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Cited by 448Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsMedical Imaging Techniques and Applications

Positron Emission Tomography Imaging With [ 18 F]flortaucipir and Postmortem Assessment of Alzheimer Disease Neuropathologic Changes

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Fleisher, Adam S., Pontecorvo, Michael J., Devous, Michael D., Lu, Ming, Arora, Anupa K., Truocchio, Stephen P., Aldea, Patricia, Flitter, Matthew +23 more·2020·JAMA Neurology
DOI 10.1001/jamaneurol.2020.0528PMC PMC7186920
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Abstract

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.

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Written from the paper’s full text.

TL;DR

In a prospective autopsy-validated diagnostic study, [18F]flortaucipir PET visual reads detected B3-level tau neurofibrillary tangles and high Alzheimer disease neuropathologic change with high sensitivity and moderate-to-high specificity. A second independent reader validation study confirmed the findings, and quantitative SUVR analysis also showed high specificity.

Key findings

In the A16 primary cohort (n = 64), flortaucipir PET met prespecified success criteria for detecting B3 NFT score: sensitivity ranged from 92.3% (95% CI, 79.7%-97.3%) to 100.0% (95% CI, 91.0%-100.0%) and specificity from 52.0% (95% CI, 33.5%-70.0%) to 92.0% (95% CI, 75.0%-97.8%) across 5 readers; majority read sensitivity was 92.3% and specificity 80.0%. For high ADNC, sensitivity ranged from 94.7% (95% CI, 82.7%-98.5%) to 100.0% (95% CI, 90.8%-100.0%) and specificity from 50.0% (95% CI, 32.1%-67.9%) to 92.3% (95% CI, 75.9%-97.9%); majority read sensitivity was 94.7% and specificity 80.8%.

  • In the full autopsy data set (n = 82), B3 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%); high 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%). Majority read results were B3 sensitivity 89.1% and specificity 86.1%, and high ADNC sensitivity 95.1% and specificity 82.9%.
  • The FR01 validation study also met prespecified success criteria. Interrater reliability was high: A16 all read scans (n = 105) showed 89.9% agreement (Fleiss κ, 0.80; P < .001), A16 primary cohort scans (n = 64) showed 88.4% agreement (Fleiss κ, 0.74; P < .001), and FR01 (n = 82) had Fleiss κ 0.82 (P < .001).
  • Quantitative SUVR analysis in 60 of 67 scans meeting quality criteria established an optimal cut point greater than 1.113, yielding sensitivity of 84.2% for B3 NFT score and 86.5% for high ADNC, with 100% specificity for both. Safety: 14 of 156 enrolled participants (9%) had at least 1 treatment-emergent adverse event; agitation (n = 3) and headache (n = 2) were most common, and 3 participants (2%) had serious adverse events within 48 hours, including 2 deaths reported as not associated with study drug or procedure.

Methods

This multicenter diagnostic study (A16 primary cohort; NCT02516046) enrolled participants older than 50 years with terminal illness and projected life expectancy less than 6 months, ranging from clinically normal cognition to dementia, at 28 sites (27 US, 1 Australia) from October 2015 through June 2018. The A16 primary cohort included 64 participants with valid evaluable flortaucipir images and autopsy; the full autopsy data set included 82 cases (64 primary cohort, 2 evaluable test cases, 16 supplemental historically collected autopsy cases), and a separate FR01 validation study (NCT03901092) reinterpreted 82 images.

  • PET imaging was acquired for 20 minutes (4 × 5-minute frames) beginning approximately 80 minutes after intravenous 370 (±10%) MBq [18F]flortaucipir; scans were visually rated by 5 blinded nuclear medicine physicians or radiologists as negative, moderate, or advanced AD tau pattern, and quantitative SUVRs used a PERSI white matter reference region and a weighted neocortical target.
  • Neuropathological assessment was performed by 2 blinded authors using NIA–AA guidelines, with AT8 immunohistochemistry for Braak NFT staging and 6E10 for amyloid plaque; primary comparisons were flortaucipir PET classification against B3 NFT score (Braak V-VI) and high ADNC level. Analyses calculated sensitivity, specificity, accuracy, predictive values, and likelihood ratios per reader and for majority read, with Wilson 95% CIs, Fleiss and simple κ statistics, and ROC analysis for the SUVR cut point.

Limitations

The paper states that the A16 cohort was older than typical symptomatic AD trial populations, had more advanced clinical disease with only 1 case of mild cognitive impairment, and lacked racial/ethnic diversity; visual reads showed best accuracy for the most advanced NFT tau load and ADNC, and earlier AD stages may meet intermediate pathological criteria or have neuritic plaque without substantial tau. The paper also states that up to 2 of 5 readers did not meet statistical specificity criteria for primary outcomes, largely from overcalling small noncontiguous temporal lobe activity, and that read errors may relate to imprecise cerebellar reference region drawing; subcortical [18F]flortaucipir retention appeared to represent off-target binding of unknown source.

  • The paper states that larger sample sizes are needed to confirm high specificity for distinguishing AD from non-AD tau pathologies.
  • Evident from the text: the primary cohort lacked structural imaging and used PET-to-PET registration; the full autopsy data set combined primary, test-case, and historically collected supplemental cases, and cognitively normal participants could remain eligible for autopsy regardless of time from scan to autopsy, which may introduce heterogeneity.

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Crossref · 10.1001/jamaneurol.2020.0528

Cites

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Claims the paper makes

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  • Findingown data

    Flortaucipir PET imaging demonstrated statistically significant sensitivity and specificity for detecting an NFT score of B3, as determined by the interpretations of at least 3 of the 5 physician readers.

    “The A16 primary cohort analysis of 64 patients met prespecified success criteria, with flortaucipir PET imaging demonstrating statistically significant sensitivity and specificity for detecting both NFT score of B3 and high level of ADNC, as determined by the interpretations of at least 3 of the 5 physican readers of the PET scans (Table 2; Figure 2).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Tau pathology does not change substantially between antemortem flortaucipir positron emission tomography imaging and postmortem assessment.
  • Findingown data

    Among the 156 enrolled participants, 14 (9%) experienced at least 1 treatment-emergent adverse event.

    “Among the 156 enrolled participants, 14 (9%) experienced at least 1 treatment-emergent adverse event (eTable 2 in the Supplement).”
    Quote in the paperNot a substantial claim
  • Findingown data

    The A16 primary cohort analysis of 64 patients met prespecified success criteria.

    “The A16 primary cohort analysis of 64 patients met prespecified success criteria, with flortaucipir PET imaging demonstrating statistically significant sensitivity and specificity for detecting both NFT score of B3 and high level of ADNC, as determined by the interpretations of at least 3 of the 5 physican readers of the PET scans (Table 2; Figure 2).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Tau pathology does not change substantially between antemortem flortaucipir positron emission tomography imaging and postmortem assessment.
  • Findingown data

    Flortaucipir PET imaging demonstrated statistically significant sensitivity and specificity for detecting a high level of Alzheimer disease neuropathologic change, as determined by the interpretations of at least 3 of the 5 physician readers.

    “The A16 primary cohort analysis of 64 patients met prespecified success criteria, with flortaucipir PET imaging demonstrating statistically significant sensitivity and specificity for detecting both NFT score of B3 and high level of ADNC, as determined by the interpretations of at least 3 of the 5 physican readers of the PET scans (Table 2; Figure 2).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Tau pathology does not change substantially between antemortem flortaucipir positron emission tomography imaging and postmortem assessment.
  • Findingown data

    In the FR01 study (n=82), Fleiss κ was 0.82 (P<.001).

    “In the FR01 study (n = 82), the Fleiss κ value was 0.82 (P < .001).”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 30
  • May combine two claims. 32

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    After removal of the 3 test cases, the remaining 64 participants were included in the A16 primary cohort, with autopsy occurring a mean (SD) 16.2 (15.0) hours from the recorded time of death and 2.6 (2.14) months after [18F]flortaucipir imaging.

    “After removal of the 3 test cases, the remaining 64 participants were included in the A16 primary cohort, with autopsy occurring a mean (SD) 16.2 (15.0) hours from the recorded time of death and 2.6 (2.14) months after [18F]flortaucipir imaging.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Before study completion, 73 participants died within 9 months of imaging, of whom 67 (92%) had a valid study autopsy.

    “Before study completion, 73 participants died within 9 months of imaging, of whom 67 (92%) had a valid study autopsy (eFigure 2 in the Supplement).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The majority read analysis for the A16 primary cohort showed B3 level sensitivity of 92.3% (95% CI, 79.7%-97.3%) and specificity of 80.0% (95% CI, 60.9%-91.1%).

    “The majority read analysis for the A16 primary cohort showed similar results for B3 level sensitivity (92.3%; 95% CI, 79.7%-97.3%) and specificity (80.0%; 95% CI, 60.9%-91.1%), and for high ADNC level sensitivity (94.7%; 95% CI, 82.7%-98.5%) and specificity (80.8%; 95% CI, 62.1%-91.5%) (Table 2).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Tau pathology does not change substantially between antemortem flortaucipir positron emission tomography imaging and postmortem assessment.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    A total of 156 participants were enrolled, underwent flortaucipir imaging, and were included in a safety assessment.

    “A total of 156 participants were enrolled in this diagnostic study, underwent flortaucipir imaging, and were included in a safety assessment (Table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Three participants (2%) experienced serious adverse events within 48 hours of the flortaucipir scan: death from acute kidney failure, death from malignant neoplasm, and nonfatal myocardial infarction during hemodialysis.

    “Three participants (2%) experienced serious adverse events within 48 hours of the flortaucipir scan: death from acute kidney failure, death from malignant neoplasm, and nonfatal myocardial infarction during hemodialysis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    For the B3 level, sensitivity ranged from 92.3% (95% CI, 79.7%-97.3%) to 100.0% (95% CI, 91.0%-100.0%), and specificity ranged from 52.0% (95% CI, 33.5%-70.0%) to 92.0% (95% CI, 75.0%-97.8%).

    “For the B3 level, sensitivity ranged from 92.3% (95% CI, 79.7%-97.3%) to 100.0% (95% CI, 91.0%-100.0%), and specificity ranged from 52.0% (95% CI, 33.5%-70.0%) to 92.0% (95% CI, 75.0%-97.8%).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Tau pathology does not change substantially between antemortem flortaucipir positron emission tomography imaging and postmortem assessment.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Agitation (n=3) and headache (n=2) were the most common treatment-emergent adverse events.

    “Agitation (n = 3) and headache (n = 2) were the most common of these events.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Of the 64 primary cohort patients, 49 (77%) had dementia, 1 (2%) had mild cognitive impairment, and 14 (22%) had normal cognition.

    “Of the 64 primary cohort patients, 49 (77%) had dementia, 1 (2%) had mild cognitive impairment, and 14 (22%) had normal cognition.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Of the 49 patients with dementia, 33 had a clinical diagnosis of Alzheimer disease and 16 had a non-Alzheimer disease clinical diagnosis at baseline.

    “Of the 49 patients with dementia, 33 had a clinical diagnosis of AD based on medical history and 16 had non-AD clinical diagnosis at baseline (eTable 1 in the Supplement).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    For the high ADNC level, sensitivity was 94.7% (95% CI, 82.7%-98.5%) to 100.0% (95% CI, 90.8%-100.0%) and specificity was 50.0% (95% CI, 32.1%-67.9%) to 92.3% (95% CI, 75.9%-97.9%).

    “For the high ADNC level, sensitivity was 94.7% (95% CI, 82.7%-98.5%) to 100.0% (95% CI, 90.8%-100.0%) and specificity was 50.0% (95% CI, 32.1%-67.9%) to 92.3% (95% CI, 75.9%-97.9%) (Table 2).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Tau pathology does not change substantially between antemortem flortaucipir positron emission tomography imaging and postmortem assessment.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Both death events were reported by the investigator as severe adverse events that were not associated with the study drug or procedure.

    “Both death events were reported by the investigator as severe adverse events that were not associated with the study drug or procedure.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    For quantitative analysis, 60 (90%) of 67 scans (primary cohort plus test cases) met scan quality criteria for SUVR calculation; 6 scans (9%) had severe inter- and within-frame motion, and 1 scan (2%) was acquired outside the allowable postinjection acquisition time window.

    “For quantitative analysis, 60 (90%) of 67 scans (primary cohort plus test cases) met the scan quality criteria for SUVR calculation; 6 scans (9%) had severe inter- and within-frame motion, and 1 scan (2%) was acquired outside of the allowable postinjection acquisition time window.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the full autopsy data set, success criteria were met for high level of ADNC, with sensitivity ranging from 95.1% to 97.6% and specificity ranging from 65.9% to 90.2%.

    “Success criteria were also met for high level of ADNC with sensitivity ranging from 95.1% (95% CI, 83.9%-98.7%) to 97.6% (95% CI 87.4%-99.6%) and specificity ranging from 65.9% (95% CI, 50.5%-78.4%) to 90.2% (95% CI, 77.5%-96.1%) (Table 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The FR01 validation study met prespecified success criteria for both the FR01 primary cohort (n=64) and full autopsy data set (n=82), demonstrating statistically significant sensitivity and specificity (95% CI lower limits >50%) of flortaucipir PET for detecting B3 NFT and high ADNC by at least 3 of 5 readers.

    “The FR01 validation study also met the prespecified success criteria for both the FR01 primary cohort (n = 64) and full autopsy data set (n = 82) analyses, demonstrating statistically significant sensitivity and specificity (above 95% CI lower limits >50%) of flortaucipir PET imaging for detecting both the NFT score of B3 NFT and high ADNC level by at least 3 of the 5 readers.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the A16 full autopsy data set majority read analysis, B3 level sensitivity was 89.1% and specificity 86.1%; high ADNC level sensitivity 95.1% and specificity 82.9%.

    “The majority read analysis for the A16 full autopsy data set showed similar results for B3 level sensitivity (89.1%; 95% CI, 77.0%-95.3%) and specificity (86.1%; 95% CI, 71.3%-93.9%), and for high ADNC level sensitivity (95.1%; 95% CI, 83.9%-98.7%) and specificity (82.9%; 95% CI, 68.7%-91.5%) (Table 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    For the A16 study, all read scans (n=105) showed 89.9% agreement (Fleiss κ=0.80; P<.001); primary cohort scans (n=64) showed 88.4% agreement (Fleiss κ=0.74; P<.001).

    “For the A16 study, all read scans (n = 105 of enrolled patients) showed 89.9% agreement (Fleiss κ, 0.80; P < .001); the primary cohort scans (n = 64) showed 88.4% agreement (Fleiss κ, 0.74; P < .001).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the full autopsy data set (n = 82), all 5 readers met success criteria (lower confidence limits of sensitivity and specificity >50%) for detecting NFT score B3, with sensitivity ranging from 89.1% to 93.5% and specificity ranging from 66.7% to 94.4%.

    “For the full autopsy data set (n = 82), all 5 readers met success criteria with lower confidence limits of sensitivity and specificity greater than 50% for the NFT score of B3 with sensitivity ranging from 89.1% (95% CI, 77.0%-95.3%) to 93.5% (95% CI, 82.5%-97.8%) and specificity ranging from 66.7% (95% CI, 50.3%-79.8%) to 94.4% (95% CI, 81.9%-98.5%).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The quantitative cut point >1.113 yielded sensitivity 84.2% for NFT score B3 and 86.5% for high ADNC, with 100% specificity for both autopsy measures.

    “This quantitative cut point yielded a sensitivity of 84.2% for an NFT score of B3 and 86.5% for a high level of ADNC, with 100% specificity for both autopsy measures (eFigure 3 in the Supplement).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    Although flortaucipir retention in the neocortex appeared to match the distribution of aggregated tau in AD at autopsy, flortaucipir retention in subcortical structures also appeared to represent off-target binding.

    “Although [18F]flortaucipir retention in the neocortex appeared to match the distribution of aggregated tau in AD at autopsy, [18F]flortaucipir retention in subcortical structures also appeared to represent off-target binding.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Neuropathological criteria for the diagnosis of Alzheimer disease were established by the National Institute on Aging-Alzheimer Association and were updated in 2012.

    “Neuropathological criteria for the diagnosis of AD were established by the National Institute on Aging–Alzheimer Association (NIA–AA)4 and were updated in 2012 to reflect the current thinking on AD pathological assessment.5,6”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [4] Hyman BT. The neuropathological diagnosis of Alzheimer’s disease: clinical-pathological studies. Neurobiol Aging. 1997; 18(4)(suppl): S27- S32. doi: 10.1016/S0197-4580(97)00066-3 9330982

      Not checked in the free run.

    • cites [5] Hyman BT, Phelps CH, Beach TG,. National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement. 2012; 8(1): 1- 13. doi: 10.1016/j.jalz.2011.10.007 22265587 PMC3266529 source

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    • cites [6] Jack CR Jr, Bennett DA, Blennow K,; Contributors. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018; 14(4): 535- 562. doi: 10.1016/j.jalz.2018.02.018 29653606 PMC5958625 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Pathological accumulation of aggregated hyperphosphorylated tau protein in neurons and glia underlies a wide range of neurodegenerative disorders.

    “Pathological accumulation of aggregated hyperphosphorylated tau protein in neurons and glia underlies a wide range of neurodegenerative disorders.11”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Querfurth HW, LaFerla FM. Alzheimer’s disease. N Engl J Med. 2010; 362(4): 329- 344. doi: 10.1056/NEJMra0909142 20107219 source

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  • Classified as probably not a substantial claim.

    Premisecitation

    Alzheimer disease is now commonly accepted as a clinicopathological entity that can be diagnosed without histopathological examination, in the presence of appropriate biomarker evidence of an underlying condition.

    “With the advent of biomarkers that enable in vivo identification of underlying AD pathological conditions, and the acceptance that AD begins years before the emergence of cognitive impairment, AD is now commonly accepted as a clinicopathological entity7,8 that can be diagnosed without histopathological examination, in the presence of appropriate biomarker evidence of an underlying condition.6,8,9”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [7] Dubois B, Feldman HH, Jacova C,. Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol. 2010; 9(11): 1118- 1127. doi: 10.1016/S1474-4422(10)70223-4 20934914

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    • cites [8] McKhann GM, Knopman DS, Chertkow H,. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011; 7(3): 263- 269. doi: 10.1016/j.jalz.2011.03.005 21514250 PMC3312024 source

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    • cites [6] Jack CR Jr, Bennett DA, Blennow K,; Contributors. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018; 14(4): 535- 562. doi: 10.1016/j.jalz.2018.02.018 29653606 PMC5958625 source

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    • cites [9] Knopman DS, Petersen RC, Jack CR Jr. A brief history of “Alzheimer disease”: multiple meanings separated by a common name. Neurology. 2019; 92(22): 1053- 1059. doi: 10.1212/WNL.0000000000007583 31028129 PMC6556090

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Tau is an intracellular protein that binds to and stabilizes axonal microtubules in neurons, thereby regulating intracellular transport.

    “Tau is an intracellular protein that binds to and stabilizes axonal microtubules in neurons, thereby regulating intracellular transport.10”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Avila J, Lucas JJ, Perez M, Hernandez F. Role of tau protein in both physiological and pathological conditions. Physiol Rev. 2004; 84(2): 361- 384. doi: 10.1152/physrev.00024.2003 15044677

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Alzheimer disease is characterized by aggregated tau-containing neurofibrillary tangles and by amyloid plaque composed largely of aggregated amyloid-β fragments.

    “Alzheimer disease (AD) is characterized by aggregated tau–containing neurofibrillary tangles (NFTs)1 and by amyloid plaque composed largely of aggregated amyloid-β (Aβ) fragments.2,3”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [1] Goedert M, Jakes R. Mutations causing neurodegenerative tauopathies. Biochim Biophys Acta. 2005; 1739(2-3): 240- 250. doi: 10.1016/j.bbadis.2004.08.007 15615642

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    • cites [2] Kidd M. Paired helical filaments in electron microscopy of Alzheimer’s disease. Nature. 1963; 197: 192- 193. doi: 10.1038/197192b0 14032480

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    • cites [3] Masters CL, Multhaup G, Simms G, Pottgiesser J, Martins RN, Beyreuther K. Neuronal origin of a cerebral amyloid: neurofibrillary tangles of Alzheimer’s disease contain the same protein as the amyloid of plaque cores and blood vessels. EMBO J. 1985; 4(11): 2757- 2763. doi: 10.1002/j.1460-2075.1985.tb04000.x 4065091 PMC554575

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Large autopsy studies have demonstrated a high sensitivity and specificity for amyloid positron emission tomography to distinguish individuals with subsequent autopsy findings of no or sparse neuritic plaque from individuals with moderate to frequent plaque.

    “For example, large autopsy studies have demonstrated a high sensitivity and specificity for amyloid PET to distinguish individuals with subsequent autopsy findings of no or sparse neuritic plaque from individuals with moderate to frequent plaque.16,17,18”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [16] Clark CM, Pontecorvo MJ, Beach TG,; 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 22749065 source

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    • cites [17] Curtis C, Gamez JE, Singh U,. Phase 3 trial of flutemetamol labeled with radioactive fluorine 18 imaging and neuritic plaque density. JAMA Neurol. 2015; 72(3): 287- 294. doi: 10.1001/jamaneurol.2014.4144 25622185 source

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    • cites [18] Sabri O, Sabbagh MN, Seibyl J,; Florbetaben Phase 3 Study Group. Florbetaben PET imaging to detect amyloid beta plaques in Alzheimer’s disease: phase 3 study. Alzheimers Dement. 2015; 11(8): 964- 974. doi: 10.1016/j.jalz.2015.02.004 25824567 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Neuropathological assessment was performed by 2 authors blinded to clinical and imaging results.

    “Neuropathological assessment was performed by 2 authors (T.G.B. and T.J.M.) blinded to clinical and imaging results and using NIA–AA diagnostic scoring guidelines.5,40”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In vitro autoradiography studies of brain tissue from symptomatic patients with Alzheimer disease have found that [18F]flortaucipir signal correlates with the level of paired helical filament tau by immunohistochemistry and binds with a dissociation constant in the approximately 0.5 nM range.

    “In vitro autoradiography studies of brain tissue from symptomatic patients with AD have found that [18F]flortaucipir signal correlates with the level of paired helical filament tau by immunohistochemistry and binds with a dissociation constant in the approximately 0.5 nM range.20”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Xia CF, Arteaga J, Chen G,. [(18)F]T807, a novel tau positron emission tomography imaging agent for Alzheimer’s disease. Alzheimers Dement. 2013; 9(6): 666- 676. doi: 10.1016/j.jalz.2012.11.008 23411393

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Studies comparing antemortem tau positron emission tomography imaging with autopsy have begun assessing the ability of flortaucipir to detect underlying neurofibrillary tangles in Alzheimer disease and non-Alzheimer disease dementias.

    “Studies comparing antemortem tau PET imaging with autopsy have begun assessing the ability of flortaucipir to detect underlying NFTs in AD and non-AD dementias.25,26,27,28,29,30,31,32,33”
    Quote in the paperSubstantial claim0 of 9 sources checked
    • cites [25] Lowe VJ, Lundt ES, Albertson SM,. Tau-positron emission tomography correlates with neuropathology findings. Alzheimers Dement. 2020; 16(3): 561- 571. doi: 10.1016/j.jalz.2019.09.079 31784374 PMC7067654 source

      Not checked in the free run.

    • cites [26] Josephs KA, Whitwell JL, Tacik P,. [18F]AV-1451 tau-PET uptake does correlate with quantitatively measured 4R-tau burden in autopsy-confirmed corticobasal degeneration. Acta Neuropathol. 2016; 132(6): 931- 933. doi: 10.1007/s00401-016-1618-1 27645292 PMC5107140 source

      Not checked in the free run.

    • cites [27] Marquié M, Normandin MD, Meltzer AC,. Pathological correlations of [F-18]-AV-1451 imaging in non-Alzheimer tauopathies. Ann Neurol. 2017; 81(1): 117- 128. doi: 10.1002/ana.24844 27997036 PMC5319193 source

      Not checked in the free run.

    • cites [28] Marquié M, Verwer EE, Meltzer AC,. Lessons learned about [F-18]-AV-1451 off-target binding from an autopsy-confirmed Parkinson’s case. Acta Neuropathol Commun. 2017; 5(1): 75. doi: 10.1186/s40478-017-0482-0 29047416 PMC5648451 source

      Not checked in the free run.

    • cites [29] McMillan CT, Irwin DJ, Nasrallah I,. Multimodal evaluation demonstrates in vivo 18F-AV-1451 uptake in autopsy-confirmed corticobasal degeneration. Acta Neuropathol. 2016; 132(6): 935- 937. doi: 10.1007/s00401-016-1640-3 27815633 PMC5154298 source

      Not checked in the free run.

    • cites [30] Smith R, Puschmann A, Schöll M,. 18F-AV-1451 tau PET imaging correlates strongly with tau neuropathology in MAPT mutation carriers. Brain. 2016; 139(pt 9): 2372- 2379. doi: 10.1093/brain/aww163 27357347 PMC4995360 source

      Not checked in the free run.

    • cites [31] Smith R, Schöll M, Honer M, Nilsson CF, Englund E, Hansson O. Tau neuropathology correlates with FDG-PET, but not AV-1451-PET, in progressive supranuclear palsy. Acta Neuropathol. 2017; 133(1): 149- 151. doi: 10.1007/s00401-016-1650-1 27900460 PMC5209394 source

      Not checked in the free run.

    • cites [32] Day GS, Gordon BA, Perrin RJ,. In vivo [18F]-AV-1451 tau-PET imaging in sporadic Creutzfeldt-Jakob disease. Neurology. 2018; 90(10): e896- e906. doi: 10.1212/WNL.0000000000005064 29438042 PMC5863493 source

      Not checked in the free run.

    • cites [33] Smith R, Wibom M, Pawlik D, Englund E, Hansson O. Correlation of in vivo [18F]flortaucipir with postmortem Alzheimer disease tau pathology. JAMA Neurol. 2019; 76(3): 310- 317. doi: 10.1001/jamaneurol.2018.3692 30508025 PMC6439731 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Flortaucipir positron emission tomography scans were evaluated by 5 readers who were blinded to clinical and neuropathological results.

    “The flortaucipir PET scans were evaluated by 5 readers who were blinded to clinical and neuropathological results.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Neuropathological assessment used National Institute on Aging-Alzheimer Association diagnostic scoring guidelines.

    “Neuropathological assessment was performed by 2 authors (T.G.B. and T.J.M.) blinded to clinical and imaging results and using NIA–AA diagnostic scoring guidelines.5,40”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [5] Hyman BT, Phelps CH, Beach TG,. National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement. 2012; 8(1): 1- 13. doi: 10.1016/j.jalz.2011.10.007 22265587 PMC3266529 source

      Not checked in the free run.

    • cites [40] Montine TJ, Phelps CH, Beach TG,; National Institute on Aging; Alzheimer’s Association. National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach. Acta Neuropathol. 2012; 123(1): 1- 11. doi: 10.1007/s00401-011-0910-3 22101365 PMC3268003 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Fleiss κ statistics were calculated to assess overall interreader agreement.

    “To assess overall interreader agreement, Fleiss κ statistics were calculated.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Scans that were considered unevaluable by at least 3 of the 5 readers were not used in any analyses.

    “Scans that were considered unevaluable (eg, head out of field of view, severe motion, acquisition start time offsets, and low counts) by at least 3 of the 5 readers were not used in any analyses.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    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.

    “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.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    In the FR01 validation study, a second set of 5 nuclear medicine physicians or radiologists reinterpreted all available scan data.

    “In a subsequent validation study (18F-AV-1415-FR01; NCT03901092), hereafter referred to as the FR01 validation study, a second set of 5 nuclear medicine physicians or radiologists reinterpreted all available scan data.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    The preplanned A16 primary cohort included all enrolled participants who had valid and evaluable flortaucipir images and who had an autopsy (n=64), and excluded the 3 test cases and 16 supplemental historically collected autopsy cases.

    “The preplanned A16 primary cohort included all enrolled participants who had valid and evaluable flortaucipir images and who had an autopsy (n = 64), and excluded the 3 test cases and 16 supplemental historically collected autopsy cases.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    A preplanned exploratory analysis was performed on the full autopsy data set (n=82).

    “A preplanned exploratory analysis was performed on the full autopsy data set (n = 82), which included the 64 patients in the primary cohort, 2 evaluable autopsies from the 3 test cases, and the 16 supplemental autopsy cases.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Five board-certified nuclear medicine physicians or radiologists independently visually rated flortaucipir positron emission tomography scans as either having or not having a pattern of flortaucipir retention consistent with Alzheimer disease.

    “Five board-certified nuclear medicine physicians or radiologists (eAppendix in the Supplement) independently visually rated flortaucipir PET scans as either having or not having a pattern of flortaucipir retention consistent with AD (Figure 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Amyloid and tau pathologies may begin independently but are highly associated with each other in symptomatic stages of AD.

    “Amyloid and tau pathologies may begin independently6,43 but are highly associated with each other in symptomatic stages of AD.44”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [6] Jack CR Jr, Bennett DA, Blennow K,; Contributors. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018; 14(4): 535- 562. doi: 10.1016/j.jalz.2018.02.018 29653606 PMC5958625 source

      Not checked in the free run.

    • cites [43] Mungas D, Tractenberg R, Schneider JA, Crane PK, Bennett DA. A 2-process model for neuropathology of Alzheimer’s disease. Neurobiol Aging. 2014; 35(2): 301- 308. doi: 10.1016/j.neurobiolaging.2013.08.007 24080173 PMC3977862

      Not checked in the free run.

    • cites [44] Monsell SE, Mock C, Roe CM,. Comparison of symptomatic and asymptomatic persons with Alzheimer disease neuropathology. Neurology. 2013; 80(23): 2121- 2129. doi: 10.1212/WNL.0b013e318295d7a1 23645594 PMC3716351

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The primary study results were further strengthened in secondary exploratory analyses that included 16 supplemental autopsy cases, establishing high specificity for detecting AD tau.

    “The primary study results were further strengthened in secondary exploratory analyses that included 16 supplemental autopsy cases, establishing a high specificity for detecting AD tau.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The A16 study demonstrated statistically significant sensitivity and specificity of flortaucipir PET for detecting tau neurofibrillary pathology (NFT score B3 corresponding to Braak stages V and VI) and high levels of ADNC neuropathologic changes (NIA-AA criteria).

    “The A16 study demonstrated statistically significant sensitivity and specificity of PET imaging with [18F]flortaucipir for detecting tau neurofibrillary pathology (NFT score of B3 corresponding with Braak stages V and VI) and high levels of ADNC neuropathologic changes (according to NIA–AA criteria).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Analyses from the National Alzheimer Coordinating Center pathological database indicated that individuals with a B2 score had clinically normal result at a rate of 25.3% (34 of 134), and 41 (37.6%) of 109 people with Aβ at autopsy had a B2 score.

    “Analyses from the National Alzheimer Coordinating Center pathological database have indicated that individuals with a B2 score had clinically normal result at a rate of 25.3% (34 of 134), and 41 (37.6%) of 109 people with Aβ at autopsy had a B2 score.5”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Hyman BT, Phelps CH, Beach TG,. National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement. 2012; 8(1): 1- 13. doi: 10.1016/j.jalz.2011.10.007 22265587 PMC3266529 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Although B3 score may predict substantial amyloid plaque, amyloid plaque is often present in the absence of B3-level NFTs, particularly in earlier stages of AD.

    “Although the presence of B3 score may predict the presence of substantial amyloid plaque, amyloid plaque is often present in the absence of B3-level NFTs, particularly in earlier stages of AD.6,48,49”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [6] Jack CR Jr, Bennett DA, Blennow K,; Contributors. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018; 14(4): 535- 562. doi: 10.1016/j.jalz.2018.02.018 29653606 PMC5958625 source

      Not checked in the free run.

    • cites [48] Bennett DA, Schneider JA, Wilson RS, Bienias JL, Arnold SE. Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function. Arch Neurol. 2004; 61(3): 378- 384. doi: 10.1001/archneur.61.3.378 15023815 source

      Not checked in the free run.

    • cites [49] Bennett DA, Schneider JA, Bienias JL, Evans DA, Wilson RS. Mild cognitive impairment is related to Alzheimer disease pathology and cerebral infarctions. Neurology. 2005; 64(5): 834- 841. doi: 10.1212/01.WNL.0000152982.47274.9E 15753419 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Further method improvements, including quantitative analysis of mesial temporal structures, may alter the sensitivity of flortaucipir to detect earlier pathological stages of NFTs.

    “Further method improvements, including quantitative analysis of mesial temporal structures,25,54,55 may alter the sensitivity of [18F]flortaucipir to detect earlier pathological stages of NFTs.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [25] Lowe VJ, Lundt ES, Albertson SM,. Tau-positron emission tomography correlates with neuropathology findings. Alzheimers Dement. 2020; 16(3): 561- 571. doi: 10.1016/j.jalz.2019.09.079 31784374 PMC7067654

      Not checked in the free run.

    • cites [54] Southekal S, Kotari V, Devous MD Sr,. Temporal lobe quantitation of flortaucipir PET images may improve detection of intermediate neurofibrillary tangle pathology in autopsy-validated cases. Alzheimers Dement. 2019; 15(7): P1486- P1487. doi: 10.1016/j.jalz.2019.08.008

      Not checked in the free run.

    • cites [55] Kotari V, Navitsky M, Southekal S,. Early tau detection and implications for disease progression. Alzheimers Dement. 2019; 15(7):P 1614- P1615. doi: 10.1016/j.jalz.2019.06.4839 PMC9972744 36855201

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    These cohort characteristics may have implications for the visual and quantitative interpretation of PET scans and for the associations with underlying pathological features.

    “These characteristics may have implications for the visual and quantitative interpretation of PET scans and for the associations with underlying pathological features.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Cortical flortaucipir PET signal in patients with non-AD dementias is generally lower than expected than that seen in typical patients with AD and, when present, tends to be greatest in anterior temporal lobes, frontal lobe and striatum/globus pallidus, and in some reports of white matter foci.

    “Cortical [18F]flortaucipir PET signal in patients with non-AD dementias is generally lower than expected than that seen in typical patients with AD and, when present, tends to be greatest in anterior temporal lobes, frontal lobe and striatum/globus pallidus, and in some reports of white matter foci.27,28,30,31,32”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [27] Marquié M, Normandin MD, Meltzer AC,. Pathological correlations of [F-18]-AV-1451 imaging in non-Alzheimer tauopathies. Ann Neurol. 2017; 81(1): 117- 128. doi: 10.1002/ana.24844 27997036 PMC5319193

      Not checked in the free run.

    • cites [28] Marquié M, Verwer EE, Meltzer AC,. Lessons learned about [F-18]-AV-1451 off-target binding from an autopsy-confirmed Parkinson’s case. Acta Neuropathol Commun. 2017; 5(1): 75. doi: 10.1186/s40478-017-0482-0 29047416 PMC5648451

      Not checked in the free run.

    • cites [30] Smith R, Puschmann A, Schöll M,. 18F-AV-1451 tau PET imaging correlates strongly with tau neuropathology in MAPT mutation carriers. Brain. 2016; 139(pt 9): 2372- 2379. doi: 10.1093/brain/aww163 27357347 PMC4995360

      Not checked in the free run.

  • May combine two claims.

    Study design and conductnone given

    The A16 study cohort was older than typical symptomatic patients with AD recruited into clinical trials, had more advanced clinical disease with only 1 case of mild cognitive impairment, and lacked racial/ethnic diversity.

    “The A16 study cohort was older than the typical symptomatic patients with AD recruited into clinical trials, had more advanced clinical disease with only 1 case of mild cognitive impairment, and lacked racial/ethnic diversity.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

    Interpretationnone given

    This level of activity may represent noise or early spread of tau.

    “This level of activity may represent noise or early spread of tau.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Earlier stages of AD may meet intermediate pathological diagnostic criteria or have neuritic plaque with moderate or frequent CERAD scores in the absence of substantial tau.

    “Earlier stages of AD may meet intermediate pathological diagnostic criteria or have neuritic plaque with moderate or frequent CERAD scores in the absence of substantial tau.6”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Jack CR Jr, Bennett DA, Blennow K,; Contributors. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018; 14(4): 535- 562. doi: 10.1016/j.jalz.2018.02.018 29653606 PMC5958625 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    PET scan read errors may also have been associated with imprecise drawing of the cerebellar reference region, resulting in reduced mean cerebellar counts and relatively increased cortical signal above the threshold.

    “PET scan read errors may also have been associated with imprecise drawing of the cerebellar reference region, resulting in reduced mean cerebellar counts and relatively increased cortical signal above the threshold.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    The source of this binding is unknown, but given these locations, it can typically be distinguished from neocortical binding in regions associated with AD pathology.

    “The source of this binding is unknown, but given these locations, it can typically be distinguished from neocortical binding in regions associated with AD pathology.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationnone given

    These types of scan read errors are potentially mitigated through improved reader training or procedural automation.

    “These types of scan read errors are potentially mitigated through improved reader training or procedural automation.”
    Quote in the paperNot a substantial claim
51 of 51

  • The paper relies on this without support.

    Tau pathology does not change substantially between antemortem flortaucipir positron emission tomography imaging and postmortem assessment.

    “Participants with cognitive impairment who did not come to autopsy within 9 months after the flortaucipir scan were either removed from the study or required to undergo a repeat flortaucipir scan for comparison with the neuropathological result. Cognitively normal patients remained eligible for autopsy, regardless of the time from scan to autopsy.”
    “After removal of the 3 test cases, the remaining 64 participants were included in the A16 primary cohort, with autopsy occurring a mean (SD) 16.2 (15.0) hours from the recorded time of death and 2.6 (2.14) months after [18F]flortaucipir imaging.”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Studies combining antemortem imaging with neuropathological validation have shown 18F-flortaucipir PET is highly sensitive for presence of high levels of AD neuropathological change, with visual rating positivity corresponding to Braak levels IV or greater.

    “Studies combining antemortem imaging with neuropathological validation have shown that 18F-flortaucipir PET is highly sensitive for presence of high levels of AD neuropathological change with visual rating positivity corresponding to Braak levels IV or greater [184, 185].”

    From The use of neuroimaging techniques in the early and differential diagnosis of dementia (2023) · cites this paper as [184]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • Current in-vivo detection of tau positivity using 18F-flortaucipir PET seems to correspond only to widespread tau pathology (Braak stages ≥IV), whereas CSF phosphorylated tau elevation can reflect earlier stages of tauopathy.

    “The current in-vivo detection of tau positivity using 18F-flortaucipir PET seems to correspond only to widespread tau pathology in the brain (ie, Braak stages ≥IV),69 whereas CSF phosphorylated tau elevation can reflect earlier stages of tauopathy.70”

    From Clinical diagnosis of Alzheimer’s disease: Recommendations of the International Working Group (2021) · cites this paper as [69]

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Fleisher, 2018, Tau PET imaging as a screening tool for clinical trials of disease modifying therapies., J Prev Alzheimers Dis, 5, S17

Cited by

Sorted by citations

Related

Authors
Fleisher, A. S., Pontecorvo, M. J., Devous, M. D., Lu, M., Arora, A. K., Truocchio, S. P., Aldea, P., Flitter, M., Locascio, T., Devine, M., Siderowf, A., Beach, T. G., Montine, T. J., Serrano, G. E., Curtis, C., Perrin, A., Salloway, S., Daniel, M., Wellman, C., Joshi, A. D., Irwin, D. J., Lowe, V. J., Seeley, W. W., Ikonomovic, M. D., Masdeu, J. C., Kennedy, I., Harris, T., Navitsky, M., Southekal, S., Mintun, M. A., & A16 Study Investigators
Affiliations
  • Avid Radiopharmaceuticals (United States) (US)
  • University of Pennsylvania (US)
  • Banner Sun Health Research Institute (US)
  • Stanford University (US)
  • Waypoint Research, Windermere, Florida
  • Banner Alzheimer’s Institute (US)
  • Butler Hospital (US)
  • Pacific Research Network, San Diego, California
  • Hospice of the Western Reserve (US)
  • ImaginAb (United States) (US)
  • Mayo Clinic (US)
  • University of California, San Francisco (US)
  • University of Pittsburgh, Pittsburgh
  • Houston Methodist (US)
Corresponding author
Fleisher, Adam S.
ORCID
Venue
JAMA Neurology
Publisher
American Medical Association (AMA)
Published
2020-07-01
Volume
77
Issue
7
Pages
829
ISSN
2168-6149 (ISSN-L)
DOI
10.1001/jamaneurol.2020.0528
PMC
PMC7186920
OpenAlex
W3019122005
Semantic Scholar
7bf74768a675a4bcb10a44e43a6c38000a6a1bea
Cited by
448
References
63
Citations by year
2026: 68 · 2025: 77 · 2024: 69 · 2023: 57 · 2022: 79 · 2021: 67 · 2020: 30
FWCI
42.50
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • JAMA Neurology (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institute on Aging (R01AG034676, U01AG006786, P01AG066597, R01AG054449, R01AG011378, P30AG019610, R01AG041851, P01AG019724, P30AG062422, P50AG023501, P50AG016574)
  • National Institute of Neurological Disorders and Stroke (R01NS089544, R21NS094489, R01NS089757, R01NS097495)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Medical Imaging Techniques and Applications
Keywords
18F-flortaucipir, Alzheimer's disease, tau PET imaging, postmortem neuropathology, Braak stages, amyloid plaques, diagnostic accuracy, immunohistochemistry, terminal illness, dementia, neurodegeneration biomarkers, amyloid PET, FDG-PET, neuroimaging validation
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Autopsy, Brain, Carbolines, Contrast Media, Female, Humans, Male, Sensitivity and Specificity, Amyloid beta-Peptides, Neurofibrillary Tangles, tau Proteins, Radiopharmaceuticals, Positron-Emission Tomography, Plaque, Amyloid, Neuroimaging

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

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