arm vein. Additional catheters may be put in place to draw blood. Each PET will take 2 hours. The MRI will take 30 60 minutes.

At each session, participants will have a brief interview, medical history, physical exam, blood and urine tests, heart tests, and memory and thinking tests. They may donate blood for DNA tests.

Detailed description:
Objectives

The primary objective is to explore if human subjects with neurodegenerative diseases exhibit different level of neuroinflammation, as measured by brain uptake of a 3rd generation \[11C\]ER176 TSPO ligand, compared to control subjects. The secondary objectives are to determine, 1) if \[11C\]ER176 TSPO brain uptake shows disease-specific patterns across different neurodegenerative diseases and/or genetic mutations, and 2) if longitudinal imaging of individual patients shows a correlation between interval change of tracer uptake and disease progression.

Study population

Adults referred with a clinical diagnosis or with an increased risk of frontotemporal dementia, amyotrophic lateral sclerosis, Alzheimer s disease, other related adult-onset neurodegenerative disorders, or healthy control subjects.

Design

Participants will undergo a general and neurological exam, a standard battery of neuropsychological tests to measure cognitive function, blood tests for analysis of TSPO polymorphisms, MRI of the brain, and PET imaging with the \[11C\]ER176 TSPO radioligand and \[11C\]PIB amyloid radioligand. Participants will be invited to return for repeat evaluations approximately 1, 2, and 3-5 years after their initial evaluation.

Outcome measures

Brain PET and MRI scans will be co-registered for anatomic definition of regions of interest, and standard uptake value (SUV) will be calculated in various brain regions. \[11C\]ER176 PET data will be analyzed with compartmental modeling. \[11C\]PIB PET and MRI data will be adjunctly used for segregating the collected data by disease subtype. For the primary objective, we will compare TSPO radioligand uptake of healthy controls compared to subjects with neurodegenerative diseases. For secondary objectives, we will determine if neuroanatomical regions of tracer uptake differ across different neurodegenerative disease subtypes, and if interval change of tracer uptake correlates with disease progression in longitudinal imaging of individual subjects.

Arms: arm 1: Participants underwent brain positron emission tomography (PET) scan with \[11C\]ER176 and/or \[11C\]PIB followed by brain magnetic resonance imaging (MRI) arm 2: Participants underwent brain positron emission tomography (PET) scan with \[11C\]ER176 and/or \[11C\]PIB followed by brain magnetic resonance imaging (MRI) arm 3: Participants underwent brain positron emission tomography (PET) scan with \[11C\]ER176 and/or \[11C\]PiB followed by brain magnetic resonance imaging (MRI)
Interventions: intervention 1: 11C-ER176 intervention 2: 11C-PIB intervention 3: Positron Emission Tomography (PET) Scan
Intervention descriptions: intervention 1: PET biomarker for inflammation intervention 2: PET biomarker for amyloid intervention 3: Participants underwent PET scan with \[11C\]ER176 and/or 11C-PIB

Protocol documents:
Prot_SAP_000.pdf: 
 
Abbreviated Title: TSPO PET in neurodegeneration
NIH IRB #: 19M0095
Version Date: 08/31/21
Title: PET imaging of neuroinflammation in neurodegenerative diseases via a novel TSPO 
radioligand
NIH Principal Investigator:  
Robert B. Innis, M.D., Ph.D.
Molecular Imaging Branch
National Institute of Mental Health
10 Center Drive
Building 10, Room B1D43J
Telephone: 301-594-1368
Fax:  301-480-3610
Email:  robert.innis@nih.gov


Abbreviated Title: TSPO PET in neurodegeneration
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Total requested accrual  
100 Adults with a diagnosis or with an increased risk of adult-onset neurodegenerative diseases      
100 Healthy Volunteers
 
Project Uses Ionizing Radiation: 
 No 
 Yes
 Medically-indicated only
 Research-related only 
 Both 
IND/IDE
 No 
Yes 
Drug/Device/# [11C]PIB/#108861, [11C]ER176/#122236________
Sponsor: _NIMH IRP________
Durable Power of Attorney 
 No
 Yes
Multi-institutional Project
 No 
 Yes
Institution#1_________________    FWA #_________ 
Date of IRB approval ______________ 
Institution#2_________________    FWA #_________ 
Date of IRB approval ______________ 
Data and Safety Monitoring Board 
 No 
 Yes 
Technology Transfer Agreement 
 No 
 Yes 
Samples are being stored 
 No  
 Yes
Covered Protocol Requiring DEC Clearance  No  
 Yes
Approved for Short Form Consent Process for Non-English Speakers  No   Yes
Flesch-Kincaid reading level of consent form: 

For Healthy adult volunteer: 8.5

For Patient of neurodegenerative diseases: 8.5

For Subject with increased risk of neurodegenerative diseases: 8.5

Assent for an adult without consent capacity: 7.7


Abbreviated Title: TSPO PET in neurodegeneration
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PRÉCIS:
Objectives
The primary objective is to explore if human subjects with neurodegenerative diseases exhibit 
different level of neuroinflammation, as measured by brain uptake of a 3rd generation 
[11C]ER176 TSPO ligand, compared to control subjects. The secondary objectives are to 
determine, 1) if [11C]ER176 TSPO brain uptake shows disease-specific patterns across different 
neurodegenerative diseases and/or genetic mutations, and 2) if longitudinal imaging of individual 
patients shows a correlation between interval change of tracer uptake and disease progression.
Study population
Adults referred with a clinical diagnosis or with an increased risk of frontotemporal dementia, 
amyotrophic lateral sclerosis, Alzheimer’s disease, other related adult-onset neurodegenerative 
disorders, or healthy control subjects.
Design
Participants will undergo a general and neurological exam, a standard battery of 
neuropsychological tests to measure cognitive function, blood tests for analysis of TSPO 
polymorphisms, MRI of the brain, and PET imaging with the [11C]ER176 TSPO radioligand and 
[11C]PIB amyloid radioligand. Participants will be invited to return for repeat evaluations 
approximately 1, 2, and 3-5 years after their initial evaluation.
Outcome measures
Brain PET and MRI scans will be co-registered for anatomic definition of regions of interest, and 
SUV will be calculated in various brain regions. [11C]ER176 PET data will be analyzed with 
compartmental modeling. [11C]PIB PET and MRI data will be adjunctly used for segregating the 
collected data by disease subtype. For the primary objective, we will compare TSPO radioligand 
uptake of healthy controls compared to subjects with neurodegenerative diseases. For secondary 
objectives, we will determine if neuroanatomical regions of tracer uptake differ across different 
neurodegenerative disease subtypes, and if interval change of tracer uptake correlates with 
disease progression in longitudinal imaging of individual subjects.


Abbreviated Title: TSPO PET in neurodegeneration
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Table of Contents 
PRÉCIS:.....................................................................................................................................................3
LIST OF ABBREVIATIONS................................................................................................................5
1.
INTRODUCTION AND BACKGROUND................................................................................5
2.
STUDY OBJECTIVES ..................................................................................................................9
3.
SUBJECTS .......................................................................................................................................9
4.
STUDY DESIGN AND METHODS.........................................................................................11
5.
MANAGEMENT OF DATA AND SAMPLES......................................................................17
6.
ADDITIONAL CONSIDERATIONS ......................................................................................19
7.
RISKS AND DISCOMFORTS ..................................................................................................19
8.
SUBJECT SAFETY MONITORING ......................................................................................21
9.
OUTCOME MEASURES...........................................................................................................22
10. STATISTICAL ANALYSIS.......................................................................................................22
11. HUMAN SUBJECTS PROTECTION.....................................................................................23
12. BENEFIT........................................................................................................................................24
13. CONSENT DOCUMENTS AND PROCESS .........................................................................24
14. DATA AND SAFETY MONITORING ...................................................................................25
15. QUALITY ASSURANCE (QA).................................................................................................26
16. REPORTING OF UNANTICIPATED PROBLEMS, ADVERSE EVENTS AND PROTOCOL 
DEVIATIONS ........................................................................................................................................26
17. ALTERNATIVES TO PARTICIPATION .............................................................................27
18. PRIVACY.......................................................................................................................................27
19. CONFIDENTIALITY..................................................................................................................27
20. CONFLICT OF INTEREST......................................................................................................27
21. RESEARCH AND TRAVEL COMPENSATION.................................................................28
22. REFERENCES..............................................................................................................................29


Abbreviated Title: TSPO PET in neurodegeneration
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LIST OF ABBREVIATIONS
AD
Alzheimer’s disease
ALS
amyotrophic lateral sclerosis
C9ORF72
chromosome 9 open reading frame 72
DLB
dementia with Lewy bodies
FTD
frontotemporal dementia
GRN
progranulin gene
HAB
high-affinity binder
IL
interleukin
LAB
low-affinity binder
MAB
mixed-affinity binder
MND
motor neuron disease
MRI
magnetic resonance imaging
PBR
peripheral benzodiazepine receptor
PD
Parkinson’s disease
PGRN
progranulin protein
PET
positron emission tomography
PIB
Pittsburgh compound B
SUV
standardized uptake value
TBK1
TANK-binding kinase 1
TNF
tumor necrosis factor
TNFR
tumor necrosis factor receptor
TREM2
triggering receptor expressed on myeloid cells 2
TSPO
18-kDa translocator protein
VT 
total (specific plus nondisplaceable) distribution volume
fP
free fraction in plasma
1. INTRODUCTION AND BACKGROUND
The rising incidence of Alzheimer’s disease (AD) and other age-related 
neurodegenerative disorders in our aging population is a looming crisis in medicine (Reitz et al, 
2011).  Neurodegenerative diseases are common, dehumanizing, and usually untreatable. Today, 
approximately 5 million adults in the US have AD or another adult-onset neurodegenerative 
disorder, or nearly 1 in 8 individuals over the age of 65. This number is expected to increase to 
11-16 million by 2050 as our aged population and life-expectancy increase. The most common 
neurodegenerative disease in those > 60 years old is AD. Other causes of dementia in aging 
adults include dementia with Lewy bodies (DLB), Parkinson’s disease (PD), vascular dementia, 
frontotemporal dementia (FTD), and frontotemporal dementia with motor neuron disease (FTD-
MND). Unfortunately, we currently lack effective disease-modifying therapies for the majority 
of these neurodegenerative diseases. It is now widely established that pathologic changes begin 
to occur in the brain decades before changes in cognition. Though it is increasingly clear that 
future treatments need to be started in pre-symptomatic patients, we currently lack imaging-
based biomarkers to track disease progression in such individuals. This has proven to be a 
significant barrier in development of new disease-modifying therapeutics. By using a third-
generation 18-kDa translocator protein (TSPO) PET radioligand, we propose to determine if 
human subjects with neurodegenerative diseases have increased levels of neuroinflammation 
compared to control subjects, and if disease-specific patterns of neuroinflammation occur in 
different neurodegenerative diseases (e.g. FTD vs AD).


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Dysregulation of the immune system is a common observation in many 
neurodegenerative diseases, including AD, PD, and ALS (Lucin and Wyss-Coray, 2009). 
Microglia are central mediators of the immune response in the CNS, can have either 
neurotrophic or neurotoxic effects, and are morphologically activated in neurodegenerative 
diseases (Streit et al, 2008; Tambuyzer et al, 2008). Recent genome-wide association studies 
have provided additional genetic evidence for the importance of neuroinflammation as a causal 
factor in neurodegenerative diseases. For example, polymorphisms in TREM2, a microglia 
receptor involved in phagocytosis, were associated with an increased risk of AD (Guerreiro et al, 
2013; Kleinberger et al, 2014; Nalls et al, 2015). Polymorphisms in IL1-beta, TNF-alpha are 
associated with an increased risk of DLB (Surendranathan et al, 2015). Double knockout of 
TNFR1 and TNFR2 results in a neuroprotective effect in an animal model of PD, accompanied 
by a simultaneous decrease in the level of microglial activation (Sriram et al, 2006).
Substantial evidence has also linked dysregulated microglial activity with FTD, in 
particular certain genetic subtypes of FTD. Mutations in the GRN gene are a common cause of 
familial FTD, and reduce expression of the secreted protein progranulin. Mouse Grn-/- 
macrophages exhibit a pro-inflammatory phenotype (Yin et al, 2010). Also, Grn-/- macrophages 
are neurotoxic in a brain slice model, and display accelerated clearance of dying cells (Kao et al, 
2011; Yin et al, 2010). PGRN binds both TNFR1 (which is broadly expressed) and TNFR2 
(which is primarily expressed by leukocytes) in a dose-dependent manner (Tang et al, 2011). 
Binding of PGRN to TNFR blocked the association of TNFR with its native ligand, TNFα. These 
results explain prior observations that PGRN inhibits TNF-induced neutrophil activation (Zhu et 
al, 2002).  In addition, Tang et al. (2011) found that PGRN blocked TNFα mediated signaling in 
human regulatory T cells, and downregulated interferon (IFN) gamma secretion in effector T 
cells. These results suggest that PGRN might directly regulate intracellular signaling by directly 
binding to TNFR and by inhibiting TNFα-mediated pathways. Other genetic subtypes of FTD 
(and FTD with motor neuron disease; FTD-MND) may also involve dysregulated microglial 
function. Hexanucleotide repeats in C9ORF72 are the most common causes of familial FTD and 
ALS (Freibaum et al, 2015). Recently, A C9ORF72 KO mouse was described, which was found 
to have strikingly abnormal and hyperactive macrophages and microglia (O'Rourke et al, 2016). 
Less common mutations in the gene TBK1, which are associated with both FTD and ALS, may 
also play a role in microglial regulation (Pottier et al, 2015). Together, both genetic and animal 
model data suggest an important role of neuroinflammation in FTD and ALS pathophysiology.
Non-invasive imaging of neuroinflammation in living human subjects can be 
accomplished through the use of PET radioligands that target the TSPO. TSPO is a 
mitochondrial protein that is highly expressed in inflammatory cells including activated 
microglia in the brain. Previous PET studies from our laboratory using a TSPO radioligand, 
[11C]PBR28, found significant correlations between brain uptake and clinical 
severity/progression of AD (Kreisl et al, 2016; Kreisl et al, 2013). Moreover, distribution of 
TSPO uptake in brain showed high correspondence with different clinical subtypes of AD that 
have distinct spatial patterns in their pathology (Kreisl et al, 2017). Small cross-sectional PET 
neuroinflammation imaging studies in FTD patients have been performed using 1st and 2nd 
generation TSPO radioligands (reviewed by Zhang, 2015). Overall, these studies saw increased 
TSPO radioligand uptake in FTD patients compared to control, with anatomical correlation 
between regional radioligand uptake and brain atrophy (Zhang, 2015). 


Abbreviated Title: TSPO PET in neurodegeneration
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We also performed a clinical [11C]PBR28 PET study in patients with FTD. All patients 
met revised criteria for frontotemporal dementia (Neary et al, 1998). Five patients were included 
(age 53.4 ± 5.9 years). Four patients met clinical criteria for behavioral variant FTD, while one 
patient met criteria for progressive nonfluent aphasia. Thirteen older controls (age 64.0 ± 5.0 
years) were included for comparison. Patients in general showed increased [11C]PBR28 binding 
in frontal cortex, which in many cases was evident on visual inspection (Fig 1). Using a region-
of-interest analysis and correcting for age, sex, education, and TSPO genotype, FTD patients had 
42% greater [11C]PBR28 binding (distribution volume corrected for free fraction of radioligand 
in plasma, VT/fP) than controls in prefrontal cortex (p = 0.034) and 45% greater binding in 
striatum (p = 0.025). These results suggest that FTD is associated with activation of microglia, 
similar to that seen in Alzheimer’s disease (Kreisl et al, 2013); albeit with different regional 
distribution. Regions of increased [11C]PBR28 binding in FTD patients correspond to those with 
expected neurodegeneration.
Fig 1. Representative [11C]PBR28 parametric images (VT/fP) for a patient with behavioral variant FTD and 
a healthy control. Both subjects are high affinity binders (non-carriers of the rs6971 TSPO 
polymorphism). Arrows show increased binding in frontal and temporal cortices.
However, 1st and 2nd generation suffer from reduced uptake in a significant fraction of the 
human population that carry a single nucleotide polymorphism (rs6791) in the TSPO gene, 
making it difficult if not impossible to analyze scans obtained from such patients. Second, the 
sensitivity and specificity of 1st and 2nd TSPO radioligands is relatively poor compared to third 
generation radioligands. Finally, few longitudinal studies of TSPO PET imaging in patients with 
neurodegeneration have been performed, especially rare forms of neurodegeneration such as 


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FTD. Such studies are needed to determine if PET imaging of neuroinflammation may be a 
suitable biomarker for future treatment trials.
We recently developed a new 3rd-generation radioligand binding for TSPO, [11C]ER176, 
which showed excellent brain uptake in eight healthy subjects as shown in Fig 2 (Ikawa et al, 
2017). An apparently unique advantage of [11C]ER176 compared to conventional TSPO 
radioligands is that it provides quantifiable distribution volume (VT) regardless of single 
nucleotide polymorphism rs6971 in the TSPO gene. Specifically, with other TSPO radioligands, 
all subjects must be pre-screened by genetic tests, and low-affinity binders (LABs) must be 
excluded from PET scans because the brain has too little uptake to quantify. In contrast, a similar 
pre-screening and exclusion process is unnecessary for [11C]ER176 because even LABs have 
substantial VT values in their brain (Fig 3). It should be noted that although subjects need not be 
excluded a priori, the results must be corrected for genotype a posteriori. This provide 
particularly significant advantage in the present study, since our potential participants are those 
having rare disorders with severe disability, additional screening for exclusion of TSPO LABs 
may result in too limited number of subjects for meaningful interpretation, especially in rare 
disease subtypes such as FTD or in genetically-defined familial cases.
Fig 2. 
Brain uptake and plasma radioactivity concentrations (conc) of [11C]ER176 in a representative HAB at 
baseline and after blockade with 90 mg of XBD173. (A) Brain time-activity curves from gray matter with 
unconstrained two-tissue compartment model fitting. (B) Time courses of parent concentration in arterial 
plasma fitted by multiplying triexponential-fitted total plasma radioactivity and sigmoid-fitted plasma 
parent fraction. 


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Fig 3. Time-stability analysis: VT obtained from both baseline scans for each genotype and blocked scans 
for HABs, as well as its identifiability, is plotted as function of duration of image acquisition. (A) VT was 
calculated for putamen using an unconstrained two-tissue compartment model with increasingly truncated 
acquisition times. Values are normalized as percentage of terminal value attained from 90 min of 
imaging. (B) Corresponding percentage SE, which is inversely proportional to identifiability, is plotted. 
Data are mean ± SD. 
2. STUDY OBJECTIVES 
a. Primary objectives
We will explore if human subjects with neurodegenerative diseases exhibit different brain 
uptake levels of the [11C]ER176 TSPO ligand compared to control subjects.
b. Secondary objectives
We will explore if, 
1) [11C]ER176 TSPO brain uptake shows disease-specific patterns across different 
neurodegenerative diseases 
2) Longitudinal imaging of individual patients shows that interval changes in tracer 
uptake correlate with disease progression.
3. SUBJECTS
a. Description of study populations 

Adults with a diagnosis or with an increased risk of FTD, ALS, AD, or a related 
adult-onset neurodegenerative disease

Accrual ceiling of 100 patients with age-related neurodegenerative diseases or 
subjects with genetically increased risk of such diseases, and 100 healthy volunteers 
who are matched for age (± 5 years) and sex

Dropouts will not be replaced

NIH employees may participate if they meet the eligibility criteria, but NIMH 
employees/staffs or NIH employees who are subordinates/relatives/co-workers of 
investigators may not participate.
b. Inclusion criteria
1) Patients will be included if they

Are age 18 or older


Abbreviated Title: TSPO PET in neurodegeneration
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
Have the ability to understand and sign an informed consent, or have a DPA or a 
court-appointed guardian (or be able to understand the DPA process to appoint a 
DPA) to provide consent for adults without consent capacity

Have been given a diagnosis by a neurologist of frontotemporal dementia, 
frontotemporal lobar degeneration, primary progressive aphasia, semantic dementia, 
motor neuron disorder, amyotrophic lateral sclerosis, primary lateral sclerosis, 
progressive bulbar palsy, corticobasal syndrome, Huntington disease, Alzheimer’s 
disease, or other related adult-onset neurodegenerative disease
2) Subjects with an increased risk of neurodegenerative diseases will be included if they

Are age 18 or older

Are able to give written informed consent

Have known family history or other risk of an adult-onset genetic 
neurodegenerative disease, and/or mutation in a gene known to cause an adult-
onset neurodegenerative disease
3) Healthy subjects will be included if they

Are age 18 or older

Are willing and able to complete all study procedures

Are able to give written informed consent

Are medically healthy

Are enrolled in 01-M-0254 “The Evaluation of Participants with Mood and 
Anxiety Disorders and Healthy Volunteers” (PI: Dr. Carlos Zarate) or 17-M-0181, 
“Recruitment and Characterization of Healthy Research Volunteers for NIMH 
Intramural Studies” (PI: Dr. Joyce Chung)
c.
Exclusion criteria
1) Patients or subjects with an increased risk of neurodegenerative diseases will be 
excluded if they

Have other major neurological or medical diseases that may cause progressive 
weakness or cognitive dysfunction, such as structural brain or spinal cord disease, 
metabolic diseases, paraneoplastic syndromes, infectious diseases, peripheral 
neuropathy or radiculopathy or other significant neurological abnormalities 

Have an unstable medical condition that, in the opinion of the investigators, 
makes participation unsafe (e.g., active infection or untreated malignancy)

Require daytime ventilator support at the time of study entry

Are unable to travel to NIH

Have recent exposure to radiation related to research (e.g., PET from other 
research) that, when combined with this study, would be above the allowable 
limits

Have inability to lie flat and/or lie still on camera bed for at least two hours, 
including claustrophobia, overweight greater than the maximum for the scanner, 
and uncontrollable behavioral symptoms, which will be screened by an interview 
with patient and/or caregiver during the screening visit 

Are pregnant or breastfeeding 


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
Participants must not have substance use disorder or alcohol use disorder. 
However, alcohol or cannabis use by themselves are not exclusion criteria, unless 
that use impairs function

Are unable to have an MRI scan (e.g., pacemakers or other implanted electrical 
devices, brain stimulators, dental implants, aneurysm clips (metal clips on the 
wall of a large artery), metallic prostheses (including metal pins and rods, heart 
valves, and cochlear implants), permanent eyeliner, implanted delivery pumps, or 
shrapnel fragments, metal fragments in the eye)

NIMH employees/staffs or NIH employees who are subordinates/relatives/co-
workers of investigators
2) Healthy subjects will be excluded if they

Have any history of medical illness or injury with the potential to affect study data 
interpretation or to be any medical contraindication to the procedures performed 
in the study, including active infection and untreated malignancy.

Have clinically significant laboratory abnormalities based on tests performed 
under screening protocol 01-M-0254 or 17-M-0181 and specified in Section 4.c 
“Screening”

Have recent exposure to radiation related to research (e.g., PET from other 
research) that, when combined with this study, would be above the allowable 
limits

Have inability to lie flat on camera bed for at least two hours, including 
claustrophobia and overweight greater than the maximum for the scanner

Are pregnant or breastfeeding 

 Participants must not have substance use disorder or alcohol use disorder. 
However, alcohol or cannabis use by themselves are not exclusion criteria, unless 
that use impairs function

Are unable to have an MRI scan (e.g., pacemakers or other implanted electrical 
devices, brain stimulators, dental implants, aneurysm clips (metal clips on the 
wall of a large artery), metallic prostheses (including metal pins and rods, heart 
valves, and cochlear implants), permanent eyeliner, implanted delivery pumps, or 
shrapnel fragments, metal fragments in the eye)

NIMH employees/staffs or NIH employees who are subordinates/relatives/co-
workers of investigators
4. STUDY DESIGN AND METHODS
a. Study overview 
This is a single center cross-sectional and longitudinal study in three groups of 
participants: patients with FTD, ALS, AD, or a related adult-onset neurodegenerative 
disease, subjects with an increased risk of such diseases due to disease-associated 
mutations, and healthy volunteers as a control group. We plan to conduct interim analysis 
on the cross-sectional part of this study once approximately 10-15 subjects’ data each in 
the patient group and the control group are collected, and determine if there is significant 
difference of [11C]ER176 brain uptake between the two groups. This will help us 
reviewing the initial pool of cross-sectional data and accordingly modifying plans for 
further cross-sectional/longitudinal data collection if necessary. 


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As noted above, participants must meet inclusion and exclusion criteria and sign an 
informed consent document. All participants will undergo brain PET scan with 
[11C]ER176 and brain MRI. Brain PET scan with [11C]PIB will be done in all participants 
except for those whose diagnosis has been confirmed by genetic testing. [11C]PIB PET 
will be obtained for differentiation of preclinical or atypical AD from normal aging or 
FTD/ALS-related neurodegenerative diseases, since AD-spectrum disorders have shown 
to be significantly overlapped in both populations (Rabinovici et al, 2011; Vlassenko et 
al, 2011). Brain MRI will be obtained for co-registration of the PET images to identify 
the anatomical structures, and the results could provide additional information such as 
atrophy pattern which is useful in differential diagnosis. 
Brain PET scans will be performed with vital sign monitoring. The [11C]ER176 PET 
scan will be associated with arterial sampling for the input function, but in patients who 
are unable to or refuse to undergo arterial sampling, the scan may be done with venous 
sampling or without any blood sampling. To develop a substitutional analysis method for 
those PET data without arterial sampling, a few venous samples will be additionally 
obtained in some subjects who undergo arterial sampling during [11C]ER176 PET scan. 
No arterial input function will be taken for [11C]PIB PET scan. The brain MRI will be 
obtained before or after the PET scan, and can be performed on the same day. The 
completion of each PET and MRI will take approximately two and one hours, 
respectively.
Number of visits and time commitment of participants
The initial visit will include the general medical history and examination, 
neurological examination, neuropsychological evaluation, and blood sampling for rs6971 
TSPO polymorphism genotyping. In the event that the subject has had a recent general 
medical history and examination, neurological examination, neuropsychological 
evaluations, or adequate brain MRI as part of enrollment in other protocols, these 
portions of the evaluation will not be duplicated. Brain MRI, [11C]ER176 PET, [11C]PIB 
PET, and neuropsychological evaluation may be scheduled on separate days from the 
initial visit, depending on the schedule of the examiner and the radiology and PET 
departments. Two PET scans may occur on the same day and, if so, be separated by at 
least 2.5 hours to allow for decay of the first injection (T1/2 = 20 min). All participants 
including healthy subjects may be asked to return to NIH after an interval of at least six 
months (but no more than 5 years) to repeat the clinical evaluations, MRI, and PET scans 
as shown in Table 1. Therefore, this protocol initially requires two to five visits for the 
first evaluation, and additional visits for the 2nd, 3rd, and 4th evaluations are helpful for the 
study but not necessary for initial enrollment. For patients and newly diagnosed patient 
participants returning for each follow-up evaluation, the capacity assessment by study 
team investigators will be repeated and the consent will be re-signed.
All procedures and their associated exposure to radiation are for research 
purposes only.


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Table 1. Number of visits/evaluations and time commitment of participants
1st evaluation
(0-6 months)
2nd evaluation
(6-18 months)
3rd evaluation
(18-30 months)
4th evaluation
(30-60 months)
1st 
Visit 
Screen
2nd 
Visit
3rd 
Visit
4th 
Visit
5th 
Visit
6th 
Visit
7th 
Visit
8th 
Visit
Capacity 
assessment in 
patients’ group 
and informed 
consent
X
X
X
X
History and 
physical exam
X
X
X
X
Lab tests*
X
X
X
X
X
X
X
X
Neuropsych 
testing**
X
X
X
X
MRI **
X 
X
X
X
Brain PET**
X
X
X
X
* Blood sampling for the rs6971 polymorphism genotyping will be done during the 1st 
evaluation. For women of child-bearing potential, a urine pregnancy test will also be 
done within 24 hours before PET ligand administration and MRI scan.
** Neuropsychological testing this may require an additional visit depending on the 
schedule of the examiner or condition of the subject. Depending on the availability of 
PET and MRI scanners, an MRI scan may be scheduled at any point in time for this 
protocol, either before or after the PET procedures, which may require an additional visit. 
If [11C]ER176 PET and [11C]PIB PET are conducted on different days, this may require 
an additional visit. Therefore, as a maximum five visits may be required in each 
evaluation period, and up to twenty visits may be required in 5 years (not shown on 
above table).
b. Recruitment
Letters will be sent to clinicians who see patients with dementia or motor neuron 
disease and to Dementia or ALS clinics with information for referring patients to the 
study. A brochure with a lay description of the protocol and contact information for the 
study team will be provided to physicians to give to their patients. The brochure may be 
sent electronically to those requesting study information. The printed brochure will be 
used in color as submitted or may be printed in black and white. The color of the 
brochure may vary. Color changes will not be used to change the emphasis of the 
brochure. The size of the brochure may vary, but all parts of the brochure, including fonts 
and pictures, will be changed proportionately to the rest of the brochure. Disproportionate 
changes in size will not be used to change the emphasis.


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The protocol and the contact for further information will be listed on 
www.clinicaltrials.gov and a description of the protocol will be included on the NINDS 
intramural clinic page. Links to the clinical trials listing or protocol description page may 
be posted electronically on websites such as those of the ALS Association, the Muscular 
Dystrophy Association, The ALS Therapy Development Initiative, ALS worldwide, the 
Northeast ALS consortium, the Association for FTD, and CurePSP.  
An advertisement describing the protocol will be posted on ResearchMatch.org, a 
national electronic, web-based recruitment tool that was created through the Clinical & 
Translational Science Awards Consortium in 2009 and is maintained at Vanderbilt 
University.  
An advertisement will be provided to the Agency for Toxic Substances and 
Disease Registry (ATSDR) who will use a notification tool that will allow persons with 
ALS (PALS) enrolled in the National ALS Registry to find out about this study (through 
www.CDC.gov).
Flyers (with tabs) for healthy volunteers may be posted electronically on websites, 
such as NIH or the other sites’ hospital websites, libraries, nursing homes and other 
advocacy groups and may be sent electronically to those requesting study information.
Recruitment strategies will also include use of Listservs, Craig’s List, advocacy 
websites, resource listings or other website postings and Study-specific page on the 
NIMH-IRP: Join A Study Website with URL (placeholder).  Short text descriptions of 
this study will also appear on Facebook. Facebook posts will be made only via official 
NIMH accounts.  Associate Investigators and members of the NIMH Marketing & 
Community Relations Unit will distribute recruitment materials.
All recruitment materials, including listserv notices, social media, letters to 
physicians, recruitment website content, and other venues will be approved by the IRB 
prior to use.
Some patients may be recruited under 17-N-0131, “Investigating Complex 
Neurodegenerative Disorders related to amyotrophic lateral sclerosis and frontotemporal 
dementia” (PI: Dr.Justin Kwan), or 00-N-0043, “Clinical and molecular manifestations of 
inherited neurological disorders” (PI: Dr. Kenneth Fischbeck). In this case, the similar 
pre-screening/screening processes or study procedures such as neurological examinations 
and neuropsychological testing that have been recently done will not be duplicated in this 
study.
Healthy volunteers will be recruited under 01-M-0254, “The Evaluation of 
Participants with Mood and Anxiety Disorders and Healthy Volunteers” (PI: Dr. Carlos 
Zarate) or 17-M-0181, “Recruitment and Characterization of Healthy Research 
Volunteers for NIMH Intramural Studies” (PI: Dr. Joyce Chung), and not under the 
current protocol. NIH Employees/staff will not be directly recruited by or through their 
supervisors or co-workers to participate in this study.


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c.
Screening 
Consent will be obtained before any study procedures, including screening 
procedures, are done. 
In patients with neurodegenerative diseases or subjects with an increased risk of 
neurodegenerative diseases, demographics, history of present illness, family history of 
neurological disorders, history of medications or surgeries/implants, general medical 
examination, neurological examination, and laboratory tests will be performed by a study 
clinician. Patients will be evaluated with their potential tolerability and willingness for 
study procedures such as arterial line and lying still in PET scanner, and their caregivers 
will be also interviewed to provide information about tolerability. If patients have had 
overlapping recent evaluations from other NIH protocols or from outside hospitals and 
the records are available, duplicate evaluations will not be performed as part of this study.
Healthy volunteers will be screened under protocol 01-M-0254, “The Evaluation 
of Participants with Mood and Anxiety Disorders and Healthy Volunteers” (PI: Dr. 
Carlos Zarate) or 17-M-0181, “Recruitment and Characterization of Healthy Research 
Volunteers for NIMH Intramural Studies” (PI: Dr. Joyce Chung). Basic screening in 
healthy volunteers will include physical exam, medical and psychiatric history, and 
laboratory tests. 
Laboratory tests for screening include CBC; acute care panel; hepatic panel; 
mineral panel; urinalysis; urine drug screen; urine pregnancy test (females); vitamin B12, 
folate, and lipid panel; hepatitis panel (A, B, C); HIV & syphilis screening test; total 
protein; uric acid; creatine kinase; cholesterol; thyroid panel; prothrombin and partial 
prothrombin tests; and EKG. The radial artery pulse is checked for the presence of 
adequate ulnar collateral flow and the absence of any metals or foreign objects in bilateral 
wrists. Screening results will be reviewed by a clinically credentialed investigator before 
the subject undergoes any specific study procedures. 
d. Study procedures
1) Neuropsychological testing 
All participants will undergo neuropsychological testing to evaluate their 
cognitive or behavioral functionalities. Such testing may include mini-mental status 
examination, Montreal Cognitive Assessment, and Clinical Dementia Rating Scale, as 
well as more comprehensive neuropsychological testing. 
If patients have had the similar recent neuropsychological testing from other NIH 
protocols or from outside hospitals and the records are available, duplicate evaluations 
will not be performed as part of this study.
2) Genetic testing
Blood tests for genotyping the rs6971 polymorphism within the TSPO gene on 
chromosome 22q13.2 will be performed in all participants, and the results will be used 
for analyzing each individual’s [11C]ER176 PET data.
3) Brain MRI
A brain MRI will be obtained for anatomic localization and will be performed on 
a 3 Tesla scanner located at the NIH Clinical Center (Bethesda, Maryland) and will take 
about one hour. Subjects will undergo safety screening prior to the MRI to rule out 
contraindications such as cardiac pacemaker. If an adequate brain MRI has been 


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performed within the last 6 months at the NIH, we will not perform a duplicate MRI scan 
and their earlier MRI will be used for anatomical localization.
Pregnancy tests:  For women able to become pregnant, urine pregnancy testing 
will be done within the 24 hours prior to any MRI or PET scan. If the pregnancy test is 
positive, PET and MRI will not be done, and the subject will be taken off the protocol.
4) PET Procedures
i.
Radioligands
[11C]ER176 and [11C]PIB will be prepared according to the IND and administered 
via an indwelling intravenous catheter over approximately one to three minutes.
ii.
Insertion of the intravenous line
An intravenous line is placed in the arm.  The venous line is used for the injection 
of radioligand and is removed at the end of the day. In some subjects, additional 
intravenous line may be placed and used for venous sampling during the PET scan. This 
venous samples will be used for developing substitutional analysis method for PET data 
obtained without arterial sampling. We will evaluate during the screening visit whether a 
subject could tolerate a second venous line or not, and the option is given as a checkbox 
in consent forms. 
iii.
Arterial Line Placement
Arterial line may be placed for [11C]ER176 scan, but not for [11C]PIB scan. After 
the presence of adequate ulnar collateral flow has been confirmed, a radial artery catheter 
will be inserted by the Anesthesiology Department or the Vascular Access Department. 
Before catheter insertion, the skin at the puncture site will be locally anesthetized. If there 
is difficulty in placing arterial line due to patient’s poor tolerability, medical 
contraindication, or other reasons, the [11C]ER176 scan may be done with venous 
sampling or without any blood sampling. We will evaluate during the screening visit 
whether a subject could tolerate an arterial line or not, and the option is given as a 
checkbox in consent forms.
iv.
PET scan
One [11C]ER176 PET and one [11C]PIB PET will be performed in each evaluation 
period of each subject. The two scans may occur on the same day or on different days. 
Brain PET imaging will be performed using a PET or PET/CT scanner for up to two 
hours. Participants will be placed on the scanner bed with their head held firmly in place 
fixed to the bed. A 68Ge, 137Cs, or CT transmission scan will be performed to measure 
and correct for attenuation. Tracer infusions will be performed when the subject is 
already on the scanner bed. After an intravenous bolus of up to 20 mCi, blood samples 
may be drawn from the arterial and/or venous catheter during the [11C]ER176 PET scan. 
We will collect about 15-25 arterial samples and/or about 4-6 venous samples. The 
arterial sampling will be initially performed continuously at earlier time points and 
discretely at later time points, but this plan can be modified if required for achieving 
better quality of data. The total amount of blood sampling volume will be about 150 mL 
in each brain scan. [11C]PIB PET scan will be done without arterial sampling. PET 
images will be acquired in three-dimensional mode with increased length of frame for a 
total of approximately two hours. If the scan lasts more than two hours, the subject may 


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be offered a break out of the camera for approximately 15 minutes. Vital signs (blood 
pressure, pulse, and respiratory rate) and EKG (either 3- or 12-lead) will be recorded no 
more than three hours before injection, and again about 15, 30, and 120 minutes after 
tracer injection. After the scan, the arterial and/or venous lines will be removed and the 
subject will be instructed to void frequently to minimize radiation exposure.
Pregnancy tests:  For women able to become pregnant, urine pregnancy testing 
will be done within the 24 hours prior to any MRI or PET scan. If the pregnancy test is 
positive, PET and MRI will not be done, and the subject will be taken off the protocol.
v.
Follow-up procedures
We will offer an opportunity to all participants to return for repeat examination, 
neuropsychological testing, MRI, and PET imaging. Such repeat evaluations may occur 
at 6-18 months, 18-30 months, and 30-60 months after initial examination. 
vi.
Relationship to other protocols
There is no specific relationship of this protocol to other protocols, although 
patients may be referred to other NIH protocols if they are eligible. Examples of current 
protocols that patients may be referred to include 13-N-0188: Natural History and 
Biomarkers of C9orf72 ALS and FTD and 15-N-0126: HERV-K Suppression Using 
Antiretroviral Therapy in Volunteers with Amyotrophic Lateral Sclerosis (ALS). If 
patients are willing, we will maintain their information in a registry to allow re-contact 
and referral to future protocols on adult-onset neurodegenerative disorders.
e.
End of participation
Results of clinical testing, neurological examination, and brain MRI may be 
shared with patients and referring physicians through the CRIS portal. 
Participants will not be told the result of [11C]ER176 PET scan since it is difficult 
to interpret. But the result of [11C]PIB PET scan may be given if the participant wanted 
and agreed to receive at the consenting process. None of participants will be informed of 
genotyping results of rs6971 TSPO polymorphism since the clinical significance is 
unknown in any population. Such practice is typical for participants undergoing PET 
studies at the NIMH, since these scans are performed for research only, and not routine 
medical care. Eligible subjects may be offered enrollment in other protocols at the NIH. 
No treatment will be offered. 
Patients will return to the referring health care provider for treatment and long-
term management between evaluations or after completion of this protocol. Patients who 
do not have an appropriate health care provider will be referred to one in the community. 
5. MANAGEMENT OF DATA AND SAMPLES
a. Storage
We will follow NIH guidelines to prevent identification of study participants and 
other violations of subject confidentiality. Information will be stored using a confidential 
case number, and no identifiers (name, address, phone number, etc.) will be used that 
could allow direct linking of database information to individual subjects. Secure e-mail 
will be used for all electronic communications of subject information between 


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investigators. Demographic and clinical data will be archived on a password-protected 
server.
All diagnostic information collected from patients will be recorded in the medical 
record and CRIS system according to the policies of the NIH Clinical Center Medical 
Records Department. Research data will be stored on secure servers or in locked cabinets 
in a room that is kept locked when unoccupied. Blood samples will be stored in locked 
freezers in laboratories of protocol investigators. All specimens will be labeled with a 
code that does not include patient identifiers.
Protocol investigators will have access to all clinical data. Laboratory staff of the 
protocol investigators will have access to coded specimens. All imaging data will be 
stored on the NIMH server under password-protected accounts accessible only to the 
principal investigator and directly involved study personnel to preserve subject privacy. 
All data are regularly backed up, either by the NIMH system administrator or by NIMH 
CIT personnel.
Any loss or destruction of samples will be reported to the IRB.
Upon termination of the protocol, data will be deposited in a repository protocol 
to facilitate future data sharing according to the initial protocol consent. Unused samples 
will be destroyed.
b. Data and sample sharing plan
This protocol is not subject to the Genomic Data Sharing (GDS) policy. It does 
not generate “large-scale” human genomic data as defined in the NIH Supplemental 
Information to the GDS Policy. Image and other research data including genetic results 
will be shared with collaborating laboratories outside of NIH: Banner Alzheimer’s 
Institute (Phoenix, AZ) under FWA #00002630, Memory and Aging Center, University 
of California San Francisco (San Francisco, CA) under FWA #00000068, and 
Georgetown University (Washington, DC) under FWA #IORG0000193.
Data may be shared with collaborating laboratories at the NIH or outside of the 
NIH and/or submitted to NIH-designated repositories and databases if consent for sharing 
was obtained. Repositories receiving data from this protocol may be open-access or 
restricted access. 
Data will be stripped of identifiers and may be coded (“de-identified”) or unlinked 
from an identifying code (“anonymized”). When coded data are shared, the key to the 
code will not be provided to collaborators, but will remain at the NIH. Data may be 
shared with investigators and institutions with an FWA or operating under the 
Declaration of Helsinki (DoH) and reported at the time of continuing review. Sharing 
with investigators without an FWA or not operating under the DoH will be submitted for 
prospective IRB approval. Submission to NIH-sponsored or supported databases and 
repositories will be reported at the time of the Continuing Review. Submission to non-
NIH sponsored or supported databases and repositories will be submitted for prospective 
IRB approval. 
Required approvals from the collaborating institution will be obtained and 
materials will be shipped in accordance with NIH and federal regulations.   


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6. ADDITIONAL CONSIDERATIONS
a. Research with investigational drugs or devices
[11C]ER176 will be prepared as described previously under IND 122236 held by 
NIMH IRP. [11C]PIB will be prepared under IND 108861 held by NIMH IRP. All these 
PET radioligands will be synthesized in recently re-established NIMH cGMP facility. 
b. Gene therapy
Not applicable.
7. RISKS AND DISCOMFORTS
Risks include those associated with: a) neurological and neuropsychological 
examinations, b) genetic tests for rs6971 TSPO polymorphism, c) MRI, d) placement of a venous 
and an arterial line, e) arterial blood sampling, f) radiation exposure from [11C]ER176, [11C]PIB, 
and the transmission scan, and g) PET scanning. 
a. Neurological and neuropsychological examinations
The clinical examinations and ratings may be tiring. The neuropsychological tests are not 
harmful, but may be frustrating or stressful. If patients do not wish to do a test, that test will 
not be administered. 
b. Genetic test for rs6971 TSPO polymorphism 
Venous blood sampling for the genetic test is associated with only minimal risk. There is 
usually some discomfort when the needle is inserted for phlebotomy. 
The result of TSPO polymorphism will be used only for later PET data analysis, and not 
shared with study participants or their family. Since the clinical significance of TSPO 
polymorphism is unknown other than different level of binding affinity to PET radioligands, 
the risk would be low even if the genetic information happens to be reidentified. 
c.
MRI
People are at risk for injury from the MRI magnet if they have pacemakers or other 
implanted electrical devices, brain stimulators, some types of dental implants, aneurysm clips 
(metal clips on the wall of a large artery), metallic prostheses (including metal pins and rods, 
heart valves, and cochlear implants), permanent eyeliner, implanted delivery pump, or 
shrapnel fragments. Welders and metal workers are also at risk for injury because of possible 
small metal fragments in the eye of which they may be unaware. Subjects will be screened 
again for these conditions before having any scan, and if they have any, they will not receive 
an MRI scan.  
It is not known if MRI is completely safe for a developing fetus. Therefore, all women of 
childbearing potential will have a urine pregnancy test performed no more than 24 hours 
before each MRI scan. The scan will not be done if the pregnancy test is positive. 
People with fear of confined spaces may become anxious during an MRI. Those with 
back problems may have back pain or discomfort from lying in the scanner. The noise from 
the scanner is loud enough to damage hearing, especially in people who already have hearing 
loss. Everyone having a research MRI scan will be fitted with hearing protection. Subjects 
will be asked to complete an MRI screening form for each MRI scan they have. There are no 
known long-term risks associated with MRI scans.


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d. Placement of a venous and/or an arterial line
Venous catheter insertion can be associated with discomfort, bruising, infection, or clot 
formation. Using proper placement techniques will minimize these risks. In case of tracer 
extravasation, we will stop the study, remove the venous line from the arm, and apply cold to 
the site.
Arterial catheterization has been shown to be a generally safe and reliable method of 
obtaining arterial blood samples (Lockwood, 1985). Placement of a radial arterial catheter 
may cause bruising or infection. There is also a risk of occlusion and microemboli. Over 
3,000 arterial catheters have been placed to date in the PET Department. Of these, only two 
complications requiring physician’s care arose. In the first case, a small radial artery 
aneurysm developed several months later, which was successfully repaired surgically. In the 
second case, a radial artery thrombosis developed 28 days later, which was also successfully 
repaired surgically.
e.
Blood sampling
Participants may have arterial (or venous) blood sampling. The total amount of blood 
drawn will not exceed 400 mL. Blood sampling may lead to the formation of small 
subcutaneous hematomas caused by blood leaking from a punctured blood vessel. Such 
hematomas cause only minor discomfort. They are not dangerous and require no treatment 
other than reassuring the patient. There is also a small risk of infection at the site of the 
needle puncture, which can be readily treated with antibiotic therapy. We will ask 
participants not to donate blood within 8 weeks prior to the study or for 8 weeks following 
the study.  
f.
Radiation exposure risks
Radiation exposure in this protocol will be from [11C]ER176, [11C]PIB, and the 
associated transmission scans. 
In our previous study with [11C]ER176, we calculated the radiation exposure of the 
radioligand from whole-body imaging in nine healthy subjects (Ikawa et al, 2017). The 
radiation exposure (rem) from a 20 mCi injection was: effective dose (0.30), with three 
highest organs kidneys (1.06), spleen (1.00), and lungs (0.77).
According to a published data with [11C]PIB, the radiation exposure (rem) from a 10 mCi 
injection is: effective dose (0.18), with three highest organs gallbladder wall (1.54), liver 
(0.70), and urinary bladder wall (0.61) (Scheinin et al, 2007).
With regard to exposure from the transmission scan, the PET Department recently 
implemented Dr. Innis’s suggestion to decrease the current (amperage) and, thereby, the 
radiation from the CT. We do not need a high resolution (high current) image for attenuation 
correction; a low resolution, like that from a line source, is perfectly adequate to correct 
attenuation in the PET emission scan. With the lowered current, the exposure to the lens of 
the eye is now 0.26 rem, about 1/3 of the previous value.
We wish to maintain flexibility in the choice of PET cameras. Among the various PET 
cameras, PET/CT has the highest exposure. In addition, we routinely include the dose from 
two transmission scans in the event that it must be repeated in a subject. The effective doses 
for two head transmission scan from a PET/CT are ~0.04. Thus, the total effective dose in 
each [11C]ER176 PET scan is 0.34 rem, and each [11C]PIB PET scan is 0.22 rem. Each 
subject will undergo one [11C]ER176 and one [11C]PIB PET scans and the total effective 
dose in six months is 0.56 rem, and may be 1.12 rem in a year if the subject is re-evaluated 


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within a year after the first evaluation. If a subject is fully re-evaluated following the 
schedule in Table 1 after one year, two years, and three to five years from the first evaluation, 
the total effective dose is 2.24 rem in five years, which is well below the limit of 5 rem per 
year established by NIH’s Radiation Safety Committee. All subjects will be asked about any 
prior research participation involving radiation exposure so that the total exposure, in 
combination with the present study, will not exceed an effective dose of 5 rem per year.
g. PET scan
PET scans, which detect injected radioactivity within the body, are not associated with 
any known physical hazards to the subject lying on the table. We routinely use a series of 
procedures to minimize the risk of discomfort during scanning sessions. Namely, the 
procedures are conducted in the presence of trained health professionals to whom participants 
will have ready access should they experience any problems. Participants can communicate 
with the trained health professionals while in the scanner and can be removed from the 
scanner and withdraw from the study at any time if they wish to do so. Participants can also 
request that the operator stop the scan.
8. SUBJECT SAFETY MONITORING
a. Parameters to be monitored
The subjects will be evaluated by a physician upon entry into the protocol and monitored 
by a physician or nurse practitioner throughout their participation in the protocol, including 
during the PET procedure. Pulse rate, blood pressure, respiratory rate, and EKG (either 3- or 
12-lead) will be recorded within three hours before tracer injection and again at about 15, 30, 
and 120 minutes after injection. Laboratory tests including CBC, blood chemistry, and 
urinalysis will be done before and after tracer administration to monitor for changes. 
A credentialed, licensed independent practitioner will be present during the neurological 
examination. Neuropsychological testing will be carried out by trained evaluators.
Testing will be performed in the NIH Clinical Center. It is anticipated that most patients 
will be evaluated as outpatients, but occasionally patients may be admitted to the inpatient 
ward for convenience. Testing will be done in outpatient clinic areas, Neurotesting Unit, day 
hospital, or NMR center with trained medical personnel and emergency equipment 
immediately available.
Procedures may be stopped for any of the following reasons:
1) The patient may request to have the procedure stopped.  
2) In the investigator’s judgment, continuing the procedure would be detrimental to the 
patient’s health and well-being.  
b. Toxicity criteria
Toxicity will be assessed according to the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) v.4.03   http://evs.nci.nih.gov/ftp1/CTCAE/About.html.
c.
Criteria for individual subject withdrawal
A patient may be taken off the protocol for any of the following reasons:
1) The patient may request to withdraw from the protocol at any time they wish.  
2) In the investigator’s judgment, continued participation in the study would be detrimental 
to the patient’s health and well-being.
3) The subject fails to comply with the requirements of the protocol.


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4) The subject's performance on testing is unreliable or they cannot be validly tested, for 
example, if their neurological status changes in such a way as to make interpretation of 
the neurological cause of their impairment impossible.
5) The patient becomes too disabled to travel to NIH for the follow-up evaluation testing. 
6) If a patient no longer has capacity to give consent and does not have a suitable DPA.                                 
9. OUTCOME MEASURES
a. Primary outcome measures
Difference of [11C]ER176 brain uptake between healthy controls and neurodegeneration 
subjects.
b. Secondary outcome measures
1) Disease-specific patterns of [11C]ER176 TSPO brain uptake across different 
neurodegenerative diseases. 
The clinical phenotype of individuals with neurodegenerative diseases differs based on 
disease subtype, which in turn reflects differences in regional neurodegeneration across 
disease subtypes. For example, patients with AD usually exhibit prominent degeneration in 
the parietal cortex and hippocampus, individuals with FTD usually exhibit degeneration in 
the frontal and/or temporal lobes, and individuals with ALS exhibit motor cortex 
degeneration. Because previous studies with 1st and 2nd generation TSPO ligands have shown 
anatomical correlation between areas of cortical neurodegeneration and increased TSPO 
ligand uptake, we anticipate that our 3rd generation TSPO ligand will reveal anatomical 
differences in ligand uptake across different neurodegenerative diseases. We will quantify 
TSPO signals in pre-selected brain regions (for example, parietal cortex, temporal cortex, 
frontal cortex, motor cortex) in each individual, and compare regional TSPO uptake across 
different brain regions as a function of disease subtype. Voxel-based morphometry analysis 
of cortical neurodegeneration will be used to determine if TSPO uptake correlates 
anatomically with regional neurodegeneration.
2) Longitudinal imaging of individual patients shows a correlation between interval change 
of tracer uptake and disease progression.
10. STATISTICAL ANALYSIS
a.
Analysis of data/ study outcomes
PET and MRI scans will be coregistered for anatomic definition of regions of interest. 
SUV will be calculated in various brain regions. Parametric images will be created using 
PMOD software (PMOD Technologies Ltd., Zurich, Switzerland). Brain imaging data 
and/or blood data will be analyzed with compartmental modeling to achieve quantitation of 
each radioligand’s target binding (e.g. VT, VT/fP, SUV ratio) using PMOD software. Cross-
sectional or longitudinal group comparison and correlation analysis with other clinical 
parameters will be conducted in each brain region using either regions-of-interest or voxel-
based image analysis method. Statistical analyses will include ANCOVA for cross-sectional 
comparison among groups, and multilevel mixed model for longitudinal comparison among 
groups. 
b.
Power analysis 
This study is exploratory and we do not know how much would [11C]ER176 brain uptake 
be different between dementia patients and healthy subjects. Thus, a formal power 
calculation is impossible. We request accrual ceiling of 100 subjects with a diagnosis or with 
an increased risk of an age-related neurodegenerative diseases and 100 age and sex-matched 
healthy volunteers. Dropouts will not be replaced.


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With regard to the interim analysis in cross-sectional part of this study, we plan to collect 
approximately 10-15 subjects in each of two groups: healthy controls and patients with 
neurodegenerative diseases. In our previous data from five FTD patients and control 
subjects scanned with [11C]PBR28, which is an older generation TSPO radioligand, the 
estimated effect size was 0.50-0.65 in ANCOVA with TSPO genotype and demographic 
factors as covariates at a significance level of 0.05. If we assume [11C]ER176 has the same 
effect size and variability with [11C]PBR28, 10-15 subjects in two groups could achieve 79-
93% power in the same statistical condition by G*Power program (v 3.0, University of 
Düsseldorf, Germany). 
Power calculation for the longitudinal study is rather limited because we don’t have any 
longitudinal preliminary data in FTD patients. If we assume that longitudinal [11C]ER176 
uptake change in FTD is almost similar to [11C]PBR28 uptake change in AD (approximately 
20% increase within 2.7 years) (Kreisl et al, 2016), a sample size of 100 could achieve 72-
99% power at a significance level of 0.05 in a multilevel mixed model with 4 repeated 
measures in 5 groups (3 subgroups of FTD, AD, and healthy control group) by GLIMMPSE 
Software v 2.0. 
11. HUMAN SUBJECTS PROTECTION
a. Subject selection
The selection of subjects will be based on the inclusion and exclusion criteria. Although 
we will attempt to recruit minority populations and women, ALS and FTD are slightly more 
prevalent in males than females. The frequency of familial neurodegenerative disorders 
occurs with different frequencies in some ethnic populations. For example in the US, ALS is 
more common in Caucasian populations (Garcia-Redondo et al, 2013; Jang et al, 2013; van 
der Zee et al, 2013). Thus, we anticipate inequities in the distribution of race and ethnicity 
compared to the general population because this reflects the disease predilection.
b.
Justification for exclusion of children
Children will be excluded because this study focuses on adult onset neurodegenerative 
disorders. Although children under the age of 18 may be carriers of genes for 
neurodegenerative disorders, they are unlikely to be symptomatic.
c.
Justification for inclusion of other vulnerable subjects and Justification for 
exclusion of other vulnerable subjects 
Vulnerable subjects who exhibit or develop symptoms of cognitive, neurological, and/or 
behavioral dysfunction will be included in this study, because these are a hallmark of the 
diseases under study. 
Protections per Policy 404 will be observed for NIH employees who meet the eligibility 
criteria. NIMH employees/staff and their immediate family members will be excluded from 
the study per NIMH policy.
Pregnant women will be excluded because this protocol involves exposure to ionizing 
radiation. Lactating women will be excluded because radioisotopes may be excreted in milk. 
d. Safeguards for vulnerable populations and sensitive procedures
Some patients who will be enrolled in this protocol may be cognitively impaired and 
unable to give fully informed consent. The patient’s ability to understand will be assessed by 
asking questions about the protocol. If the assessment indicates lack of capacity for consent, 
and the patient already has a DPA or a court-appointed guardian or wishes to designate a 


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DPA to continue in the protocol, consultation with the Human Subjects Protection Unit 
(HSPU)/Ability to Consent Assessment Team (ACAT) will be obtained to determine the 
suitability of the DPA or the court-appointed guardian. If the DPA/court-appointed guardian 
is determined to be acceptable, consent will be obtained from the DPA/court-appointed 
guardian and the patient will be asked to give assent to continue in the study. If the patient 
does not have capacity to consent and does not have an acceptable DPA/court-appointed 
guardian, they will be dropped from the study.
Patients will be assessed for their ability to tolerate scanning procedures by interviews 
with patients/caregivers during the screening process.
Pregnancy testing will be performed before PET and MRI scanning for any participants 
of child-bearing potential. 
Protections per policy 404 will be followed for NIH employees and staff participating in 
this study. 
12. BENEFIT
a.
Benefit
This study offers no direct benefit to individual subjects but will lead to generalizable 
knowledge about RA and myositis, and development of novel inflammatory biomarkers.
13. CONSENT DOCUMENTS AND PROCESS
a. Designation of those obtaining consent
All study investigators obtaining informed consent have completed the NIMH HSPU 
‘Elements of Successful Informed Consent’ training. 
b. Consent procedures 
All participants will receive a verbal explanation in terms suited to their comprehension 
of the purposes, procedures and potential risks of the study and of their rights as research 
participants. Participants will have the opportunity to carefully review the written consent 
form and ask questions regarding this study prior to signing. 
Each subject, and their DPA/court-appointed guardian when applicable, will receive an 
oral and written explanation of the purposes and potential risks of participation in this 
protocol. Specifically, they will be told that (a) the information derived may eventually lead 
to better understanding of their illness; (b) some PET imaging as used in this study might 
offer diagnostic interpretation, which will not be disclosed; (c) a confidential code number 
will be used to ensure that information cannot be linked or traced to any person or family; (d) 
data will be used for research purposes only; and (e) subjects will be given ample opportunity 
to ask questions of the study investigators. 
If, in the opinion of the study staff, PI, or subject, the study participation is adversely 
affecting the subject's emotional and or physical well-being, the individual circumstances 
will be reviewed to determine what additional steps should be taken, such as termination of 
the study and making appropriate referrals to address their underlying health problems. If the 
subject desires not to proceed further with testing, we will end these sessions at any time 
point.
FTLD, AD, and other related neurodegenerative diseases may impair cognition and/or 
behavior and therefore, as a function of their underlying illness, some patients may not have 
the ability to consent for research. We do not wish to exclude such patients from this study 
because they are representative of the patient population.    


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Study team investigators will review the informed consent document with the patient 
followed by a quiz to determine understanding, reasoning, and choice. If the patient does not 
pass the capacity quiz and he/she already has a Durable Power of Attorney (DPA) or a court-
appointed guardian, appropriateness of the DPA as a Legally Authorized Representative 
(LAR) for research participation will be assessed by the Human Subjects Protection Unit 
(HSPU)/Ability to Consent Assessment Team (ACAT), while the appropriateness of a court-
appointed guardian as a LAR would have been already established in a court of law. Once 
appropriateness is established, the LAR will sign the consent form and the patient will sign 
the assent form. 
In the patients who does not pass the capacity quiz and who do not have a DPA or a 
court-appointed guardian, but who are capable of understanding the DPA process when 
assessed by HSPU/ACAT, he/she may assign a DPA to authorize the individual’s research 
participation provided HSPU/ACAT finds the DPA is appropriate. In this case, the assigned 
DPA will sign the consent form and the patient will sign the assent form.
Some subjects who pass the capacity quiz during the first evaluation may be at high risk 
for losing the capacity to consent in future evaluations. These subjects will be asked to sign 
the consent form during the first evaluation. Additionally, during the first evaluation, we will 
also encourage these subjects to complete a Research Advance Directive so we have it 
available should they lose capacity to consent during future evaluations. Besides this, if any 
questions remain even after a subject has passed the capacity quiz, the HSPU/ACAT will be 
consulted. 
The capacity assessment by study team investigators will be repeated and the consent will 
be re-signed for patients and newly diagnosed patient participants returning for the 2nd, 3rd, or 
4th evaluation (see Table 1 under Study Design and Methods section).
In the case that the patient does not have a DPA or a court-appointed guardian, lacks the 
capacity to provide informed consent, and lacks the ability to fill out an NIH Advance 
Directive and assign a holder of a DPA, then the patient will not be included in the study.
In all cases, the HSPU/ACAT will monitor the consenting and/or assenting processes.
 
c.
Consent documents
The consent forms contain all required elements. Four different consent forms are 
submitted with the present protocol: healthy volunteers, patients with neurodegenerative 
diseases, and subjects with increased risk of neurodegenerative diseases.
An assent document is appended for patients without capacity for consent.
14. DATA AND SAFETY MONITORING
a. Data and safety monitor
Data and safety will be monitored by an independent safety monitor (ISM) for this study: 
Dr. Bryan Smith, MD. Dr. Smith is a board-certified neurologist with full clinical privileges 
at the NIH Clinical Center.  
b. Data and safety monitoring plan
The PI will prepare a report on data and safety parameters for the Independent Monitor 
approximately every 12 months. The Independent monitor will provide a written monitoring 
report to be submitted to the IRB at the time of continuing review.


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c.
Criteria for stopping the study or suspending enrollment or procedures
In the event of a serious adverse event related to the research, or if new data shed light on the 
danger of any procedures used, the study team, including the PI, will suspend further testing 
until the IRB and investigators have reviewed the safety information and determined whether 
to continue the study.
15. QUALITY ASSURANCE (QA)
As per ICH-GCP 5.18 and FDA 21 CFR 312.50 clinical protocols are required to be 
adequately monitored. Monitoring for the NIH site will be conducted according to the “NIMH 
Intramural Program Guidelines for Monitoring of Clinical Trials”. Monitors under contract to the 
NIMH OCD ORO will visit the NIH site to monitor aspects of the study in accordance with the 
appropriate regulations and the approved protocol. The objectives of a monitoring visit will be: 
1) to verify the existence of signed informed consent documents and documentation of the ICF 
process for each monitored subject; 2) to verify the prompt and accurate recording of all 
monitored data points, and prompt reporting of all SAEs; 3) to compare abstracted information 
from clinical databases (e.g. CTDB) with individual subjects’ records and source documents 
(subjects’ charts, laboratory analyses and test results, physicians’ progress notes, nurses’ notes, 
and any other relevant original subject information); and 4) to help ensure investigators are in 
compliance with the protocol. The monitors also will inspect the clinical site regulatory files to 
ensure that regulatory requirements (Office for Human Research Protections-OHRP), FDA, and 
applicable guidelines (ICH-GCP) are being followed. During the monitoring visits, the 
investigator (and/or designee) and other study personnel will be available to discuss the study 
progress and monitoring visit.
The investigator (and/or designee) will make study documents (e.g., consent forms, clinical 
database records and pertinent hospital/sources or clinical records readily available for inspection 
by the local IRB, FDA, the site monitors, and the NIMH staff for confirmation of the study data.
A specific protocol monitoring plan will be discussed with the Principal Investigator and 
study staff. The plan will outline the frequency of monitoring visits based on such factors as 
study enrollment, data collection status and regulatory obligations.
16. REPORTING OF UNANTICIPATED PROBLEMS, ADVERSE EVENTS AND 
PROTOCOL DEVIATIONS
Reportable events for this protocol will be tracked and reported in compliance with 
Policy 801.
a. For Research Radioligand Studied under IND
The PI will report SAEs according to the requirements of 21 CFR 312.64(b). The PI will 
record nonserious AEs. 
17. ALTERNATIVES TO PARTICIPATION 
Subjects do not receive any treatment in this study or forego any treatment in order to 
participate in this study. The alternative, therefore, is not to participate. 
18. PRIVACY
All research activities will be conducted in as private a setting as possible.
19. CONFIDENTIALITY
a. For research data and investigator medical records


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Data will be kept in password-protected computers. Only study investigators will 
have access to the data. This study collects sensitive medical information. The PI will 
train study staff regarding obtaining and handling potentially sensitive and private 
information about co-workers through staff discussions and written branch/section 
procedures.
b.
For stored samples
Blood samples will be stored in secured freezers on the NIH campus. Subject name 
and identifying information will be removed and we will assign the samples a code. The 
key to the code will be kept in a separate, secure area. Only study investigators will have 
access to data. 
c.
Special precautions
Every necessary step will be taken to prevent identification of study participants and 
other violations of subject confidentiality. Information will be stored using a confidential 
case number, and no identifiers (name, address, phone number, etc.) will be used that 
could allow direct linking of database information to individual subjects. Where 
temporary linking of information with identifiers is needed, such identifiers will be 
temporarily attached to the data, and will be removed after information has been encoded. 
Secured e-mail will be used for all electronic communications of subject information 
between investigators.
Demographic and clinical data will be archived in EXCEL on a password protected 
PC server and the Clinical Trial Database (CTDB). Clinical Safety Monitoring data will 
be archived together with other data. Laboratory test results will be stored on the CRIS. 
Only study investigators and internal/external monitors will have access to the samples 
and data. De-identified results from this clinical trial will be posted on 
http://www.clinicaltrials.gov. 
20. CONFLICT OF INTEREST
a. Distribution of NIH guidelines
NIH guidelines on conflict of interest have been distributed to all investigators. 
 
b. Conflict of interest 
There are no conflicts-of-interest to report. 
21. RESEARCH AND TRAVEL COMPENSATION 
All participants will be compensated for time and research-related inconveniences. 
Reimbursement is based on NIH standards for time devoted to the research project. 
Participants will be paid for each portion of the study they have completed whether or not 
they opt for early withdrawal from participation. Without any delay of study procedures or 
unanticipated inconvenience, the total possible compensation is $670 in healthy subjects and 
$860 in patients’ group per each evaluation period. If the investigators need to delay study 
procedures or if additional time is need for completion, subjects may receive additional 
compensation in accordance with NIH guidelines.  


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Patients and their escort will receive support for travel, meals and lodging according to 
NIH travel policy guidelines. Lodging may be provided directly or reimbursed according to 
NIH guidelines.
Employees and staff who participate during work hours must have permission from their 
supervisor. NIH employees must either participate outside of work hours or take leave in 
order to receive compensation.  
Healthy subjects
Visit 1 to NIH
Neuropsychological testing
$90
Blood test for genetics
$10
Visit 2 to NIH
PET scanning
$150
Arterial catheter
$60
Antecubital venous catheter(s)
$30
Pregnancy test
$10
Movement restriction
$10
Visit 3 to NIH
PET scanning
$150
Antecubital venous catheter(s)
$30
Pregnancy test
$10
Movement restriction
$10
Visit 4 to NIH
MRI
$100
Pregnancy test
$10
Total
$670
Patients or Subjects with increased risk of neurodegenerative diseases
Visit 1 to NIH
Clinical evaluation and 
screening procedures
$90
Blood test for genetics
$10
Escort fee
$20


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Visit 2 to NIH
Neuropsychological testing
$90
Escort fee
$20
Visit 3 to NIH
PET scanning
$150
Arterial catheter
$60
Antecubital venous catheter(s)
$30
Pregnancy test
$10
Movement restriction
$10
Escort fee
$20
Visit 4 to NIH
PET scanning
$150
Antecubital venous catheter(s)
$30
Pregnancy test
$10
Movement restriction
$10
Escort fee
$20
Visit 5 to NIH
MRI
$100
Pregnancy test
$10
Escort fee
$20
Total
$860
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