Characterization of tau positron emission tomography tracer [<sup>18</sup>F]AV‐1451 binding to postmortem tissue in Alzheimer's disease, primary tauopathies, and other dementias

Sander, Kerstin; Lashley, Tammaryn; Gami, P; Gendron, Thibault; Lythgoe, Mark F.; Rohrer, Jonathan D.; Schott, Jonathan M.; Révész, Tamás; Fox, Nick C.; Årstad, Erik

doi:10.1016/j.jalz.2016.01.003

Cited by 167 publications

(221 citation statements)

References 29 publications

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“…It is therefore plausible that the high expression of 4R tau in the Tau(4RD*LM)-YFP(2) cells is seeded by the 4R component of tau prions in AD and CTE. It is noteworthy that the [ 18 F]AV-1451 PET tracer selectively binds to pathologic tau in AD patient samples compared with PSP and PiD patient samples (57)(58)(59), suggesting a conformation difference may exist between tau in AD versus tau in the isoform-specific tauopathies. Our conclusion, that AD prions contain both 3R and 4R tau isoforms, whereas PSP and PiD contain either 4R or 3R, respectively, provides one possible explanation for the results reported for [ 18 F]AV-1451.…”

Section: Discussionmentioning

confidence: 99%

Tau prions from Alzheimer’s disease and chronic traumatic encephalopathy patients propagate in cultured cells

Woerman

Aoyagi

Patel

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

149

130

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Tau prions are thought to aggregate in the central nervous system, resulting in neurodegeneration. Among the tauopathies, Alzheimer's disease (AD) is the most common, whereas argyrophilic grain disease (AGD), corticobasal degeneration (CBD), chronic traumatic encephalopathy (CTE), Pick's disease (PiD), and progressive supranuclear palsy (PSP) are less prevalent. Brain extracts from deceased individuals with PiD, a neurodegenerative disorder characterized by three-repeat (3R) tau prions, were used to infect HEK293T cells expressing 3R tau fused to yellow fluorescent protein (YFP). Extracts from AGD, CBD, and PSP patient samples, which contain four-repeat (4R) tau prions, were transmitted to HEK293 cells expressing 4R tau fused to YFP. These studies demonstrated that prion propagation in HEK cells requires isoform pairing between the infecting prion and the recipient substrate. Interestingly, tau aggregates in AD and CTE, containing both 3R and 4R isoforms, were unable to robustly infect either 3R-or 4R-expressing cells. However, AD and CTE prions were able to replicate in HEK293T cells expressing both 3R and 4R tau. Unexpectedly, increasing the level of 4R isoform expression alone supported the propagation of both AD and CTE prions. These results allowed us to determine the levels of tau prions in AD and CTE brain extracts.argyrophilic grain disease | corticobasal degeneration | Pick's disease | progressive supranuclear palsy | tauopathies

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Section: Discussionmentioning

confidence: 99%

Tau prions from Alzheimer’s disease and chronic traumatic encephalopathy patients propagate in cultured cells

Woerman

Aoyagi

Patel

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

149

130

View full text Add to dashboard Cite

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“…These tracers showed in vitro high specificity to tau pathology (specifically to 3r/4r paired helical filamentous tau aggregates that are characteristic of AD), although the agreement between tracer binding and tau immunohistochemistry appears more complex. [67][68][69][70][71] The favourable pharmacokinetics of those tracers [72][73][74] completed the requirements for Phase I. A number of rather small and non-consecutive Phase II studies have already reported good discrimination between healthy volunteers and AD patients, 67,[75][76][77][78] with preliminary evidence, available for only one of the tracers (AV-1451), supporting the agreement between antemortem PET quantification of the tracer retention and postmortem evidence of tau pathology in the same non-AD patients, a carrier of a MAPT mutation (p.R406W), and two patients with corticobasal degeneration, although questions remain about the specific target of the tracer 58,79,80 (Phase II, SA 2).…”

Section: Sa3mentioning

confidence: 99%

Strategic roadmap for an early diagnosis of Alzheimer's disease based on biomarkers

Frisoni

Boccardi

Barkhof

et al. 2017

The Lancet Neurology

511

480

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Biomarkers sensitive to functional impairment, neuronal loss, tau, and amyloid pathology based on MR, PET, and CSF studies are increasingly used to diagnose Alzheimer's disease (AD), but clinical validation is incomplete, hampering reimbursement by payers, widespread clinical implementation, and impacting on health care quality. An expert group convened to develop a strategic research agenda to foster the clinical validation of AD biomarkers. These demonstrated sufficient evidence of analytical validity (phase I of a structured framework adapted from oncology). Research priorities were identified based on incomplete clinical validity (phases II and III), and clinical utility (phases IV and V). Priorities included: definition of the assays; reading procedures and thresholds for normality; performance in detecting early disease; accounting for the effect of covariates; diagnostic algorithms comprising combinations of biomarkers; and developing best practice guidelines for the use of biomarkers in qualified memory clinics in the context of phase IV studies. 5 GlossaryBiomarker. An objective measure of a biological or pathogenic process with the purpose of evaluating disease risk or prognosis, guiding clinical diagnosis or monitoring therapeutic interventions. While the term originally referred to traceable substances produced by or introduced into an organism, it later evolved to any measurable parameter, including those obtained via imaging procedures.Roadmap. Objective-oriented, structured, and efficient action plan. In science and technology also called "strategic research agenda".Alzheimer's disease (AD) dementia. Traditionally and according to the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria, Alzheimer's disease was defined as a syndrome with progressive cognitive impairment severe enough to impact on daily activities. A diagnosis of Alzheimer's disease could only be made after exclusion of other possible causes. 1 Sixty-five to 80% of cases of patients fulfilling these criteria have Alzheimer's pathology (plaques and tangles), the remainder having a range of other pathologies. In order to increase diagnostic certainty, contemporary criteria for AD dementia incorporate biomarker evidence for different aspects of Alzheimer's pathology, including imaging (magnetic resonance imaging -MRI -measures of atrophy; 18 F-fluorodeoxyglucose-positron emission tomography -FDG-PET -measures of cerebral hypometabolism; amyloid PET measures of fibrillar β-amyloid -A -deposition) and cerebrospinal fluid -CSF (decreased levels of A42, increased levels of tau and phospho-tau). 2,3 Alzheimer's disease process. Recognizing that AD pathology is present many years before symptoms emerge, new criteria classify the disease process on a continuum from asymptomatic to prodromal and finally to dementia stage. 4 Individuals at the asymptomatic stage can only be identified by biomarkers of Alzheimer's pathology. None...

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“…Autoradiography studies using human brain tissue samples from multiple neurodegenerative disorders have largely confirmed the specific binding of FTP to paired helical filaments (PHF) tau-containing neurofibrillary tangles and dystrophic neurites in AD brains. In comparison, FTP binding is absent or very low in tau aggregates comprised by straight filaments as well as in alpha-synuclein or TDP-43 deposits [6–9]. …”

Section: Introductionmentioning

confidence: 99%

18F-Flortaucipir Binding in Choroid Plexus: Related to Race and Hippocampus Signal

Lee

Jacobs

Marquié

et al. 2018

JAD

102

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Background On target 18F-Flortaucipir (FTP) binding of Alzheimer’s disease tau aggregates and off-target binding of melanocytes have been demonstrated with autoradiography. Objective We aimed to investigate the hypothesis that if binding in choroid plexus (CP) is due to melanocytes, the signal would be elevated in Black/African American (B/AA) compared to White (W) participants. In addition, we examined whether CP signal affects measurements in adjacent regions, and whether correcting for spill-in effects has an influence on associations between hippocampus (HC) FTP and amyloid or cognition. Methods FTP race differences in 147 Harvard Aging Brain Study participants (23 B/AA, 124W) were examined in CP, HC, HC covaried for CP, amygdala, inferior temporal gyrus, entorhinal cortex, and fusiform regions. Associations between CP FTP and other regions-of-interest (ROIs) were probed to assess spill-in effects. A statistical regression approach to attenuate CP spill-in was tested by relating adjusted HC SUVR residuals and unadjusted HC SUVR to race, cognition and amyloid. All analyses were covaried for age, sex, education and amyloid deposition, and Bonferroni-corrected for multiple comparisons. Results B/AA individuals had elevated CP and HC SUVR (p < 0.007), whereas other ROI SUVR and HC SUVR covaried for CP SUVR did not show race differences (p > 0.05). CP SUVR was associated with HC SUVR (p < 10−14), but with no other ROI SUVR (p > 0.05). When adjusting HC SUVR for CP SUVR, no race differences in residual HC SUVR were detected, and relationships with amyloid and memory became apparent. Conclusion Melanocyte FTP binding may account partially for high CP signal. This off-target binding affects mainly HC FTP measurements, which should be interpreted with caution.

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Characterization of tau positron emission tomography tracer [¹⁸F]AV‐1451 binding to postmortem tissue in Alzheimer's disease, primary tauopathies, and other dementias

Abstract: [F]AV-1451 binds to tau in AD, and some other tauopathies. However, evidence for a non-tau binding site and lack of correlation between tracer binding and antibody staining suggest that reliable quantification of tau load with this tracer is problematic.

Cited by 167 publications

References 29 publications

Tau prions from Alzheimer’s disease and chronic traumatic encephalopathy patients propagate in cultured cells

Tau prions from Alzheimer’s disease and chronic traumatic encephalopathy patients propagate in cultured cells

Strategic roadmap for an early diagnosis of Alzheimer's disease based on biomarkers

18F-Flortaucipir Binding in Choroid Plexus: Related to Race and Hippocampus Signal

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Characterization of tau positron emission tomography tracer [18F]AV‐1451 binding to postmortem tissue in Alzheimer's disease, primary tauopathies, and other dementias

Abstract: [F]AV-1451 binds to tau in AD, and some other tauopathies. However, evidence for a non-tau binding site and lack of correlation between tracer binding and antibody staining suggest that reliable quantification of tau load with this tracer is problematic.

Cited by 167 publications

References 29 publications

Tau prions from Alzheimer’s disease and chronic traumatic encephalopathy patients propagate in cultured cells

Tau prions from Alzheimer’s disease and chronic traumatic encephalopathy patients propagate in cultured cells

Strategic roadmap for an early diagnosis of Alzheimer's disease based on biomarkers

18F-Flortaucipir Binding in Choroid Plexus: Related to Race and Hippocampus Signal

Contact Info

Product

Resources

About

Characterization of tau positron emission tomography tracer [¹⁸F]AV‐1451 binding to postmortem tissue in Alzheimer's disease, primary tauopathies, and other dementias