Relationships between flortaucipir PET tau binding and amyloid burden, clinical diagnosis, age and cognition

Pontecorvo, Michael J.; Devous, Michael D.; Navitsky, Michael; Lu, Ming; Salloway, Stephen; Schaerf, Frederick W.; Jennings, Danna; Arora, Ankit; McGeehan, Anne; Lim, Nathaniel; Xiong, Hui; Joshi, Abhinay D.; Siderowf, Andrew; Mintun, Mark A.; investigators, F-Av -A

doi:10.1093/brain/aww334

Cited by 262 publications

(333 citation statements)

References 57 publications

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“…We and others have previously shown that [F-18]-AV-1451 binds with strong affinity to paired helical filament (PHF)-tau aggregates in AD brains and those that form as a function of age [11,13,12,24,31]. In agreement with these observations, patients clinically diagnosed with dementia of AD type and mild cognitive impairment (MCI) exhibit significantly higher in vivo [F-18]-AV-1451 retention than cognitively normal individuals in regions that are known to contain an elevated burden of tau lesions in AD [10,7,8,3,30,25,6,19]. …”

Section: Introductionmentioning

confidence: 65%

[F-18]-AV-1451 binding correlates with postmortem neurofibrillary tangle Braak staging

et al. 2017

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[F-18]-AV-1451, a PET tracer specifically developed to detect brain neurofibrillary tau pathology, has the potential to facilitate accurate diagnosis of Alzheimer’s disease (AD), staging of brain tau burden and monitoring disease progression. Recent PET studies show that patients with mild cognitive impairment and AD dementia exhibit significantly higher in vivo [F-18]-AV-1451 retention than cognitively normal controls. Importantly, PET patterns of [F-18]-AV-1451 correlate well with disease severity and seem to match the predicted topographic Braak staging of neurofibrillary tangles (NFTs) in AD, although this awaits confirmation. We studied the correlation of autoradiographic binding patterns of [F-18]-AV-1451 and the stereotypical spatiotemporal pattern of progression of NFTs using legacy postmortem brain samples representing different Braak NFT stages (I-VI). We performed [F-18]-AV-1451 phosphor-screen autoradiography and quantitative tau measurements (stereologically-based NFT counts and biochemical analysis of tau pathology) in three brain regions (entorhinal cortex, superior temporal sulcus and visual cortex) in a total of 22 cases: low Braak (I-II, n=6), intermediate Braak (III-IV, n=7) and high Braak (V-VI, n=9). Strong and selective [F-18]-AV-1451 binding was detected in all tangle-containing regions matching precisely the observed pattern of PHF-tau immunostaining across the different Braak stages. As expected, no signal was detected in the white matter or other non-tangle containing regions. Quantification of [F-18]-AV-1451 binding was very significantly correlated with the number of NFTs present in each brain region and with the total tau and phospho-tau content as reported by Western blot and ELISA. [F-18]-AV-1451 is a promising biomarker for in vivo quantification of brain tau burden in AD. Neuroimaging–pathologic studies conducted on postmortem material from individuals imaged while alive are now needed to confirm these observations.

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Section: Introductionmentioning

confidence: 65%

[F-18]-AV-1451 binding correlates with postmortem neurofibrillary tangle Braak staging

et al. 2017

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“…In addition to our two main analyses with local and inferior temporal tau, we have included a supplemental figure and table exploring the relationship between atrophy and entorhinal tau. Elevated AV-1451 in the medial temporal lobes has previously been related to increasing age by other research groups (Brier et al, 2016; Gordon et al, 2016; Jack et al, 2016; Pontecorvo et al, 2017; Schöll et al, 2016), and there is some research indicating that entorhinal tau may be more closely associated with higher levels of amyloid than inferior temporal tau burden (Vemuri et al, 2017). Fig.…”

Section: Methodsmentioning

confidence: 90%

The association between tau PET and retrospective cortical thinning in clinically normal elderly

et al. 2017

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Tau pathology has been associated with neuronal loss at autopsy, but the temporal evolution of tau pathology and atrophy remains unclear. Here, we investigate the association between cross-sectional AV-1451-PET as a marker of tau pathology and cortical thickness cross-sectionally. We also investigated retrospective rates of cortical thinning over the three years preceding the AV-1451 scan in a clinically normal cohort of 103 older adults from the Harvard Aging Brain Study. Tau measurements were Geometric Transfer Matrix partial volume corrected standardized uptake value ratios (SUVRs) with a cerebellar gray reference region. Thirty-four FreeSurfer-defined cortical regions of interest (ROIs) were used for both thickness and AV-1451 in each hemisphere, with seven additional volumetric ROIs. We examined “local” relationships between AV-1451 and cortical thickness in the same ROI, as well as inferior temporal AV-1451 and all thickness ROIs. All models included baseline age and sex, both interacting with time in retrospective longitudinal models, as covariates. Cross-sectional models controlled for the number of days between the two scans. Cross-sectional local comparisons revealed significant associations between elevated AV-1451 and thinner cortical ROIs predominantly in temporal regions, while analyses associating inferior temporal AV-1451 with all cortical ROIs showed a widespread pattern of significant relationships, which was strongest in temporal and parietal cortices. In our retrospective longitudinal analyses, we saw significant relationships in temporal and parietal regions. Significant local relationships were seen in right superior temporal, middle temporal, temporal pole, and fusiform, as well as the left cuneus and banks of the left superior temporal sulcus. Significant relationships between inferior temporal AV-1451 and faster thinning were observed in right temporal regions (middle temporal and fusiform) and bilateral parahippocampal cortices. We observed significant negative relationships between local and inferior temporal AV-1451 signal and both cross-sectional cortical thickness and rates of thinning in lateral and medial temporal regions. This is an important early step toward elucidating the relationship between tau pathology and retrospective longitudinal atrophy in aging and preclinical AD.

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“…The current patient groupings thus represent one approach to phenotypic heterogeneity in AD and are not meant to imply that PCA patients who subsequently develop memory deficits follow the same disease course as purely amnestic AD patients. Fourth, the present study did not compare the ability of PET tau and amyloid imaging results to account for clinical symptoms, nor did it consider possible interactions between tau and amyloid pathology (Ittner & Götz, ; see also Pontecorvo et al, ). Fifth, tau PET imaging data from cognitively normal controls were not available.…”

Section: Discussionmentioning

confidence: 96%

Tau PET imaging predicts cognition in atypical variants of Alzheimer's disease

Phillips

Das

McMillan

et al. 2017

Human Brain Mapping

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Accumulation of paired helical filament tau contributes to neurodegeneration in Alzheimer's disease (AD). F-flortaucipir is a positron emission tomography (PET) radioligand sensitive to tau in AD, but its clinical utility will depend in part on its ability to predict cognitive symptoms in diverse dementia phenotypes associated with selective, regional uptake. We examined associations between F-flortaucipir and cognition in 14 mildly-impaired patients (12 with cerebrospinal fluid analytes consistent with AD pathology) who had amnestic (n = 5) and non-amnestic AD syndromes, including posterior cortical atrophy (PCA, n = 5) and logopenic-variant primary progressive aphasia (lvPPA, n = 4). Amnestic AD patients had deficits in memory; lvPPA in language; and both amnestic AD and PCA patients in visuospatial function. Associations with cognition were tested using sparse regression and compared to associations in anatomical regions-of-interest (ROIs). F-flortaucipir uptake was expected to show regionally-specific correlations with each domain. In multivariate analyses, uptake was elevated in neocortical areas specifically associated with amnestic and non-amnestic syndromes. Uptake in left anterior superior temporal gyrus accounted for 67% of the variance in language performance. Uptake in right lingual gyrus predicted 85% of the variance in visuospatial performance. Memory was predicted by uptake in right fusiform gyrus and cuneus as well as a cluster comprising right anterior hippocampus and amygdala; this eigenvector explained 57% of the variance in patients' scores. These results provide converging evidence for associations between F-flortaucipir uptake, tau pathology, and patients' cognitive symptoms.

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Relationships between flortaucipir PET tau binding and amyloid burden, clinical diagnosis, age and cognition

Cited by 262 publications

References 57 publications

[F-18]-AV-1451 binding correlates with postmortem neurofibrillary tangle Braak staging

[F-18]-AV-1451 binding correlates with postmortem neurofibrillary tangle Braak staging

The association between tau PET and retrospective cortical thinning in clinically normal elderly

Tau PET imaging predicts cognition in atypical variants of Alzheimer's disease

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