Pre/post-natal exposure to microplastic as a potential risk factor for autism spectrum disorder.

In common with the increase in environmental pollution in the past 10 years, there has also been a recent increase in the prevalence of autism spectrum disorder (ASD). In this regard, we hypothesized that exposure to microplastics is a potential risk factor for ASD. To evaluate the validity of this hypothesis, we initially examined the accumulation of polyethylene (PE) in the brains of mice and then assessed the behavioral effects using mouse models at different life stages, namely, prenatal, post-weaning, puberty, and adult models. Based on typical behavioral assessments of autistic traits in the model mice, we established that ASD-like traits were induced in mice after PE feeding. In addition, we examined the induction of ASD-like traits in response to microplastic exposure using positron emission tomography, magnetic resonance spectroscopy, quantitative real-time polymerase chain reaction, microarray, and microbiome analysis. We believe these findings provide evidence in microplastics as a potential risk factor for ASD.

Decreased in vivo glutamate/GABA ratio correlates with the social behavior deficit in a mouse model of autism spectrum disorder.

To diagnose autism spectrum disorder (ASD), researchers have sought biomarkers whose alterations correlate with the susceptibility to ASD. However, biomarkers closely related to the pathophysiology of ASD are lacking. Even though excitation/inhibition (E/I) imbalance has been suggested as an underlying mechanism of ASD, few studies have investigated the actual ratio of glutamate (Glu) to γ-aminobutyric acid (GABA) concentration in vivo. Moreover, there are controversies in the directions of E/I ratio alterations even in extensively studied ASD animal models. Here, using proton magnetic resonance spectroscopy (1H-MRS) at 9.4T, we found significant differences in the levels of different metabolites or their ratios in the prefrontal cortex and hippocampus of Cntnap2-/- mice compared to their wild-type littermates. The Glu/GABA ratio, N-acetylaspartate (NAA)/total creatine (tCr) ratio, and tCr level in the prefrontal cortex were significantly different in Cntnap2-/- mice compared to those in wild-type mice, and they significantly correlated with the sociability of mice. Moreover, receiver operating characteristic (ROC) analyses indicated high specificity and selectivity of these metabolites in discriminating genotypes. These results suggest that the lowered Glu/GABA ratio in the prefrontal cortex along with the changes in the other metabolites might contribute to the social behavior deficit in Cntnap2-/- mice. Our results also demonstrate the utility of 1H-MRS in investigating the underlying mechanisms or the diagnosis of ASD.

Low-Dose PET Imaging of Tumors in Lung and Liver Regions Using Internal Motion Estimation.

Motion estimation and compensation are necessary for improvement of tumor quantification analysis in positron emission tomography (PET) images. The aim of this study was to propose adaptive PET imaging with internal motion estimation and correction using regional artificial evaluation of tumors injected with low-dose and high-dose radiopharmaceuticals. In order to assess internal motion, molecular sieves imitating tumors were loaded with 18F and inserted into the lung and liver regions in rats. All models were classified into two groups, based on the injected radiopharmaceutical activity, to compare the effect of tumor intensity. The PET study was performed with injection of F-18 fluorodeoxyglucose (18F-FDG). Respiratory gating was carried out by external trigger device. Count, signal to noise ratio (SNR), contrast and full width at half maximum (FWHM) were measured in artificial tumors in gated images. Motion correction was executed by affine transformation with estimated internal motion data. Monitoring data were different from estimated motion. Contrast in the low-activity group was 3.57, 4.08 and 6.19, while in the high-activity group it was 10.01, 8.36 and 6.97 for static, 4 bin and 8 bin images, respectively. The results of the lung target in 4 bin and the liver target in 8 bin showed improvement in FWHM and contrast with sufficient SNR. After motion correction, FWHM was improved in both regions (lung: 24.56%, liver: 10.77%). Moreover, with the low dose of radiopharmaceuticals the PET image visualized specific accumulated radiopharmaceutical areas in the liver. Therefore, low activity in PET images should undergo motion correction before quantification analysis using PET data. We could improve quantitative tumor evaluation by considering organ region and tumor intensity.

Comparison of Five Conductivity Tensor Models and Image Reconstruction Methods Using MRI.

Imaging of the electrical conductivity distribution inside the human body has been investigated for numerous clinical applications. The conductivity tensors of biological tissue have been obtained from water diffusion tensors by applying several models, which may not cover the entire phenomenon. Recently, a new conductivity tensor imaging (CTI) method was developed through a combination of B1 mapping, and multi-b diffusion weighted imaging. In this study, we compared the most recent CTI method with the four existing models of conductivity tensors reconstruction. Two conductivity phantoms were designed to evaluate the accuracy of the models. Applied to five human brains, the conductivity tensors using the four existing models and CTI were imaged and compared with the values from the literature. The conductivity image of the phantoms by the CTI method showed relative errors between 1.10% and 5.26%. The images by the four models using DTI could not measure the effects of different ion concentrations subsequently due to prior information of the mean conductivity values. The conductivity tensor images obtained from five human brains through the CTI method were comparable to previously reported literature values. The images by the four methods using DTI were highly correlated with the diffusion tensor images, showing a coefficient of determination (R2) value of 0.65 to 1.00. However, the images by the CTI method were less correlated with the diffusion tensor images and exhibited an averaged R2 value of 0.51. The CTI method could handle the effects of different ion concentrations as well as mobilities and extracellular volume fractions by collecting and processing additional B1 map data. It is necessary to select an application-specific model taking into account the pros and cons of each model. Future studies are essential to confirm the usefulness of these conductivity tensor imaging methods in clinical applications, such as tumor characterization, EEG source imaging, and treatment planning for electrical stimulation.

Porphyrin-Based Tumor-Targeting Theranostic Agent: Gd-TDAP.

The aim of this work was to evaluate a tumor-targeting porphyrin-based gadolinium complex (Gd-TDAP) for use as an MR/optical imaging agent and potential therapeutic agent. Gd-TDAP had higher longitudinal relaxivity (11.8 mM-1 s-1) than a commercial MRI contrast agent (Omniscan; 3.7 mM-1 s-1) in HSA solution (0.67 mM) at 3 T. The tumor-targeting characteristics were confirmed by T1-weighted MR imaging and optical imaging using an orthotopic brain tumor mouse model, which showed 1.3-fold higher uptake in tumor compared to normal brain tissues. The cell fraction data using U87MG glioblastoma cells indicated the potential for gadolinium neutron capture therapy (Gd-NCT), which requires gadolinium to be inside the cell nucleus. In addition, porphyrin derivatives can be used for photodynamic therapy (PDT), and the results demonstrated that Gd-TDAP has great potential not only as a bimodal imaging agent but also for treatment.

Nanovesicles derived from iron oxide nanoparticles-incorporated mesenchymal stem cells for cardiac repair.

Because of poor engraftment and safety concerns regarding mesenchymal stem cell (MSC) therapy, MSC-derived exosomes have emerged as an alternative cell-free therapy for myocardial infarction (MI). However, the diffusion of exosomes out of the infarcted heart following injection and the low productivity limit the potential of clinical applications. Here, we developed exosome-mimetic extracellular nanovesicles (NVs) derived from iron oxide nanoparticles (IONPs)-incorporated MSCs (IONP-MSCs). The retention of injected IONP-MSC-derived NVs (IONP-NVs) within the infarcted heart was markedly augmented by magnetic guidance. Furthermore, IONPs significantly increased the levels of therapeutic molecules in IONP-MSCs and IONP-NVs, which can reduce the concern of low exosome productivity. The injection of IONP-NVs into the infarcted heart and magnetic guidance induced an early shift from the inflammation phase to the reparative phase, reduced apoptosis and fibrosis, and enhanced angiogenesis and cardiac function recovery. This approach can enhance the therapeutic potency of an MSC-derived NV therapy.

Validation of conductivity tensor imaging using giant vesicle suspensions with different ion mobilities.

BACKGROUND: Electrical conductivity of a biological tissue at low frequencies can be approximately expressed as a tensor. Noting that cross-sectional imaging of a low-frequency conductivity tensor distribution inside the human body has wide clinical applications of many bioelectromagnetic phenomena, a new conductivity tensor imaging (CTI) technique has been lately developed using an MRI scanner. Since the technique is based on a few assumptions between mobility and diffusivity of ions and water molecules, experimental validations are needed before applying it to clinical studies. METHODS: We designed two conductivity phantoms each with three compartments. The compartments were filled with electrolytes and/or giant vesicle suspensions. The giant vesicles were cell-like materials with thin insulating membranes. We controlled viscosity of the electrolytes and the giant vesicle suspensions to change ion mobility and therefore conductivity values. The conductivity values of the electrolytes and giant vesicle suspensions were measured using an impedance analyzer before CTI experiments. A 9.4-T research MRI scanner was used to reconstruct conductivity tensor images of the phantoms. RESULTS: The CTI technique successfully reconstructed conductivity tensor images of the phantoms with a voxel size of [Formula: see text]. The relative [Formula: see text] errors between the conductivity values measured by the impedance analyzer and those reconstructed by the MRI scanner was between 1.1 and 11.5. CONCLUSIONS: The accuracy of the new CTI technique was estimated to be high enough for most clinical applications. Future studies of animal models and human subjects should be pursued to show the clinical efficacy of the CTI technique.

The correlation of neuropsychological evaluation with 11C-PiB and 18F-FC119S amyloid PET in mild cognitive impairment and Alzheimer disease.

For the diagnosis of mild cognitive impairment (MCI) and Alzheimer disease (AD), variable neuroimaging and neuropsychological tests have been used. We aimed to evaluate the correlation of neuropsychological domain with new amyloid positron emission tomography (PET) study and to validate the availability of new PET tracer.We enrolled 20 patients who underwent C-PiB-PET/CT, new PET tracer F-FC119S PET/CT from November, 2014 to July, 2015. Among them, 10 patients were diagnosed with AD and 10 patients with MCI. The current version of Seoul Neuropsychological Screening Battery (SNSB) II was performed for cognitive evaluation. Each parameter of SNSB was compared between 2 patient groups. Spearman correlation analysis between value of SNSB domain and standardized uptake value ratio (SUVR) of PET was also performed.The AD group presented significant poor z-score in Korean-Boston Naming Test(K-BNT) (P = .01),copy score of Rey Complex Figure Test (RCFT) (P = .049), immediate (P = .028)and delayed memory of Seoul Verbal Learning Test (SVLT) (P = .028), recognition of RCFT (P = .004), "animal" of Controlled Oral Word Association Test (COWAT) (P = .041), color reading of Korean-Color Word Stroop test (K-CWST) (P = .014), and Digit Symbol Coding (DSC) (P = .007) compared with MCI group. That means, except attention domain, all other cognitive domains were relatively impaired in AD compared with MCI. In correlation analysis, we found that poor performances on copy score of RCFT in MCI groups were associated with great beta amyloid burden in frontal area in both C-PiB-PET/CT and F-FC119S PET/CT. In AD group, F-FC119S PET presented more extensive correlation in each cognitive domain with multiple cortical areas compared with C-PiB-PET.The degree of amyloid burden assessed on F-FC119S PET was significantly correlated with neuropsychological test in AD, and also MCI patients. The combination of neuropsychological evaluation with novel F-FC119S PET/CT can be used for valid biomarker for MCI and AD.

Clinical Usefulness of 18F-FC119S Positron-Emission Tomography as an Auxiliary Diagnostic Method for Dementia: An Open-Label, Single-Dose, Evaluator-Blind Clinical Trial.

BACKGROUND AND PURPOSE: The aim of this study was to determine the diagnostic performance and safety of a new ¹8F-labeled amyloid tracer, ¹8F-FC119S. METHODS: This study prospectively recruited 105 participants, comprising 53 with Alzheimer's disease (AD) patients, 16 patients with dementia other than AD (non-AD), and 36 healthy controls (HCs). In the first screening visit, the Seoul Neuropsychological Screening Battery cognitive function test was given to the dementia group, while HC subjects completed the Korean version of the Mini Mental State Examination. Individuals underwent ¹8F-FC119S PET, ¹8F-fluorodeoxyglucose (FDG) PET, and brain MRI. The diagnostic performance of ¹8F-FC119S PET for AD was compared to a historical control (comprising previously reported and currently used amyloid-beta PET agents), ¹8F-FDG PET, and MRI. The standardized uptake value (SUV) ratio (ratio of the cerebral cortical SUV to the cerebellar SUV) was measured for each PET data set to provide semiquantitative analysis. All adverse effects during the clinical trial periods were monitored. RESULTS: Visual assessments of the ¹8F-FC119S PET data revealed a sensitivity of 92% and a specificity of 84% in detecting AD. ¹8F-FC119S PET demonstrated equivalent or better diagnostic performance for AD detection than the historical control, ¹8F-FDG PET (sensitivity of 80.0% and specificity of 76.0%), and MRI (sensitivity of 98.0% and specificity of 50.0%). The SUV ratios differed significantly between AD patients and the other groups, at 1.44±0.17 (mean±SD) for AD, 1.24±0.09 for non-AD, and 1.21±0.08 for HC. No clinically significant adverse effects occurred during the trial periods. CONCLUSIONS: ¹8F-FC119S PET provides high sensitivity and specificity in detecting AD and therefore may be considered a useful diagnostic tool for AD.

Monitoring Physiological Changes in Neutron-Exposed Normal Mouse Brain Using FDG-PET and DW-MRI.

We monitored a physiological response in a neutron-exposed normal mouse brain using two imaging tools, [18F]fluro-deoxy-D-glucose positron emission tomography ([18F]FDG-PET) and diffusion weighted-magnetic resonance imaging (DW-MRI), as an imaging biomarker. We measured the apparent diffusion coefficient (ADC) of DW-MRI and standardized uptake value (SUV) of [18F]FDG-PET, which indicated changes in the cellular environment for neutron irradiation. This approach was sensitive enough to detect cell changes that were not confirmed in hematoxylin and eosin (H&E) results. Glucose transporters (GLUT) 1 and 3, indicators of the GLUT capacity of the brain, were significantly decreased after neutron irradiation, demonstrating that the change in blood-brain-barrier (BBB) permeability affects the GLUT, with changes in both SUV and ADC values. These results demonstrate that combined imaging of the same object can be used as a quantitative indicator for in vivo pathological changes. In particular, the radiation exposure assessment of combined imaging, with specific integrated functions of [18F]FDG-PET and MRI, can be employed repeatedly for noninvasive analysis performed in clinical practice. Additionally, this study demonstrated a novel approach to assess the extent of damage to normal tissues as well as therapeutic effects on tumors.

Radiation-Induced Changes in Tumor Vessels and Microenvironment Contribute to Therapeutic Resistance in Glioblastoma.

Glioblastoma (GBM) is a largely fatal and highly angiogenic malignancy with a median patient survival of just over 1 year with radiotherapy (RT). The effects of RT on GBM remain unclear, although increasing evidence suggests that RT-induced alterations in the brain microenvironment affect the recurrence and aggressiveness of GBM. Glioma stem cells (GSCs) in GBM are resistant to conventional therapies, including RT. This study aimed to investigate the effect of radiation on tumor growth and the GSC microenvironment in a mouse model of glioma. To evaluate the growth-inhibitory effects of ionizing radiation on GSCs, tumor volume was measured via anatomical magnetic resonance imaging (MRI) after the intracranial injection of 1 × 104 human patient-derived GSCs (83NS cells), which exhibit marked radioresistance. When a tumor mass of ~5 mm3 was detected in each animal, 10 Gy of cranial irradiation was administered. Tumor progression was observed in the orthotopic xenografted GSC tumor (primary tumor) from a detectable tumor mass (5 mm3) to a lethal tumor mass (78 mm3) in ~7 d in the non-irradiated group. In the RT group, tumor growth was halted for almost 2 weeks after administering 10 Gy cranial irradiation, with tumor growth resuming thereafter and eventually approaching a lethal mass (56 mm3) 21 d after radiation. Radiation therapy yielded good therapeutic effects, with a 2-fold increase in GSC glioma survival; however, tumor relapse after RT resulted in higher mortality for the mice with a smaller tumor volume (p = 0.029) than the non-irradiated tumor-bearing mice. Moreover, tumor regrowth after IR resulted in different phenotypes associated with glioma aggressiveness compared with the non-irradiated mice; the apparent diffusion coefficient by diffusion MRI decreased significantly (p < 0.05, 0 Gy vs. 10 Gy) alongside decreased angiogenesis, abnormal vascular dilatation, and upregulated CD34, VWF, AQP1, and AQP4 expression in the tumor. These findings demonstrate that radiation affects GSCs in GBM, potentially resulting in therapeutic resistance by changing the tumor microenvironment. Thus, the results of this study suggest potential therapeutic targets for overcoming the resistance of GBMs to RT.

In Vivo Measurement of Brain Tissue Response After Irradiation: Comparison of T2 Relaxation, Apparent Diffusion Coefficient, and Electrical Conductivity.

Radiation therapy (RT) has been widely used as a powerful treatment tool to address cancerous tissues because of its ability to control cell growth. Its ionizing radiation damages the DNA of cancerous tissues, leading to cell death. Medical imaging, however, still has limitations regarding the reliability of its assessment of tissue response and in predicting the treatment effect because of its inability to provide contrast information on the gradual, minute tissue changes after RT. A recently developed magnetic resonance (MR)-based conductivity imaging method may provide direct, highly sensitive information on this tissue response because its contrast mechanism is based on the concentration and mobility of ions in intracellular and extracellular spaces. In this feasibility study, we applied T2-weighted, diffusion-weighted, and electrical conductivity imaging to mouse brain, thus, using the MR imaging to map the tissue response after radiation exposure. To evaluate the degree of response, we measured the T2 relaxation, apparent diffusion coefficient (ADC), and electrical conductivity of brain tissues before and after irradiation. The conductivity images, which showed significantly higher sensitivity than other MR imaging methods, indicated that the contrast is distinguishable in different ways at different areas of the brain. Future studies will focus on verifying these results and the long-term evaluation of conductivity changes using various irradiation methods for clinical applications.

Preliminary 19F-MRS Study of Tumor Cell Proliferation with 3'-deoxy-3'-fluorothymidine and Its Metabolite (FLT-MP).

The thymidine analogue 3'-deoxy-3'-[18F]fluorothymidine, or [18F]fluorothymidine ([18F]FLT), is used to measure tumor cell proliferation with positron emission tomography (PET) imaging technology in nuclear medicine. FLT is phosphorylated by thymidine kinase 1 (TK1) and then trapped inside cells; it is not incorporated into DNA. Imaging with 18F-radiolabeled FLT is a noninvasive technique to visualize cellular proliferation in tumors. However, it is difficult to distinguish between [18F]FLT and its metabolites by PET imaging, and quantification has not been attempted using current imaging methods. In this study, we successfully acquired in vivo19F spectra of natural or nonradioactive 3'-deoxy-3'-fluorothymidine ([19F]FLT) and its monophosphate metabolite (FLT-MP) in a tumor xenograft mouse model using 9.4T magnetic resonance imaging (MRI). This preliminary result demonstrates that 19F magnetic resonance spectroscopy (MRS) with FLT is suitable for the in vivo assessment of tumor aggressiveness and for early prediction of treatment response.

Preliminary PET Study of 18F-FC119S in Normal and Alzheimer's Disease Models.

To evaluate the efficacy of 18F-FC119S as a positron emission tomography (PET) radiopharmaceutical for the imaging of Alzheimer's disease (AD), we studied the drug absorption characteristics and distribution of 18F-FC119S in normal mice. In addition, we evaluated the specificity of 18F-FC119S for ß-amyloid (Aß) in the AD group of an APP/PS1 mouse model and compared it with that in the wild-type (WT) group. The behavior of 18F-FC119S in the normal mice was characteristic of rapid brain uptake and washout patterns. In most organs, including the brain, 18F-FC119S reached its maximum concentration within 1 min and was excreted via the intestine. Brain PET imaging of 18F-FC119S showed highly specific binding of the molecule to Aß in the cortex and hippocampus. The brain uptake and binding values for the AD group were higher than those for the WT group. These results indicated that 18F-FC119S would be a candidate PET imaging agent for targeting Aß plaque.

Head-to-head comparison of 11C-PiB and 18F-FC119S for Aß imaging in healthy subjects, mild cognitive impairment patients, and Alzheimer's disease patients.

As a new beta amyloid (Aß) positron emission tomography (PET) tracer, F-FC119S has shown higher cortical uptake in patients with Alzheimer's disease (AD) than that in healthy control subjects without adverse effects in a previous preliminary study. The aim of this study was to compare F-FC119S PET and C-PiB PET in healthy control (HC) subjects, mild cognitive impairment (MCI) patients, and AD patients.A total of 48 subjects, including 28 HC subjects, 10 MCI patients, and 10 AD patients, underwent static F-FC119S PET (30 minutes after intravenous [i.v.] injection) and C-PiB PET (40 minutes after i.v. injection) on the same day. Both PET images were visually and quantitatively assessed. Standardized uptake value ratios (SUVRs) were calculated for each brain region using the cerebellar cortex as a reference region.None (0%) of the 28 HC subjects and 4 (40%) of 10 MCI patients had positive scans on both PET images. Of the 10 AD patients, 7 (70%) had positive scans on C-PiB PET while 6 (60%) had positive scans on F-FC119S PET. Overall, 47 (98%) of 48 participants showed identical results based on visual analysis. Cortical SUVR of F-FC119S was higher in AD patients (1.38 ±â€Š0.16), followed by that in MCI patients (1.24 ±â€Š0.10) and in HC subjects (1.14 ±â€Š0.05). Compared with C-PiB PET, F-FC119S PET yielded a higher effect size (d = 2.02 vs. 1.67) in AD patients and a slightly lower effect size (d = 1.26 vs. 1.38) in MCI patients. In HC subjects, the nonspecific binding of F-FC119S to white matter (with the frontal cortex-to-white matter SUV ratio of 0.76) was slightly lower than that of C-PiB (ratio of 0.73). There was a significant linear correlation (slope = 0.41, r = 0.78, P < 0.001) between C-PiB and F-FC119S cortical SUVR.We could safely obtain images similar to C-PiB PET imaging Aß in the brain using F-FC119S PET. Therefore, F-FC119S might be suitable for imaging Aß deposition.

Improved tumor-targeting MRI contrast agents: Gd(DOTA) conjugates of a cycloalkane-based RGD peptide.

Two new MRI contrast agents, Gd-DOTA-c(RGD-ACP-K) (1) and Gd-DOTA-c(RGD-ACH-K) (2), which were designed by incorporating aminocyclopentane (ACP)- or aminocyclohexane (ACH)-carboxylic acid into Gd-DOTA (gadolinium-tetraazacyclo dodecanetetraacetic acid) and cyclic RGDK peptides, were synthesized and evaluated for tumor-targeting ability in vitro and in vivo. Binding affinity studies showed that both 1 and 2 exhibited higher affinity for integrin receptors than cyclic RGDyK peptides, which were used as a reference. These complexes showed high relaxivity and good stability in human serum and have the potential to improve target-specific signal enhancement in vivo MR images.