Preclinical characterization of [18F]D2-LW223: an improved metabolically stable PET tracer for imaging the translocator protein 18 kDa (TSPO) in neuroinflammatory rodent models and non-human primates.

Positron emission tomography (PET) targeting translocator protein 18 kDa (TSPO) can be used for the noninvasive detection of neuroinflammation. Improved in vivo stability of a TSPO tracer is beneficial for minimizing the potential confounding effects of radiometabolites. Deuteration represents an important strategy for improving the pharmacokinetics and stability of existing drug molecules in the plasma. This study developed a novel tracer via the deuteration of [18F]LW223 and evaluated its in vivo stability and specific binding in neuroinflammatory rodent models and nonhuman primate (NHP) brains. Compared with LW223, D2-LW223 exhibited improved binding affinity to TSPO. Compared with [18F]LW223, [18F]D2-LW223 has superior physicochemical properties and favorable brain kinetics, with enhanced metabolic stability and reduced defluorination. Preclinical investigations in rodent models of LPS-induced neuroinflammation and cerebral ischemia revealed specific [18F]D2-LW223 binding to TSPO in regions affected by neuroinflammation. Two-tissue compartment model analyses provided excellent model fits and allowed the quantitative mapping of TSPO across the NHP brain. These results indicate that [18F]D2-LW223 holds significant promise for the precise quantification of TSPO expression in neuroinflammatory pathologies of the brain.

Assessment of whole-body and regional body fat using abdominal quantitative computed tomography in Chinese women and men.

BACKGROUND: Being overweight or obese has become a serious public health concern, and accurate assessment of body composition is particularly important. More precise indicators of body fat composition include visceral adipose tissue (VAT) mass and total body fat percentage (TBF%). Study objectives included examining the relationships between abdominal fat mass, measured by quantitative computed tomography (QCT), and the whole-body and regional fat masses, measured by dual energy X-ray absorptiometry (DXA), as well as to derive equations for the prediction of TBF% using data obtained from multiple QCT slices. METHODS: Whole-body and regional fat percentage were quantified using DXA in Chinese males (n = 68) and females (n = 71) between the ages of 24 and 88. All the participants also underwent abdominal QCT measurement, and their VAT mass and visceral fat volume (VFV) were assessed using QCT and DXA, respectively. RESULTS: DXA-derived TBF% closely correlated with QCT abdominal fat percentage (r = 0.89-0.93 in men and 0.76-0.88 in women). Stepwise regression showed that single-slice QCT data were the best predictors of DXA-derived TBF%, DXA android fat percentage and DXA gynoid fat percentage. Cross-validation analysis showed that TBF% and android fat percentage could be accurately predicted using QCT data in both sexes. There were close correlations between QCT-derived and DXA-derived VFV (r = 0.97 in men and 0.93 in women). CONCLUSION: Clinicians can assess the TBF% and android and gynoid fat percentages of Chinese women and men by analysing existing abdominal CT-derived data using the QCT technique.

A PET-based radiomics nomogram for individualized predictions of seizure outcomes after temporal lobe epilepsy surgery.

PURPOSE: To establish and validate a novel nomogram based on clinical characteristics and [18F]FDG PET radiomics for the prediction of postsurgical seizure freedom in patients with temporal lobe epilepsy (TLE). PATIENTS AND METHODS: 234 patients with drug-refractory TLE patients were included with a median follow-up time of 24 months after surgery. The correlation coefficient redundancy analysis and LASSO Cox regression were used to characterize risk factors. The Cox model was conducted to develop a Clinic-PET nomogram to predict the relapse status in the training set (n = 171). The nomogram's performance was estimated through discrimination, calibration, and clinical utility. The prognostic prediction model was validated in the test set (n = 63). RESULTS: Eight radiomics features were selected to assess the radiomics score (radscore) of the operation side (Lat_radscore) and the asymmetric index (AI) of the radiomics score (AI_radscore). AI_radscor, Lat_radscor, secondarily generalized seizures (SGS), and duration between seizure onset and surgery (Durmon) were significant predictors of seizure-free outcomes. The final model had a C-index of 0.68 (95 %CI: 0.59-0.77) for complete freedom from seizures and time-dependent AUROC was 0.65 at 12 months, 0.65 at 36 months, and 0.59 at 60 months in the test set. A web application derived from the primary predictive model was displayed for economic and efficient use. CONCLUSIONS: A PET-based radiomics nomogram is clinically promising for predicting seizure outcomes after temporal lobe epilepsy surgery.

Alterations of apparent diffusion coefficient from ultra high b-values in the bilateral thalamus and striatum in MRI-negative drug-resistant epilepsy.

OBJECTIVE: Subcortical nuclei such as the thalamus and striatum have been shown to be related to seizure modulation and termination, especially in drug-resistant epilepsy. Enhance diffusion-weighted imaging (eDWI) technique and tri-component model have been used in previous studies to calculate apparent diffusion coefficient from ultra high b-values (ADCuh). This study aimed to explore the alterations of ADCuh in the bilateral thalamus and striatum in MRI-negative drug-resistant epilepsy. METHODS: Twenty-nine patients with MRI-negative drug-resistant epilepsy and 18 healthy controls underwent eDWI scan with 15 b-values (0-5000 s/mm2). The eDWI parameters including standard ADC (ADCst), pure water diffusion (D), and ADCuh were calculated from the 15 b-values. Regions-of-interest (ROIs) analyses were conducted in the bilateral thalamus, caudate nucleus, putamen, and globus pallidus. ADCst, D, and ADCuh values were compared between the MRI-negative drug-resistant epilepsy patients and controls using multivariate generalized linear models. Inter-rater reliability was assessed using the intra-class correlation coefficient (ICC) and Bland-Altman (BA) analysis. False discovery rate (FDR) method was applied for multiple comparisons correction. RESULTS: ADCuh values in the bilateral thalamus, caudate nucleus, putamen, and globus pallidus in MRI-negative drug-resistant epilepsy were significantly higher than those in the healthy control subjects (all p < 0.05, FDR corrected). SIGNIFICANCE: The alterations of the ADCuh values in the bilateral thalamus and striatum in MRI-negative drug-resistant epilepsy might reflect abnormal membrane water permeability in MRI-negative drug-resistant epilepsy. ADCuh might be a sensitive measurement for evaluating subcortical nuclei-related brain damage in epilepsy patients. PLAIN LANGUAGE SUMMARY: This study aimed to explore the alterations of apparent diffusion coefficient calculated from ultra high b-values (ADCuh) in the subcortical nuclei such as the bilateral thalamus and striatum in MRI-negative drug-resistant epilepsy. The bilateral thalamus and striatum showed higher ADCuh in epilepsy patients than healthy controls. These findings may add new evidences of subcortical nuclei abnormalities related to water and ion hemostasis in epilepsy patients, which might help to elucidate the underlying epileptic neuropathophysiological mechanisms and facilitate the exploration of therapeutic targets.

Age-related changes in lumbar bone mineral density measured using quantitative computed tomography in healthy female cynomolgus monkeys.

Background: Cynomolgus monkeys are widely used in studies related to osteoporosis, and there is no evidence of age-related changes in volumetric bone mineral density (vBMD) measured using quantitative computed tomography (QCT) in nonhuman primates. This study aimed to describe changes in the characteristics of lumbar vBMD with age, to analyze the relationship between lumbar vBMD and body composition, and to investigate the precision of QCT measurements in healthy female cynomolgus monkeys. Methods: Age-related changes in lumbar vBMD were described using cubic regression models, and the accumulated bone loss rates (ABLR) of the lumbar spine were calculated. Spearman rank correlation and ridge regression analysis were used to investigate the relationship of the average lumbar vBMD and body components. Thirty animals were selected to analyze the short-term in vivo precision of the QCT measurements. The precision was expressed as the root-mean-square coefficient of variation (RMS-CV%) or root-mean-square standard deviation (RMS-SD). Results: A total of 72 healthy female cynomolgus monkeys, aged 1-25 years, were included in this study. The average lumbar vBMD of female cynomolgus monkeys increased with age until the age of 10 years, around which it reached peak bone mass, with a relatively marked decline after the age of 13 years. The ABLRs of female cynomolgus monkeys in the premenopausal (13-19 years) and postmenopausal age groups (20-25 years) were -4.9% and -21.2%, respectively. Ridge regression analysis showed that age and subcutaneous adipose tissue (SAT) contributed positively to the average lumbar vBMD in animals aged ≤10 years, whereas in animals aged >10 years, age contributed negatively to lumbar vBMD. The RMS-CV% (RMS-SD) of the lumbar vBMD measured using QCT ranged from 0.47% to 1.60% (1.91-6.31 mg/cm3). Conclusions: Age-related changes in lumbar vBMD measured using QCT in healthy female monkeys showed similar trends to those in humans. Age and SAT may affect the lumbar vBMD in female cynomolgus monkeys. QCT revealed good precision in measuring the lumbar vBMD in female cynomolgus monkeys.

18F-FDG PET/CT and PET/MRI fusion imaging for neuroendocrine carcinoma of the tongue: A case report.

Neuroendocrine carcinoma (NEC) involving the tongue is a rare and aggressive disease that is more common in middle-aged and elderly males. We report a case of a 56-year-old male who presented to our hospital with sore throat and was found to have a mass in the left root of the tongue. 18F-FDG PET/CT revealed intense FDG uptake in the mass of the tongue base, as well as different uptake of FDG in the mid-posterior mediastinal mass, right adrenal gland, and enlarged lymph nodes in the neck and mediastinum. Gadolinium-enhanced MRI clearly showed the extent of the tongue lesion, additionally suggesting the presence of brain metastases. 18F-FDG PET/MRI fusion images of the neck were obtained on the workstation, which may have a higher diagnostic value for tongue NEC. The patient underwent a biopsy of the mass in the left root of the tongue and was pathologically diagnosed with NEC. Whole-body 18F-FDG PET/CT and regional PET/MRI fusion images have complementary roles in the diagnosis of tongue NEC, and the former is mainly applied to determine the clinical stage of the disease and to guide treatment.

Analysis of serum bone turnover markers in female cynomolgus monkeys of different ages.

Objective: The purpose of this study was to examine bone turnover markers, estradiol, parathyroid hormone, and 25 hydroxyvitamin D, in cynomolgus monkeys at different ages to improve our understanding of the changes in bone turnover markers throughout the life cycle of cynomolgus monkeys and to provide a basis for the establishment of a non-human primate model of osteoporosis. Methods: Total Body Bone Mineral Density and Total Body Bone Mineral Content were measured using Dual-Energy X-Ray Absorptiometry in cynomolgus monkeys at different ages. Serum bone turnover marker' levels were measured using enzyme immunoassays at each age group, and the relationship between bone turnover markers and age was assessed by Spearman rank correlation analysis to investigate the relationship between bone turnover markers and age in female cynomolgus monkeys. Results: Total Body Bone Mineral Density in female cynomolgus monkeys peaked at 10 years of age and then formed a plateau that was maintained until old age. Procollagen I Aminoterminal Propeptide, Bone Alkaline Phosphatase, Osteocalcin, and C-Terminal Telopeptide Of Type I Collagen peaked at 1 to 3 years of age and gradually decreased with age, leveling off by 10 years of age. Estradiol, parathyroid hormone, and 25 hydroxyvitamin D, follicle-stimulating hormone, luteinizing hormone, were not significantly different among age groups. Conclusion: This paper provides data on trends in bone turnover markers throughout the life cycle of female cynomolgus monkeys, which are similar to human changes.

The precision study of dual energy X-ray absorptiometry for bone mineral density and body composition measurements in female cynomolgus monkeys.

Background: Dual-energy X-ray absorptiometry (DXA) is a well-accepted tool for monitoring skeletal and body composition changes in biomedical studies. The nonhuman primate model is suitable for studies exploring the pathogenesis of and novel treatments for osteoporosis. Our objectives are to determine the precision of DXA detection in cynomolgus monkeys and to identify the difference in precision in lumbar bone mineral density (BMD) with various segment selections. Methods: Thirty adult female cynomolgus monkeys underwent duplicate total body DXA scans. Total body bone mineral density (BMDTB) and body composition, including bone mineral content (BMCTB), lean mass (LMTB), and fat mass (FMTB), were analyzed by enCORE software, while lumbar BMD was obtained by manual region-of-interest analysis. The precision was represented as the root-mean-square standard deviation (RMS-SD) and coefficient of variation (RMS-CV%), and least significant changes (LSCs) were reported. Results: The RMS-SD (RMS-CV%) of the repeated DXA analyses for BMDTB, BMCTB, LMTB and FMTB were 0.002 g/cm2 (0.50%), 0.90 g (0.42%), 0.015 kg (0.49%), and 0.031 kg (2.71%), respectively. The regional BMD precision (RMS-CV%) of the lumbar spine with various combinations ranged from 0.70% to 1.09%, The LSCs with 80% statistical confidence (LSC80) ranged from 1.27% to 1.97%, and LSC95 ranged from 1.94% to 3.01%. Conclusions: DXA provided excellent reproducibility in the measurements of BMD and body composition in nonhuman primates. We find DXA reliable for total and regional measurement in skeletal research and the evaluation of osteoporosis treatment with monkeys as animal models.

Electroclinical and Multimodality Neuroimaging Characteristics and Predictors of Post-Surgical Outcome in Focal Cortical Dysplasia Type IIIa.

Focal cortical dysplasia (FCD) type IIIa is an easily ignored cause of intractable temporal lobe epilepsy. This study aimed to analyze the clinical, electrophysiological, and imaging characteristics in FCD type IIIa and to search for predictors associated with postoperative outcome in order to identify potential candidates for epilepsy surgery. We performed a retrospective review including sixty-six patients with FCD type IIIa who underwent resection for drug-resistant epilepsy. We evaluated the clinical, electrophysiological, and neuroimaging features for potential association with seizure outcome. Univariate and multivariate analyses were conducted to explore their predictive role on the seizure outcome. We demonstrated that thirty-nine (59.1%) patients had seizure freedom outcomes (Engel class Ia) with a median postsurgical follow-up lasting 29.5 months. By univariate analysis, duration of epilepsy (less than 12 years) (p = 0.044), absence of contralateral insular lobe hypometabolism on PET/MRI (p Log-rank = 0.025), and complete resection of epileptogenic area (p Log-rank = 0.004) were associated with seizure outcome. The incomplete resection of the epileptogenic area (hazard ratio = 2.977, 95% CI 1.218-7.277, p = 0.017) was the only independent predictor for seizure recurrence after surgery by multivariate analysis. The results of past history, semiology, electrophysiological, and MRI were not associated with seizure outcomes. Carefully included patients with FCD type IIIa through a comprehensive evaluation of their clinical, electrophysiological, and neuroimaging characteristics can be good candidates for resection. Several preoperative factors appear to be predictive of the postoperative outcome and may help in optimizing the selection of ideal candidates to benefit from epilepsy surgery.