Alzheimer's Disease
Conditions
Keywords
inflammation, aging, mild cognitive impairment
Brief summary
This study is being done to learn about inflammation and amyloid in Alzheimer's disease. A type of brain scan called a PET scan is used measure 1) inflammation and 2) abnormal accumulation of a the amount of a certain protein fragment called beta-amyloid (plaques) in the brain. These are thought to be involved in Alzheimer's disease. The investigators will also perform brain MRI and do tests to measure the participants' memory and thinking.
Detailed description
This study is being done to determine the relationship between inflammation, cognitive impairment, and amyloid burden in elderly subjects with different clinical and biomarker profiles of Alzheimer's disease (AD). Participants will undergo amyloid PET imaging with 18F-Florbetaben with target number of completers being 15 amyloid-positive elders with impairment, 15 amyloid-positive elders with normal cognition, 15 amyloid-negative elders with impairment, and 15 amyloid-negative elders with normal cognition. Subjects will undergo screen that includes neuropsychological testing, brain MRI, and PET imaging with 18F-florbetaben to define the above 4 groups. Subjects will have 11C-PBR28 PET imaging to measure the 18 kDa translocator protein (a marker of inflammation). Subjects will have the option to have lumbar puncture performed to measure CSF concentrations of amyloid,tau, phospho-tau, and inflammatory markers.
Interventions
DRUG11C-PBR28
11C-PBR28 is a PET radioligand that binds to the 18 kDa translocator protein (TSPO), a marker of inflammation. 11C-PBR28 has previously been administered in humans. 11C-PBR28 will be administered at activity of up to 20 mCi per injection.
DRUG18F-Florbetaben
18F-Florbetaben (Neuraceq) has FDA approval for human use in evaluation of Alzheimer's disease. 18F-Florbetaben will be administered at activity up to 8.1 mCi per injection.
PROCEDURELumbar puncture (optional)
Subjects have the option to have lumbar puncture performed for the measurement of inflammatory markers in cerebrospinal fluid.
Sponsors
National Institute on Aging (NIA)
Patrick Lao
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
1. Age 60 and older. 2. Meet criteria for either a) amnestic mild cognitive impairment (single or mixed domain) or mild Alzheimer's disease, or b) have no cognitive impairment based on history, exam, neuropsychological testing, and consensus diagnosis. MCI and mild AD patients must have Clinical Dementia Rating scale score of 0.5 or 1. Unimpaired subjects must have Clinical Dementia Rating scale score of 0. 3. Subjects unable to provide informed consent must have a surrogate decision maker 4. Written and oral fluency in English or Spanish. 5. Able to participate in all scheduled evaluations and to complete all required tests and procedures. 6. In the opinion of the investigator, the subject must be considered likely to comply with the study protocol and to have a high probability of completing the study.
Exclusion criteria
1. Past or present history of certain brain disorders other than MCI or AD. 2. Certain significant medical conditions, which make study procedures of the current study unsafe. 3. Contraindication to MRI scanning. 4. Conditions precluding entry into the scanners (e.g., morbid obesity, claustrophobia, etc.). 5. Exposure to research related radiation in the past year that, when combined with this study, would place subjects above the allowable limits. 6. Low affinity binding on TSPO genetic screen. 7. Participation in the last year in a clinical trial for a disease modifying drug for AD. 8. Inability to have a catheter in subject's vein for the injection of radioligand. 9. Inability to have blood drawn from subject's veins.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 11C-PBR28 Binding | Up to 1 year from screening | In vivo quantification radioligand binding to TSPO expression on microglia in the brain, reported as standardized uptake value ratio (SUVR). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 18F-Florbetaben Binding | Up to 1 year from screening | In vivo quantification of radioligand binding to Amyloid-Beta protein in the brain, reported as standardized uptake value ratio (SUVR). |
| Cerebral Spinal Fluid (CSF) Biomarkers | Up to 1 year from screening | Protein analysis of cerebral spinal fluid. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Amyloid-positive With Cognitive Impairment (AD) Amyloid-positive patients who already have cognitive impairment at the time of enrollment | 24 |
| Amyloid-positive Without Impairment (Preclinical AD) Cognitively normal subjects who are amyloid-positive | 8 |
| Amyloid-negative With Cognitive Impairment Participants with cognitive impairment due to suspected non-AD pathophysiology | 11 |
| Amyloid-negative Without Impairment (Normal Aging) Cognitively normal subjects who are amyloid-negative on PET and lack signs of neurodegeneration from other biomarkers | 17 |
| Total | 60 |
Baseline characteristics
| Characteristic | Amyloid-positive With Cognitive Impairment (AD) | Amyloid-positive Without Impairment (Preclinical AD) | Amyloid-negative With Cognitive Impairment | Amyloid-negative Without Impairment (Normal Aging) | Total |
|---|---|---|---|---|---|
| Age, Continuous | 65.2 years STANDARD_DEVIATION 8.7 | 73.8 years STANDARD_DEVIATION 3.1 | 75.8 years STANDARD_DEVIATION 9.8 | 67.6 years STANDARD_DEVIATION 3.8 | 68.8 years STANDARD_DEVIATION 8.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 0 Participants | 1 Participants | 2 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants | 8 Participants | 10 Participants | 15 Participants | 54 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 1 Participants | 6 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 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 | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 24 Participants | 6 Participants | 10 Participants | 11 Participants | 51 Participants |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 7 Participants | 5 Participants | 20 Participants |
| Sex: Female, Male Male | 20 Participants | 4 Participants | 4 Participants | 12 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 24 | 0 / 8 | 0 / 11 | 0 / 17 |
| other Total, other adverse events | 0 / 24 | 0 / 8 | 0 / 11 | 2 / 17 |
| serious Total, serious adverse events | 0 / 24 | 0 / 8 | 0 / 11 | 0 / 17 |
Outcome results
Primary
11C-PBR28 Binding
In vivo quantification radioligand binding to TSPO expression on microglia in the brain, reported as standardized uptake value ratio (SUVR).
Time frame: Up to 1 year from screening
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amyloid-positive With Cognitive Impairment (AD) | 11C-PBR28 Binding | 1.25 SUVR | Standard Deviation 0.18 |
| Amyloid-positive Without Impairment (Preclinical AD) | 11C-PBR28 Binding | 1.15 SUVR | Standard Deviation 0.16 |
| Amyloid-negative With Cognitive Impairment | 11C-PBR28 Binding | 1.16 SUVR | Standard Deviation 0.16 |
| Amyloid-negative Without Impairment (Normal Aging) | 11C-PBR28 Binding | 1.02 SUVR | Standard Deviation 0.13 |
Secondary
18F-Florbetaben Binding
In vivo quantification of radioligand binding to Amyloid-Beta protein in the brain, reported as standardized uptake value ratio (SUVR).
Time frame: Up to 1 year from screening
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amyloid-positive With Cognitive Impairment (AD) | 18F-Florbetaben Binding | 1.64 SUVR | Standard Deviation 0.18 |
| Amyloid-positive Without Impairment (Preclinical AD) | 18F-Florbetaben Binding | 1.51 SUVR | Standard Deviation 0.14 |
| Amyloid-negative With Cognitive Impairment | 18F-Florbetaben Binding | 1.17 SUVR | Standard Deviation 0.14 |
| Amyloid-negative Without Impairment (Normal Aging) | 18F-Florbetaben Binding | 1.12 SUVR | Standard Deviation 0.06 |
Secondary
Cerebral Spinal Fluid (CSF) Biomarkers
Protein analysis of cerebral spinal fluid.
Time frame: Up to 1 year from screening
Population: Some participants did not wish to do this procedure, so data was not collected from these participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amyloid-positive With Cognitive Impairment (AD) | Cerebral Spinal Fluid (CSF) Biomarkers | 3.14 ng/mL | Standard Deviation 1.69 |
| Amyloid-positive Without Impairment (Preclinical AD) | Cerebral Spinal Fluid (CSF) Biomarkers | 4.21 ng/mL | Standard Deviation 1.74 |
| Amyloid-negative With Cognitive Impairment | Cerebral Spinal Fluid (CSF) Biomarkers | 3.26 ng/mL | Standard Deviation 2.99 |
| Amyloid-negative Without Impairment (Normal Aging) | Cerebral Spinal Fluid (CSF) Biomarkers | 2.05 ng/mL | Standard Deviation 0.57 |