Devous, Michael D.

AbstractBackgroundPositron emission tomography (PET) imaging with [18F]flortaucipir allows for in‐vivo visualization of aggregated tau in Alzheimer’s disease (AD). The FDA‐approved label for [18F]flortaucipir PET provides a standardized, clinically applicable definition of tau‐PET positivity by visual interpretation. Here, we studied the concordance between this visual interpretation and quantitative approaches employed in research.MethodWe included 2692 participants (cognitively unimpaired [CU] and impaired [CI, MCI or AD dementia]) from four cohorts (Mayo Clinic Study of Aging and ADRC, ADNI, A4, and A05) with available [18F]flortaucipir PET (mean age: 70.2 y, 50.0% females). Three trained readers assessed each [18F]flortaucipir PET scan according to the FDA‐approved method. Visual reads were compared to an established approach for defining tau‐PET positivity based on SUVR values in a temporal meta‐ROI (Jack, et al. Alzheimers Dement. 2017). Previously defined “lenient” (SUVR = 1.22) and “conservative” (SUVR = 1.30) cut‐points were explored. In addition, visual reads were compared to tau‐PET positivity as defined by a scheme based on the expected spatial progression of tau pathology from the medial temporal lobe (MTL) to the temporal neocortex (NEO) (Ossenkoppele, et al. Nat Med. 2022; cut‐points: SUVRMTL = 1.30, SUVRNEO = 1.37).ResultConcordance between visual and quantitative approaches was limited (Figure 1): the “lenient” and MTL‐NEO methods yielded high rates of quantitative‐positive, visual‐negative scans (73‐52% and 26‐18% for CU and CI, respectively), while the “conservative” cut‐point failed to detect 45% and 13% of the CU and CI visual‐positive scans, respectively. The prevalence of tau‐PET positivity in Aβ‐negative individuals was highest with the “lenient” cut‐point (∼24%) and lowest with visual interpretation (∼3%) (Figure 2). Visual‐positive, quantitative‐negative individuals were more frequently Aβ‐positive than visual‐negative, quantitative‐positive individuals (“lenient”: 86% vs 50%, p<0.001; “conservative”: 87% vs 58%, p<0.001; MTL‐NEO: 85% vs 70%, p = 0.005). Among visually‐positive participants, 164 (28%) showed a tau deposition pattern that deviated from the expected MTL to NEO progression (Figure 3).ConclusionVisual and quantitative methods for [18F]flortaucipir PET are non‐exchangeable. Tau‐PET positivity based on visual interpretation aligns better with Aβ‐pathology. A significant number of visually‐positive participants showed a pattern of tau accumulation that deviated from the expected stereotypical spatial progression and was not detected by standard quantitative methods.

AbstractBackgroundPositron emission tomography (PET) imaging with [18F]flortaucipir allows for in‐vivo visualization of aggregated tau in Alzheimer’s disease (AD). The FDA‐approved label for [18F]flortaucipir PET provides a standardized, clinically applicable definition of tau‐PET positivity by visual interpretation. Here, we studied the concordance between this visual interpretation and quantitative approaches employed in research.MethodWe included 2692 participants (cognitively unimpaired [CU] and impaired [CI, MCI or AD dementia]) from four cohorts (Mayo Clinic Study of Aging and ADRC, ADNI, A4, and A05) with available [18F]flortaucipir PET (mean age: 70.2 y, 50.0% females). Three trained readers assessed each [18F]flortaucipir PET scan according to the FDA‐approved method. Visual reads were compared to an established approach for defining tau‐PET positivity based on SUVR values in a temporal meta‐ROI (Jack, et al. Alzheimers Dement. 2017). Previously defined “lenient” (SUVR = 1.22) and “conservative” (SUVR = 1.30) cut‐points were explored. In addition, visual reads were compared to tau‐PET positivity as defined by a scheme based on the expected spatial progression of tau pathology from the medial temporal lobe (MTL) to the temporal neocortex (NEO) (Ossenkoppele, et al. Nat Med. 2022; cut‐points: SUVRMTL = 1.30, SUVRNEO = 1.37).ResultConcordance between visual and quantitative approaches was limited (Figure 1): the “lenient” and MTL‐NEO methods yielded high rates of quantitative‐positive, visual‐negative scans (73‐52% and 26‐18% for CU and CI, respectively), while the “conservative” cut‐point failed to detect 45% and 13% of the CU and CI visual‐positive scans, respectively. The prevalence of tau‐PET positivity in Aß‐negative individuals was highest with the “lenient” cut‐point (∼24%) and lowest with visual interpretation (∼3%) (Figure 2). Visual‐positive, quantitative‐negative individuals were more frequently Aß‐positive than visual‐negative, quantitative‐positive individuals (“lenient”: 86% vs 50%, p<0.001; “conservative”: 87% vs 58%, p<0.001; MTL‐NEO: 85% vs 70%, p = 0.005). Among visually‐positive participants, 164 (28%) showed a tau deposition pattern that deviated from the expected MTL to NEO progression (Figure 3).ConclusionVisual and quantitative methods for [18F]flortaucipir PET are non‐exchangeable. Tau‐PET positivity based on visual interpretation aligns better with Aß‐pathology. A significant number of visually‐positive participants showed a pattern of tau accumulation that deviated from the expected stereotypical spatial progression and was not detected by standard quantitative methods.

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 [ 18 F]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 [ 18 F]flortaucipir PET imaging, and scans were interpreted by 5 independent nuclear medicine physicians or radiologists. Supplemental autopsy [ 18 F]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 [ 18 F]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 [ 18 F]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 [ 18 F]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.

At autopsy, individuals with Alzheimer’s disease (AD) exhibit heterogeneity in the distribution of neurofibrillary tangles in neocortical and hippocampal regions. Subtypes of AD, defined using an algorithm based on the relative number of tangle counts in these regions, have been proposed—hippocampal sparing (relative sparing of the hippocampus but high cortical load), limbic predominant (high hippocampal load but lower load in association cortices), and typical (balanced neurofibrillary tangles counts in the hippocampus and association cortices) AD—and shown to be associated with distinct antemortem clinical phenotypes. The ability to distinguish these AD subtypes from the more typical tau signature in vivo could have important implications for clinical research. Flortaucipir positron emission tomography (PET) images acquired from 45 amyloid-positive participants, defined clinically as mild cognitive impairment or AD, aged 50–92 years, 56% female, and estimated to be Braak V-VI based on their PET pattern of tau pathology, were studied. By translating the neuropathologic algorithm to flortaucipir PET scans, patterns of tau pathology consistent with autopsy findings, and with a similar prevalence, were identified in vivo. 6/45 (13%) participants were identified as hippocampal sparing and 6/45 (13%) as limbic predominant AD subtypes. Hippocampal sparing participants were significantly younger than those assigned to the other two subtypes. Worse performance on delayed recall was associated with increased hippocampal tau signal, and worse performance on the trail making test B-A was associated with lower values of the hippocampus to cortex ratio. Prospective studies can further validate the flortaucipir SUVR cut-points and the phenotype of the corresponding AD subtypes.