The Relationship Between Frontostriatal Connectivity and Striatal Dopamine Function in Schizophrenia: An 18F-DOPA PET and Diffusion Tensor Imaging Study in Treatment Responsive and Resistant Patients

Objective@#Striatal dopamine dysfunction caused by cortical abnormalities is a leading hypothesis of schizophrenia. Although prefrontal cortical pathology is negatively correlated with striatal dopamine synthesis, the relationship between structural frontostriatal connectivity and striatal dopamine synthesis has not been proved in patients with schizophrenia with different treatment response. We therefore investigated the relationship between frontostriatal connectivity and striatal dopamine synthesis in treatment-responsive schizophrenia (non-TRS) and compared them to treatment-resistant schizophrenia (TRS) and healthy controls (HC). @*Methods@#Twenty-four patients with schizophrenia and twelve HC underwent [18F] DOPA PET scans to measure dopamine synthesis capacity (the influx rate constant Kicer) and diffusion 3T MRI to measure structural connectivity (fractional anisotropy, FA). Connectivity was assessed in 2 major frontostriatal tracts. Associations between Kicer and FA in each group were evaluated using Spearman’s rho correlation coefficients. @*Results@#Non-TRS showed a negative correlation (r=-0.629, p=0.028) between connectivity of dorsolateral prefrontal cortex-associative striatum (DLPFC-AST) and dopamine synthesis capacity of associative striatum but this was not evident in TRS (r=-0.07, p=0.829) and HC (r=-0.277, p=0.384). @*Conclusion@#Our findings are consistent with the hypothesis of dysregulation of the striatal dopaminergic system being related to prefrontal cortex pathology localized to connectivity of DLPFC-AST in non-TRS, and also extend the hypothesis to suggest that different mechanisms underlie the pathophysiology of non-TRS and TRS.

Evaluation of Near-infrared Fluorescence-conjugated Peptides for Visualization of Human Epidermal Receptor 2-overexpressed Gastric Cancer

Purpose@#A near-infrared (NIR) fluorescence imaging is a promising tool for cancer-specific image guided surgery. Human epidermal receptor 2 (HER2) is one of the candidate markers for gastric cancer. In this study, we aimed to synthesize HER2-specific NIR fluorescence probes and evaluate their applicability in cancer-specific image-guided surgeries using an animal model. @*Materials and Methods@#An NIR dye emitting light at 800 nm (IRDye800CW; Li-COR) was conjugated to trastuzumab and an HER2-specific affibody using a click mechanism. HER2 affinity was assessed using surface plasmon resonance. Gastric cancer cell lines (NCI-N87 and SNU-601) were subcutaneously implanted into female BALB/c nu (6–8 weeks old) mice.After intravenous injection of the probes, biodistribution and fluorescence signal intensity were measured using Lumina II (Perkin Elmer) and a laparoscopic NIR camera (InTheSmart). @*Results@#Trastuzumab-IRDye800CW exhibited high affinity for HER2 (KD =2.093(3) pM).Fluorescence signals in the liver and spleen were the highest at 24 hours post injection, while the signal in HER2-positive tumor cells increased until 72 hours, as assessed using the Lumina II system. The signal corresponding to the tumor was visually identified and clearly differentiated from the liver after 72 hours using a laparoscopic NIR camera. AffibodyIRDye800CW also exhibited high affinity for HER2 (KD =4.71 nM); however, the signal was not identified in the tumor, probably owing to rapid renal clearance. @*Conclusions@#Trastuzumab-IRDye800CW may be used as a potential NIR probe that can be injected 2–3 days before surgery to obtain high HER2-specific signal and contrast. Affibodybased NIR probes may require modifications to enhance mobilization to the tumor site.

Protective Effects of N-Acetylcysteine against Radiation-Induced Oral Mucositis In Vitro and In Vivo / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#Radiation-induced oral mucositis limits delivery of high-dose radiation to targeted cancers. Therefore, it is necessary to develop a treatment strategy to alleviate radiation-induced oral mucositis during radiation therapy. We previously reported that inhibiting reactive oxygen species (ROS) generation suppresses autophagy. Irradiation induces autophagy, suggesting that antioxidant treatment may be used to inhibit radiation-induced oral mucositis. @*Materials and Methods@#We determined whether treatment with N-acetyl cysteine (NAC) could attenuate radiation-induced buccal mucosa damage in vitro and in vivo. The protective effects of NAC against oral mucositis were confirmed by transmission electron microscopy and immunocytochemistry. mRNA and protein levels of DNA damage and autophagy-related genes were measured by quantitative real-time polymerase chain reaction and western blot analysis, respectively. @*Results@#Rats manifesting radiation-induced oral mucositis showed decreased oral intake, loss of body weight, and low survival rate. NAC intake slightly increased oral intake, body weight, and the survival rate without statistical significance. However, histopathologic characteristics were markedly restored in NAC-treated irradiated rats. LC3B staining of rat buccal mucosa revealed that NAC treatment significantly decreased the number of radiation-induced autophagic cells. Further, NAC inhibited radiation-induced ROS generation and autophagy signaling. In vitro, NAC treatment significantly reduced the expression of NRF2, LC3B, p62, and Beclin-1 in keratinocytes compared with that after radiation treatment. @*Conclusion@#NAC treatment significantly inhibited radiation-induced autophagy in keratinocytes and rat buccal mucosa and may be a potentially safe and effective option for the prevention of radiation-induced buccal mucosa damage.

Promotion of Nuclear Medicine-Related Sciences in Developing Countries / 대한핵의학회잡지

No abstract available.

Development of tau PET Imaging Ligands and their Utility in Preclinical and Clinical Studies / 대한핵의학회잡지

The pathological features of Alzheimer's disease are senile plaques which are aggregates of β-amyloid peptides and neurofibrillary tangles in the brain. Neurofibrillary tangles are aggregates of hyperphosphorylated tau proteins, and these induce various other neurodegenerative diseases, such as progressive supranuclear palsy, corticobasal degeneration, frontotemporal lobar degeneration, frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), and chronic traumatic encephalopathy. In the case of Alzheimer's disease, the measurement of neurofibrillary tangles associated with cognitive decline is suitable for differential diagnosis, disease progression assessment, and to monitor the effects of therapeutic treatment. This review discusses considerations for the development of tau ligands for imaging and summarizes the results of the first-in-human and preclinical studies of the tau tracers that have been developed thus far. The development of tau ligands for imaging studies will be helpful for differential diagnosis and for the development of therapeutic treatments for tauopathies including Alzheimer's disease.

Development of tau PET Imaging Ligands and their Utility in Preclinical and Clinical Studies / 대한핵의학회잡지

The pathological features of Alzheimer's disease are senile plaques which are aggregates of β-amyloid peptides and neurofibrillary tangles in the brain. Neurofibrillary tangles are aggregates of hyperphosphorylated tau proteins, and these induce various other neurodegenerative diseases, such as progressive supranuclear palsy, corticobasal degeneration, frontotemporal lobar degeneration, frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), and chronic traumatic encephalopathy. In the case of Alzheimer's disease, the measurement of neurofibrillary tangles associated with cognitive decline is suitable for differential diagnosis, disease progression assessment, and to monitor the effects of therapeutic treatment. This review discusses considerations for the development of tau ligands for imaging and summarizes the results of the first-in-human and preclinical studies of the tau tracers that have been developed thus far. The development of tau ligands for imaging studies will be helpful for differential diagnosis and for the development of therapeutic treatments for tauopathies including Alzheimer's disease.

Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease: Methodology and Baseline Sample Characteristics

OBJECTIVE: The Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's disease (KBASE) aimed to recruit 650 individuals, aged from 20 to 90 years, to search for new biomarkers of Alzheimer's disease (AD) and to investigate how multi-faceted lifetime experiences and bodily changes contribute to the brain changes or brain pathologies related to the AD process. METHODS: All participants received comprehensive clinical and neuropsychological evaluations, multi-modal brain imaging, including magnetic resonance imaging, magnetic resonance angiography, [11C]Pittsburgh compound B-positron emission tomography (PET), and [18F]fluorodeoxyglucose-PET, blood and genetic marker analyses at baseline, and a subset of participants underwent actigraph monitoring and completed a sleep diary. Participants are to be followed annually with clinical and neuropsychological assessments, and biannually with the full KBASE assessment, including neuroimaging and laboratory tests. RESULTS: As of March 2017, in total, 758 individuals had volunteered for this study. Among them, in total, 591 participants–291 cognitively normal (CN) old-aged individuals, 74 CN young- and middle-aged individuals, 139 individuals with mild cognitive impairment (MCI), and 87 individuals with AD dementia (ADD)–were enrolled at baseline, after excluding 162 individuals. A subset of participants (n=275) underwent actigraph monitoring. CONCLUSION: The KBASE cohort is a prospective, longitudinal cohort study that recruited participants with a wide age range and a wide distribution of cognitive status (CN, MCI, and ADD) and it has several strengths in its design and methodologies. Details of the recruitment, study methodology, and baseline sample characteristics are described in this paper.

Distinct Clinical Characteristics Depending on Cerebral Amyloid Positivity in Patients with Alzheimer Disease Dementia

OBJECTIVE: The present study investigated the clinical characteristics of Alzheimer's disease (AD) dementia with low brain amyloid-beta (Aβ-AD) burden comparing with AD dementia with high amyloid-beta burden (Aβ+AD). We also developed a prediction model for the amyloid positivity on ¹¹C-labelled Pittsburgh Compound B (PiB) positron emission tomography (PET) with distinct clinical variables in AD dementia patients. METHODS: Fifty-nine clinically defined AD dementia individuals, who participated in the Korean Brain Aging Study for Early diagnosis and prediction of AD (KBASE) study, were included. All the subjects received comprehensive clinical evaluations and PiB-PET. Based on cerebral PiB retention, all subjects were divided into Aβ+AD (n=47) and Aβ-AD (n=12) subgroups. To develop a prediction model for amyloid positivity, stepwise multiple logistic regression analysis was conducted. RESULTS: When compared to Aβ+AD, Aβ-AD showed older age, later age-at-onset, and lower education. In regard of risk factors for dementia, Aβ-AD had higher frequency of hypertension and diabetes mellitus as well as lower frequency of apolipoprotein E (APOE) ε4 allele. Although there was no between group difference in Clinical Dementia Rating (CDR) or CDR sum-of-boxes scores, mini-mental state examination and constructional recall scores were higher for Aβ-AD than Aβ+AD. The final amyloid positivity prediction model included APOE4 genotype, hypertension, and diabetes mellitus. CONCLUSION: The findings from this study indicated that clinically diagnosed AD dementia may have high possibility of not being pathological AD if they have older age and higher vascular risks, and did not have APOE4 genotype.

Correlation between Frailty Level and Adverse Health-related Outcomes of Community-Dwelling Elderly, One Year Retrospective Study / 가정의학회지

BACKGROUND: Frailty is considered to be a clinical syndrome characterized by decreased physiological reserves associated with a greater risk of health-related problems, hospitalization, and death. The current study examined hospitalization, falls, cognitive decline and disability between robust, prefrail and frail elderly in one year. METHODS: 110 participants aged 65 or more who visited two senior welfare centers in Seoul from February 2008 to June 2008 were surveyed again from March 2009 to June 2009 with demographic characteristics, number of chronic diseases and medication, study of osteoporotic fractures (SOF) frailty index, instrumental activity of daily living (IADL), depression, mini-mental state examination-Korean version (MMSE-K), falling history and admission history within one year. These results were compared with participants' previous survey done one year ago. RESULTS: Among total 110 subjects, 48 (44%) robust, 30 (27%) prefrail, and 32 (29%) frail subjects changed to 26 (24%), 54 (49%), and 30 (27%) respectively over the year. There were statistical significances in age, number of chronic disease, depressive mood, MMSE, falls, hospitalization, IADL disability contributing to frailty (P < 0.05). Frailty defined by SOF frailty index was associated with greater risk of adverse outcomes. Frail subjects had a higher age-adjusted risk of cognitive function decline (odds ratio [OR], 3.57), disability (OR, 9.64), fall (OR, 5.42), and hospitalization (OR, 4.45; P < 0.005). CONCLUSION: The frailty index like SOF frailty index might predict risk of falls, disability, hospitalization, and cognitive decline in the elderly, emphasizing special attention to the individuals showing frailty in outpatient examination.

Radiolabeling of NOTA and DOTA with Positron Emitting 68Ga and Investigation of In Vitro Properties / 핵의학분자영상

PURPOSE: We established radiolabeling conditions of NOTA and DOTA with a generator-produced PET radionuclide 68Ga and studied in vitro characteristics such as stability, serum protein binding, octanol/water distribution, and interference with other metal ions. MATERIALS AND METHODS: Various concentrations of NOTA.3HCl and DOTA.4HCl were labeled with 1 mL 68GaCl3 (0.18~5.75 mCi in 0.1 M HCl) in various pH. NOTA.3HCl (0.373 mM) was labeled with 68GaCl3 (0.183~0.232 mCi/0.1 M HCl 1.0 mL) in the presense of CuCl2, FeCl2, InCl3, FeCl3, GaCl3, MgCl2 or CaCl2 (0~6.07 mM) at room temperature. The labeling efficiencies of 68Ga-NOTA and 68Ga-DOTA were checked by ITLC-SG using acetone or saline as mobile phase. Stabilities, protein bindings, and octanol distribution coefficients of the labeled compounds also were investigated. RESULTS: 68Ga-NOTA and 68Ga-DOTA were labeled optimally at pH 6.5 and pH 3.5, respectively, and the chelates were stable for 4 hr either in the reaction mixture at room temperature or in the human serum at 37 degreesC. NOTA was labeled at room temperature while DOTA required heating for labeling. 68Ga-NOTA labeling efficiency was reduced by CuCl2, FeCl2, InCl2, FeCl3 or GaCl3, however, was not influenced by MgCl2 or CaCl2. The protein binding was low (2.04~3.32%). Log P value of 68Ga-NOTA was -3.07 indicating high hydrophilicity. CONCLUSION: We found that NOTA is a better bifunctional chelating agent than DOTA for 68Ga labeling. Although, 68Ga-NOTA labeling is interfered by various metal ions, it shows high stability and low serum protein binding.

A Convenient Radiolabeling of 11C(R)-PK11195 Using Loop Method in Automatic Synthesis Module / 핵의학분자영상

PURPOSE: ((R)-1-(2-chlorophenyl)-N-1-[11C]methyl-N-(1-propyl)-3-isoquinoline carboxamide ((R)-PK11195) is a specific ligand for the peripheral type benzodiazepine receptor and a marker of activated microglia, used to measure inflammation in neurologic disorders. We report here that a direct and simple radiosynthesis of [11C](R)-PK11195 inmild condition using NaH suspension in DMF and one-step loop method. MATERIALS AND METHODS: (R)-NDesmethyl- PK11195 (1 mg) in DMSO (0.1 mL) and NaH suspension in DMF (0.1 mL) were injected into a semi-prep HPLC loop. [11C]methyl iodide was passed through HPLC loop at room temperature. Purification was performed using semi-preparative HPLC. Aliquots eluted at 11.3 min were collected and analyzed by analytical HPLC and mass spectrometer. RESULTS: The labeling efficiency of [11C](R)-PK11195 was 71.8+/-8.5%. The specific activity was 11.8 +/-6.4 GBq/micromol and radiochemical purity was higher than 99.2%. The mass spectrum of the product eluted at 11.3 min showed m/z peaks at 353.1 (M+1), indicating the mass and structure of (R)-PK11195. CONCLUSION: By the one-step loop method with the [11C]CH3I automated synthesis module, [11C](R)-PK11195 could be easily prepared in high radiochemical yield using NaH suspension in DMF.

Inpatient Smoking Cessation Program and Its Success Rate for Abstinence among Korean Smokers / 가정의학회지

BACKGROUND: Inpatient smoking cessation programs have been known to be quite effective for smoking cessation, but it was rarely conducted among Koreans. This study was to investigate the effect of inpatient smoking cessation program among Korean smokers. METHODS: From March 1 to April 30, 2008, we carried out a randomized controlled trial for inpatient smoking cessation program among 70 smokers who were 18 years of age or over and admitted to a university hospital in Seoul, Korea. For the intervention group, a trained doctor conducted the systematic educational program for smoking cessation of 30 minutes to an hour. For the control group, they were advised with a 3-minute explanation for smoking cessation. We assessed the abstinence rates of study participants at 1 week, 1 month, and 3 months after discharge. RESULTS: In 3 months after the discharge, the abstinence rate for the intervention group was 37.1% while that of the control group was 14.3%. In simple logistic regression analysis, the smokers among the intervention group were 3.5 times more likely to abstain than those in the control group. After controlling for confounding factors, the smokers among the intervention group was 11.4 times more likely to abstain than those in the control group. CONCLUSION: For Korean smokers, the inpatient smoking cessation program showed a higher success rate of abstinence compared to simple advice and limited counselling.

Quality Control of Residual Solvents in 18FFDG Preparations by Gas Chromatography / 핵의학분자영상

PURPOSE: Analysis of volatile organic solvents in 2-deoxy-2-[18F] fluoro-D-glucose ([18F]FDG) preparations was performed by gas chromatography (GC), in accordance with USP. MATERIALS AND METHODS: Analyses were carried out on a Hewlett-Packard 6890 gas chromatography equipped with an FID. RESULTS: We determined the amounts of ethanol and acetonitrile on every batch of our routine [18F]FDG preparations, ranging between 5000 ppm and 100 ppm. In our routine preparation of [18F]FDG, the amount of acetonitrile and ethanol in the final product were well below the maximum allowable limit described in the USP. CONCLUSION: Our [18F]FDG preparations were in accordance with the suggested USP maximum allowable levels of the quality control analysis of volatile organic compounds.

Radiosynthesis of 11C6-OH-BTA-1 in Different Media and Confirmation of Reaction By-products / 핵의학분자영상

PURPOSE: [11C]6-OH-BTA-1 ([N-methyl-11C]2-(4'-methylaminophenyl)-6-hydroxybenzothiazole, 1), a -amyloid imaging agent for the diagnosis of Alzheimer's disease in PET, can be labeled with higher yield by a simple loop method. During the synthesis of [11C]1, we found the formation of by-products in various solvents, e.g., methylethylketone (MEK), cyclohexanone (CHO), diethylketone (DEK), and dimethylformamide (DMF). MATERIALS AND METHODS: In Automated radiosynthesis module, 1 mg of 4-aminophenyl-6-hydroxybenzothiazole (4) in 100 l of each solvent was reacted with [11C]methyl triflate in HPLC loop at room temperature (RT). The reaction mixture was separated by semi-preparative HPLC. Aliquots eluted at 14.4, 16.3 and 17.6 min were collected and analyzed by analytical HPLC and LC/MS spectrometer. RESULTS: The labeling efficiencies of [11C]1 were 86.0+/-5.5%, 59.7+/-2.4%, 29.9+/-1.8%, and 7.6+/-0.5% in MEK, CHO, DEK and DMF, respectively. The LC/MS spectra of three products eluted at 14.4, 16.3 and 17.6 mins showed m/z peaks at 257.3 (M+1), 257.3 (M+1) and 271.3 (M+1), respectively, indicating their structures as 1, 2-(4'-aminophenyl)-6-methoxybenzothiazole (2) and by-product (3), respectively. Ratios of labeling efficiencies for the three products ([11C]1:[11C]2:[11C]3) were 86.0+/-5.5%:5.0+/-3.4%:1.5+/-1.3% in MEK, 59.7+/-2.4%:4.7+/-3.2%:1.3+/-0.5% in CHO, 9.9+/-1.8%:2.0+/-0.7%:0.3+/-0.1% in DEK and 7.6+/-0.5%:0.0%:0.0% in DMF, respectively. CONCLUSION: The labeling efficiency of [11C]1 was the highest when MEK was used as a reaction solvent. As results of mass spectrometry, 1 and 2 were conformed. 3 was presumed.

The Effects of Abciximab(ReoPro(r))-Coated Stents on Extracellular Matrix Synthesis and Apoptosis

BACKGROUND AND OBJECTIVES: The most important mechanism of coronary stent restenosis is neointimal hyperplasia (NIH). In addition to neointimal cell proliferation, synthesis of the extracellular matrix (ECM) may be important for the induction of NIH. The effects of the abciximab (ReoPro(r))-coated stent on the ECM synthesis and cellular apoptosis in coronary stent restenosis were observed. MATERIALS AND METHODS: Twenty one abciximab-coated stents and 21 control stents were placed in porcine coronary arteries and histopathologic analyses were performed at 14 days, 28 days and 56 days after the stenting procedures, respectively. Each specimen was analyzed by hematoxylin and eosin staining, modified Movat, immunohistochemical staining and TUNEL analysis. RESULTS: The area of neointima in the abciximab-coated stents was reduced by 45.7% and 45.5% of the control stents at 28 days and 56 days after stenting, respectively (1.9+/-0.5 vs. 3.5+/-0.7 mm2, 2.4+/-0.5 vs. 4.4+/-0.6 mm2, p=0.012, 0.001, respectively). The content ratio of the proteoglycan of the abciximab-coated stents was reduced by 23% at 14 days (12.4+/-4.4 vs. 16.1+/-4.3%, respectively, p=0.041) and the content ratio of collagen in the abciximab-coated stents was reduced by 19.7% and 25% at 28 days and 56 days, respectively (27.7+/-5.0 vs. 34.5+/-8.7%, 36.6+/-10.5 vs. 48.8+/-12.7%, p=0.021, 0.001, respectively). The proliferating cell nuclear antigen index of neointima for the abciximab-coated stents was reduced by 22.2% at 14 days (10.5+/-5.4 vs. 13.5+/-8.4%, respectively, p=0.022). There was no significant difference in the apoptosis, as was determined by TUNEL analysis between the two groups on the 56-day follow-up after stenting. CONCLUSION: The Abciximabcoated stent inhibits ECM synthesis, but it does not inhibit apoptosis in a porcine stent restenosis model.

The Clinical Effects of Nicorandil during Percutaneous Coronary Intervention in Patients with Unstable Angina

BACKGROUND AND OBJECTIVES: The purpose of the study was to evaluate the clinical effect of Nicorandil during percutaneous coronary intervention (PCI) in patients with unstable angina (UA). SUBJECTS AND METHODS: Two hundred patients (61+/-10 years, male 143) with UA were randomly assigned to two groups: intravenous Isosorbide dinitrate (Group I, n=100) and intravenous Nicorandil (Group II, n=100). PCI was performed 12-48 hours after infusion of the agents. The post-procedural cardiac enzymes, 6-month MACE (major adverse cardiac event) and left ventricular ejection fraction (LVEF) were compared between the two groups. RESULTS: Successful PCI was performed in 96 patients (Group I=54, Group II=42). Patients requiring either emergent coronary angiography, temporary pacemaker or platelet glycoprotein IIb/IIIa receptor blocker were excluded. No significant differences were observed between the two groups in terms of the clinical and coronary angiographic characteristics. The level of creatine kinase-MB was elevated in 9 (17%) and 6 patients (14%), troponin T in 16 (30%) and 6 (14%) and troponin I in 25 (46%) and 9 (21%) patients of Groups I and II, respectively, after the PCI. The elevation of all troponins was lower in Group II (28 vs. 10 patients, p=0.01). MACE developed in 9 (17%) and 5 (12%) patients of Groups I and II (p=NS), respectively, during the 6-month clinical follow-up. The LVEF was higher in Group II than in Group I on follow-up echocardiography (65.4+/-7.2% vs. 71.0+/-6.7%, p=0.003). CONCLUSION: Nicorandil may have a myocardial protective effect during PCI in patients with UA.

A study on the possibility of bacteremia in patients undergoing orthodontic treatment with fixed appliance / 대한치과교정학회지

The purpose of this study was to investigate a possibility of chronic or intermittent bacteremia in patients undergoing orthodontic treatment with fixed orthodontic appliance. Orthodontic patients who had been injured by orthodontic appliances and/or suffered from gingivitis were selected. They had not taken any antibiotics for 1 month. The number of subjects were 21 including 7 males and 14 females. Blood samples of the subjects were cultured and, IgG, IgA and IgM levels in the serum were quantified. The author found following results. 1. No bacterial growth was found in 7-day culture of all the samples. 2. The immunoglobulin levels in serum were confined in normal range. 3. This study could not deny the possibility of transient bacteremia episode undergoing orthodontic treatment.