In Vivo Comparison of Tau Radioligands 18F-THK-5351 and 18F-THK-5317.
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ABSTRACT:
SUBMITTER: Betthauser TJ
PROVIDER: S-EPMC5425312 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background: Brain 18F-AV-45 amyloid positron emission tomography (PET) in Taiwanese patients with familial Alzheimer's disease with the amyloid precursor protein (APP) p.D678H mutation tends to involve occipital and cerebellar cortical areas. However, tau pathology in patients with this specific Taiwan mutation remains unknown. In this study, we aimed to study the Tau PET images in these patients. Methods: Clinical features, brain magnetic resonance imaging/computed tomography (MRI/CT), and brain 18F-THK-5351 PET were recorded in five patients with the APP p.D678H mutation and correlated with brain 18F-AV-45 PET images. We also compared the tau deposition patterns among five patients with familial mild cognitive impairment (fMCI), six patients with sporadic amnestic mild cognitive impairment (sMCI), nine patients with mild to moderate dementia due to Alzheimer's disease (AD), and 12 healthy controls (HCs). All of the subjects also received brain 18F-AV-45 PET. Results: The nine patients with sAD and six patients with sMCI had a positive brain AV-45 PET scans, while the 12 HCs had negative brain AV-45 PET scans. All five patients with fMCI received a tau PET scan with the age at onset ranging from 46 to 53 years, in whom increased standard uptake value ratio (SUVR) of 18F-THK-5351 was noted in all seven brain cortical areas compared with the HCs. In addition, the SUVRs of 18F-THK-5351 were increased in the frontal, medial parietal, lateral parietal, lateral temporal, and occipital areas (P < 0.001) in the patients with sAD compared with the HCs. The patients with fMCI had a significant higher SUVR of 18F-THK-5351 in the cerebellar cortex compared to the patients with sMCI. The correlations between regional SUVR and Mini-Mental State Examination score and between regional SUVR and clinical dementia rating (sum box) scores within volumes of interest of Braak stage were statistically significant. Conclusion: Tau deposition was increased in the patients with fMCI compared to the HCs. Increased regional SUVR in the cerebellar cortical area was a characteristic finding in the patients with fMCI. As compared between amyloid and tau PET, the amyloid deposition is diffuse, but tau deposition is limited to the temporal lobe in the patients with fMCI.
| S-EPMC6538951 | biostudies-literature
Project description:BackgroundSemantic variant primary progressive aphasia (svPPA) is a subtype of primary progressive aphasia characterized by two-way anomia and disturbance in word comprehension, with focal atrophy in the left temporal lobe. [18F]THK-5351 was originally developed to trace tau protein. However, it has recently been suggested that [18F]THK-5351 binds to monoamine oxidase B in astrocytes, which reflects gliosis. Herein, the authors present two cases involving patients with early-stage svPPA who underwent [18F]THK-5351 positron emission tomography (PET) imaging, and examined whether [18F]THK-5351 PET imaging is more sensitive to neurodegenerative lesions than conventional imaging modalities such as magnetic resonance imaging (MRI) and cerebral blood flow (CBF)-single photon emission computed tomography (SPECT).Case presentationTwo patients, 64- and 79-year-old men, without notable medical or family history, exhibited disturbances in word comprehension and mild anomia with fluent speech and spared repetition. In both cases, surface dyslexia was observed but prosopagnosia was absent. Although mild depression was detected in 1 of the 2 patients, no behavioral disorders were present in either case. In both cases, MRI revealed atrophy in the anterior and inferior portions of the left temporal lobe. Technetium-99-ethyl cysteinate dimer ([99mTc]ECD) SPECT revealed hypoperfusion in the left temporal lobe. Alzheimer's disease was ruled out by [11C]Pittsburgh Compound-B (PiB) PET scan. Both patients fulfilled the diagnostic criteria for svPPA. Because of mild language deficits and lack of right temporal atrophy, they were considered to be at an early stage of the disease. In both cases, [18F]THK-5351 retention was observed in bilateral temporal lobes, predominantly on the left side. Comparison of different imaging modalities suggested that [18F]THK-5351 was more sensitive in detecting neurodegenerative change in the right temporal lobe than MRI and [99mTc]ECD SPECT.Conclusions[18F]THK-5351 retention was clearly demonstrated at an early stage of svPPA. Results of the present study suggest that [18F]THK-5351 PET imaging may facilitate very early diagnosis of the disease.
| S-EPMC6205153 | biostudies-literature
Project description:[18F]THK5351, a recently-developed positron emission tomography (PET) tracer for measuring tau neurofibrillary tangle accumulation, may help researchers examine aging, disease, and tau pathology in living human brains. We examined THK5351 tracer pharmacokinetics to define an optimal acquisition time for static late images.Primary measurements were calculation of regional values of distribution volume ratios (DVR) and standardized uptake value ratios (SUVR) in 6 healthy older control and 10 Alzheimer's disease (AD) participants. We examined associations between DVR and SUVR, searching for a 20 min SUVR time window that was stable and comparable to DVR. We additionally examined diagnostic group differences in this 20 min SUVR.In healthy controls, [18F]THK5351 uptake was low, with increased temporal relative to frontal binding. In AD, regional uptake was substantially higher than in healthy controls, with temporal exceeding frontal binding. Retention in cerebellar gray matter, which was used as the reference region, was low compared to other regions. Both DVR and SUVR values showed minimal change over time after 40 min. SUVR 20-40, 30-50, and 40-60 min were most consistently correlated with DVR; SUVR 40-60 min, the most stable time window, was used in further analyses. Significant (AD > healthy control) group differences existed in temporoparietal regions, with marginal medial temporal differences. We found high basal ganglia SUVR 40-60 min signal, with no group differences.We examined THK5351, a new PET tracer for measuring tau accumulation, and compared multiple analysis methods for quantifying regional tracer uptake. SUVR 40-60 min performed optimally when examining 20 min SUVR windows, and appears to be a practical method for quantifying relative regional tracer retention. The results of this study offer clinical potential, given the usefulness of THK5351-PET as a biomarker of tau pathology in aging and disease.
| S-EPMC4927104 | biostudies-literature
Project description:Imaging biomarkers support the diagnosis of Alzheimer's disease (AD). We aimed to determine whether combining automated brain volumetry on MRI and quantitative measurement of tau deposition on [18F] THK-5351 PET can aid discrimination of AD spectrum. From a prospective database in an IRB-approved multicenter study (NCT02656498), 113 subjects (32 healthy control, 55 mild cognitive impairment, and 26 Alzheimer disease) with baseline structural MRI and [18F] THK-5351 PET were included. Cortical volumes were quantified from FDA-approved software for automated volumetric MRI analysis (NeuroQuant). Standardized uptake value ratio (SUVR) was calculated from tau PET images for 6 composite FreeSurfer-derived regions-of-interests approximating in vivo Braak stage (Braak ROIs). On volumetric MRI analysis, stepwise logistic regression analyses identified the cingulate isthmus and inferior parietal lobule as significant regions in discriminating AD from HC and MCI. The combined model incorporating automated volumes of selected brain regions on MRI (cingulate isthmus, inferior parietal lobule, hippocampus) and SUVRs of Braak ROIs on [18F] THK-5351 PET showed higher performance than SUVRs of Braak ROIs on [18F] THK-5351 PET in discriminating AD from HC (0.98 vs 0.88, P = 0.033) but not in discriminating AD from MCI (0.85 vs 0.79, P = 0.178). The combined model showed comparable performance to automated volumes of selected brain regions on MRI in discriminating AD from HC (0.98 vs 0.94, P = 0.094) and MCI (0.85 vs 0.78; P = 0.065).
| S-EPMC8121780 | biostudies-literature
Project description:The 18F-THK-5351 radiotracer has been used to detect the in vivo tau protein distribution in patients with tauopathy, such as Alzheimer's disease and corticobasal syndrome. In addition, 18F-THK-5351 can also monitor neuroinflammatory process due to high affinity to astrogliosis. We aimed to explore 18F-THK-5351 distribution patterns and characteristics in patients with recent ischemic stroke.Fifteen patients received 18F-THK-5351 positron emission tomography (PET) and diffusion tensor imaging (DTI) approximately 3 months after ischemic stroke. A region of interest (ROI) was placed in the peri-ischemic area and was mirrored on the contralateral side as the control, and a proportional value was derived from the ratio of the peri-ischemic ROI value over the mirrored ROI value. Increased 18F-THK-5351 retention was observed in the areas around and remote from the stroke location. The proportional 18F-THK-5351 values were negatively correlated with the proportional fractional anisotropy values (r?=?-?0.39, P?=?0.04).18F-THK-5351 PET imaging provides a potential tool for in vivo visualization of the widespread ischemia-related changes associated with a microstructural disruption in recent ischemic stroke patients.
| S-EPMC6047954 | biostudies-literature
Project description:Positron-emission-tomography (PET) imaging of tau pathology has facilitated development of anti-tau therapies. While members of the arylquinoline and pyridoindole families have been the most frequently used tau radioligands so far, analyses of their comparative performance in vivo are scantly documented. Here, we conducted a head-to-head PET comparison of the arylquinoline 18FT807 and the pyridoindole 18FTHK5117 PET in a mouse model of tau pathology. PET recordings were obtained in groups of (N = 5-7) P301S and wild-type (WT) mice at 6 and 9 months of age. Volume-of-interest based analysis (standard-uptake-value ratio, SUVR) was used to calculate effect sizes (Cohen's d) for each tracer and age. Statistical parametric mapping (SPM) was used to assess regional similarity (dice coefficient) of tracer binding alterations for the two tracers. Immunohistochemistry staining of neurofibrillary tangles was performed for validation ex vivo. Significantly elevated 18F-T807 binding in the brainstem of P301S mice was already evident at 6 months (+14%, p < 0.01, d = 1.64), and increased further at 9 months (+23%, p < 0.001, d = 2.70). 18F-THK5117 indicated weaker increases and effect sizes at 6 months (+5%, p < 0.05, d = 1.07) and 9 months (+10%, p < 0.001, d = 1.49). Regional similarity of binding of the two tracers was high (71%) at 9 months. 18F-T807 was more sensitive than 18F-THK5117 to tau pathology in this model, although both tracers present certain obstacles, which need to be considered in the design of longitudinal preclinical tau imaging studies.
| S-EPMC5999706 | 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: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.
| S-EPMC8175317 | 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:PurposeThe pattern of flortaucipir tau PET uptake is topographically similar to the pattern of magnetic susceptibility in progressive supranuclear palsy (PSP); both with increased signal in subcortical structures such as the basal ganglia and midbrain, suggesting that they may be closely related. However, their relationship remains unknown since no studies have directly compared these two modalities in the same PSP cohort. We hypothesized that some flortaucipir uptake in PSP is associated with magnetic susceptibility, and hence iron deposition. The aim of this study was to evaluate the regional relationship between flortaucipir uptake and magnetic susceptibility and to examine the effects of susceptibility on flortaucipir uptake in PSP.MethodsFifty PSP patients and 67 cognitively normal controls were prospectively recruited and underwent three Tesla MRI and flortaucipir tau PET scans. Quantitative susceptibility maps were reconstructed from multi-echo gradient-echo MRI images. Region of interest (ROI) analysis was performed to obtain flortaucipir and susceptibility values in the subcortical regions. Relationships between flortaucipir and susceptibility signals were evaluated using partial correlation analysis in the subcortical ROIs and voxel-based analysis in the whole brain. The effects of susceptibility on flortaucipir uptake were examined by using the framework of mediation analysis.ResultsBoth flortaucipir and susceptibility were greater in PSP compared to controls in the putamen, pallidum, subthalamic nucleus, red nucleus, and cerebellar dentate (p<0.05). The ROI-based and voxel-based analyses showed that these two signals were positively correlated in these five regions (r = 0.36-0.59, p<0.05). Mediation analysis showed that greater flortaucipir uptake was partially explained by susceptibility in the putamen, pallidum, subthalamic nucleus, and red nucleus, and fully explained in the cerebellar dentate.ConclusionsThese results suggest that some of the flortaucipir uptake in subcortical regions in PSP is related to iron deposition. These findings will contribute to our understanding of the mechanisms underlying flortaucipir tau PET findings in PSP and other neurodegenerative diseases.
| S-EPMC10868646 | biostudies-literature