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Flortaucipir F18 PET imaging detected Alzheimer's disease pathology with a high degree of accuracy, the case-control A16 study suggested.

Visual reads of [¹⁸F] flortaucipir PET scans corresponded with postmortem neurofibrillary tangle levels of V and VI and with Alzheimer's neuropathologic change, according to Adam Fleisher, MD, chief medical officer of Avid Radiopharmaceuticals in Philadelphia, and colleagues (Avid is a subsidiary of Eli Lilly, which owns a license to the flortaucipir F18 patent).

Flortaucipir F18 PET scans predicted of tau pathology (Braak stage V or VI, indicating tau deposition in wide areas of the neocortex) 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%), they reported in .

Flortaucipir F18 PET also predicted a high level of Alzheimer's -- a combination of neurofibrillary tangles and amyloid plaque scores -- 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%), they added.

The study shows that flortaucipir F18 PET accurately estimates the density and distribution of aggregated tau neurofibrillary tangles in Alzheimer's disease, Fleisher said.

"It also demonstrates that a positive flortaucipir scan is highly associated with sufficient levels of beta-amyloid plaque to meet neuropathologic diagnostic criteria for Alzheimer's disease with high levels of Alzheimer's disease neuropathologic change," Fleisher told MedPage Today.

"These data support the potential for a single biomarker to provide determinant diagnostic information in patients with cognitive impairment being evaluated for Alzheimer's disease," he added. "Amyloid imaging alone can only rule out Alzheimer's disease since both pathologies are required for an Alzheimer's disease diagnosis, and amyloid can be present in the absence of tau neurofibrillary tangles."

The publication in JAMA Neurology comes days after the meeting to discuss Avid's new drug application for flortaucipir F18. "The meeting was cancelled because the issues FDA intended to raise with the advisory committee were resolved by negotiation of the proposed clinical indication," Fleisher said.

In an , William Jagust, MD, of the University of California Berkeley, noted that "the most important implication of this report is obvious: when visually interpreted by raters trained to recognize an Alzheimer's disease pattern, [¹⁸F]flortaucipir PET performed in living patients is likely to detect advanced tau and AD pathologies."

The findings add credence to the diagnostic use of flortaucipir F18 PET to identify Alzheimer's disease, Jagust added. A recent of 719 participants, including people with normal cognition and non-Alzheimer's dementias, found approximately 90% sensitivity and specificity of flortaucipir F18 PET to detect clinical Alzheimer's disease, he noted.

In the A16 study, Fleisher and co-authors enrolled 156 terminally ill older adults from 2015 to 2018 to assess flortaucipir's ability to predict Braak stage V or VI pathology. All participants had flortaucipir F18 PET imaging. Scans were interpreted by five independent nuclear medicine physicians or radiologists.

The researchers also looked at supplemental imaging and pathological samples from 16 historically collected cases and conducted a second study (FR01 validation study) from March 26 to April 26, 2019, in which five new readers assessed the original PET images for comparison to autopsy.

The A16 data included 64 autopsies. Mean delay between PET scan and autopsy was 2.6 months. Of these 64 patients, 49 had dementia, one had mild cognitive impairment, and 14 had normal cognition. Mean age was 82.5; 53% of participants were women and 97% were white. At autopsy, 39 people had tangle pathology consistent with Braak stage V or VI and 25 people showed earlier-stage tau patterns.

To count as a positive scan, flortaucipir 18 signal in Alzheimer's brain regions had to be 65% higher than the cerebellum signal. Success was defined as having at least three of the five readers above the lower bounds of the 95% CI for both sensitivity and specificity of 50% or greater.

Both the A16 study and the FR01 validation study met the pre-specified success criteria. Among the 156 enrolled participants, 14 people experienced at least one treatment-emergent adverse event, most commonly agitation (three people) and headache (two people). Three participants (2%) experienced serious adverse events within 48 hours of the flortaucipir scan, including one death from acute kidney failure, one from malignant neoplasm, and a nonfatal myocardial infarction during hemodialysis. Both death events were reported as not being associated with the study drug or procedure.

The findings have implications for therapeutic trials, Jagust observed. "Amyloid PET has become a mainstay of amyloid beta-lowering trials for both participant selection and treatment monitoring," he wrote. Adding flortaucipir F18 PET may help monitor outcomes of anti-tau therapies or test whether anti-amyloid therapies can affect tau, he noted.

The researchers listed several limitations of their study: the A16 cohort was older than typical patients in the Alzheimer's clinical trial and had more advanced clinical disease. The sample lacked racial and ethnic diversity. PET scan read errors may have been due to imprecise drawing of the cerebellar reference region and could be mitigated in the future by improved reader training or automation, they noted.

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