Dementia
Conditions
Keywords
Fronto Temporal Dementia, Amyloid, Neuroinflammation
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.
Interventions
DRUG11C-ER176
PET biomarker for inflammation
DRUG11C-PIB
PET biomarker for amyloid
DIAGNOSTIC_TESTPositron Emission Tomography (PET) Scan
Participants underwent PET scan with \[11C\]ER176 and/or 11C-PIB
Sponsors
National Institute of Mental Health (NIMH)
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* INCLUSION CRITERIA: 1\. Patients will be included if they * Are age 18 or older * 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 National Institute of Mental Health (NIMH) Intramural Studies (PI: Dr. Joyce Chung)
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 * Participants must not have substance use disorder or alcohol use disorder. However, alcohol or cannabis use by themselves are not
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Up to 90 minutes during scan | Participants underwent brain positron emission tomography (PET) scan with \[11C\]ER176 and standard uptake value (SUV) was measured over 90 minutes and divided by SUV of the cerebellum to determine difference of \[11C\]ER176 brain uptake |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Healthy Volunteers Participants underwent brain positron emission tomography (PET) scan with \[11C\]ER176 and/or \[11C\]PIB followed by brain magnetic resonance imaging (MRI) | 6 |
| Subjects With Chromosome 9 Open Reading Frame 72 (C9ORF72) Participants underwent brain positron emission tomography (PET) scan with \[11C\]ER176 and/or \[11C\]PIB followed by brain magnetic resonance imaging (MRI) | 3 |
| Subjects With Frontotemporal Dementia (FTD) Participants underwent brain positron emission tomography (PET) scan with \[11C\]ER176 and/or \[11C\]PIB followed by brain magnetic resonance imaging (MRI) | 4 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 |
| Overall Study | Withdrawn due to the 2019 pandemic | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Healthy Volunteers | Subjects With Chromosome 9 Open Reading Frame 72 (C9ORF72) | Subjects With Frontotemporal Dementia (FTD) | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 0 Participants | 1 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 3 Participants | 3 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 3 Participants | 4 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 5 Participants | 3 Participants | 4 Participants | 12 Participants |
| Sex: Female, Male Female | 5 Participants | 2 Participants | 3 Participants | 10 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 3 | 0 / 4 |
| other Total, other adverse events | 0 / 6 | 0 / 3 | 0 / 4 |
| serious Total, serious adverse events | 0 / 6 | 0 / 3 | 0 / 4 |
Outcome results
Primary
Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min)
Participants underwent brain positron emission tomography (PET) scan with \[11C\]ER176 and standard uptake value (SUV) was measured over 90 minutes and divided by SUV of the cerebellum to determine difference of \[11C\]ER176 brain uptake
Time frame: Up to 90 minutes during scan
Population: All participants who completed the PET scan
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Volunteers | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Medial Temporal Lobe, Left | 1.08451324 SUV Ratio (SUVR) | Standard Deviation 0.07643309 |
| Healthy Volunteers | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Parietal Lobe, Right | 1.020202657 SUV Ratio (SUVR) | Standard Deviation 0.069903326 |
| Healthy Volunteers | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Occipital Lobe | 1.054680093 SUV Ratio (SUVR) | Standard Deviation 0.054134358 |
| Healthy Volunteers | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Medial Temporal Lobe, Right | 1.080818839 SUV Ratio (SUVR) | Standard Deviation 0.054571041 |
| Healthy Volunteers | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Temporal Pole, Right | 1.083264223 SUV Ratio (SUVR) | Standard Deviation 0.089675769 |
| Healthy Volunteers | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Lateral Temporal Lobe, Left | 1.000872064 SUV Ratio (SUVR) | Standard Deviation 0.095177072 |
| Healthy Volunteers | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Temporal Pole, Left | 1.174033153 SUV Ratio (SUVR) | Standard Deviation 0.144718189 |
| Healthy Volunteers | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Lateral Temporal Lobe, Right | 0.970093545 SUV Ratio (SUVR) | Standard Deviation 0.056699904 |
| Healthy Volunteers | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Perisylvian Cortex, Right | 1.090685411 SUV Ratio (SUVR) | Standard Deviation 0.071228603 |
| Healthy Volunteers | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Parietal Lobe, Left | 1.073048863 SUV Ratio (SUVR) | Standard Deviation 0.083878696 |
| Healthy Volunteers | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Dorsolateral Prefrontal Cortex | 1.154816988 SUV Ratio (SUVR) | Standard Deviation 0.106845173646 |
| Healthy Volunteers | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Orbitofrontal Lobe | 1.217485758 SUV Ratio (SUVR) | Standard Deviation 0.088415727 |
| Healthy Volunteers | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Dorsomedial Prefrontal Cortex | 0.996700383 SUV Ratio (SUVR) | Standard Deviation 0.071340712 |
| Healthy Volunteers | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Perisylvian Cortex, Left | 1.143352336 SUV Ratio (SUVR) | Standard Deviation 0.102185733 |
| Healthy Volunteers | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Basal Ganglia + Thalamus | 1.005308052 SUV Ratio (SUVR) | Standard Deviation 0.120193318 |
| Subjects With Frontotemporal Dementia (FTD) | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Occipital Lobe | 1.029642393 SUV Ratio (SUVR) | Standard Deviation 0.019495596 |
| Subjects With Frontotemporal Dementia (FTD) | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Dorsomedial Prefrontal Cortex | 0.989731836 SUV Ratio (SUVR) | Standard Deviation 0.093928709 |
| Subjects With Frontotemporal Dementia (FTD) | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Orbitofrontal Lobe | 1.267286508 SUV Ratio (SUVR) | Standard Deviation 0.045403115 |
| Subjects With Frontotemporal Dementia (FTD) | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Parietal Lobe, Left | 1.034142945 SUV Ratio (SUVR) | Standard Deviation 0.01253728 |
| Subjects With Frontotemporal Dementia (FTD) | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Medial Temporal Lobe, Right | 1.126409887 SUV Ratio (SUVR) | Standard Deviation 0.037945068 |
| Subjects With Frontotemporal Dementia (FTD) | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Lateral Temporal Lobe, Left | 1.009331898 SUV Ratio (SUVR) | Standard Deviation 0.006341876 |
| Subjects With Frontotemporal Dementia (FTD) | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Parietal Lobe, Right | 1.031347183 SUV Ratio (SUVR) | Standard Deviation 0.03211946 |
| Subjects With Frontotemporal Dementia (FTD) | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Medial Temporal Lobe, Left | 1.064745227 SUV Ratio (SUVR) | Standard Deviation 0.093063402 |
| Subjects With Frontotemporal Dementia (FTD) | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Lateral Temporal Lobe, Right | 0.953890974 SUV Ratio (SUVR) | Standard Deviation 0.022213838 |
| Subjects With Frontotemporal Dementia (FTD) | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Temporal Pole, Left | 1.105735482 SUV Ratio (SUVR) | Standard Deviation 0.006722645 |
| Subjects With Frontotemporal Dementia (FTD) | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Temporal Pole, Right | 1.133115055 SUV Ratio (SUVR) | Standard Deviation 0.117352842 |
| Subjects With Frontotemporal Dementia (FTD) | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Basal Ganglia + Thalamus | 1.000347379 SUV Ratio (SUVR) | Standard Deviation 0.046553725 |
| Subjects With Frontotemporal Dementia (FTD) | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Dorsolateral Prefrontal Cortex | 1.243023793 SUV Ratio (SUVR) | Standard Deviation 0.20560563 |
| Subjects With Frontotemporal Dementia (FTD) | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Perisylvian Cortex, Left | 1.132367538 SUV Ratio (SUVR) | Standard Deviation 0.049940532 |
| Subjects With Frontotemporal Dementia (FTD) | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Perisylvian Cortex, Right | 1.112003017 SUV Ratio (SUVR) | Standard Deviation 0.09381086 |
| Subjects With Chromosome 9 Open Reading Frame 72 (C9ORF72) | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Temporal Pole, Right | 0.869347972 SUV Ratio (SUVR) | Standard Deviation 0.213594461 |
| Subjects With Chromosome 9 Open Reading Frame 72 (C9ORF72) | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Medial Temporal Lobe, Left | 1.032603069 SUV Ratio (SUVR) | Standard Deviation 0.036960689 |
| Subjects With Chromosome 9 Open Reading Frame 72 (C9ORF72) | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Parietal Lobe, Right | 0.848570905 SUV Ratio (SUVR) | Standard Deviation 0.190475917 |
| Subjects With Chromosome 9 Open Reading Frame 72 (C9ORF72) | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Orbitofrontal Lobe | 1.047192088 SUV Ratio (SUVR) | Standard Deviation 0.146706043 |
| Subjects With Chromosome 9 Open Reading Frame 72 (C9ORF72) | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Dorsomedial Prefrontal Cortex | 0.905523672 SUV Ratio (SUVR) | Standard Deviation 0.048246962 |
| Subjects With Chromosome 9 Open Reading Frame 72 (C9ORF72) | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Dorsolateral Prefrontal Cortex | 0.936561195 SUV Ratio (SUVR) | Standard Deviation 0.190544723 |
| Subjects With Chromosome 9 Open Reading Frame 72 (C9ORF72) | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Basal Ganglia + Thalamus | 0.991325953 SUV Ratio (SUVR) | Standard Deviation 0.017050753 |
| Subjects With Chromosome 9 Open Reading Frame 72 (C9ORF72) | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Occipital Lobe | 0.971346796 SUV Ratio (SUVR) | Standard Deviation 0.048140098 |
| Subjects With Chromosome 9 Open Reading Frame 72 (C9ORF72) | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Parietal Lobe, Left | 0.918176888 SUV Ratio (SUVR) | Standard Deviation 0.114668223 |
| Subjects With Chromosome 9 Open Reading Frame 72 (C9ORF72) | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Lateral Temporal Lobe, Right | 0.868920257 SUV Ratio (SUVR) | Standard Deviation 0.052268097 |
| Subjects With Chromosome 9 Open Reading Frame 72 (C9ORF72) | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Lateral Temporal Lobe, Left | 0.928285311 SUV Ratio (SUVR) | Standard Deviation 0.046290454 |
| Subjects With Chromosome 9 Open Reading Frame 72 (C9ORF72) | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Perisylvian Cortex, Right | 0.941024006 SUV Ratio (SUVR) | Standard Deviation 0.055892402 |
| Subjects With Chromosome 9 Open Reading Frame 72 (C9ORF72) | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Temporal Pole, Left | 0.951727887 SUV Ratio (SUVR) | Standard Deviation 0.184135923 |
| Subjects With Chromosome 9 Open Reading Frame 72 (C9ORF72) | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Medial Temporal Lobe, Right | 1.006852539 SUV Ratio (SUVR) | Standard Deviation 0.041618527 |
| Subjects With Chromosome 9 Open Reading Frame 72 (C9ORF72) | Standard Uptake Value Ratio Compared to the Cerebellum (SUVR) Area Under the Curve (AUC) (60-90min) | Perisylvian Cortex, Left | 1.029305407 SUV Ratio (SUVR) | Standard Deviation 0.066022192 |