Elevated 18F-AV-1451 PET tracer uptake detected in incidental imaging findings.
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ABSTRACT:
SUBMITTER: Lockhart SN
PROVIDER: S-EPMC5384840 | biostudies-literature |
REPOSITORIES: biostudies-literature
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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.
| S-EPMC6357510 | biostudies-literature
Project description:The 18F-AV-1451 PET tracer binds to tau, an Alzheimer's disease biomarker. The standardized uptake value ratio (SUVR) 80-100 min window is widely used to quantify tau binding, although 18F-AV-1451 continues increasing relative to a reference region in regions with tau deposition. Left uncorrected, acquisition time inaccuracies can lead to errors from -4% to 6% in 20-min SUVR measurements in subjects with Alzheimer's disease. In 40 subjects with scans from 75-115 min following 18F-AV-1451 injection, we created 20-min reconstructions (4×5 min) of start-times ranging from 75-85 min, as proxies of offset scans and calculated the mean in regions of interest (ROIs). We developed a segmented least squares (SLS) method to obtain error-minimizing weighting coefficients for 18F-AV-1451 ROIs that best predict SUVR 80-100 from weighted means of SUVRs from offset start-times. We compared residual errors of our SLS method to those in: 1) uncorrected offset 20-min-SUVRs; 2) the mean of five-min frames within the 80-100 window; and 3) a least-squares interpolation method. We evaluated errors induced by start-time offset on SUVRs for each method. TheSLS, which corrected using least-squares coefficients of 5-min components, consistently reduced errors across all offset starttimes. Effect size analysis for simulated clinical longitudinal 18F-AV-1451 drug trials showed that uncorrected 20-min offset SUVRs would require up to 20% more participants to detect treatment effects compared with using SLS. Correction of SUVR scan-time errors by SLS minimizes errors compared with other correction methods and may be extended to other scanners and tracers.
| S-EPMC6475617 | 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:18F-T807 is a PET radiotracer developed for imaging tau protein aggregates, which are implicated in neurologic disorders including Alzheimer disease and traumatic brain injury (TBI). The current study characterizes 18F-T807 pharmacokinetics in human subjects using dynamic PET imaging and metabolite-corrected arterial input functions. Methods: Nine subjects (4 controls, 3 with a history of TBI, 2 with mild cognitive impairment due to suspected Alzheimer disease) underwent dynamic PET imaging for up to 120 min after bolus injection of 18F-T807 with arterial blood sampling. Total volume of distribution (VT) was estimated using compartmental modeling (1- and 2-tissue configurations) and graphical analysis techniques (Logan and multilinear analysis 1 [MA1] regression methods). Reference region-based methods of quantification were explored including Logan distribution volume ratio (DVR) and static SUV ratio (SUVR) using the cerebellum as a reference tissue. Results: The percentage of unmetabolized 18F-T807 in plasma followed a single exponential with a half-life of 17.0 ± 4.2 min. Metabolite-corrected plasma radioactivity concentration fit a biexponential (half-lives, 18.1 ± 5.8 and 2.4 ± 0.5 min). 18F-T807 in gray matter peaked quickly (SUV > 2 at ∼5 min). Compartmental modeling resulted in good fits, and the 2-tissue model with estimated blood volume correction (2Tv) performed best, particularly in regions with elevated binding. VT was greater in mild cognitive impairment subjects than controls in the occipital, parietal, and temporal cortices as well as the posterior cingulate gyrus, precuneus, and mesial temporal cortex. High focal uptake was found in the posterior corpus callosum of a TBI subject. Plots from Logan and MA1 graphical methods became linear by 30 min, yielding regional estimates of VT in excellent agreement with compartmental analysis and providing high-quality parametric maps when applied in voxelwise fashion. Reference region-based approaches including Logan DVR (t* = 55 min) and SUVR (80- to 100-min interval) were highly correlated with DVR estimated using 2Tv (R2 = 0.97, P < 0.0001). Conclusion:18F-T807 showed rapid clearance from plasma and properties suitable for tau quantification with PET. Furthermore, simplified approaches using DVR (t* = 55 min) and static SUVR (80-100 min) with cerebellar reference tissue were found to correlate highly with compartmental modeling outcomes.
| S-EPMC5334185 | biostudies-literature
Project description:To assess volume loss and flortaucipir uptake in patients with semantic dementia (SD) over time. Eight SD patients (3 female) underwent clinical evaluations, flortaucipir positron emission tomography, and brain magnetic resonance imaging at 2 visits. Voxel-level comparisons of magnetic resonance imaging gray and white matter volume loss and flortaucipir positron emission tomography uptake were performed in SPM12, comparing SD patients to controls at each visit. T-tests on difference images and paired t-tests of flortaucipir uptake were also performed. At the voxel level, SD patients showed asymmetric, bilateral gray volume loss in the temporal lobes, which, via visual inspection, extended posteriorly at follow-up. White matter loss and flortaucipir uptake were noted in SD patients in the left temporal lobe only, which appeared to extend posteriorly, without involvement of the right hemisphere at follow-up. Longitudinal analyses did not support significant changes in flortaucipir uptake between visits. The biological mechanisms of flortaucipir signal in suspected underlying TAR-DNA binding protein 43 pathology are unknown. A 1-year interval is not sufficient time to demonstrate significant longitudinal flortaucipir uptake changes in SD.
| S-EPMC7365267 | biostudies-literature
Project description:PurposeOff-target binding in the reference region is a challenge for recent tau tracers 18F-AV-1451 and 18F-THK5351. The conventional standardized uptake value ratio (SUVR) method relies on the average uptake from an unaffected tissue sample, and therefore is susceptible to biases from off-target binding as well as variability among individuals in the reference region. We propose a new method, standardized uptake value peak-alignment (SUVP), to reduce the bias of the SUVR, and improve the quantitative assessment of tau deposition.MethodsThe SUVP normalizes uptake values by their mode and standard deviation. Instead of using a reference region, the SUVP derives the contrast from unaffected voxels over the whole brain. Using SUVP and SUVR methods, we evaluated the global and regional tau binding of 18F-THK5351 and 18F-AV-1451 on two independent cohorts (N = 18 and 32, respectively), each with cognitively normal (NL) subjects and Alzheimer's disease (AD) subjects.ResultsBoth tracers showed significantly increased binding for AD in the targeted cortical areas. In the temporal cortex, SUVP had a higher classification success rate (CSR) than SUVR (0.96 vs 0.89 for 18F-THK5351; 0.86 vs 0.75 for 18F-AV-1451), as well as higher specificity under fixed sensitivity around 0.80 (0.70 vs 0.45 specificity for 18F-THK5351; 1.00 vs 0.78 for 18F-AV-1451). In the cerebellar cortex, an AD-NL group difference with effect size (Cohen's d) of 0.62 was observed for AV-1451, confirming the limitation of the SUVR approach using this region as a reference. A smaller cerebellar effect size (0.09) was observed for THK5351.ConclusionThe SUVP method reduces the bias of the reference region and improves the NL-AD classification compared to the SUVR approach.
| S-EPMC6174003 | biostudies-literature
Project description: Not available
| S-EPMC5154298 | biostudies-literature
Project description:Tau PET has allowed for critical insights into in vivo patterns of tau accumulation and change in individuals early in the Alzheimer's disease (AD) continuum. A key methodological step in tau PET analyses is the selection of a reference region, but there is not yet consensus on the optimal region especially for longitudinal tau PET analyses. This study examines how reference region selection influences results related to disease stage at baseline and over time. Longitudinal flortaucipir ([18F]-AV1451) PET scans were examined using several common reference regions (e.g., eroded subcortical white matter, inferior cerebellar gray matter) in 62 clinically unimpaired amyloid negative (CU A-) individuals, 73 CU amyloid positive (CU A+) individuals, and 64 amyloid positive individuals with mild cognitive impairment (MCI A+) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cross-sectionally, both reference regions resulted in robust group differences between CU A-, CU A+, and MCI A+ groups, along with significant associations with CSF phosphorylated tau (pTau-181). However, these results were more focally specific and akin to Braak Staging when using eroded white matter, whereas effects with inferior cerebellum were globally distributed across most cortical regions. Longitudinally, utilization of eroded white matter revealed significant accumulation greater than zero across more regions whereas change over time was diminished using inferior cerebellum. Interestingly, the inferior temporal target region seemed most robust to reference region selection with expected cross-sectional and longitudinal signal across both reference regions. With few exceptions, baseline tau did not significantly predict longitudinal change in tau in the same region regardless of reference region. In summary, reference region selection deserves further evaluation as this methodological step may lead to disparate findings. Inferior cerebellar gray matter may be more sensitive to cross-sectional flortaucipir differences, whereas eroded subcortical white matter may be more sensitive for longitudinal analyses examining regional patterns of change.
| S-EPMC8785682 | biostudies-literature
Project description:ObjectiveTo evaluate 18F-AV-1451 tau PET binding among microtubule-associated protein tau (MAPT) mutation carriers.MethodsUsing a case-control study, we quantitatively and qualitatively compared tau PET scans in 10 symptomatic and 3 asymptomatic MAPT mutation carriers (n = 13, age range 42-67 years) with clinically normal (CN) participants (n = 241, age range 42-67 years) and an Alzheimer disease (AD) dementia cohort (n = 30, age range 52-67 years). Eight participants had MAPT mutations that involved exon 10 (N279K n = 5, S305N n = 2, P301L n = 1) and tend to form 4R tau pathology, and 5 had mutations outside exon 10 (V337M n = 2, R406W n = 3) and tend to form mixed 3R/4R tau pathology.ResultsTau PET signal was qualitatively and quantitatively different between participants with AD, CN participants, and MAPT mutation carriers, with the greatest signal intensity in those with AD and minimal regional signal in MAPT mutation carries with mutations in exon 10. However, MAPT mutation carriers with mutations outside exon 10 had uptake levels within the AD range, which was significantly higher than both MAPT mutation carriers with mutations in exon 10 and controls.ConclusionsTau PET shows higher magnitude of binding in MAPT mutation carriers who harbor mutations that are more likely to produce AD-like tau pathology (e.g., in our series, the non-exon 10 families tend to accumulate mixed 3R/4R aggregates). Exon 10 splicing determines the balance of 3R and 4R tau isoforms, with some mutations involving exon 10 predisposing to a greater proportion of 4R aggregates and consequently a lower level of AV-1451 binding, as seen in this case series, thus supporting the notion that this tau PET ligand has specific binding properties for AD-like tau pathology.
| S-EPMC5858948 | biostudies-literature
Project description:The PET ligand [18F]AV-1451 was developed to bind tau pathology in Alzheimer's disease, but increased binding has been shown in both genetic tauopathies and in semantic dementia, a disease strongly associated with TDP-43 pathology. Here we assessed [18F]AV-1451 binding in behavioral variant frontotemporal dementia due to a hexanucleotide repeat expansion in C9orf72, characterized by TDP-43 pathology. We show that the C9orf72 mutation increases binding in frontotemporal cortex, with a distinctive distribution of binding compared with healthy controls.
| S-EPMC6186940 | biostudies-literature