Flortaucipir PET Tracer Accurately Supports Alzheimer Disease Pathology

Adam S. Fleisher, MD, MAS, chief medical officer, Avid Radiopharmaceuticals, Eli Lilly

Adam S. Fleisher, MD, MAS

Data from a study of [¹⁸F]flortaucipir positron emission tomography (PET) suggest that the tau tracer can support a pathological diagnosis of Alzheimer disease by identifying the underlying presence of neurofibrillary tangles (NFTs) at the B3 level (Braak stages V to VI) and high levels of Alzheimer disease neuropathologic change (ADNC) per National Institute on Aging—Alzheimer Association (NIA–AA) criteria.¹

The diagnostic study included 82 individuals with or without dementia from the A16 study,² and ultimately, the visual reads of [¹⁸F]flortaucipir PET scans corresponded with postmortem Braak stages V and VI levels of cortical NFTs with high levels of sensitivity and at least moderate specificity. The 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). Elevated levels of ADNC 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).

“In appropriate clinical cases of adults who have undergone adequate neurological assessment and have been evaluated for Alzheimer disease or other causes of cognitive decline, PET imaging with [¹⁸F]flortaucipir may help in establishing a diagnosis of Alzheimer disease,” study author Adam S. Fleisher, MD, MAS, chief medical officer, Avid Radiopharmaceuticals, Eli Lilly, and colleagues wrote. “Further research is required into the potential value of [¹⁸F]flortaucipir imaging in earlier clinicopathological stages of disease.”

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The study included 156 patients enrolled in the A16 study who underwent [¹⁸F]flortaucipir PET imaging from October 2015 to June 2018 at 28 study sites. Of those, 67 of the 73 who died during the study had valid autopsies. Three autopsies were evaluated as test cases and removed from the primary cohort, and supplemental autopsy [¹⁸F]flortaucipir images and pathological samples were also collected from 16 historically collected cases. A second study—the 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.

Of the 64 patients in the primary cohort from A16, the mean age was 82.5 (standard deviation [SD], 9.6) years. In total, 77% (n = 49) had dementia, 2% (n = 1) had mild cognitive impairment (MCI), and 22% (n = 14) had normal cognition. Among the 156 enrolled participants, 9% (n = 14) experienced at least 1 treatment-emergent adverse event (AE).

The [¹⁸F]flortaucipir PET images were visually assessed and then compared with immunohistochemical tau pathology. An AD tau pattern of flortaucipir retention was assessed for correspondence with both 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 ADNC. Success was defined as having ≥3 of the 5 readers above the lower bounds of the 95% CI for both sensitivity and specificity of 50% or greater.

For the full cohort data set (n = 81), Fleisher et al. noted that all 5 readers met the success criteria. For NFTs, sensitivity ranged from 89.1% (95% CI, 77.0—95.3) to 93.5% (95% CI, 82.5–97.8) and specificity from 66.7% (95% CI, 50.3–79.8) to 94.4% (95% CI, 81.9–98.5). For a high level of ADNC, sensitivity ranged from 95.1% (95% CI, 83.9–98.7) to 97.6% (95% CI 87.4–99.6) and specificity from 65.9% (95% CI, 50.5–78.4) to 90.2% (95% CI, 77.5–96.1)

For the A16 data set, similar results were observed. B3 level NFTs sensitivity was 89.1% (95% CI, 77.0—95.3) and specificity was 86.1% (95% CI, 71.3–93.9), and high ADNC level sensitivity was 95.1% (95% CI, 83.9–98.7) and specificity was 82.9% (95% CI, 68.7–91.5).

Fleisher and colleagues noted that the full autopsy data set included 26 impaired participants with a non-Alzheimer clinical diagnosis, of which 19 had less than high levels of ADNC at autopsy. In 16 of those 19, the [¹⁸F]flortaucipir PET images were accurately interpreted as not being consistent with an Alzheimer pattern.

In an accompanying editorial, William J. Jagust, MD, noted that while the study’s most pertinent implication is obvious—[¹⁸F]flortaucipir PET is likely to detect advanced tau and Alzheimer disease pathologies in living patients—this is the “next step in validating methods that are crucial to improving our understanding of brain aging and Alzheimer.”³

“These results also have implications for the research arena, especially therapeutic trials. Amyloid PET has become a mainstay of Aβ-lowering trials for both participant selection and treatment monitoring,” Jagust noted. “The addition of [¹⁸F]flortaucipir PET could be useful in monitoring the outcomes of anti-tau therapies and in testing whether anti-Aβ therapies can affect tau. In addition, because tau compared with Aβ is more strongly associated with neurodegeneration and cognition, [¹⁸F]flortaucipir PET could provide a useful measure of disease stage or progression for both participant selection and outcome assessment.”

REFERENCES

1. Fleisher AS, Pontecorvo MJ, Devous Sr MD, et al. Positron Emission Tomography Imaging With [18F]flortaucipir and Postmortem Assessment of Alzheimer Disease Neuropathologic Changes. JAMA Neurol. Published online April 27, 2020. doi:10.1001/jamaneurol.2020.0528

2. Clark CM, Pontecorvo MJ, Beach TG, et al; AV-45-A16 Study Group. Cerebral PET with florbetapir compared with neuropathology at autopsy for detection of neuritic amyloid-β plaques: a prospective cohort study. Lancet Neurol. 2012;11(8):669-678. doi:10.1016/S1474-4422(12)70142-4

3. Jagust WJ. Imaging Tau Pathology—The Next Step. JAMA Neurol. Published online April 27, 2020. doi:10.1001/jamaneurol.2020.0520