Key Points Questions What is the association between flortaucipir positron emission tomography (PET) imaging visual classification using a clinically applicable and US Food and Drug Administration–approved method and 18-month cognitive and functional decline in patients with clinically diagnosed mild cognitive impairment and dementia owing to Alzheimer disease (AD)? Findings In this analysis of 2 open-label clinical trials, visual read of an advanced flortaucipir PET AD pattern was associated with an increased risk of 18-month cognitive and functional decline compared with other scan patterns. Meaning Clinically applicable visual reads of flortaucipir PET scans may provide valuable information regarding the risk of near-term clinical deterioration among patients with clinically diagnosed mild cognitive impairment or dementia owing to AD.

Importance:Positron emission tomography (PET) may increase the diagnostic accuracy and confirm the underlying neuropathologic changes of Alzheimer disease (AD). Objective:To determine the accuracy of antemortem [18F]flortaucipir PET images for predicting the presence of AD-type tau pathology at autopsy. Design, Setting, and Participants:This diagnostic study (A16 primary cohort) was conducted from October 2015 to June 2018 at 28 study sites (27 in US sites and 1 in Australia). Individuals with a terminal illness who were older than 50 years and had a projected life expectancy of less than 6 months were enrolled. All participants underwent [18F]flortaucipir PET imaging, and scans were interpreted by 5 independent nuclear medicine physicians or radiologists. Supplemental autopsy [18F]flortaucipir images and pathological samples were also collected from 16 historically collected cases. A second study (FR01 validation study) was conducted from March 26 to April 26, 2019, in which 5 new readers assessed the original PET images for comparison to autopsy. Main Outcomes and Measures:[18F]flortaucipir PET images were visually assessed and compared with immunohistochemical tau pathology. An AD tau pattern of flortaucipir retention was assessed for correspondence with a postmortem B3-level (Braak stage V or VI) pathological pattern of tau accumulation and to the presence of amyloid-β plaques sufficient to meet the criteria for high levels of AD neuropathological change. Success was defined as having at least 3 of the 5 readers above the lower bounds of the 95% CI for both sensitivity and specificity of 50% or greater. Results:A total of 156 patients were enrolled in the A16 study and underwent [18F]flortaucipir PET imaging. Of these, 73 died during the study, and valid autopsies were performed for 67 of these patients. Three autopsies were evaluated as test cases and removed from the primary cohort (n = 64). Of the 64 primary cohort patients, 34 (53%) were women and 62 (97%) were white; mean (SD) age was 82.5 (9.6) years; and 49 (77%) had dementia, 1 (2%) had mild cognitive impairment, and 14 (22%) had normal cognition. Prespecified success criteria were met for the A16 primary cohort. The flortaucipir PET scans predicted a B3 level of tau pathology, with sensitivity ranging from 92.3% (95% CI, 79.7%-97.3%) to 100.0% (95% CI, 91.0%-100.0%) and specificity ranging from 52.0% (95% CI, 33.5%-70.0%) to 92.0% (95% CI, 75.0%-97.8%). A high level of AD neuropathological change was predicted with sensitivity of 94.7% (95% CI, 82.7%-98.5%) to 100.0% (95% CI, 90.8%-100.0%) and specificity of 50.0% (95% CI, 32.1%-67.9%) to 92.3% (95% CI, 75.9%-97.9%). The FR01 validation study also met prespecified success criteria. Addition of the supplemental autopsy data set and 3 test cases, which comprised a total of 82 patients and autopsies for both the A16 and FR01 studies, resulted in improved specificity and comparable overall accuracy. Among the 156 enrolled participants, 14 (9%) experienced at least 1 treatment-emergent adverse event. Conclusions and Relevance:This study's findings suggest that PET imaging with [18F]flortaucipir could be used to identify the density and distribution of AD-type tau pathology and the presence of high levels of AD neuropathological change, supporting a neuropathological diagnosis of AD.

This study examined the feasibility of using quantitation to augment interpretation of florbetapir PET amyloid imaging.A total of 80 physician readers were trained on quantitation of florbetapir PET images and the principles for using quantitation to augment a visual read. On day 1, the readers completed a visual read of 96 scans (46 autopsy-verified and 50 from patients seeking a diagnosis). On day 2, 69 of the readers reinterpreted the 96 scans augmenting their interpretation with quantitation (VisQ method) using one of three commercial software packages. A subset of 11 readers reinterpreted all scans on day 2 based on a visual read only (VisVis control). For the autopsy-verified scans, the neuropathologist's modified CERAD plaque score was used as the truth standard for interpretation accuracy. Because an autopsy truth standard was not available for scans from patients seeking a diagnosis, the majority VisQ interpretation of the three readers with the best accuracy in interpreting autopsy-verified scans was used as the reference standard.Day 1 visual read accuracy was high for both the autopsy-verified scans (90%) and the scans from patients seeking a diagnosis (87.3%). Accuracy improved from the visual read to the VisQ read (from 90.1% to 93.1%, p < 0.0001). Importantly, access to quantitative information did not decrease interpretation accuracy of the above-average readers (> 90% on day 1). Accuracy in interpreting the autopsy-verified scans also increased from the first to the second visual read (VisVis group). However, agreement with the reference standard (best readers) for scans from patients seeking a diagnosis did not improve with a second visual read, and in this cohort the VisQ group was significantly improved relative to the VisVis group (change 5.4% vs. -1.1%, p < 0.0001).These results indicate that augmentation of visual interpretation of florbetapir PET amyloid images with quantitative information obtained using commercially available software packages did not reduce the accuracy of readers who were already performing with above average accuracy on the visual read and may improve the accuracy and confidence of some readers in clinically relevant cases.

EXPEDITION3 was a placebo-controlled Phase 3 study assessing the effect of solanezumab (a monoclonal antibody that binds soluble amyloid-beta peptides) on cognitive decline over 80 weeks in patients with mild Alzheimer's disease (AD). Topline results showed EXPEDITION 3 did not meet its primary endpoint. A large subset of subjects underwent amyloid PET imaging with florbetapir F 18, and a smaller subset of those also underwent tau PET imaging with flortaucipir F 18. Amyloid PET scanning (20 min scans, 50 min post injection 10 mCi florbetapir F 18) was done at screening and at week 80. SUVr values were calculated from standard atlas-based cortical and whole cerebellar regions. Longitudinal measures were normalized by a subject-specific MRI-derived white matter region to reduce variability in longitudinal amyloid PET estimate. Tau PET scanning (30 min scans, 75 min post injection of 6.5 mCi flortaucipir F 18, aka AV-1451) was done at baseline, week 40 and week 80. Flortaucipir SUVr was calculated from a large atlas-based cortical region normalized by a parametrically derived subject-specific white matter reference region. In this initial analysis, solanezumab treatment effects on florbetapir amyloid and flortaucipir tau PET imaging were evaluated with analysis of co-variance (ANCOVA) and mixed effects model repeated measurement (MMRM), respectively. The association of baseline florbetapir amyloid and flortaucipir tau PET to cognitive and functional decline in the placebo arm was also evaluated. There was no significant difference between solanezumab (n=791) vs placebo (n=805) on change in amyloid SUVr by florbetapir PET (p=0.131). There was a significant increase of flortaucipir PET SUVr over the 80 week study, but there was no significant difference (p=0.685) between solanezumab (n=107) vs placebo (n=97). In the placebo arm, the subgroups with higher levels of baseline tau SUVr, but not amyloid SUVr, declined significantly more (p< 0.05) on ADAS-Cog14 and MMSE, but not on CDR sum of boxes. PET imaging biomarkers are playing an increasing role in better characterizing the enrolled population and understanding the downstream impact of therapeutic drugs on underlying AD pathology. Initial analyses of EXPEDITION 3 data supports the hypothesis that flortaucipir PET may stratify risk of cognitive decline during the trial.

245 Objectives We evaluated whether quantitation by FDA-cleared software as an adjunct to visual interpretation (VisQ method) improves accuracy of florbetapir scan interpretation in lower accuracy readers ( Methods 22 physicians were trained to quantitateflorbetapir images as an adjunct to visual interpretation. Each reader then visually interpreted, without access to quantitation information, 46 florbetapir PET images from subjects autopsied within one year of PET scan and 50 images from patients seeking diagnosis for cognitive decline. Next, the readers reviewed all 96 images again, using a software package to calculate a quantitative estimate (SUVr) of florbetapir activity and applied the VisQ method. For each case, the reader compared the SUVr to normal ranges. For scans in which the initial visual read and quantitative result were discordant, readers reassessed their original interpretation in light of the quantitation, reinspected images and verified ROI placement (a potential source of error in SUVr calculation) to resolve any discordance. They then provided a final VisQ interpretation. Results With visual interpretation, the mean accuracy (compared to pathology truth standard) on the 46 autopsy verified cases was 89.5%. 7 of the 22 readers were identified as lower accuracy ( Conclusions Accuracy and interreader reliability significantly increased after applying the VisQ method that incorporates quantitative estimates of florbetapir PET amyloid binding (SUVr). To test the generality of these findings studies are ongoing with additional software packages.

Objectives This was a phase II trial to assess flurpiridaz F 18 for safety and compare its diagnostic performance for positron emission tomography (PET) myocardial perfusion imaging (MPI) with Tc-99m single-photon emission computed tomography (SPECT) MPI with regard to image quality, interpretative certainty, defect magnitude, and detection of coronary artery disease (CAD) (>= 50% stenosis) on invasive coronary angiography (ICA).Background In pre-clinical and phase I studies, flurpiridaz F 18 has shown characteristics of an essentially ideal MPI tracer.Methods One hundred forty-three patients from 21 centers underwent rest-stress PET and Tc-99m SPECT MPI. Eighty-six patients underwent ICA, and 39 had low-likelihood of CAD. Images were scored by 3 independent, blinded readers.Results A higher percentage of images were rated as excellent/good on PET versus SPECT on stress (99.2% vs. 88.5%, p < 0.01) and rest (96.9% vs. 66.4, p < 0.01) images. Diagnostic certainty of interpretation (percentage of cases with definitely abnormal/normal interpretation) was higher for PET versus SPECT (90.8% vs. 70.9%, p < 0.01). In 86 patients who underwent ICA, sensitivity of PET was higher than SPECT (78.8% vs. 61.5%, respectively, p < 0.02). Specificity was not significantly different (PET: 76.5% vs. SPECT: 73.5%). Receiver-operating characteristic curve area was 0.82 +/- 0.05 for PET and 0.70 +/- 0.06 for SPECT (p = 0.04). Normalcy rate was 89.7% with PET and 97.4% with SPECT (p = NS). In patients with CAD on ICA, the magnitude of reversible defects was greater with PET than SPECT (p = 0.008). Extensive safety assessment revealed that flurpiridaz F 18 was safe in this cohort.Conclusions In this phase 2 trial, PET MPI with flurpiridaz F 18 was safe and superior to SPECT MPI for image quality, interpretative certainty, and overall CAD diagnosis. (J Am Coll Cardiol 2013;61:469-77) (C) 2013 by the American College of Cardiology Foundation

444 Objectives Flurpiridaz F 18 is a novel PET myocardial perfusion imaging (MPI) tracer. In this multi-center Phase 2 study, rest-stress flurpiridaz F 18 PET and SPECT MPI were compared for evaluation of stress induced myocardial perfusion abnormalities in patients (Pts) with coronary artery disease (CAD). Methods 84 Pts from 21 centers, underwent coronary angiography and rest-stress flurpiridaz F 18 PET (PET) and SPECT MPI. Tc-99m labeled tracer was used for all stress and 81% of rest SPECT. The mean age of Pts was 64.5 years (range: 36-85) and 68 were males. In each Pt, 17 myocardial segments were visually scored on rest and stress images by 3 independent, blinded readers. For each Pt, summed difference scores (SDS) were determined from segmental scores. Percent narrowing in each coronary artery was quantitatively and blindly determined and ≥50% luminal diameter narrowing was considered significant. Of the 84 Pts, 52 had CAD and 32 had insignificant CAD or normal coronary arteries. Results There were 105 diseased coronary arteries in 52 patients; 40 left anterior descending, 30 left circumflex and 35 right coronary arteries. In patients with at least one diseased artery, the mean±SD PET SDS score ranged among the three readers from 6.8±5.75 to 9.4±7.51 and the SPECT SDS score ranged from 4.1±4.75 to 5.7±6.51. The differences in SDS scores between PET and SPECT were statistically significant in all readers (p Conclusions These data suggest that as compared to Tc-99m SPECT, flurpiridaz F 18 PET MPI demonstrates more severe and extensive stress induced perfusion abnormalities in myocardial regions that are supplied by diseased coronary arteries and in patients with multivessel CAD. Research Support Lantheus Medical Imagin

18F-labeled BMS747158 is a novel myocardial perfusion imaging tracer that targets mitochondrial complex 1. The objectives of this phase I study were to evaluate radiation dosimetry, biodistribution, human safety, tolerability, and early elimination of 18F activity in urine after injection of a single dose of the tracer at rest in healthy subjects. Methods: Thirteen healthy subjects were injected with 170–244 MBq (4.6–6.6 mCi) of BMS747158 intravenously. Dynamic PET was obtained over the heart for 10 min, followed by sequential whole-body imaging for 5 h. Blood samples and urinary excretion were collected for up to 8 h. Heart rate, electrocardiogram, and blood pressure were monitored before and during imaging. The residence times were determined from multiexponential regression of organ region-of-interest data normalized by injected dose. Absorbed dose estimates for all target organs were determined using MIRD schema with OLINDA/EXM software. Results: The organ receiving the largest mean absorbed dose was the kidneys at 0.066 mSv/MBq (0.24 rem/mCi), followed by the heart wall at 0.048 mSv/MBq (0.18 rem/mCi). The mean effective dose was 0.019 mSv/MBq (0.072 rem/mCi). The heart exhibited high and sustained retention of BMS747158 from the earliest images through approximately 5 h after injection. There were no drug-related adverse events, and the tracer was well tolerated in all subjects. Mean urinary excretion was 4.83 percentage injected dose (range, 0.64–12.41 percentage injected dose). Conclusion: These preliminary data suggest that 18F-labeled BMS747158 appears to be well tolerated and has a unique potential for myocardial perfusion PET.