Impact of [11C]methionine PET with Bayesian penalized likelihood reconstruction on glioma grades based on new WHO 2021 classification.

OBJECTIVE: The uptake of [11C]methionine in positron emission tomography (PET) imaging overlapped in earlier images of tumors. Bayesian penalized likelihood (BPL) reconstruction increases the quantitative values of tumors compared with conventional ordered subset-expectation maximization (OSEM). The present study aimed to grade glioma malignancy based on the new WHO 2021 classification using [11C]methionine PET images reconstructed using BPL. METHODS: We categorized 32 gliomas in 28 patients as grades 2/3 (n = 15) and 4 (n = 17) based on the WHO 2021 classification. All [11C]methionine images were reconstructed using OSEM + time-of-flight (TOF) and BPL + TOF (ß = 200). Maximum standardized uptake value (SUVmax) and tumor-to-normal tissue ratio (T/Nmax) were measured at each lesion. RESULTS: The mean SUVmax was 4.65 and 4.93 in grade 2/3 and 6.38 and 7.11 in grade 4, and the mean T/Nmax was 7.08 and 7.22 in grade 2/3 and 9.30 and 10.19 in grade 4 for OSEM and BPL, respectively. The BPL significantly increased these values in grade 4 gliomas. The area under the receiver operator characteristic (ROC) curve (AUC) for SUVmax was the highest (0.792) using BPL. CONCLUSIONS: The BPL increased mean SUVmax and mean T/Nmax in lesions with higher contrast such as grade 4 glioma. The discrimination power between grades 2/3 and 4 in SUVmax was also increased using [11C]methionine PET images reconstructed with BPL.

Clinical application of MAO-B PET using 18F-THK5351 in neurological disorders.

Monoamine oxidase B (MAO-B) is an enzyme localized to the outer mitochondrial membrane and highly concentrated in astrocytes. Temporal changes in regional MAO-B levels can be used as an index of astrocytic proliferation, known as activated astrocytes or astrogliosis. MAO-B is a marker to evaluate the degree of astrogliosis. Therefore, MAO-B positron emission tomography (PET) is a powerful imaging technique for visualizing and quantifying ongoing astrogliosis through the estimate of regional MAO-B levels. Each neurodegenerative disorder generally has a characteristic distribution pattern of astrogliosis secondary to neuronal loss and pathological protein aggregation. Therefore, by imaging astrogliosis, MAO-B PET can be used as a neurodegeneration marker for identifying degenerative lesions. Any inflammation in the brain usually accompanies astrogliosis starting from an acute phase to a chronic phase. Therefore, by imaging astrogliosis, MAO-B PET can be used as a neuroinflammation marker for identifying inflammatory lesions. MAO-B levels are high in gliomas originating from astrocytes but low in lymphoid tumors. Therefore, MAO-B PET can be used as a brain tumor marker for identifying astrocytic gliomas by imaging MAO-B levels and distinguishing between astrocytic and lymphoid tumors. This review summarizes the clinical application of MAO-B PET using 18F-THK5351 as markers for neurodegeneration, neuroinflammation, and brain tumors in neurological disorders. Because we assume that MAO-B PET is clinically applied to an individual patient, we focus on visual inspection of MAO-B images at the individual patient level. Geriatr Gerontol Int 2024; 24: 31-43.

18 F-THK5351 PET Can Evaluate Tumor Extension in Intravascular Large B-Cell Lymphoma : Comparison With 11C-Methionine PET and 18F-FDG PET.

ABSTRACT: A 79-year-old man presenting with gait disturbance and cognitive decline was diagnosed with intravascular large B-cell lymphoma (IVLBCL) by random skin biopsy. Some IVLBCL lesions were identified by PET examinations using 11 C-methionine, 18 F-FDG, and 18 F-THK5351. 11 C-methionine and 18 F-FDG uptake, which likely reflects the presence of the lymphoma cells themselves, increased clearly in the left putamen but weakly in the left deep white matter. 18 F-THK5351 uptake increased in all lesions, likely reflecting perivascular astrogliosis caused by IVLBCL. Hence, 18 F-THK5351 PET can evaluate tumor extension in IVLBCL lesions where 11 C-methionine and 18 F-FDG PET may fail in its visualization.

Brain PET Imaging of 11C-Methionine, 18F-FDG, and 18F-THK5351 in a Case of Lymphomatoid Granulomatosis.

ABSTRACT: A 52-year-old woman complained of upper respiratory symptoms and subsequently developed Wallenberg syndrome. Chest CT and brain MRI revealed multiple nodular lesions in the lungs and brain. She was pathologically diagnosed with low-grade lymphomatoid granulomatosis by lung biopsy. Brain PET examinations using 11C-methionine, 18F-FDG, and 18F-THK5351 were performed. Uptake of 11C-methionine and 18F-FDG was slightly increased in some lesions, likely reflecting the degree of inflammatory cell infiltration. 18F-THK5351 uptake was significantly increased in all lesions, likely reflecting the degree of reactive astrogliosis. This case illustrates the utility of PET studies for diagnosing lymphomatoid granulomatosis and provides insight into its pathophysiology.

Adenosine A2A Receptor Occupancy by Caffeine After Coffee Intake in Parkinson's Disease.

BACKGROUND: Coffee intake can decrease the risk for Parkinson's disease (PD). Its beneficial effects are allegedly mediated by caffeine through adenosine A2A receptor (A2A R) antagonist action. OBJECTIVE: We aimed to calculate occupancy rates of striatal A2A Rs by caffeine after coffee intake in PD. METHODS: Five patients with PD underwent 11 C-preladenant positron emission tomography scanning at baseline and after intake of coffee containing 129.5 mg (n = 3) or 259 mg (n = 2) of caffeine. Concurrently, serum caffeine levels were measured. RESULTS: The mean serum caffeine level (µg/mL) was 0.374 at baseline and increased to 4.48 and 8.92 by 129.5 and 259 mg of caffeine, respectively. The mean occupancy rates of striatal A2A Rs by 129.5 and 259 mg of caffeine were 54.2% and 65.1%, respectively. CONCLUSIONS: A sufficient A2A R occupancy can be obtained by drinking a cup of coffee, which is equivalent to approximately 100 mg of caffeine. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Test-retest reproducibility of cerebral adenosine A2A receptor quantification using [11C]preladenant.

OBJECTIVE: To evaluate the reproducibility of cerebral adenosine A2A receptor (A2AR) quantification using [11C]preladenant ([11C]PLN) and PET in a test-retest study. METHODS: Eight healthy male volunteers were enrolled. Dynamic 90 min PET scans were performed twice at the same time of the day to avoid the effect of diurnal variation. Subjects refrained from caffeine from 12 h prior to scanning, and serum caffeine was measured before radioligand injection. Arterial blood was sampled repeatedly during scanning and the fraction of the parent compound in plasma was determined. Total distribution volume (VT) was estimated using 1- and 2-tissue compartment models (1-TCM and 2-TCM, respectively) and Logan graphical analysis (Logan plot) (t* = 30 min). Plasma-free fraction (fP) of [11C]PLN was measured and used for correction of VT values. Distribution volume ratio (DVR) was calculated from VT of target and reference regions and obtained by noninvasive Logan graphical reference tissue model (LGAR) (t* = 30 min). Absolute test-retest variability (aTRV), and intra-class correlation coefficient (ICC) of VT and DVR were calculated as indexes of repeatability. Correlation between DVR and serum concentration of caffeine (a nonselective A2AR blocker) was analyzed by Pearson's correlation analysis. RESULTS: Regional time-activity curves were well described by 2-TCM models. Estimation of VT by 2-TCM produced some erroneous values; therefore, the more robust Logan plot was selected as the appropriate model. Global mean aTRV was 20% for VT and 14% for VT/fP (ICC, 0.72 for VT and 0.87 for VT/fP). Global mean aTRV of DVR was 13% for Logan plot and 10% for LGAR (ICC, 0.70 for Logan plot and 0.81 for LGAR). DVR estimates using LGAR and Logan plot were in good agreement (r2 = 0.96). Coefficients of variation for VT, VT/fP, DVR (Logan plot), and DVR (LGAR) were 47%, 47%, 27%, and 18%, respectively. Despite low serum caffeine levels, significant concentration-dependent effects on [11C]PLN binding to target regions were observed (p < 0.01). CONCLUSIONS: In this study, moderate test-retest reproducibility and large inter-subject differences were observed with [11C]PLN PET, possibly attributable to competition by baseline amount of caffeine. Analysis of plasma caffeine concentration is recommended during [11C]PLN PET studies. TRIAL REGISTRATION: UMIN000030040.

Occupancy of adenosine A2A receptors by istradefylline in patients with Parkinson's disease using 11C-preladenant PET.

Istradefylline, an adenosine A2A receptor (A2AR) antagonist, is effective as an adjunct to levodopa and can alleviate "off" time and motor symptoms in patients with Parkinson's disease (PD). The present study aimed to calculate occupancy rates of A2ARs by administrating istradefylline 20 mg or 40 mg, which is the currently approved dose for PD in Japan. Additionally, A2AR availability was compared between patients with PD and healthy controls. Ten patients with PD under levodopa therapy and six age-matched healthy controls were included. The patients underwent a total of two 11C-preladenant positron emission tomography scans before and after the administration of istradefylline 20 mg or 40 mg (both n = 5). Binding potential (BPND) was calculated to estimate A2AR availability in the ventral striatum, caudate, and putamen. Maximal A2AR occupancy and ED50 were estimated by modeling the dose-occupancy curves. All patients were around the middle stage of PD, and their characteristics were clinically heterogeneous. Maximal A2AR occupancy and ED50 were 93.5% and 28.6 mg in the ventral striatum, 69.5% and 10.8 mg in the caudate, and 66.8% and 14.8 mg in the putamen, respectively. There were no significant differences in BPND values in the ventral striatum (P = 0.42), caudate (P = 0.72), and putamen (P = 0.43) between the PD and control groups. In conclusion, the present study shows that istradefylline binds to A2ARs dose-dependently. A sufficient occupancy of A2ARs could be obtained by administrating the approved dose of istradefylline.

PET Imaging of 18F-FDG, 11C-methionine, 11C-flumazenil, and 11C-4DST in Progressive Multifocal Leukoencephalopathy.

The use of positron emission tomography (PET) imaging in progressive multifocal leukoencephalopathy (PML) has rarely been reported. We herein report a set of PET images in a 63-year-old patient with PML. In PML lesions, the uptake of 18F-fluorodeoxyglucose, 11C-methionine, 11C-flumazenil, and [methyl-11C]4'-thiothymidine was decreased, increased, decreased, and unchanged, respectively. These results suggest that glucose metabolism decreased, protein synthesis increased, neuronal integrity decreased, and the DNA synthesis and cellular proliferation of host cells were not activated in PML lesions. These results may reflect very little infiltration by inflammatory cells and active infection with JC virus in this case.

Adenosine A1 receptors measured with 11 C-MPDX PET in early Parkinson's disease.

Adenosine A1 receptors (A1 Rs) interact negatively with dopamine D1 receptors (D1 Rs) in neurons of the basal ganglia's direct pathway, while adenosine A2A receptors (A2A Rs) negatively interact with dopamine D2 receptors (D2 Rs) in indirect-pathway neurons. The aim of this study was to investigate the cerebral density of A1 Rs in Parkinson's disease (PD) in its early stages, using PET scans with the radioligand 8-dicyclopropylmethyl-1-11 C-methyl-3-propylxanthine (11 C-MPDX). We studied 10 drug-naïve patients with early PD. Each patient was also examined for dopamine transporters (DATs) and D2 Rs by PET using 11 C-2-ß-carbomethoxy-3-ß-(4-fluorophenyl)-tropane (11 C-CFT) and 11 C-raclopride (11 C-RAC), respectively. Ten elderly, healthy volunteers were recruited as controls for 11 C-MPDX PET scanning and eight elderly volunteers were recruited as controls for 11 C-CFT and 11 C-RAC PET scanning. The PET scans revealed a decrease in the uptake ratio index (URI) of 11 C-CFT and an increase in the URI of 11 C-RAC in patients. In the temporal lobe, the binding potential for 11 C-MPDX was higher in the patient group than in healthy subjects, but not in the other regions examined, including the striatum. In patients, we observed motor-symptom asymmetry and a relationship between parkinsonism and the striatal density of DATs, but not A1 R density. In the putamen of early PD, asymmetrical down-regulation of A2A Rs is likely a compensatory mechanism in response to a decrease in dopamine. However, our study suggests that A1 Rs are unaltered in the putamen of early PD.

Initial Evaluation of an Adenosine A2A Receptor Ligand, 11C-Preladenant, in Healthy Human Subjects.

11C-preladenant is a selective antagonist for mapping of cerebral adenosine A2A receptors (A2ARs) by PET. This is a first-in-human study to examine the safety, radiation dosimetry, and brain imaging of 11C-preladenant in healthy human subjects. Methods: Dynamic 11C-preladenant PET scans (90 min) were obtained in 5 healthy male subjects. During the scan, arterial blood was sampled at various time intervals, and the fraction of the parent compound in plasma was determined. For anatomic coregistration, T1-weighted MRI was performed. The total distribution volume (VT) was estimated using 1- and 2-tissue-compartment models (1T and 2T, respectively). The distribution volume ratio (DVR) was calculated from VT of target and reference region and obtained with a noninvasive Logan graphical reference tissue method (t* = 30 min). The applicability of a shortened protocol as an alternative to the 90-min PET scan was investigated. Tracer biodistribution and dosimetry were determined in 3 healthy male subjects, using serial whole-body PET scans acquired over 2 h after 11C-preladenant injection. Results: There were no serious adverse events in any of the subjects throughout the study period. 11C-preladenat readily entered the brain, with a peak uptake in the putamen and head of the caudate nucleus 30-40 min after tracer injection. Other brain regions showed rapid clearance of radioactivity. The regional distribution of 11C-preladenant was consistent with known A2AR densities in the brain. At pseudoequilibrium (reached at 40 min after injection), stable target-to-cerebellar cortex ratios of around 3.8-10.0 were obtained. The 2T fit better than the 1T in the low-density A2AR regions. In contrast, there were no significant differences between 1T and 2T in the high-A2AR-density regions. DVRs in the putamen and head of the caudate nucleus were around 3.8-10.3 when estimated using a Logan graphical reference tissue method with cerebellum as the reference region. PET scanning at 50 or 70 min can provide the stable DVR estimates within 10% or 5% differences at most, respectively. The radioactivity was mainly excreted through the hepatobiliary system after 11C-preladenant injection. As a result, the absorbed dose (µGy/MBq) was highest in the gallbladder wall (mean ± SD, 17.0 ± 2.5) and liver (11.7 ± 2.1). The estimated effective dose for 11C-preladenant was 3.7 ± 0.4 µSv/MBq. Conclusion: This initial evaluation indicated that 11C-preladenat is suitable for imaging of A2ARs in the brain.

Adenosine A(2A) receptors measured with [C]TMSX PET in the striata of Parkinson's disease patients.

Adenosine A(2A) receptors (A2ARs) are thought to interact negatively with the dopamine D(2) receptor (D2R), so selective A2AR antagonists have attracted attention as novel treatments for Parkinson's disease (PD). However, no information about the receptor in living patients with PD is available. The purpose of this study was to investigate the relationship between A2ARs and the dopaminergic system in the striata of drug-naïve PD patients and PD patients with dyskinesia, and alteration of these receptors after antiparkinsonian therapy. We measured binding ability of striatal A2ARs using positron emission tomography (PET) with [7-methyl-(11)C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine ([(11)C]TMSX) in nine drug-naïve patients with PD, seven PD patients with mild dyskinesia and six elderly control subjects using PET. The patients and eight normal control subjects were also examined for binding ability of dopamine transporters and D2Rs. Seven of the drug-naïve patients underwent a second series of PET scans following therapy. We found that the distribution volume ratio of A2ARs in the putamen were larger in the dyskinesic patients than in the control subjects (p<0.05, Tukey-Kramer post hoc test). In the drug-naïve patients, the binding ability of the A2ARs in the putamen, but not in the head of caudate nucleus, was significantly lower on the more affected side than on the less affected side (p<0.05, paired t-test). In addition, the A2ARs were significantly increased after antiparkinsonian therapy in the bilateral putamen of the drug-naïve patients (p<0.05, paired t-test) but not in the bilateral head of caudate nucleus. Our study demonstrated that the A2ARs in the putamen were increased in the PD patients with dyskinesia, and also suggest that the A2ARs in the putamen compensate for the asymmetrical decrease of dopamine in drug-naïve PD patients and that antiparkinsonian therapy increases the A2ARs in the putamen. The A2ARs may play an important role in regulation of parkinsonism in PD.

Development of PET radiopharmaceuticals and their clinical applications at the Positron Medical Center.

The Positron Medical Center has developed a large number of radiopharmaceuticals and 36 radiopharmaceuticals have been approved for clinical use for studying aging and geriatric diseases, especially brain functions. Positron emission tomography (PET) has been used to provide a highly advanced PET-based diagnosis. The current status of the development of radiopharmaceuticals, and representative clinical and methodological results are reviewed.