Imaging pinpointed density, distribution of Alzheimer’s disease-type tau pathology

PET imaging with an investigational tau-targeted radiotracer may be another tool to detect the neuropathologic changes of Alzheimer’s disease (AD), researchers reported.

PET with [18F]flortaucipir identified the density and distribution of AD-type tau pathology, according to Adam S. Fleisher, MD, MAS, of Avid Radiopharmaceuticals in Philadelphia, and co-authors in the A16 Study. Avid/Eli Lilly are the developers of [18F]flortaucipir.

Specifically, [18F]flortaucipir PET scans predicted a neurofibrillary tangle B3 level of tau pathology, with sensitivity ranging from 92.3% (95% CI, 79.7% to 97.3%) to 100% (95% CI, 91.0% to 100%) and specificity ranging from 52% (95% CI, 33.5% to 70%) to 92% (95% CI, 75% to 97.8%),” they wrote in JAMA Neurology.

In addition, a high level of AD neuropathological change was predicted via the flortaucipir PET images with a sensitivity of 94.7% (95% CI, 82.7% to 98.5%) to 100% (95% CI, 90.8% to 100%) and a specificity of 50% (95% CI, 32.1% to 67.9%) to 92.3% (95% CI, 75.9% to 97.9%), the authors stated.

“In appropriate clinical cases of adults who have undergone adequate neurological assessment and have been evaluated for AD or other causes of cognitive decline, PET imaging with [18F]flortaucipir may help in establishing a diagnosis of AD,” they concluded.

In an editorial accompanying the study, William J. Jagust, MD, of the University of California Berkeley wrote that “the most important implication of this report is obvious: when visually interpreted by raters trained to recognize an AD pattern, [18F]flortaucipir PET performed in living patients is likely to detect advanced tau and AD pathologies.”

Jagust also noted that the results have implications for therapeutic trials. He explained that amyloid PET has “become a mainstay” of amyloid-β (Aβ)-lowering trials for selecting participants and for tracking treatment.

“The addition of [18F]flortaucipir PET could be useful in monitoring the outcomes of anti-tau therapies and in testing whether anti-Aß therapies can affect tau,” he stated.

However, Jagust mentioned some shortcomings of the study. First, the raters were trained experts, yet some still had relatively low specificity ratings. Also, the study results did not offer promising results as a tool for early detection, especially in asymptomatic people, he said.

“Almost all of the participants [in the study] who met the Braak stage V to VI pathological criteria had a cognitive impairment, a likely result given the strong association between this Braak stage and cognition,” he wrote. But Braak III to IV pathology still “involves tau in the hippocampus and some neocortical regions and is commonly seen in both older people with normal cognition and those with mild cognitive impairment [MCI] or dementia.”

Only 17 people in the study had intermediate Braak stage III to IV tau pathology, while just four had positive PET scans, so “these results are discouraging for selecting individuals with primary age-related tauopathy or those with intermediate levels of tau pathology who may be in the early stages of AD,” Jagust noted.

Other study limitations included the fact that some of the participants were older than typical symptomatic patients with AD, and they had more advanced clinical disease. There also was a lack of racial/ethnic diversity as 97% of the cohort was white.

The primary study (A16 cohort) was conducted at 27 sites in the U.S., along with one Australian site, between Oct. 2015 and June 2018. The authors enrolled terminally-ill patients (ages >50 years) with a projected life expectancy of ≤6 months.

All 156 patients underwent [18F]flortaucipir PET imaging, and scans were interpreted by five independent nuclear medicine physicians or radiologists. Supplemental autopsy, flortaucipir images, and pathological samples were also utilized from 16 historically collected cases.

A second study (FR01 validation cohort) was conducted from March 2019 to April 2019, where five new readers reinterpreted the original [18F]flortaucipir PET images for comparison with autopsy.

The neuropathological assessment from autopsies was performed by two clinicians using National Institute on Aging-Alzheimer Association (NIA-AA)) diagnostic scoring guidelines, and who were blinded to the clinical and imaging results. A neurofibrillary tangle (NFT) score of B3, including Braak stages V and VI, was considered positive.

Of the 156-patient cohort, 73 died during the study and 67 valid autopsies were performed, three of which were evaluated as test cases and removed from the A16 cohort. The researchers used the autopsy results and scans of the three test cases to confirm and assess the adequacy of the planned trial methods. The mean delay between scan and autopsy was 2.6 months.

The final 64-patient A16 cohort was 53% women with a mean age of 82.5 years. More than three-fourths (77%) had dementia, while 22% had normal cognition and (2%) had MCI.

The [18F]flortaucipir PET images were visually interpreted by the readers and were then 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 Aß plaques sufficient to meet NIA-AA criteria for high levels of AD neuropathological change.

Success was defined as having at least three of five readers above the lower bounds of the 95% CI for both sensitivity and specificity of ≥50%.

Study investigators reported 14 of the 156 enrolled patients, 9%, experienced at least one treatment-emergent adverse event (AE), including headache and agitation. While 2% of participants experienced serious AEs within 48 hours of the flortaucipir scan, including one death from acute kidney failure and one from malignant neoplasm, neither were associated with the study drug or procedure, according to the authors.

  1. Visual reads of [18F]flortaucipir PET scans corresponded with postmortem Braak stages V and VI levels of cortical neurofibrillary tangles and high levels of Alzheimer’s disease neuropathological change.

  2. PET imaging with [18F]flortaucipir may be able to identify the density and distribution of AD-type tau pathology.

Shalmali Pal, Contributing Writer, BreakingMED™

The studies were funded by Avid Radiopharmaceuticals/Eli Lilly. Many co-authors are employees of one or both companies.

Fleisher reported a relationship with Eli Lilly. Co-authors reported support from, and/or relationships with, the NIH, the Robert Wood Johnson Foundation, The Elsie and Marvin Dekelboum Family Foundation, the Liston Family Foundation, the Robert H. and Clarice Smith and Abigail van Buren Alzheimer’s Disease Research Program, the Alexander Family Foundation, the GHR Foundation, Dr Corinne Schuler, the Mayo Foundation for Medical Education and Research, and the Nantz Funds of the Houston Methodist Foundation.Avid Radiopharmaceuticals, Vivid Genomics and Prothena Biosciences, Banner Alzheimer’s Institute, GE Healthcare, Eli Lilly, and Seimens Molecular Imaging.

Jagust reported relationships with Genentech, Banner Alzheimer Institute, CuraSen, and Bioclinica.

Cat ID: 481

Topic ID: 95,481,282,404,464,485,494,33,361,255,60,481