Alzheimer's Disease
Conditions
Brief summary
This study is designed to test the relationship between measurements of brain amyloid using florbetapir F 18 PET imaging and true levels of amyloid plaque density as measured by histopathological assessment. The study will address the following specific aims: 1. To expand the number of subjects included in the A07 (NCT00857415) trial correlation analysis (measuring the correlation between the global visual rating of brain amyloid plaque density on an independent blinded read of the florbetapir F 18 PET scan and the cortical amyloid plaque density at autopsy as assessed by histopathology for subjects in the autopsy cohort). 2. To determine the sensitivity and specificity of an independent blinded visual read assessment of the florbetapir F 18 PET scan (Aβ+ or Aβ-) versus the final blinded neuropathological assessment made at autopsy.
Interventions
DRUGflorbetapir F 18
No study drug administered in this trial. Study subjects previously dosed with 18F-AV-45 in study 18F-AV-45-A07 (NCT00857415) are followed to autopsy in this extension study.
Sponsors
Avid Radiopharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Subjects are enrolled in this study if they: * Met entrance criteria and were enrolled and imaged in trial 18F-AV-45-A07 (NCT00857415) * Gave informed consent for the 18F-AV-45-A07 (NCT00857415) study procedures and brain donation consistent with the legal requirements of the State in which they are enrolled and the State in which they die * Consent to participate in the 18F-AV-45-A16 (NCT01447719) extension protocol, if required by the IRB * Reconfirm their consent to a research brain autopsy, if required by the IRB.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Correlation of Florbetapir-PET Image and Amyloid Plaque Density | at autopsy within 24 months of florbetapir PET scan | Spearman's rank order correlation of the median visual read of the florbetapir-PET image and the amyloid plaque density assessed post-mortem by quantitative immunohistochemistry (IHC) averaged across 6 brain regions (precuneus, parietal cortex, frontal cortex, temporal cortex, posterior cingulate, anterior cingulate). Spearman's rank order correlation ranges from -1 to +1. A value of -1 indicates perfect negative correlation, and a value of +1 indicates a perfect positive correlation. |
| Sensitivity Analysis in All Autopsy Population | at autopsy within 24 months of florbetapir PET scan | Sensitivity of florbetapir-PET scan to detect moderate to frequent amyloid plaques. Plaque density was calculated using CERAD (Consortium to Establish a Registry for AD) criteria. Florbetpir-PET scans were read by five independent readers blinded to clinical information using the binary read method (amyloid positive/negative). |
| Specificity Analysis in All Autopsy Population | at autopsy within 24 months of florbetapir PET scan | Specificity of florbetapir-PET scan to detect moderate to frequent amyloid plaques. Plaque density was calculated using CERAD criteria. Florbetpir-PET scans were read by five independent readers blinded to clinical information using the binary read method (amyloid positive/negative). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Specificity Analysis in Subjects With Autopsy Within 1 Year of Scan | at autopsy within 12 months of florbetapir PET scan | Specificity of florbetapir-PET scan to detect moderate to frequent amyloid plaques. Plaque density was calculated using CERAD criteria. Florbetpir-PET scans were read by five independent readers blinded to clinical information using the binary read method (amyloid positive/negative). |
| Sensitivity Analysis in Subjects With Autopsy Within 1 Year of Scan | at autopsy within 12 months of florbetapir PET scan | Sensitivity of florbetapir-PET scan to detect moderate to frequent amyloid plaques. Plaque density was calculated using CERAD criteria. Florbetpir-PET scans were read by five independent readers blinded to clinical information using the binary read method (amyloid positive/negative). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Median Sensitivity and Specificity vs. CERAD Diagnosis | at autopsy within 24 months of florbetapir PET scan | Median sensitivity and specificity for 5 independent readers to detect moderate to frequent amyloid plaques (per CERAD criteria). |
| Individual Reader Results (Autopsy Within 1 Year of Scan) | at autopsy within 12 months of florbetapir PET scan | Reader results (number of false negatives and number of false positives) for blinded independent readers. There were a total of 28 positive and 18 negative scans based on histopathology at autopsy. |
| Individual Reader Results (All Scans With Autopsy) | at autopsy within 24 months of florbetapir PET scan | Reader results (number of false negatives and number of false positives) for blinded independent readers. There were a total of 39 positive and 20 negative scans based on histopathology at autopsy. |
Countries
United States
Participant flow
Pre-assignment details
Demographic results are only provided for primary analysis populations of subjects who came to autopsy. Demographic characteristics for the entire population of 152 subjects are reported with the results of study A07 (NCT00857415).
Participants by arm
| Arm | Count |
|---|---|
| All Autopsy Population Group of subjects with valid images who came to autopsy within 2 years of scan | 59 |
| Total | 59 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Family withdrew autopsy consent | 7 |
| Overall Study | Image acquisition failure | 2 |
| Overall Study | Invalid image or not imaged | 3 |
| Overall Study | Subject still living at end of study | 79 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | All Autopsy Population |
|---|---|
| Age, Continuous | 79.4 years STANDARD_DEVIATION 12.64 |
| Baseline clinical diagnosis AD diagnosis | 29 participants |
| Baseline clinical diagnosis Mild cognitive impairment | 5 participants |
| Baseline clinical diagnosis No history of cognitive impairment | 12 participants |
| Baseline clinical diagnosis Other dementing disorder | 13 participants |
| Region of Enrollment United States | 59 participants |
| Sex: Female, Male Female | 30 Participants |
| Sex: Female, Male Male | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 |
Outcome results
Primary
Correlation of Florbetapir-PET Image and Amyloid Plaque Density
Spearman's rank order correlation of the median visual read of the florbetapir-PET image and the amyloid plaque density assessed post-mortem by quantitative immunohistochemistry (IHC) averaged across 6 brain regions (precuneus, parietal cortex, frontal cortex, temporal cortex, posterior cingulate, anterior cingulate). Spearman's rank order correlation ranges from -1 to +1. A value of -1 indicates perfect negative correlation, and a value of +1 indicates a perfect positive correlation.
Time frame: at autopsy within 24 months of florbetapir PET scan
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Subjects With Moderate or Frequent Plaques at Autopsy | Correlation of Florbetapir-PET Image and Amyloid Plaque Density | 0.76 Correlation coefficient |
Comparison: Spearman's Rank Order Correlation of the median semiquantitative read (three readers) and the quantitative IHC measurement of cortical amyloid plaque density averaged across six brain regions.p-value: <0.000195% CI: [0.62, 0.85]Spearman's Rank Order Correlation test
Primary
Sensitivity Analysis in All Autopsy Population
Sensitivity of florbetapir-PET scan to detect moderate to frequent amyloid plaques. Plaque density was calculated using CERAD (Consortium to Establish a Registry for AD) criteria. Florbetpir-PET scans were read by five independent readers blinded to clinical information using the binary read method (amyloid positive/negative).
Time frame: at autopsy within 24 months of florbetapir PET scan
Population: 39 of 59 subjects from all autopsy population had moderate to frequent neuritic plaques at autopsy
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Subjects With Moderate or Frequent Plaques at Autopsy | Sensitivity Analysis in All Autopsy Population | Florbetapir PET positive (majority interpretation) | 36 participants |
| Subjects With Moderate or Frequent Plaques at Autopsy | Sensitivity Analysis in All Autopsy Population | Florbetapir PET negative (majority interpretation) | 3 participants |
Comparison: Proportion of subjects who had a positive scan based on majority of 5 blinded readers95% CI: [78, 98]
Primary
Specificity Analysis in All Autopsy Population
Specificity of florbetapir-PET scan to detect moderate to frequent amyloid plaques. Plaque density was calculated using CERAD criteria. Florbetpir-PET scans were read by five independent readers blinded to clinical information using the binary read method (amyloid positive/negative).
Time frame: at autopsy within 24 months of florbetapir PET scan
Population: 20 of 59 subjects from the all autopsy population had no or sparse neuritic plaques at autopsy
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Subjects With Moderate or Frequent Plaques at Autopsy | Specificity Analysis in All Autopsy Population | Florbetapir PET positive (majority interpretation) | 0 participants |
| Subjects With Moderate or Frequent Plaques at Autopsy | Specificity Analysis in All Autopsy Population | Florbetapir PET negative (majority interpretation) | 20 participants |
Comparison: Proportion of subjects who had a negative scan based on majority of 5 blinded readers95% CI: [80, 100]
Secondary
Sensitivity Analysis in Subjects With Autopsy Within 1 Year of Scan
Sensitivity of florbetapir-PET scan to detect moderate to frequent amyloid plaques. Plaque density was calculated using CERAD criteria. Florbetpir-PET scans were read by five independent readers blinded to clinical information using the binary read method (amyloid positive/negative).
Time frame: at autopsy within 12 months of florbetapir PET scan
Population: 28 of 46 subjects who died within 1 year of scan had moderate to frequent neuritic plaques at autopsy
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Subjects With Moderate or Frequent Plaques at Autopsy | Sensitivity Analysis in Subjects With Autopsy Within 1 Year of Scan | Florbetapir PET positive (majority interpretation) | 27 participants |
| Subjects With Moderate or Frequent Plaques at Autopsy | Sensitivity Analysis in Subjects With Autopsy Within 1 Year of Scan | Florbetapir PET negative (majority interpretation) | 1 participants |
Comparison: Proportion of subjects who had a positive scan based on majority of 5 blinded readers95% CI: [80, 100]
Secondary
Specificity Analysis in Subjects With Autopsy Within 1 Year of Scan
Specificity of florbetapir-PET scan to detect moderate to frequent amyloid plaques. Plaque density was calculated using CERAD criteria. Florbetpir-PET scans were read by five independent readers blinded to clinical information using the binary read method (amyloid positive/negative).
Time frame: at autopsy within 12 months of florbetapir PET scan
Population: 18 of 46 subjects who died within 1 year of scan had no or sparse neuritic plaques at autopsy
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Subjects With Moderate or Frequent Plaques at Autopsy | Specificity Analysis in Subjects With Autopsy Within 1 Year of Scan | Florbetapir PET positive (majority interpretation) | 0 participants |
| Subjects With Moderate or Frequent Plaques at Autopsy | Specificity Analysis in Subjects With Autopsy Within 1 Year of Scan | Florbetapir PET negative (majority interpretation) | 18 participants |
Comparison: Proportion of subjects who had a negative scan based on majority of 5 blinded readers95% CI: [78, 100]
Other Pre-specified
Individual Reader Results (All Scans With Autopsy)
Reader results (number of false negatives and number of false positives) for blinded independent readers. There were a total of 39 positive and 20 negative scans based on histopathology at autopsy.
Time frame: at autopsy within 24 months of florbetapir PET scan
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Subjects With Moderate or Frequent Plaques at Autopsy | Individual Reader Results (All Scans With Autopsy) | Reader 5 - False Positives | 2 florbetapir PET scans |
| Subjects With Moderate or Frequent Plaques at Autopsy | Individual Reader Results (All Scans With Autopsy) | Reader 3 - False Positives | 1 florbetapir PET scans |
| Subjects With Moderate or Frequent Plaques at Autopsy | Individual Reader Results (All Scans With Autopsy) | Reader 1 - False Negatives | 3 florbetapir PET scans |
| Subjects With Moderate or Frequent Plaques at Autopsy | Individual Reader Results (All Scans With Autopsy) | Reader 1 - False Positives | 1 florbetapir PET scans |
| Subjects With Moderate or Frequent Plaques at Autopsy | Individual Reader Results (All Scans With Autopsy) | Reader 2 - False Negatives | 2 florbetapir PET scans |
| Subjects With Moderate or Frequent Plaques at Autopsy | Individual Reader Results (All Scans With Autopsy) | Reader 2 - False Positives | 1 florbetapir PET scans |
| Subjects With Moderate or Frequent Plaques at Autopsy | Individual Reader Results (All Scans With Autopsy) | Reader 3 - False Negatives | 5 florbetapir PET scans |
| Subjects With Moderate or Frequent Plaques at Autopsy | Individual Reader Results (All Scans With Autopsy) | Reader 4 - False Negatives | 3 florbetapir PET scans |
| Subjects With Moderate or Frequent Plaques at Autopsy | Individual Reader Results (All Scans With Autopsy) | Reader 4 - False Positives | 0 florbetapir PET scans |
| Subjects With Moderate or Frequent Plaques at Autopsy | Individual Reader Results (All Scans With Autopsy) | Reader 5 - False Negatives | 12 florbetapir PET scans |
Other Pre-specified
Individual Reader Results (Autopsy Within 1 Year of Scan)
Reader results (number of false negatives and number of false positives) for blinded independent readers. There were a total of 28 positive and 18 negative scans based on histopathology at autopsy.
Time frame: at autopsy within 12 months of florbetapir PET scan
Population: Includes only those subjects with time from scan to autopsy less than one year.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Subjects With Moderate or Frequent Plaques at Autopsy | Individual Reader Results (Autopsy Within 1 Year of Scan) | Reader 1 - False Negatives | 1 florbetapir PET scans |
| Subjects With Moderate or Frequent Plaques at Autopsy | Individual Reader Results (Autopsy Within 1 Year of Scan) | Reader 5 - False Negatives | 7 florbetapir PET scans |
| Subjects With Moderate or Frequent Plaques at Autopsy | Individual Reader Results (Autopsy Within 1 Year of Scan) | Reader 1 - False Positives | 1 florbetapir PET scans |
| Subjects With Moderate or Frequent Plaques at Autopsy | Individual Reader Results (Autopsy Within 1 Year of Scan) | Reader 2 - False Negatives | 0 florbetapir PET scans |
| Subjects With Moderate or Frequent Plaques at Autopsy | Individual Reader Results (Autopsy Within 1 Year of Scan) | Reader 2 - False Positives | 1 florbetapir PET scans |
| Subjects With Moderate or Frequent Plaques at Autopsy | Individual Reader Results (Autopsy Within 1 Year of Scan) | Reader 3 - False Negatives | 3 florbetapir PET scans |
| Subjects With Moderate or Frequent Plaques at Autopsy | Individual Reader Results (Autopsy Within 1 Year of Scan) | Reader 3 - False Positives | 0 florbetapir PET scans |
| Subjects With Moderate or Frequent Plaques at Autopsy | Individual Reader Results (Autopsy Within 1 Year of Scan) | Reader 4 - False Negatives | 1 florbetapir PET scans |
| Subjects With Moderate or Frequent Plaques at Autopsy | Individual Reader Results (Autopsy Within 1 Year of Scan) | Reader 4 - False Positives | 0 florbetapir PET scans |
| Subjects With Moderate or Frequent Plaques at Autopsy | Individual Reader Results (Autopsy Within 1 Year of Scan) | Reader 5 - False Positives | 2 florbetapir PET scans |
Other Pre-specified
Median Sensitivity and Specificity vs. CERAD Diagnosis
Median sensitivity and specificity for 5 independent readers to detect moderate to frequent amyloid plaques (per CERAD criteria).
Time frame: at autopsy within 24 months of florbetapir PET scan
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Subjects With Moderate or Frequent Plaques at Autopsy | Median Sensitivity and Specificity vs. CERAD Diagnosis | Sensitivity | 92 percentage of true positives/negatives |
| Subjects With Moderate or Frequent Plaques at Autopsy | Median Sensitivity and Specificity vs. CERAD Diagnosis | Specificity | 95 percentage of true positives/negatives |