Parametric methods for [18F]flortaucipir PET.
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ABSTRACT:
SUBMITTER: Golla SS
PROVIDER: S-EPMC7044757 | biostudies-literature |
REPOSITORIES: biostudies-literature
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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: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.
| S-EPMC6357510 | biostudies-literature
Project description:IntroductionPositron 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.MethodsWe 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.ResultsGlobal 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.DiscussionThis 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.
| S-EPMC7699207 | biostudies-literature
Project description:Purpose[18F]-labeled positron emission tomography (PET) radioligands permit in vivo assessment of Alzheimer's disease biomarkers, including aggregated neurofibrillary tau (NFT) with [18F]flortaucipir. Due to structural similarities of flortaucipir with some monoamine oxidase A (MAO-A) inhibitors, this study aimed to evaluate flortaucipir binding to MAO-A and MAO-B and any potential impact on PET interpretation.Methods[18F]Flortaucipir autoradiography was performed on frozen human brain tissue slices, and PET imaging was conducted in rats. Dissociation constants were determined by saturation binding, association and dissociation rates were measured by kinetic binding experiments, and IC50 values were determined by competition binding.ResultsUnder stringent wash conditions, specific [18F]flortaucipir binding was observed on tau NFT-rich Alzheimer's disease tissue and not control tissue. In vivo PET experiments in rats revealed no evidence of [18F]flortaucipir binding to MAO-A; pre-treatment with MAO inhibitor pargyline did not impact uptake or wash-out of [18F]flortaucipir. [18F]Flortaucipir bound with low nanomolar affinity to human MAO-A in a microsomal preparation in vitro but with a fast dissociation rate relative to MAO-A ligand fluoroethyl-harmol, consistent with no observed in vivo binding in rats of [18F]flortaucipir to MAO-A. Direct binding of flortaucipir to human MAO-B was not detected in a microsomal preparation. A high concentration of flortaucipir (IC50 of 1.3 μM) was found to block binding of the MAO-B ligand safinamide to MAO-B on microsomes suggesting that, at micromolar concentrations, flortaucipir weakly binds to MAO-B in vitro.ConclusionThese data suggest neither MAO-A nor MAO-B binding will contribute significantly to the PET signal in cortical target areas relevant to the interpretation of [18F]flortaucipir.
| S-EPMC9399028 | biostudies-literature
Project description:Primary progressive apraxia of speech (PPAOS) is a term used to describe a neurodegenerative condition in which apraxia of speech (AOS; a planning and/or programming deficit) occurs in the absence of aphasia (a language deficit). PPAOS is strongly associated with 4-repeat tau pathology. Elevated flortaucipir ([18F]AV-1451; FTP) uptake has been observed cross-sectionally in patients with PPAOS and those with aphasia. Here, we evaluated longitudinal changes in previously-identified regions of uptake and their relationship with clinical presentation. Thirteen patients who were diagnosed with PPAOS (5 female) at presentation underwent FTP PET imaging at two visits (mean 1 year interval). Median age was 72, with a median of 4 years disease duration at initial testing. Beta-amyloid status was assessed with Pittsburgh Compound B (PiB), where a global PiB ratio>1.48 was deemed amyloid positive (n = 4). FTP uptake was assessed as cortical to cerebellar crus ratios (SUVr) in cortical regions of interest. A single hierarchical linear model (HLM) compared PPAOS patients to 52 cognitively unimpaired controls of similar age and sex. Annualized SUVr change was the outcome, predicted by region, clinical status, and age. Person-specific effects accounted for intra-patient correlations and contralateral regions were included as repeated measures. Changes in clinical measures were assessed using Wilcoxon signed-rank tests; statistically significant changes in the Montreal Cognitive Assessment, MDS-UPDRS, motor section, and PSP Rating Scale were noted between visits. Changes in FTP SUVr were greater for patients than controls. The strongest changes in PPAOS patients were in the precentral gyrus, pallidum, and mid and superior frontal gyri, per the HLM. Qualitatively, larger changes were seen in patients who had developed aphasia by the time of their baseline scan (n = 5). While the biological mechanisms of FTP signal in non-AD tauopathies are unknown, this study demonstrates the utility of FTP in tracking disease progression in 4R tauopathies.
| S-EPMC7060829 | biostudies-literature
Project description:Nonamnestic Alzheimer disease (AD) variants, including posterior cortical atrophy and the logopenic variant of primary progressive aphasia, differ from amnestic AD in distributions of tau aggregates and neurodegeneration. We evaluated whether 18F-flortaucipir (also called 18F-AV-1451) PET, targeting tau aggregates, detects these differences, and we compared the results with MRI measures of gray matter (GM) atrophy. Methods: Five subjects with posterior cortical atrophy, 4 subjects with the logopenic variant of primary progressive aphasia, 6 age-matched patients with AD, and 6 control subjects underwent 18F-flortaucipir PET and MRI. SUV ratios and GM volumes were compared using regional and voxel-based methods. Results: The subgroups showed the expected 18F-flortaucipir-binding patterns. Group effect sizes were generally stronger with 18F-flortaucipir PET than with MRI volumes. There were moderate-to-high correlations between regional GM atrophy and 18F-flortaucipir uptake. 18F-flortaucipir binding and GM atrophy correlated similarly to cognitive test performance. Conclusion:18F-flortaucipir binding corresponds to the expected neurodegeneration patterns in nonamnestic AD, with potential for earlier detection of pathology than is possible with MRI atrophy measures.
| S-EPMC6348438 | biostudies-literature
Project description:IntroductionWe previously reported genetic associations of the top Alzheimer's disease (AD) risk alleles with amyloid deposition and neurodegeneration. Here, we report the association of these variants with [18F]flortaucipir standardized uptake value ratio (SUVR).MethodsWe analyzed the [18F]flortaucipir scans of 352 cognitively normal (CN), 160 mild cognitive impairment (MCI), and 54 dementia (DEM) participants from Alzheimer's Disease Neuroimaging Initiative (ADNI)2 and 3. We ran step-wise regression with log-transformed [18F]flortaucipir meta-region of interest SUVR as the outcome measure and genetic variants, age, sex, and apolipoprotein E (APOE) ε4 as predictors. The results were visualized using parametric mapping at familywise error cluster-level-corrected P < .05.ResultsAPOE ε4 showed significant (P < .05) associations with tau deposition across all disease stages. Other significantly associated genes include variants in ABCA7 in CN, CR1 in MCI, BIN1 and CASS4 in MCI and dementia participants.DiscussionWe found significant associations to tau deposition for ABCA7, BIN1, CASS4, and CR1, in addition to APOE ε4. These four variants have been previously associated with tau metabolism through model systems.
| S-EPMC9092485 | biostudies-literature
Project description:This study aimed to determine the pattern of [18F]flortaucipir uptake in individuals affected by Gerstmann-Sträussler-Scheinker disease (GSS) associated with the PRNP F198S mutation. The aims were to: 1) determine the pattern of [18F]flortaucipir uptake in two GSS patients; 2) compare tau distribution by [18F]flortaucipir PET imaging among three groups: two GSS patients, two early onset Alzheimer's disease patients (EOAD), two cognitively normal older adults (CN); 3) validate the PET imaging by comparing the pattern of [18F]flortaucipir uptake, in vivo, with that of tau neuropathology, post-mortem. Scans were processed to generate standardized uptake value ratio (SUVR) images. Regional [18F]flortaucipir SUVR was extracted and compared between GSS patients, EOADs, and CNs. Neuropathology and tau immunohistochemistry were carried out post-mortem on a GSS patient who died 9 months after the [18F]flortaucipir scan. The GSS patients were at different stages of disease progression. Patient A was mildly to moderately affected, suffering from cognitive, psychiatric, and ataxia symptoms. Patient B was moderately to severely affected, suffering from ataxia and parkinsonism accompanied by psychiatric and cognitive symptoms. The [18F]flortaucipir scans showed uptake in frontal, cingulate, and insular cortices, as well as in the striatum and thalamus. Uptake was greater in Patient B than in Patient A. Both GSS patients showed greater uptake in the striatum and thalamus than the EOADs and greater uptake in all evaluated regions than the CNs. Thioflavin S fluorescence and immunohistochemistry revealed that the anatomical distribution of tau pathology is consistent with that of [18F]flortaucipir uptake. In GSS patients, the neuroanatomical localization of pathologic tau, as detected by [18F]flortaucipir, suggests correlation with the psychiatric, motor, and cognitive symptoms. The topography of uptake in PRNP F198S GSS is strikingly different from that seen in AD. Further studies of the sensitivity, specificity, and anatomical patterns of tau PET in diseases with tau pathology are warranted.
| S-EPMC6205777 | biostudies-literature
Project description:The aim of this study was to investigate the test-retest (TRT) repeatability of various parametric quantification methods for [18F]Flortaucipir positron emission tomography (PET). We included eight subjects with dementia or mild cognitive impairment due to Alzheimer's disease and six cognitively normal subjects. All underwent two 130-min dynamic [18F]Flortaucipir PET scans within 3 ± 1 weeks. Data were analyzed using reference region models receptor parametric mapping (RPM), simplified reference tissue method 2 (SRTM2) and reference logan (RLogan), as well as standardized uptake value ratios (SUVr, time intervals 40-60, 80-100 and 110-130 min post-injection) with cerebellar gray matter as reference region. We obtained distribution volume ratio or SUVr, first for all brain regions and then in three tau-specific regions-of-interest (ROIs). TRT repeatability (%) was defined as |retest-test|/(average (test + retest)) × 100. For all methods and across ROIs, TRT repeatability ranged from (median (IQR)) 0.84% (0.68-2.15) to 6.84% (2.99-11.50). TRT repeatability was good for all reference methods used, although semi-quantitative models (i.e. SUVr) performed marginally worse than quantitative models, for instance TRT repeatability of RPM: 1.98% (0.78-3.58) vs. SUVr80-100: 3.05% (1.28-5.52), p < 0.001. Furthermore, for SUVr80-100 and SUVr110-130, with higher average SUVr, more variation was observed. In conclusion, while TRT repeatability was good for all models used, quantitative methods performed slightly better than semi-quantitative methods.
| S-EPMC7705644 | biostudies-literature
Project description:Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by neuroglial tau pathology. A new staging system for PSP pathology postmortem has been described and validated. We used a data-driven approach to test whether postmortem pathologic staging in PSP can be reproduced in vivo with 18F-flortaucipir PET. Methods: Forty-two patients with probable PSP and 39 controls underwent 18F-flortaucipir PET. Conditional inference tree analyses on regional binding potential values identified absent/present pathology thresholds to define in vivo staging. Following the postmortem staging approach for PSP pathology, we evaluated the combinations of absent/present pathology (or abnormal/normal PET signal) across all regions to assign each participant to in vivo stages. ANOVA was applied to analyze differences among means of disease severity between stages. In vivo staging was compared with postmortem staging in 9 patients who also had postmortem confirmation of the diagnosis and stage. Results: Stage assignment was estimable in 41 patients: 10, 26, and 5 patients were classified in stage I/II, stage III/IV, and stage V/VI, respectively, whereas 1 patient was not classifiable. Explorative substaging identified 2 patients in stage I, 8 in stage II, 9 in stage III, 17 in stage IV, and 5 in stage V. However, the nominal 18F-flortaucipir--derived stage was not associated with clinical severity and was not indicative of pathology staging postmortem. Conclusion: 18F-flortaucipir PET in vivo does not correspond to neuropathologic staging in PSP. This analytic approach, seeking to mirror in vivo neuropathology staging with PET-to-autopsy correlational analyses, might enable in vivo staging with next-generation tau PET tracers; however, further evidence and comparisons with postmortem data are needed.
| S-EPMC7612961 | biostudies-literature