Molecular Imaging and Biology最新文献

Purpose: Many patients with Alzheimer's disease (AD) also have psychosis, and it has been reported that these patients have more severely impaired cognitive functions than patients without psychosis. The glutamatergic system in the brain is known to play an important role in memory and learning in the neural circuits. However, there has been limited research on how antipsychotic drugs affect the glutamatergic system of AD. Therefore, we aimed to investigate the effects of aripiprazole on the glutamatergic system in an animal model of AD using functional molecular imaging.

Procedures: In this study, 5xFAD mice were used as the animal model. At the age of 5 months, the mice were divided into wild-type, vehicle control, and aripiprazole-treated groups (n = 6 per group). The aripiprazole-treated group was administered aripiprazole for 2 months at a dose of 1 mg·kg^-1·day^-1. At 7 months of age, the animals underwent behavioral tests and glutamate positron emission tomography (PET) scans.

Results: The aripiprazole-treated group exhibited alleviated memory impairment in a novel object recognition test. Moreover, this group displayed 7-8% higher binding in the glutamate PET scan than the vehicle-treated 5xFAD group. Postmortem examination confirmed the recovery of glutamatergic damage.

Conclusions: The administration of aripiprazole alleviated memory impairment and restored the damaged glutamatergic system in 5xFAD mice. Although the use of aripiprazole in AD patients may be a constraint in terms of safety, we confirmed the possibility that the administration of antipsychotic drugs can be effective in AD.

Background: To investigate the potential utility of quantitative parameters obtained by ¹⁸F-fibroblast activation protein inhibitor positron emission tomography/computed tomography ([¹⁸F]AlF-NOTA-FAPI-04 PET/CT) in the assessment of organ involvement and disease activity in IgG4-related disease (IgG4-RD).

Methods: This study enrolled patients who underwent [¹⁸F]AlF-NOTA-FAPI-04 PET/CT scans at the Department of Rheumatology, The First Affiliated Hospital, Zhejiang University School of Medicine from August 2021 to August 2022. The PET/CT images of the included patients were re-evaluated by PET center technicians, and the maximal standardized uptake value (SUV_max), metabolic lesion volume (MLV), and total lesion FAPI (TL-FAPI) were used to evaluate the involved organs and tissues that abnormally accumulated [¹⁸F]AlF-NOTA-FAPI-04. The clinical and laboratory data of patients are also systematically collected and analyzed.

Results: Among the patients included in this study, 12 patients met the IgG4-RD classification criteria established by the American College of Rheumatology in 2019. Among them, 8 were males and 4 were females, with an average age of 59.3 ± 11.5 years. 50% of IgG4-RD patients were found with more organ involvement on PET/CT than physical examination, ultrasonography, and computed tomography. IgG4 levels (Rho = 0.594, p = 0.042) and IgG4-RI (Rho = 0.647, p = 0.023) were significantly positively correlated with TL-FAPI. After linear regression analysis, only TL-FAPI showed a predictive value of RI (R² = 0.356, B = 0.008, p = 0.041).

Conclusions: [¹⁸F]AlF-NOTA-FAPI-04 PET/CT is a useful tool for identifying asymptomatic organ involvement and assessing disease activity. The TL-FAPI as an indicator was positively correlated with IgG4-RD disease activity.

Purpose: To evaluate the potential of whole-body dynamic (WBD) 2-deoxy-2-[¹⁸F]fluoro-D-glucose positron emission tomography/computed tomography ([¹⁸F]FDG PET/CT) multiparametric imaging in the differential diagnosis between benign and malignant lung lesions.

Procedures: We retrospectively analyzed WBD PET/CT scans from patients with lung lesions performed between April 2020 and March 2023. Multiparametric images including standardized uptake value (SUV), metabolic rate (MR_FDG) and distribution volume (DV_FDG) were visually interpreted and compared. We adopted SUV_max, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) for semi-quantitative analysis, MR_max and DV_max values for quantitative analysis. We also collected the patients' clinical characteristics. The variables above with P-value < 0.05 in the univariate analysis were entered into a multivariate logistic regression. The statistically significant metrics were plotted on receiver-operating characteristic (ROC) curves.

Results: A total of 60 patients were included for data evaluation. We found that most malignant lesions showed high uptake on MR_FDG and SUV images, and low or absent uptake on DV_FDG images, while benign lesions showed low uptake on MR_FDG images and high uptake on DV_FDG images. Most malignant lesions showed a characteristic pattern of gradually increasing FDG uptake, whereas benign lesions presented an initial rise with rapid fall, then kept stable at a low level. The AUC values of MR_max and SUV_max are 0.874 (95% CI: 0.763-0.946) and 0.792 (95% CI: 0.667-0.886), respectively. DeLong's test showed the difference between the areas is statistically significant (P < 0.001).

Conclusions: Our study demonstrated that dynamic [¹⁸F]FDG PET/CT imaging based on the Patlak analysis was a more accurate method of distinguishing malignancies from benign lesions than conventional static PET/CT scans.

Introduction: Combined radiotherapy and immune checkpoint inhibition is a potential treatment option for head and neck squamous cell carcinoma (HNSCC). Immunocompetent mouse models can help to successfully develop radio- immunotherapy combinations and to increase our understanding of the effects of radiotherapy on the tumor microenvironment for future clinical translation. Therefore, the aim of this study was to develop a homogeneous, reproducible HNSCC model originating from the Mouse Oral Cancer 1 (MOC1) HNSCC cell line, and to explore the radiotherapy-induced changes in its tumor microenvironment, using flow cytometry and PD-L1 microSPECT/CT imaging.

Materials and methods: In vivo growing tumors originating from the parental MOC1 line were used to generate single cell derived clones. These clones were screened in vitro for their ability to induce programmed cell death ligand 1 (PD-L1) and major histocompatibility complex class I (MHC-I) following IFNγ exposure. Clones with different IFNγ sensitivity were inoculated in C57BL/6 mice and assessed for tumor outgrowth. The composition of the tumor microenvironment of a stably growing (non)irradiated MOC1-derived clone was assessed by immunohistochemistry, flow cytometry and PD-L1 microSPECT/CT.

Results: Low in vitro inducibility of MHC-I and PD-L1 by IFNγ was associated with increased tumor outgrowth of MOC1 clones in vivo. Flow cytometry analysis of cells derived from a stable in vivo growing MOC1 clone MOC1.3D5^low showed expression of MHC-I and PD-L1 on several cell populations within the tumor. Upon irradiation, MHC-I and PD-L1 increased on leukocytes (CD45.2⁺) and cancer associated fibroblasts (CD45.2^-/EpCAM^-/CD90.1⁺). Furthermore, PD-L1 microSPECT/CT showed increased tumor uptake of radiolabeled PD-L1 antibodies with a heterogeneous spatial distribution of the radio signal, which co-localized with PD-L1⁺ and CD45.2⁺ areas.

Discussion: PD-L1 and MHC-I inducibility by IFNγ in vitro is associated with tumor outgrowth of MOC1 clones in vivo. In tumors originating from a stably growing MOC1-derived clone, expression of these immune-related markers was induced by irradiation shown by flow cytometry on several cell populations within the tumor microenvironment such as immune cells and cancer associated fibroblasts. PD-L1 microSPECT/CT showed increased tumor uptake following radiotherapy, and autoradiography showed correlation of uptake with areas that are heavily infiltrated by immune cells. Knowledge of radiotherapy-induced effects on the tumor microenvironment in this model can help optimize timing and dosage for radio- immunotherapy combination strategies in future research.

Purpose: To ensure comparable PET/CT image quality between or within centres, clinical inter-system performance comparisons following European Association of Nuclear Medicine Research Ltd. (EARL) guidelines is required. In this work the performance of the long axial field-of-view Biograph Vision Quadra is compared to its predecessor, the short axial field-of-view Biograph Vision.

Procedures: To this aim, patients with suspected tumour lesions received a single weight-based (3 MBq/kg) 2-deoxy-2-[¹⁸F]fluoro-D-glucose injection and underwent routine clinical ( $\sim$ 15 min) scans on the Vision and 3-min scans on the Quadra in listmode in balanced order. Image quality (IQ), image noise (IN), and tumour demarcation (TD) were assessed visually by four nuclear medicine physicians using a 5-point Likert scale and semiquantitative analysis was performed using standardised uptake values (SUVs). Inter-reader agreement was tested using Wilcoxon's signed rank test and the SUVs were statistically compared using a paired t-test.

Results: Twenty patients (mean age, 60 years ± 8.8 [standard deviation], 16 male) were enrolled. Inter-reader agreement ranged from good to very good for IQ and IN (0.62 ≤ W ≤ 0.81), and fair for TD (0.29 ≤ W ≤ 0.39). Furthermore, a significant difference was found for TD (p = 0.015) between the systems, showing improved TD for the Quadra.

Conclusion: This study demonstrates that the Quadra can be used in routine clinical practice with multiple PET/CT systems or in multicentre studies. This system provides comparable diagnostic image quality and semiquantitative accuracy, improved TD, and has the advantage of shorter scan durations.

Purpose: Indeterminate renal masses are increasingly incidentally found on cross-sectional imaging. ^99mTc-sestamibi single-photon emission computed tomography/computed tomography (SPECT/CT) scans can be used to identify oncocytomas and oncocytic renal neoplasms, including a subset of chromophobe renal cell carcinomas (chRCCs), which are viewed as false-positive.

Procedure: Patients imaged with renal sestamibi scans between 2014 and 2023 were reviewed. Those patients with solitary tumors that were originally classified as chRCC were included in the analysis. Imaging with SPECT/CT from the liver dome down had been carried out 75 min after the administration of 925 MBq of ^99mTc-sestamibi. All available H&E and immunostained slides were re-reviewed and classified according to WHO 2022 criteria. Confirmatory immunohistochemical stains were performed in tumors considered morphologically suspicious for non-chRCC entities.

Result: A total of 18 patients with solitary tumors were included in the final analysis. 13/18 (72.2%) tumors in this cohort remained classified as chRCC, with 4/18 (22.2%) being eosinophilic-variant chRCC. The reclassified tumors (5/18 [27.8%]) included 2/18 (11.1%) low-grade oncocytic tumor (LOT), 1/18 (5.5%) eosinophilic vacuolated tumor (EVT), and 2/18 (11.1%) unclassified low-grade oncocytic neoplasms. As such, only 2/9 (22.2%) qualitatively "hot" tumors were chRCC other than eosinophilic-variant and only 1/9 (11.1%) "cold" tumors was a histology other than chRCC.

Conclusion: Based on current histopathologic classification methods, it is likely that the "false-positive" rate of uptake on renal sestamibi scans with chRCC has been over-stated. Further study is warranted to better refine the optimal utility of renal sestamibi scans for non-invasive risk stratification of indeterminate renal masses.

Purpose: Thyroid-stimulating hormone receptor (TSHR) is a G-protein coupled receptor that is highly expressed on benign and malignant thyroid tissues. TSHR binding and activation has long been a component of thyroid cancer molecular imaging and radiotherapy, by promoting expression of the sodium-iodide symporter (NIS) and incorporation of I-131 into thyroid hormones. Here, we report the radiosynthesis and preclinical evaluation of a Zirconium-89 (⁸⁹Zr) labeled TSHR antibody to serve as a positron emission tomography (PET) diagnostic correlate for therapeutic agents targeting TSHR without reliance on NIS.

Procedures: TSHR human monoclonal antibody K1-70 was conjugated to chelator desferrioxamine-p-benzyl-isothiocyanate, followed by labeling with Zr-89, yielding the radiotracer ⁸⁹Zr-DFO-TSHR-Ab. The in vitro cellar uptake and binding affinity of ⁸⁹Zr-DFO-TSHR-Ab were analyzed in three new TSHR stable overexpressing tumor cell lines and their corresponding wild types (WT) with low or no TSHR expression. ⁸⁹Zr-DFO-TSHR-Ab PET/CT imaging of TSHR expression was evaluated in tumor mouse models bearing one TSHR-positive tumor and other negative control with or without the coinjection of antibody K1-70, and then verified by radiotracer biodistribution study and tumor immunohistochemistry (IHC).

Results: The conjugate DFO-TSHR-Ab was labeled with Zr-89 at 37 °C for 60 min and purified by PD-10 column in radiochemical yields of 68.8 ± 9.9%, radiochemical purities of 98.7 ± 0.8%, and specific activities of 19.1 ± 2.7 mCi/mg (n = 5). In vitro cell studies showed ⁸⁹Zr-DFO-TSHR-Ab had significantly high uptake on TSHR expressing tumor cells with nanomolar affinity and high potency. Preclinical PET/CT imaging revealed that ⁸⁹Zr-DFO-TSHR-Ab selectively detected TSHR expressing thyroid tumors and displayed improved in vivo performance with the coinjection of unlabeled TSHR antibody K1-70 leading to higher uptake in TSHR expressing tumors than parental WT tumors and physiologic tissues; this observation was confirmed by the biodistribution and immunostaining analyses.

Conclusions: We synthesized ⁸⁹Zr-labeled antibody K1-70 as a new radiopharmaceutical for PET imaging of TSHR. ⁸⁹Zr-DFO-TSHR-Ab has high radioactive uptake and retention in TSHR expressing tumors and cleared quickly from most background tissues in mouse models. Our study demonstrated that ⁸⁹Zr-DFO-TSHR-Ab has the potential for PET imaging of TSHR-positive thyroid cancer and monitoring TSHR-targeted therapy.

Purpose: Develop a universal lesion recognition algorithm for PET/CT and PET/MRI, validate it, and explore factors affecting performance.

Procedures: The 2022 AutoPet Challenge's 1014 PET/CT dataset was used to train the lesion detection model based on 2D and 3D fractional-residual (F-Res) models. To extend this to PET/MRI, a network for converting MR images to synthetic CT (sCT) was developed, using 41 sets of whole-body MR and corresponding CT data. 38 patients' PET/CT and PET/MRI data were used to verify the universal lesion recognition algorithm. Image quality was assessed using signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR). Total lesion glycolysis (TLG), metabolic tumor volume (MTV), and lesion count were calculated from the resultant lesion masks. Experienced physicians reviewed and corrected the model's outputs, establishing the ground truth. The performance of the lesion detection deep-learning model on different PET images was assessed by detection accuracy, precision, recall, and dice coefficients. Data with a detection accuracy score (DAS) less than 1 was used for analysis of outliers.

Results: Compared to PET/CT, PET/MRI scans had a significantly longer delay time (135 ± 45 min vs 61 ± 12 min) and lower SNR (6.17 ± 1.11 vs 9.27 ± 2.77). However, CNR values were similar (7.37 ± 5.40 vs 5.86 ± 6.69). PET/MRI detected more lesions (with a mean difference of -3.184). TLG and MTV showed no significant differences between PET/CT and PET/MRI (TLG: 119.18 ± 203.15 vs 123.57 ± 151.58, p = 0.41; MTV: 36.58 ± 57.00 vs 39.16 ± 48.34, p = 0.33). A total of 12 PET/CT and 14 PET/MRI datasets were included in the analysis of outliers. Outlier analysis revealed PET/CT anomalies in intestines, ureters, and muscles, while PET/MRI anomalies were in intestines, testicles, and low tracer uptake regions, with false positives in ureters (PET/CT) and intestines/testicles (PET/MRI).

Conclusion: The deep learning lesion detection model performs well with both PET/CT and PET/MRI. SNR, CNR and reconstruction parameters minimally impact recognition accuracy, but delay time post-injection is significant.

Purpose: We explore the use of intravenously delivered fluorescent perfluorocarbon (PFC) nanoemulsion tracers and multi-spectral cryo-fluorescence tomography (CFT) for whole-body tracer imaging in murine inflammation models. CFT is an emerging technique that provides high-resolution, three-dimensional mapping of probe localization in intact animals and tissue samples, enabling unbiased validation of probe biodistribution and minimizes reliance on laborious histological methods employing discrete tissue panels, where disseminated populations of PFC-labeled cells may be overlooked. This methodology can be used to streamline the development of new generations of non-invasive, cellular-molecular imaging probes for in vivo imaging.

Procedures: Mixtures of nanoemulsions with different fluorescent emission wavelengths were administered intravenously to naïve mice and models of acute inflammation, colitis, and solid tumor. Mice were euthanized 24 h post-injection, frozen en bloc, and imaged at high resolution (~ 50 µm voxels) using CFT at multiple wavelengths.

Results: PFC nanoemulsions were visualized using CFT within tissues of the reticuloendothelial system and inflammatory lesions, consistent with immune cell (macrophage) labeling, as previously reported in in vivo magnetic resonance and nuclear imaging studies. The CFT signals show pronounced differences among fluorescence wavelengths and tissues, presumably due to autofluorescence, differential fluorescence quenching, and scattering of incident and emitted light.

Conclusions: CFT is an effective and complementary methodology to in vivo imaging for validating PFC nanoemulsion biodistribution at high spatial localization, bridging the resolution gap between in vivo imaging and histology.