Evaluation of a visual interpretation method for tau-PET with 18F-flortaucipir.
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ABSTRACT: Introduction
Positron emission tomography targeting tau (tau-PET) is a promising diagnostic tool for the identification of Alzheimer's disease (AD). Currently available data rely on quantitative measures, and a visual interpretation method, critical for clinical translation, is needed.Methods
We developed a visual interpretation method for 18F-flortaucipir tau-PET and tested it on 274 individuals (cognitively normal controls, patients with mild cognitive impairment [MCI], AD dementia, and non-AD diagnoses). Two readers interpreted 18F-flortaucipir PET using two complementary indices: a global visual score and a visual distribution pattern.Results
Global visual scores were reliable, correlated with global cortical 18F-flortaucipir standardized uptake value ratio (SUVR) and were associated with clinical diagnosis and amyloid status. The AD-like 18F-flortaucipir pattern had good sensitivity and specificity to identify amyloid-positive patients with AD dementia or MCI.Discussion
This 18F-flortaucipir visual rating scheme is associated with SUVR quantification, clinical diagnosis, and amyloid status, and constitutes a promising approach to tau measurement in clinical settings.
SUBMITTER: Sonni I
PROVIDER: S-EPMC7699207 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
Publications
Evaluation of a visual interpretation method for tau-PET with <sup>18</sup>F-flortaucipir.
Sonni Ida I Lesman Segev Orit H OH Baker Suzanne L SL Iaccarino Leonardo L Korman Deniz D Rabinovici Gil D GD Jagust William J WJ Landau Susan M SM La Joie Renaud R
Alzheimer's & dementia (Amsterdam, Netherlands) 20201128 1
<h4>Introduction</h4>Positron emission tomography targeting tau (tau-PET) is a promising diagnostic tool for the identification of Alzheimer's disease (AD). Currently available data rely on quantitative measures, and a visual interpretation method, critical for clinical translation, is needed.<h4>Methods</h4>We developed a visual interpretation method for <sup>18</sup>F-flortaucipir tau-PET and tested it on 274 individuals (cognitively normal controls, patients with mild cognitive impairment [MC ...[more]
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Project description:BackgroundThe tau positron emission tomography (PET) ligand 18F-flortaucipir binds to paired helical filaments of tau in aging and Alzheimer's disease (AD), but its utility in detecting tau aggregates in frontotemporal dementia (FTD) is uncertain.MethodsWe performed 18F-flortaucipir imaging in patients with the FTD syndromes (n = 45): nonfluent variant primary progressive aphasia (nfvPPA) (n = 11), corticobasal syndrome (CBS) (n = 10), behavioral variant frontotemporal dementia (bvFTD) (n = 10), semantic variant primary progressive aphasia (svPPA) (n = 2) and FTD associated pathogenic genetic mutations microtubule-associated protein tau (MAPT) (n = 6), chromosome 9 open reading frame 72 (C9ORF72) (n = 5), and progranulin (GRN) (n = 1). All patients underwent MRI and β-amyloid biomarker testing via 11C-PiB or cerebrospinal fluid. 18F-flortaucipir uptake in patients was compared to 53 β-amyloid negative normal controls using voxelwise and pre-specified region of interest approaches.ResultsOn qualitative assessment, patients with nfvPPA showed elevated 18F-flortacupir binding in the left greater than right inferior frontal gyrus. Patients with CBS showed elevated binding in frontal white matter, with higher cortical gray matter uptake in a subset of β-amyloid-positive patients. Five of ten patients with sporadic bvFTD demonstrated increased frontotemporal binding. MAPT mutation carriers had elevated 18F-flortaucipir retention primarily, but not exclusively, in mutations with Alzheimer's-like neurofibrillary tangles. However, tracer retention was also seen in patients with svPPA, and the mutations C9ORF72, GRN predicted to have TDP-43 pathology. Quantitative region-of-interest differences between patients and controls were seen only in inferior frontal gyrus in nfvPPA and left insula and bilateral temporal poles in MAPT carriers. No significant regional differences were found in CBS or sporadic bvFTD. Two patients underwent postmortem neuropathological examination. A patient with C9ORF72, TDP-43-type B pathology, and incidental co-pathology of scattered neurofibrillary tangles in the middle frontal, inferior temporal gyrus showed corresponding mild 18F-flortaucipir retention without additional uptake matching the widespread TDP-43 type B pathology. A patient with sporadic bvFTD demonstrated punctate inferior temporal and hippocampus tracer retention, corresponding to the area of severe argyrophilic grain disease pathology.Conclusions18F-flortaucipir in patients with FTD and predicted tauopathy or TDP-43 pathology demonstrated limited sensitivity and specificity. Further postmortem pathological confirmation and development of FTD tau-specific ligands are needed.
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Project description:[18F]Flortaucipir is a PET tau tracer used to visualize tau binding in Alzheimer's disease (AD) in vivo. The present study evaluated the performance of several methods to obtain parametric images of [18F]flortaucipir. One hundred and thirty minutes dynamic PET scans were performed in 10 AD patients and 10 controls. Parametric images were generated using different linearization and basis function approaches. Regional binding potential (BPND) and volume of distribution (VT) values obtained from the parametric images were compared with corresponding values derived using the reversible two-tissue compartment model (2T4k_VB). Performance of SUVr parametric images was assessed by comparing values with distribution volume ratio (DVR) and SRTM-derived BPND estimates obtained using non-linear regression (NLR). Spectral analysis (SA) (r2 = 0.92; slope = 0.99) derived VT correlated well with NLR-derived VT. RPM (r2 = 0.95; slope = 0.98) derived BPND correlated well with NLR-derived DVR. Although SUVr80-100 min correlated well with NLR-derived DVR (r2 = 0.91; slope = 1.09), bias in SUVr appeared to depend on uptake time and underlying level of specific binding. In conclusion, RPM and SA provide parametric images comparable to the NLR estimates. Individual SUVr values are biased compared with DVR and this bias requires further study in a larger dataset in order to understand its consequences.
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Project description:PurposeThis study aims to determine whether comparable target regions of interest (ROIs) and cut-offs can be used across [18F]flortaucipir, [18F]RO948, and [18F]MK6240 tau positron emission tomography (PET) tracers for differential diagnosis of Alzheimer's disease (AD) dementia vs either cognitively unimpaired (CU) individuals or non-AD neurodegenerative diseases.MethodsA total of 1755 participants underwent tau PET using either [18F]flortaucipir (n = 975), [18F]RO948 (n = 493), or [18F]MK6240 (n = 287). SUVR values were calculated across four theory-driven ROIs and several tracer-specific data-driven (hierarchical clustering) regions of interest (ROIs). Diagnostic performance and cut-offs for ROIs were determined using receiver operating characteristic analyses and the Youden index, respectively.ResultsComparable diagnostic performance (area under the receiver operating characteristic curve [AUC]) was observed between theory- and data-driven ROIs. The theory-defined temporal meta-ROI generally performed very well for all three tracers (AUCs: 0.926-0.996). An SUVR value of approximately 1.35 was a common threshold when using this ROI.ConclusionThe temporal meta-ROI can be used for differential diagnosis of dementia patients with [18F]flortaucipir, [18F]RO948, and [18F]MK6240 tau PET with high accuracy, and that using very similar cut-offs of around 1.35 SUVR. This ROI/SUVR cut-off can also be applied across tracers to define tau positivity.
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Project description:Radiotracer [18F]Flortaucipir is an FDA-approved diagnostic agent for PET imaging of density and distribution of abnormal tau protein deposition (tauopathies) in Alzheimer's disease. A high-yield automated method for routine GMP-compliant [18F]Flortaucipir production is desired to meet increasing clinical need. In this work, we reported an automated radiosynthesis of [18F]Flortaucipir in a RNplus Research module and the quality control (QC) tests for human use under full GMP compliance. Briefly, automated radiosynthesis of [18F]Flortaucipir was processed via nucleophilic radiofluorination of precursor AV1622 and followed by acid hydrolysis in a RNplus Research module, which included the radiosynthesis, semi-preparative high-performance liquid chromatography (HPLC) purification, and the final formulation via solid phase extraction (SPE). The final products were obtained in non-decay corrected radiochemical yields of 14.8-16.6% (n = 3) within total synthesis time of 55 min. The radiochemical purities of [18F]Flortaucipir were > 99.9% and the molar activities were 247.9-384.8 GBq/µmol at end of synthesis. The results of QC tests met all the specifications for human use. In conclusion, [18F]Flortaucipir was reproducibly achieved with desired radiochemical yield and high radiochemical purity and molar activity. Three GMP compliant validation runs and QC results demonstrated the efficacy of this method for automated production of [18F]Flortaucipir for human use.
| S-EPMC8255216 | biostudies-literature
Project description:Purpose[18F]flortaucipir binds to paired helical filament tau and accurately identifies tau in Alzheimer's disease (AD). However, "off-target" binding interferes with the quantification of [18F]flortaucipir in several brain regions. Recently, other tau PET tracers have been developed. Here, we compare [18F]flortaucipir with the novel tau tracer [18F]RO948 head-to-head in vivo.MethodsWe included 18 participants with AD, three with amyloid-β-positive amnestic mild cognitive impairment, and four healthy controls. All underwent [18F]flortaucipir (80-100 min) and [18F]RO948 (70-90) PET scans within approximately 1 month. Four study participants underwent 0-100-min dynamic scanning. Standardized uptake value ratios (SUVRs) were created using an inferior cerebellar reference region.ResultsNeocortical tracer retention was highly comparable using both SUVR and distribution volume ratio-1 values obtained from dynamic scans. However, [18F]RO948 retention was significantly higher in the entorhinal cortex and lower in the basal ganglia, thalamus, and choroid plexus compared with [18F]flortaucipir. Increased off-target binding was observed with age for both tracers. Several cases exhibited strong [18F]RO948 retention in the skull/meninges. This extra-cerebral signal, however, did not affect diagnostic accuracy and remained relatively unchanged when re-examining a subsample after 1 year. Kinetic modeling showed an increase in [18F]flortaucipir SUVR over the scanning interval, compared with a plateau for [18F]RO948.Conclusion[18F]RO948 and [18F]flortaucipir bound comparably in neocortical regions, but [18F]RO948 showed higher retention in the medial temporal lobe and lower intracerebral "off-target" binding. Time-dependent bias of SUVR estimates may prove less of a factor with [18F]RO948, compared with previous tau ligands.
| S-EPMC6974501 | biostudies-literature
Project description:PurposeSeveral [18F]Flortaucipir cutoffs have been proposed for tau PET positivity (T+) in Alzheimer's disease (AD), but none were data-driven. The aim of this study was to establish and validate unsupervised T+ cutoffs by applying Gaussian mixture models (GMM).MethodsAmyloid negative (A-) cognitively normal (CN) and amyloid positive (A+) AD-related dementia (ADRD) subjects from ADNI (n=269) were included. ADNI (n=475) and Geneva Memory Clinic (GMC) cohorts (n=98) were used for validation. GMM-based cutoffs were extracted for the temporal meta-ROI, and validated against previously published cutoffs and visual rating.ResultsGMM-based cutoffs classified less subjects as T+, mainly in the A- CN (<3.4% vs >28.5%) and A+ CN (<14.5% vs >42.9%) groups and showed higher agreement with visual rating (ICC=0.91 vs ICC<0.62) than published cutoffs.ConclusionWe provided reliable data-driven [18F]Flortaucipir cutoffs for in vivo T+ detection in AD. These cutoffs might be useful to select participants in clinical and research studies.
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Project description:IntroductionTau-targeted positron emission tomography (tau-PET) is a potential tool for the differential diagnosis of Alzheimer's disease (AD) and to clarify the distribution of tau deposition. In addition to the quantitative analysis of tau-PET scans, visual reading supports the assessment of tau loading for clinical diagnosis. This study aimed to propose a method for visually interpreting tau-PET using the [18F] Florzolotau tracer and investigate the performance and utility of the visual reading.Materials and methodsA total number of 46 individuals with 12 cognitively unimpaired subjects (CU), 20 AD patients with mild cognitive impairment (AD-MCI), and 14 AD with dementia (AD-D) patients with both [18F]Florbetapir amyloid PET and [18F]Florzolotau tau PET scans were included. Clinical information, cognitive assessment, and amyloid PET scan results were recorded. For visual interpretation, a modified rainbow colormap was created and a regional tau uptake scoring system was proposed to evaluate the degree of tracer uptake and its spatial distribution within five cortical regions. Each region was scored on a scale of [0, 2] as compared to the background, and that resulted in a global scale range of [0, 10]. Four readers interpreted [18F]Florzolotau PET using the visual scale. The global and regional standardized uptake value ratios (SUVr) were also calculated for analysis.ResultsThe result indicates the average global visual scores were 0 ± 0 in the CU group, 3.43 ± 3.35 in the AD-MCI group, and 6.31 ± 2.97 in the AD-D group (p < 0.001). The consensus among the four observers on image scores was high with an intraclass correlation coefficient of 0.880 (95% CI: 0.767-0.936). The average global visual score was significantly associated with global SUVr (r = 0.884, p < 0.0001) and with the CDR-sum of box (r = 0.677, p < 0.0001).ConclusionThe visual reading method generated a visual score of [18F]Florzolotau tau-PET with good sensitivity and specificity to identify AD-D or CU individuals from the other patients. The preliminary result also showed that the global visual scores are significantly and reliably correlated with global cortical SUVr, and associated well with the clinical diagnosis and cognitive performance.
| S-EPMC10213356 | biostudies-literature