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Accurate quantification of amyloid positron emission tomography (PET) is essential for early detection of and intervention in Alzheimer's disease (AD) but there is still a lack of studies comparing the performance of various automated methods. This study compared the PET-only method and PET-and-MRI-based method with a pre-trained deep learning segmentation model. A large sample of 1180 participants in the Catholic Aging Brain Imaging (CABI) database was analyzed to calculate the regional standardized uptake value ratio (SUVR) using both methods. The logistic regression models were employed to assess the discriminability of amyloid-positive and negative groups through 10-fold cross-validation and area under the receiver operating characteristics (AUROC) metrics. The two methods showed a high correlation in calculating SUVRs but the PET-MRI method, incorporating MRI data for anatomical accuracy, demonstrated superior performance in predicting amyloid-positivity. The parietal, frontal, and cingulate importantly contributed to the prediction. The PET-MRI method with a pre-trained deep learning model approach provides an efficient and precise method for earlier diagnosis and intervention in the AD continuum.

Introduction: Despite prior research on the association between sarcopenia and cognitive impairment in the elderly, a comprehensive model that integrates various brain pathologies is still lacking., Methods: We used data from 528 non-demented older adults with or without sarcopenia in the Catholic Aging Brain Imaging (CABI) database, containing magnetic resonance imaging scans, positron emission tomography scans, and clinical data. We also measured three key components of sarcopenia: skeletal muscle index (SMI), hand grip strength (HGS), and the five times sit-to-stand test (5STS)., Results: All components of sarcopenia were significantly correlated with global cognitive function, but cortical thickness and amyloid-beta (Aβ) retention had distinctive relationships with each measure. In the path model, brain atrophy resulting in cognitive impairment was mediated by Aβ retention for SMI and periventricular white matter hyperintensity for HGS, but directly affected by the 5STS., Discussion: Treatments targeting each sub-domain of sarcopenia should be considered to prevent cognitive decline., Highlights: We identified distinct impacts of three sarcopenia measures on brain structure and Aβ. Muscle mass is mainly associated with Aβ and has an influence on the brain atrophy. Muscle strength linked with periventricular WMH and brain atrophy. Muscle function associated with cortical thinning in specific brain regions. Interventions on sarcopenia may be important to ease cognitive decline in the elderly., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Alzheimer's disease (AD) accounts for 60-70% of the population with dementia. Mild cognitive impairment (MCI) is a diagnostic entity defined as an intermediate stage between subjective cognitive decline and dementia, and about 10-15% of people annually convert to AD. We aimed to investigate the most robust model and modality combination by combining multi-modality image features based on demographic characteristics in six machine learning models. A total of 196 subjects were enrolled from four hospitals and the Alzheimer's Disease Neuroimaging Initiative dataset. During the four-year follow-up period, 47 (24%) patients progressed from MCI to AD. Volumes of the regions of interest, white matter hyperintensity, and regional Standardized Uptake Value Ratio (SUVR) were analyzed using T1, T2-weighted-Fluid-Attenuated Inversion Recovery (T2-FLAIR) MRIs, and amyloid PET (αPET), along with automatically provided hippocampal occupancy scores (HOC) and Fazekas scales. As a result of testing the robustness of the model, the GBM model was the most stable, and in modality combination, model performance was further improved in the absence of T2-FLAIR image features. Our study predicts the probability of AD conversion in MCI patients, which is expected to be useful information for clinician's early diagnosis and treatment plan design., (© 2024. The Author(s).)

Background: Application of visual scoring scales for regional atrophy in Alzheimer's disease (AD) in clinical settings is limited by their high time cost and low intra/inter-rater agreement., Objective: To provide automated atrophy scoring using objective volume driven from deep-learning segmentation methods for AD subtype classification using magnetic resonance imaging (MRI)., Methods: We enrolled 3,959 participants (1,732 cognitively normal [CN], 1594 with mild cognitive impairment [MCI], and 633 with AD). The occupancy indices for each regional volume were calculated by dividing each volume by the size of the lateral and inferior ventricular volumes. MR images from 355 participants (119 CN, 119 MCI, and 117 AD) from three different centers were used for validation. Two neuroradiologists performed visual assessments of the medial temporal, posterior, and global cortical atrophy scores in the frontal lobe using T1-weighted MR images. Images were also analyzed using the deep learning-based segmentation software, Neurophet AQUA. Cutoff values for the three scores were determined using the data distribution according to age. The scoring results were compared for consistency and reliability., Results: Four volumetric-driven scoring results showed a high correlation with the visual scoring results for AD, MCI, and CN. The overall agreement with human raters was weak-to-moderate for atrophy scoring in CN participants, and good-to-almost perfect in AD and MCI participants. AD subtyping by automated scores also showed usefulness as a research tool., Conclusions: Determining AD subtypes using automated atrophy scoring for late-MCI and AD could be useful in clinical settings or multicenter studies with large datasets., Competing Interests: This article utilized the segmentation tool, AQUA developed by Neurophet Research Institute, Inc., Seoul, South Korea. Y.S.C, R.E.K, H.W.K, H.L, M.L, D.K, and H.K.L are employees of Neurophet Inc. All other authors have no conflict of interest to report., (© 2024 – The authors. Published by IOS Press.)

Objective: : Cognitive reserve has emerged as a concept to explain the variable expression of clinical symptoms in the pathology of Alzheimer's disease (AD). The association between years of education, a proxy of cognitive reserve, and resting-state functional connectivity (rFC), a representative intermediate phenotype, has not been explored in the preclinical phase, considering risk factors for AD. We aimed to evaluate whether the relationship between years of education and rFC in cognitively preserved older adults differs depending on amyloid-beta deposition and APOE ε4 carrier status as effect modifiers., Methods: : A total of 121 participants underwent functional magnetic resonance imaging, [ 18 F] flutemetamol positron emission tomography-computed tomography, APOE genotyping, and a neuropsychological battery. Potential interactions between years of education and AD risk factors for rFC of AD-vulnerable neural networks were assessed with whole-brain voxel-wise analysis., Results: : We found a significant education years-by- APOE ε4 carrier status interaction for the rFC from the seed region of the central executive (CEN) and dorsal attention networks. Moreover, there was a significant interaction of rFC between right superior occipital gyrus and the CEN seed region by APOE ε4 carrier status for memory performances and overall cognitive function., Conclusion: : In preclinical APOE ε4 carriers, higher years of education were associated with higher rFC of the AD vulnerable network, but this contributed to lower cognitive function. These results contribute to a deeper understanding of the impact of cognitive reserve on sensitive functional intermediate phenotypic markers in the preclinical phase of AD.

When attempts to lose body fat mass frequently fail, breath acetone (BA) monitoring may assist fat mass loss during a low-carbohydrate diet as it can provide real-time body fat oxidation levels. This randomized controlled study aimed to evaluate the effectiveness of monitoring BA levels and providing feedback on fat oxidation during a three-week low-carbohydrate diet intervention. Forty-seven participants (mean age = 27.8 ± 4.4 years, 53.3% females, body mass index = 24.1 ± 3.4 kg m -2 ) were randomly assigned to three groups (1:1:1 ratio): daily BA assessment with a low-carbohydrate diet, body weight assessment (body scale (BS)) with a low-carbohydrate diet, and low-carbohydrate diet only. Primary outcome was the change in fat mass and secondary outcomes were the changes in body weight and body composition. Forty-five participants completed the study (compliance rate: 95.7%). Fat mass was significantly reduced in all three groups (all P < 0.05); however, the greatest reduction in fat mass was observed in the BA group compared to the BS (differences in changes in fat mass, -1.1 kg; 95% confidence interval: -2.3, -0.2; P = 0.040) and control (differences in changes in fat mass, -1.3 kg; 95% confidence interval: -2.1, -0.4; P = 0.013) groups. The BA group showed significantly greater reductions in body weight and visceral fat mass than the BS and control groups (all P < 0.05). In addition, the percent body fat and skeletal muscle mass were significantly reduced in both BA and BS groups (all P < 0.05). However, no significant differences were found in changes in body fat percentage and skeletal muscle mass between the study groups. Monitoring BA levels, which could have motivated participants to adhere more closely to the low-carbohydrate diet, to assess body fat oxidation rates may be an effective intervention for reducing body fat mass (compared to body weight assessment or control conditions). This approach could be beneficial for individuals seeking to manage body fat and prevent obesity., (© 2024 IOP Publishing Ltd.)

Background: Recent interest has surged in the locus coeruleus (LC) for its early involvement in Alzheimer's disease (AD), notably concerning the apolipoprotein ɛ4 allele (APOE4)., Objective: This study aimed to discern LC functional connectivity (FC) variations in preclinical AD subjects, dissecting the roles of APOE4 carrier status and amyloid-β (Aβ) deposition., Methods: A cohort of 112 cognitively intact individuals, all Aβ-positive, split into 70 APOE4 noncarriers and 42 carriers, underwent functional MRI scans, neuropsychological assessments, and APOE genotyping. The research utilized seed to voxel analysis for illustrating LC rsFC discrepancies between APOE4 statuses and employed a general linear model to examine the interactive influence of APOE4 carrier status and Aβ deposition on LC FC values., Results: The investigation revealed no significant differences in sex, age, or SUVR between APOE4 carriers and noncarriers. It found diminished LC FC with the occipital cortex in APOE4 carriers and identified a significant interaction between APOE4 carrier status and temporal lobe SUVR in LC FC with the occipital cortex. This interaction suggested a proportional increase in LC FC for APOE4 carriers. Additional notable interactions were observed affecting LC FC with various brain regions, indicating a proportional decrease in LC FC for APOE4 carriers., Conclusions: These findings confirm that APOE4 carrier status significantly influences LC FC in preclinical AD, showcasing an intricate relationship with regional Aβ deposition. This underscores the critical role of genetic and pathological factors in early AD pathophysiology, offering insights into potential biomarkers for early detection and intervention strategies.

Objectives: Alzheimer's disease (AD) is characterised by amyloid-beta accumulation (A), tau aggregation (T) and neurodegeneration (N). Vascular (V) burden has been found concomitantly with AD pathology and has synergistic effects on cognitive decline with AD biomarkers. We determined whether cognitive trajectories of AT(N) categories differed according to vascular (V) burden., Methods: We prospectively recruited 205 participants and classified them into groups based on the AT(N) system using neuroimaging markers. Abnormal V markers were identified based on the presence of severe white matter hyperintensities., Results: In A+ category, compared with the frequency of Alzheimer's pathological change category (A+T-), the frequency of AD category (A+T+) was significantly lower in V+ group (31.8%) than in V- group (64.4%) (p=0.004). Each AT(N) biomarker was predictive of cognitive decline in the V+ group as well as in the V- group (p<0.001). Additionally, the V+ group showed more severe cognitive trajectories than the V- group in the non-Alzheimer's pathological changes (A-T+, A-N+; p=0.002) and Alzheimer's pathological changes (p<0.001) categories., Conclusion: The distribution and longitudinal outcomes of AT(N) system differed according to vascular burdens, suggesting the importance of incorporating a V biomarker into the AT(N) system., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

In recent years, fibroblast activation protein (FAP) has emerged as an important target for the diagnosis and therapy of various tumors due to its high expression on the cell surface of cancer-associated fibroblasts, which are the major components of the tumor stroma. In this study, we synthesized and evaluated 18 F-labeled FAP inhibitors (FAPIs) for FAP imaging. Two silicon fluoride acceptor (SiFA)-conjugated FAPIs were synthesized: one containing a γ-carboxy-l-glutamic acid (Gla) residue ( 1 ) and another containing two Gla residues ( 2 ). Both ligands exhibited high binding affinities for FAP. 18 F/ 19 F exchange reactions on both ligands were performed in the presence of 2% water. This resulted in the formation of radioligands [ 18 F] 1 and [ 18 F] 2 in high radiochemical yields. Radioligand [ 18 F] 2 , with a more favorable partition coefficient, was selected for the U87MG cell binding study, and the results showed FAP-specific binding of the radioligand to the cells. An ex vivo biodistribution study in U87MG tumor-bearing mice 60 min after injection demonstrated a 5.8-fold higher tumor accumulation of [ 18 F] 2 than that of [ 18 F] 1 . Furthermore, PET and ex vivo biodistribution studies of [ 18 F] 2 in U87MG tumor-bearing mice showed high and persistent tumor uptake over time, which was significantly blocked by the preinjection of FAPI-04. Our results indicate that [ 18 F]SiFA-(Gla) 2 -conjugated FAPI ([ 18 F] 2 ) has the potential for FAP imaging.

Objective: We examined the effects of short-term KD on exercise efficiency and hormonal response during and after the graded exercise testing., Methods: Fourteen untrained healthy adults (8 males, 6 females, age 26.4 ± 3.1 [SD] years; BMI 24.8 ± 4.6 kg/m 2 ; peak VO 2 max 54.0 ± 5.8 ml/kg FFM/min) completed 3-days of a mixed diet (MD) followed by another 3-days of KD after 3-days of washout period. Upon completion of each diet arm, participants underwent graded exercise testing with low- (LIE; 40% of VO 2 max), moderate- (MIE; 55%), and high-intensity exercise (HIE; 70%). Exercise efficiency was calculated as work done (kcal/min)/energy expenditure (kcal/min)., Results: Fat oxidation during the recovery period was higher in KD vs. MD. Despite identical workload during HIE, participants after having KD vs. MD showed higher energy expenditure and lower exercise efficiency (10.1 ± 0.7 vs. 12.5 ± 0.3%, p  < .01). After KD, free fatty acid (FFA) concentrations were higher during MIE and recovery vs. resting, and beta-hydroxybutylate (BOHB) was lower at HIE vs. resting. Cortisol concentrations after KD was higher during recovery vs. resting, with no significant changes during graded exercise testing after MD., Conclusions: Our data suggest that short-term KD is favorable to fat metabolism leading increased circulating FFA and BOHB during LIE to MIE. However, it is notable that KD may cause 1) exercise inefficiency manifested by increased energy expenditure and 2) elevated exercise stress during HIE and recovery. Trial registration: KCT0005172, International Clinical Trials Registry Platform.

Recent studies have demonstrated the pivotal role of locus coeruleus (LC) and salience network (SN) resting state functional connectivity (rsFC) changes in the early stage of Alzheimer's disease (AD). Moreover, sex has been a crucial point of discussion in understanding AD pathology. We aimed to demonstrate the sex-related disparities in the functional connectivity (FC) of the SN and LC in preclinical AD. A total of 89 cognitively normal patients with evidence of amyloid beta (Aβ) accumulation ([18F] flutemetamol +) were recruited in the study. A seed-to-voxel analysis was conducted to measure the LC and SN rsFC differences between sexes. In addition, sex by Aβ interactive effects on FC values were analyzed with a general linear model. There were statistically significant sex by regional standardized uptake value ratio (SUVR) interactions in the LC FC with the parietal, frontal, and occipital cortices. Moreover, there was a significant sex by global SUVR interaction in the SN FC with the temporal cortex. The findings suggest that there are differential patterns of LC FC and SN FC in males and females with preclinical AD, which interact with regional Aβ deposition.

Background: Education years, as a measure of cognitive reserve, have been shown to affect the progression of Alzheimer's disease (AD), both pathologically and clinically. However, inconsistent results have been reported regarding the association between years of education and intermediate structural changes in AD-vulnerable brain regions, particularly when AD risk factors were not considered during the preclinical phase., Objective: This study aimed to examine how Aβ deposition and APOE ε4 carrier status moderate the relationship between years of education and cortical volume in AD-vulnerable regions among cognitively normal older adults., Methods: A total of 121 participants underwent structural MRI, [ 18 F] flutemetamol PET-CT imaging, and neuropsychological battery assessment. Multiple regression analysis was conducted to examine the interaction between years of education and the effects of potential modifiers on cortical volume. The associations between cortical volume and neuropsychological performance were further explored in subgroups categorized based on AD risk factors., Results: The cortical volume of the left lateral occipital cortex and bilateral fusiform gyrus demonstrated a significant differential association with years of education, depending on the presence of Aβ deposition and APOE ε4 carrier status. Furthermore, a significant relationship between the cortical volume of the bilateral fusiform gyrus and AD-nonspecific cognitive function was predominantly observed in individuals without AD risk factors., Conclusion: AD risk factors exerted varying influences on the association between years of education and cortical volume during the preclinical phase. Further investigations into the long-term implications of these findings would enhance our understanding of cognitive reserves in the preclinical stages of AD., Competing Interests: HL, DK, RK, YC, and JL were employed by NEUROPHET Inc. The data processing services provided by NEUROPHET Inc. were used to enhance the quality and analysis of the brain imaging data collected during the study. Authors declare that the research outcomes and conclusions remain unbiased and are not influenced by any commercial interests associated with NEUROPHET Inc.’s products or services. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kim, Kim, Um, Wang, Kim, Choe, Lee, Kim, Lim, Lee and Kang.)

Purpose: The aim of this study was to investigate the association between methionine (MET) metabolism and endocrine function of the pituitary gland in patients with suprasellar region tumor., Materials and Methods: Twenty patients with intracranial germinoma were included in this study. Initial staging and all surveillance MET PET/CT scans and comparable serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), and thyroid stimulating hormone (TSH) were analyzed. The patients were divided into two groups according to tumor location, with tumors in the suprasellar region (condition) or not (control). MET uptake of the pituitary gland (i.e., SUVR [standardized uptake value ratio]) and levels of FSH, LH, TSH were compared in the condition and control groups and in the before and after treatment phases of each group., Results: The SUVR in the control group was like that found in normal pituitary glands in previous studies, whereas the SUVR of the untreated condition group was high and that of treated condition group was low with significance compared to the control group. Serum levels of pituitary hormones in before and after treatment condition groups were significantly lower than those in the control group. The FSH and LH levels of curatively treated patients in the control group were positively correlated with SUVR with respective ß values of 3.71 and 0.98 (p < .001). The TSH level of the treated condition group was negatively correlated with SUVR (ß = -1.02, p < .001)., Conclusion: This study is the first known investigation to examine the association between MET metabolism and endocrine function of the pituitary gland, and it confirmed that MET metabolism reflects endocrine function. A future study validating the result of correlation analysis is warranted., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Although the standardized uptake value ratio (SUVR) method is objective and simple, cut-off optimization using global SUVR values may not reflect focal increased uptake in the cerebrum. The present study investigated clinical and neuroimaging characteristics according to focally increased β-amyloid (Aβ) uptake and global Aβ status., Methods: We recruited 968 participants with cognitive continuum. All participants underwent neuropsychological tests and 498 18 F-florbetaben (FBB) amyloid positron emission tomography (PET) and 470 18 F-flutemetamol (FMM) PET. Each PET scan was assessed in 10 regions (left and right frontal, lateral temporal, parietal, cingulate, and striatum) with focal-quantitative SUVR-based cutoff values for each region by using an iterative outlier approach., Results: A total of 62 (6.4%) subjects showed increased focal Aβ uptake with subthreshold global Aβ status [global (-) and focal (+) Aβ group, G(-)F(+) group]. The G(-)F(+) group showed worse performance in memory impairment ( p  < 0.001), global cognition ( p  = 0.009), greater hippocampal atrophy ( p  = 0.045), compared to those in the G(-)F(-). Participants with widespread Aβ involvement in the whole region [G(+)] showed worse neuropsychological ( p  < 0.001) and neuroimaging features ( p  < 0.001) than those with focal Aβ involvement G(-)F(+)., Conclusion: Our findings suggest that individuals show distinctive clinical outcomes according to focally increased Aβ uptake and global Aβ status. Thus, researchers and clinicians should pay more attention to focal increased Aβ uptake in addition to global Aβ status., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kim, Choe, Park, Kim, Kim, Jang, Kim, Na, Cho, Moon and Seo.)

Metal chelator-based contrast agents are used as tumor navigators for cancer diagnosis. Although approved metal chelators show excellent contrast performance in magnetic resonance imaging (MRI), large doses are required for cancer diagnoses due to rapid clearance and nonspecific accumulation throughout the body, which can compromise safety. The present study describes an enzyme-responsive metal delivery system, in which enzyme overexpressed in the tumor microenvironment selectively activates the tumor uptake of gadolinium (Gd). Gd was loaded into enzyme-responsive macrocyclam (ErMC) modified with a PEGylated enzyme-cleavable peptide resulting in Gd@ErMC. The PEGylated shell layer protected Gd@ErMC from nonspecific binding in the blood, increasing the half-life of the contrast agent. Specific cleavage of the PEGylated shell layer by the enzyme selectively liberated Gd from Gd@ErMC at the tumor site. Evaluation of the in vivo distribution of Gd@ErMC in tumor-bearing mice by MRI and positron emission tomography (PET) showed that Gd@ErMC had an extended half-life and was highly specific. Histological and serological analysis of Gd@ErMC-treated mice showed that this agent was safe. This novel enzyme-responsive contrast agent delivery system shows promise as specific theranostic agent for MR-guided radiotherapy., Competing Interests: The authors declare no potential conflicts of interest., (© 2022 The Authors. Bioengineering & Translational Medicine published by Wiley Periodicals LLC on behalf of American Institute of Chemical Engineers.)

Background: The standard Centiloid (CL) method was proposed to harmonize and quantify global 18 F-labeled amyloid beta (Aβ) PET ligands using MRI as an anatomical reference. However, there is need for harmonizing and quantifying regional Aβ uptakes between ligands using CT as an anatomical reference. In the present study, we developed and validated a CT-based regional direct comparison of 18 F-florbetaben (FBB) and 18 F-flutemetamol (FMM) Centiloid (rdcCL)., Methods: For development of MRI-based or CT-based rdcCLs, the cohort consisted of 63 subjects (20 young controls (YC) and 18 old controls (OC), and 25 participants with Alzheimer's disease dementia (ADD)). We performed a direct comparison of the FMM-FBB rdcCL method using MRI and CT images to define a common target region and the six regional VOIs of frontal, temporal, parietal, posterior cingulate, occipital, and striatal regions. Global and regional rdcCL scales were compared between MRI-based and CT-based methods. For clinical validation, the cohort consisted of 2245 subjects (627 CN, 933 MCI, and 685 ADD)., Results: Both MRI-based and CT-based rdcCL scales showed that FMM and FBB were highly correlated with each other, globally and regionally (R 2 = 0.96~0.99). Both FMM and FBB showed that CT-based rdcCL scales were highly correlated with MRI-based rdcCL scales (R 2 = 0.97~0.99). Regarding the absolute difference of rdcCLs between FMM and FBB, the CT-based method was not different from the MRI-based method, globally or regionally (p value = 0.07~0.95). In our clinical validation study, the global negative group showed that the regional positive subgroup had worse neuropsychological performance than the regional negative subgroup (p < 0.05). The global positive group also showed that the striatal positive subgroup had worse neuropsychological performance than the striatal negative subgroup (p < 0.05)., Conclusions: Our findings suggest that it is feasible to convert regional FMM or FBB rdcSUVR values into rdcCL scales without additional MRI scans. This allows a more easily accessible method for researchers that can be applicable to a variety of different conditions., (© 2022. The Author(s).)

Background: The relationship of specific body composition in the thighs and brain amyloid-beta (Aβ) deposition remained unclear, although there were growing evidence that higher muscle and fat mass in thighs had a protective effect against cardiometabolic syndromes. To determine whether muscle mass and fat mass in the thighs affected amyloid-beta (Aβ) positivity differently in relation to gender, we investigated the association of muscle mass and fat mass with Aβ positivity using positron emission tomography (PET) in individuals without dementia., Methods: We recruited 240 participants (134 [55.8%] males, 106 [44.2%] females) without dementia ≥45 years of age who underwent Aβ PET, bioelectrical impedance analysis (BIA) and dual-energy X-ray absorptiometry (DEXA) scans of the hip in the health promotion center at Samsung Medical Center in Seoul, Korea. Lower extremity skeletal muscle mass index (LASMI) was measured using BIA, and gluteofemoral fat percentage (GFFP) was estimated using DEXA scans of the hip. We investigated the associations of LASMI and GFFP with Aβ positivity using logistic regression analyses after controlling for age, APOE4 genotype, and cognitive stage., Results: Higher muscle mass in the thighs, measured as LASMI (odds ratio [OR]=0.27, 95% confidence interval [CI] 0.08 to 0.84, p=0.031) was associated with a lesser risk of Aβ positivity in only females. Higher fat mass in the thighs, measured as GFFP (OR=0.84, 95% CI 0.73 to 0.95, p=0.008) was associated with a lesser risk of Aβ positivity in only males. However, the association between LAMSI (p for interaction= 0.810), GFFP (p for interaction= 0.075) and Aβ positivity did not significantly differ by gender. Furthermore, LAMSI only negatively correlated with centiloid (CL) values in females (r=-0.205, p=0.037), and GFFP only negatively correlated with CL values only in males (r=-0.253, p=0.004)., Conclusions: Our findings highlight the importance of recognizing that gender differences exist with respect to the specific body composition to potentially protect against Aβ deposition. Therefore, our results may help in designing gender-specific strategies for controlling body composition to prevent Aβ deposition., (© 2022. The Author(s).)

Background: Cortical deposition of β-amyloid (Aβ) plaque is one of the main hallmarks of Alzheimer's disease (AD). While Aβ positivity has been the main concern so far, predicting whether Aβ (-) individuals will convert to Aβ (+) has become crucial in clinical and research aspects. In this study, we aimed to develop a classifier that predicts the conversion from Aβ (-) to Aβ (+) using artificial intelligence., Methods: Data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort regarding patients who were initially Aβ (-). We developed an artificial neural network-based classifier with baseline age, gender, APOE ε4 genotype, and global and regional standardized uptake value ratios (SUVRs) from positron emission tomography. Ten times repeated 10-fold cross-validation was performed for model measurement, and the feature importance was assessed. To validate the prediction model, we recruited subjects at the Samsung Medical Center (SMC)., Results: A total of 229 participants (53 converters) from the ADNI dataset and a total of 40 subjects (10 converters) from the SMC dataset were included. The average area under the receiver operating characteristic values of three developed models are as follows: Model 1 (age, gender, APOE ε4) of 0.674, Model 2 (age, gender, APOE ε4, global SUVR) of 0.814, and Model 3 (age, gender, APOE ε4, global and regional SUVR) of 0.841. External validation result showed an AUROC of 0.900., Conclusion: We developed prediction models regarding Aβ positivity conversion. With the growing recognition of the need for earlier intervention in AD, the results of this study are expected to contribute to the screening of early treatment candidates., (© 2022. The Author(s).)

Hepsin, a cell surface serine protease, is a potential biomarker for the detection of prostate cancer due to its high expression in prostate cancer but not in normal prostate. This study aimed to develop a radioligand for positron emission tomography (PET) imaging of hepsin. Six leucine-arginine (Leu-Arg) dipeptide derivatives (two diastereomers for each of three ligands) were synthesized and evaluated for their binding affinities and selectivity for hepsin. Based on the binding assay, a nat Cu-1,4,7,10-tetraazacyclododecane- N , N ', N ″, N ‴-tetraacetic acid (DOTA)-conjugated ligand ( 3B ) was selected for the development of a PET radioligand. [ 64 Cu] 3B was synthesized by labeling the DOTA-conjugated compound 11B with [ 64 Cu]CuCl 2 at 80 ° C for 20 min. The radioligand was evaluated for prostate cancer cell binding and PET imaging in a prostate tumor mouse model. The results demonstrated that [ 64 Cu] 3B exhibited high binding to LNCaP cells, intermediate binding to 22Rv1 cells, and low binding to PC3 cells. PET studies of [ 64 Cu] 3B in mice, implanted with 22Rv1 and PC3 cells on each flank, revealed that the radioligand uptake was high and persistent in the 22Rv1 tumors over time, whereas it was low in PC3 tumors. The results of this study suggest that [ 64 Cu] 3B is a promising PET radioligand for hepsin imaging.

Objectives: The relationship of body mass index (BMI) changes and variability with amyloid-β (Aβ) deposition remained unclear, although there were growing evidence that BMI is associated with the risk of developing cognitive impairment or AD dementia. To determine whether BMI changes and BMI variability affected Aβ positivity, we investigated the association of BMI changes and BMI variability with Aβ positivity, as assessed by PET in a non-demented population., Methods: We retrospectively recruited 1,035 non-demented participants ≥50 years of age who underwent Aβ PET and had at least three BMI measurements in the memory clinic at Samsung Medical Center. To investigate the association between BMI change and variability with Aβ deposition, we performed multivariable logistic regression. Further distinctive underlying features of BMI subgroups were examined by employing a cluster analysis model., Results: Decreased (odds ratio [OR] = 1.68, 95% confidence interval [CI] 1.16-2.42) or increased BMI (OR = 1.60, 95% CI 1.11-2.32) was associated with a greater risk of Aβ positivity after controlling for age, sex, APOE e4 genotype, years of education, hypertension, diabetes, baseline BMI, and BMI variability. A greater BMI variability (OR = 1.73, 95% CI 1.07-2.80) was associated with a greater risk of Aβ positivity after controlling for age, sex, APOE e4 genotype, years of education, hypertension, diabetes, baseline BMI, and BMI change. We also identified BMI subgroups showing a greater risk of Aβ positivity., Conclusion: Our findings suggest that participants with BMI change, especially those with greater BMI variability, are more vulnerable to Aβ deposition regardless of baseline BMI. Furthermore, our results may contribute to the design of strategies to prevent Aβ deposition with respect to weight control., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kang, Kim, Chang, Cheon, Choe, Jang, Kim, Koh, Na, Kim and Seo.)

A number of researchers in Korea have tried to set-up the production of radionuclides and develop new radiopharmaceuticals for several decades. Thanks to their 60-year endeavor to advance the field of radiopharmaceutical sciences, now we have a lot of research units and facilities in Korea. Still, there are huge number of issues to be solved in radiopharmaceutical sciences; however, our efforts will be continued to develop new radiopharmaceuticals and to apply the new radiopharmaceuticals into nuclear medicine field., Competing Interests: Conflict of InterestRan Ji Yoo, Yun-Sang Lee, Kyo Chu Lee, Dong Wook Kim, Dong-Yeon Kim, Yearn Seong Choe, and Jae Min Jeong declare no conflict of interests., (© The Author(s), under exclusive licence to Korean Society of Nuclear Medicine 2022.)

We investigated which factors might explain the differences between the frequencies of brain β-amyloid (Aβ) deposition in Korean and European cognitively normal individuals (CNs). We recruited 434 Korean CNs from the Samsung Medical Center (SMC) and 323 European CNs from the US Alzheimer's Disease Neuroimaging Initiative (ADNI). The Korean CNs showed lower education duration (11.8 ± 4.8 years vs. 16.8 ± 2.5 years, p < 0.001) than the European CNs. The frequency of Aβ (+) was higher in the European CNs (32.8%) than in the Korean CNs (20.0%; p < 0.001). In the SMC genome-wide association study (GWAS), 10 variants (including rs7481773 on chromosome 11, located near the brain-derived neurotrophic factor gene) exceeded the genome-wide significance level (p < 5 × 10 -8 ). Especially, rs7481773 carriers showed more rapid decline in memory function than non-carriers (p = 0.048). However, this association was not observed in the ADNI GWAS. Our findings suggested that the different frequencies of Aβ (+) between CN Koreans and Europeans might be related to decreased cognitive reserve or genetic factors., (Copyright © 2022. Published by Elsevier Inc.)

We report a breath hydrogen analyzer based on Pd-coated SnO 2 nanorods (Pd-SnO 2 NRs) sensor integrated into a miniaturized gas chromatography (GC) column. The device can measure a wide range of hydrogen (1-100 ppm), within 100 s, using a small volume of human breath (1 mL) without pre-concentration. Especially, the mini-GC integrated with Pd-SnO 2 NRs can detect 1 ppm of H 2 , as a lower detection limit, at a low operating temperature of 152 °C. Furthermore, when the breath hydrogen analyzer was exposed to a mixture of interfering gases, such as carbon dioxide, nitrogen, methane, and acetone, it was found to be capable of selectively detecting only H 2 . We found that the Pd-SnO 2 NRs were superior to other semiconducting metal oxides that lack selectivity in H 2 detection. Our study reveals that the Pd-SnO 2 NRs integrated into the mini-GC device can be utilized in breath hydrogen analyzers to rapidly and accurately detect hydrogen due to its high selectivity and sensitivity.

Purpose: Neuroinflammation is considered an important pathway associated with several diseases that result in cognitive decline. 18 F-THK5351 positron emission tomography (PET) signals might indicate the presence of neuroinflammation, as well as Alzheimer's disease-type tau aggregates. β-amyloid (Aβ)-negative (Aβ-) amnestic mild cognitive impairment (aMCI) may be associated with non-Alzheimer's disease pathophysiology. Accordingly, we investigated associations between 18 F-THK5351 PET positivity and cognitive decline among Aβ- aMCI patients., Materials and Methods: The present study included 25 amyloid PET negative aMCI patients who underwent a minimum of two follow-up neuropsychological evaluations, including clinical dementia rating-sum of boxes (CDR-SOB). The patients were classified into two groups: 18 F-THK5351-positive and -negative groups. The present study used a linear mixed effects model to estimate the effects of 18 F-THK5351 PET positivity on cognitive prognosis among Aβ- aMCI patients., Results: Among the 25 Aβ- aMCI patients, 10 (40.0%) were 18 F-THK5351 positive. The patients in the 18 F-THK5351-positive group were older than those in the 18 F-THK5351-negative group (77.4±2.2 years vs. 70.0±5.5 years; p <0.001). There was no difference between the two groups with regard to the proportion of apolipoprotein E ε4 carriers. Interestingly, however, the CDR-SOB scores of the 18 F-THK5351-positive group deteriorated at a faster rate than those of the 18 F-THK5351-negative group (B=0.003, p =0.033)., Conclusion: The results of the present study suggest that increased 18 F-THK5351 uptake might be a useful predictor of poor prognosis among Aβ- aMCI patients, which might be associated with increased neuroinflammation (ClinicalTrials.gov NCT02656498)., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2022.)

In this study, we introduce cobalt (Co)-doped zinc oxide (ZnO) spherical beads (SBs), synthesized using a sonochemical process, and their utilization for an acetone sensor that can be applied to an exhalation diagnostic device. The sonochemically synthezied Co-doped ZnO SBs were polycrystalline phases with sizes of several hundred nanometers formed by the aggregation of ZnO nanocrystals. As the Co doping concentration increased, the amount of substitutionally doped Co 2+ in the ZnO nanocrystals increased, and we observed that the fraction of Co 3+ in the Co-doped ZnO SBs increased while the fraction of oxygen vacancies decreased. At an optimal Co-doping concentration of 2 wt%, the sensor operating temperature decreased from 300 to 250 °C, response to 1 ppm acetone improved from 3.3 to 7.9, and minimum acetone detection concentration was measured at 43 ppb (response, 1.75). These enhancements are attributed to the catalytic role of Co 3+ in acetone oxidation. Finally, a sensor fabricated using 2 wt% Co-doped ZnO SBs was installed in a commercially available exhalation diagnostic device to successfully measure the concentration of acetone in 1 ml of exhaled air from a healthy adult, returning a value of 0.44 ppm., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Neuroinflammation involves activation of glial cells in the brain, and activated microglia play a particularly important role in neurodegenerative diseases such as Alzheimer's disease (AD). In this study, we developed 5-cyano- N -(4-(4-(2-[ 18 F]fluoroethyl)piperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide ([ 18 F] 1 ) for PET imaging of colony-stimulating factor 1 receptor (CSF1R), an emerging target for neuroinflammation imaging. Non-radioactive ligand 1 exhibited binding affinity comparable to that of a known CSF1R inhibitor, 5-cyano- N -(4-(4-methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide (CPPC). Therefore, we synthesized radioligand [ 18 F] 1 by radiofluorination of chlorine-substituted precursor 7 in 13-15% decay-corrected radiochemical yield. Dynamic PET/CT images showed higher uptake in the lipopolysaccharide (LPS)-treated mouse brain than in control mouse brain. Ex vivo biodistribution study conducted at 45 min after radioligand injection showed that the brain uptake in LPS mice increased by 78% compared to that of control mice and was inhibited by 22% in LPS mice pretreated with CPPC, indicating specificity of [ 18 F] 1 for CSF1R. A metabolism study demonstrated that the radioligand underwent little metabolism in the mouse brain. Taken together, these results suggest that [ 18 F] 1 may hold promise as a radioligand for CSF1R imaging.

Purpose: The purpose of this study was to investigate the value of C-11 methionine (MET) positron emission tomography (PET)/computed tomography (CT) in patients with intracranial germinoma (IG)., Material and Methods: We conducted a retrospective analysis of 21 consecutive patients with pathologically confirmed IGs and eight patients with intracranial non-germinomas (INGs) located in a similar region. Clinical characteristics, imaging findings, and tumor markers such as α-fetoprotein (AFP) and β-human chorionic gonadotropin (HCG) were used as clinical variables. Maximum standardized uptake value (SUVmax), tumor-to-normal tissue (T/N) ratio, and visual scoring of tumor were used as MET PET parameters., Results: All IGs were well visualized on MET PET with a three-grade visual scoring system. In addition, SUVmax of IGs was higher than that of INGs (P = 0.005). Pre-treatment (Pre-Tx) T/N ratio was significantly correlated with pre-Tx serum HCG (P = 0.031). Moreover, MET PET parameters showed significant associations with tumor location, sex, KRAS variant, and symptoms., Conclusion: MET PET/CT could be a useful diagnostic tool in patients suspected of having IGs. In addition, the MET avidity of tumor is a potential surrogate biomarker of HCG, which has been used as a diagnostic marker for IGs. Tumor MET parameters also had significant differences according to tumor locations, sex, symptoms, and KRAS mutation. However, MET avidity of tumors had no significant prognostic value., Competing Interests: The authors have declared that no competing interests exist.

Background: Alzheimer's disease (AD) and normal pressure hydrocephalus (NPH) commonly coexist., Objective: We aimed to characterize an overlapping syndrome of AD and NPH that presents with gait disturbance, ventriculomegaly on magnetic resonance imaging, and significant amyloid deposition on positron emission tomography (PET)., Methods: Of 114 patients who underwent cerebrospinal fluid (CSF) drainage for a possible diagnosis of NPH between 2015 and 2020 in Samsung Medical Center, we identified 24 patients (21.1%) with the NPH patients with amyloid deposition on PET, which we referred to as hydrocephalic AD in this study. We compared their clinical and imaging findings with those of 123 typical AD without hydrocephalic signs/symptoms. We also investigated the frequency and potential predictors of the tap test response in hydrocephalic AD., Results: Evans' index was 0.36±0.03, and a disproportionately enlarged subarachnoid space was present in 54.2% of the hydrocephalic AD patients. The mean age (75.2±7.3 years) and the APOE4 frequency (68.2%) did not differ from those of AD controls. However, the hydrocephalic AD patients showed better memory and language performance, and a thinner cingulate cortex. About 42% of the hydrocephalic AD patients responded to the tap test, of whom seven underwent shunt surgery. Cognition did not improve, whereas gait improved after shunt surgery in all., Conclusion: Hydrocephalic AD has different neuropsychological and imaging characteristics from typical AD. Future studies are warranted to further investigate the effect of CSF removal on their clinical course and to elucidate the pathophysiological interaction between amyloid and NPH.

Purpose: In this study, we used machine learning to develop a new method derived from a ligand-independent amyloid (Aβ) positron emission tomography (PET) classifier to harmonise different Aβ ligands., Methods: We obtained 107 paired 18 F-florbetaben (FBB) and 18 F-flutemetamol (FMM) PET images at the Samsung Medical Centre. To apply the method to FMM ligand, we transferred the previously developed FBB PET classifier to test similar features from the FMM PET images for application to FMM, which in turn developed a ligand-independent Aβ PET classifier. We explored the concordance rates of our classifier in detecting cortical and striatal Aβ positivity. We investigated the correlation of machine learning-based cortical tracer uptake (ML-CTU) values quantified by the classifier between FBB and FMM., Results: This classifier achieved high classification accuracy (area under the curve = 0.958) even with different Aβ PET ligands. In addition, the concordance rate of FBB and FMM using the classifier (87.5%) was good to excellent, which seemed to be higher than that in visual assessment (82.7%) and lower than that in standardised uptake value ratio cut-off categorisation (93.3%). FBB and FMM ML-CTU values were highly correlated with each other (R = 0.903)., Conclusion: Our findings suggested that our novel classifier may harmonise FBB and FMM ligands in the clinical setting which in turn facilitate the biomarker-guided diagnosis and trials of anti-Aβ treatment in the research field., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

For extremely sensitive acetone sensors, here, we introduced an alcohol-assisted surfactant-free Langmuir-Blodgett process to rapidly assemble a single-layered two-dimensional (2D) network as a suitable percolation strategy of metal oxide semiconductor nanomaterials. The single-layered 2D network formation mechanism was investigated using zinc oxide (ZnO) nanobeads (NBs). Furthermore, the correlation between the response of the gas sensor and the average percolation number of the ZnO NBs, controlled by multi-stacking the 2D network, was investigated. It was inferred that a reduction in the number of percolations led to maximization of the response. Additionally, the versatility of the optimal percolation strategy was experimentally verified by confirming similar results to that achieved with ZnO NBs when utilizing different sizes, shapes, and compositions of metal oxides. Finally, the practical effectiveness of our extremely sensitive strategy was solidified by illustrating the response enhancement in a commercial exhalation diagnostic system that measures the amount of acetone in only 1 mL of exhalation.

Recently developed tau imaging radiopharmaceuticals show specific uptake in tau protein-rich regions in human brains without off-target binding. These radiopharmaceuticals and their nonradioactive reference ligands are generally obtained in low (radio)chemical yields. In the present study, we investigated high-yield synthesis of 18 F-RO948 ([ 18 F]1) and its nonradioactive ligand (1). The ligand 1 was synthesized by a Suzuki-Miyaura coupling reaction between 9-(4-methoxybenzyl)-9H-pyrrolo[2,3-b:4,5-c']dipyridin-2-yl trifluoromethanesulfonate (3) and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4), followed by oxidative removal of the para-methoxybenzyl (PMB) group with ceric ammonium nitrate (CAN). This two-step reaction gave 1 in 55.8% yield. The precursor for [ 18 F]1 was synthesized from 3 and 2-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (6). The resulting PMB-protected precursor 8 was obtained in 74.5% yield. [ 18 F]1 was synthesized by radiofluorination of 8 (radiochemical conversion (RCC): 95.7 ± 1.7%), followed by deprotection of the PMB group with CAN. This one-pot, two-step radiochemical synthesis followed by HPLC purification gave [ 18 F]1 in high decay-corrected radiochemical yield (54-60%). The RCC of [ 18 F]fluoride to [ 18 F]1 in our two-step synthesis method was similar to that in a one-step radiofluorination reaction of a tert-butoxycarbonyl (BOC)-protected precursor 10 that proceeds with concomitant thermal deprotection of the BOC group. Taken together, the results of this study suggest that this high-yield synthesis method is useful for the synthesis of 18 F-labeled (NH)heteroarene compounds., (© 2020 John Wiley & Sons, Ltd.)

Background: The presence of ß-amyloid (Aß) in the brain can be identified using amyloid PET. In clinical practice, the amyloid PET is interpreted based on dichotomous visual rating, which renders focal Aß accumulation be read as positive for Aß. However, the prognosis of patients with focal Aß deposition is not well established. Thus, we investigated cognitive trajectories of patients with focal Aß deposition., Methods: We followed up 240 participants (112 cognitively unimpaired [CU], 78 amnestic mild cognitive impairment [aMCI], and 50 Alzheimer's disease (AD) dementia [ADD]) for 2 years from 9 referral centers in South Korea. Participants were assessed with neuropsychological tests and 18 F-flutemetamol (FMM) positron emission tomography (PET). Ten regions (frontal, precuneus/posterior cingulate (PPC), lateral temporal, parietal, and striatum of each hemisphere) were visually examined in the FMM scan, and participants were divided into three groups: No-FMM, Focal-FMM (FMM uptake in 1-9 regions), and Diffuse-FMM. We used mixed-effects model to investigate the speed of cognitive decline in the Focal-FMM group according to the cognitive level, extent, and location of Aß involvement, in comparison with the No- or Diffuse-FMM group., Results: Forty-five of 240 (18.8%) individuals were categorized as Focal-FMM. The rate of cognitive decline in the Focal-FMM group was faster than the No-FMM group (especially in the CU and aMCI stage) and slower than the Diffuse-FMM group (in particular in the CU stage). Within the Focal-FMM group, participants with FMM uptake to a larger extent (7-9 regions) showed faster cognitive decline compared to those with uptake to a smaller extent (1-3 or 4-6 regions). The Focal-FMM group was found to have faster cognitive decline in comparison with the No-FMM when there was uptake in the PPC, striatum, and frontal cortex., Conclusions: When predicting cognitive decline of patients with focal Aß deposition, the patients' cognitive level, extent, and location of the focal involvement are important.

Background and Objectives: Amyloid-beta protein may lead to sleep disturbance and eventually develop cognitive impairment. Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is a predictor of neurodegeneration, yet there have been limited studies evaluating the relationship between cognitive decline and amyloid accumulation in iRBD patients. The aim of this study is to investigate the clinical and sleep characteristics of iRBD patients and its association with amyloid deposition. Methods: We enroll 23 iRBD patients (mean age, 65.8 years; male, 73.9%), and their mean history of clinically suspected RBD was 6.5 years. All underwent 18F-flutemetamol amyloid PET completed polysomnography (PSG) and questionnaires. Patients were classified into two groups according to amyloid deposition as amyloid positive and negative. Clinical and sleep parameters were compared between groups and were correlated with amyloid deposition, calculated as a standardized uptake value ratio (SUVR). Results: Four patients (17.4%) were revealed to be amyloid positive, and they showed increased percentage of wake after sleep onset (WASO), stage N1, and stage N2 sleep and worse on the Stroop Word Color Test compared to amyloid negative patients. Global SUVR was correlated with total sleep time, sleep efficiency, WASO, and N1 sleep, and these sleep parameters were associated with a part of default mode network of brains such as orbitofrontal, dorsolateral pre-frontal, and left temporal areas. Conclusion: iRBD patients with amyloid deposition have worse sleep quality than patients without amyloid. Relationship between fragmented sleep and amyloid deposition in the default mode network may be crucial to elucidate the disease progress of iRBD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Lee, Cho, Choe, Seo and Joo.)

Background and Purpose: We aimed to determine whether lobar cerebellar microbleeds or concomitant lobar cerebellar and deep microbleeds, in the presence of lobar cerebral microbleeds, attribute to underlying advanced cerebral amyloid angiopathy pathology or hypertensive arteriopathy., Methods: We categorized 71 patients with suspected cerebral amyloid angiopathy markers (regardless of the presence of deep and cerebellar microbleeds) into 4 groups according to microbleed distribution: L (strictly lobar cerebral, n=33), L/LCbll (strictly lobar cerebral and strictly lobar cerebellar microbleeds, n=13), L/Cbll/D (lobar, cerebellar, and deep microbleeds, n=17), and L/D (lobar and deep, n=8). We additionally categorized patients with cerebellar microbleeds into 2 groups according to dentate nucleus involvement: strictly lobar cerebellar (n=16) and dentate (n=14). We then compared clinical characteristics, Aβ (amyloid-β) positivity on PET (positron emission tomography), magnetic resonance imaging cerebral amyloid angiopathy markers, and cerebral small vessel disease burden among groups., Results: The frequency of Aβ positivity was higher in the L and L/LCbll groups (81.8% and 84.6%) than in the L/Cbll/D and L/D groups (37.5% and 29.4%; P <0.001), while lacune numbers were lower in the L and L/LCbll groups (1.7±3.3 and 1.7±2.6) than in the L/Cbll/D and L/D groups (8.0±10.3 and 13.4±17.7, P =0.001). The L/LCbll group had more lobar cerebral microbleeds than the L group (93.2±121.8 versus 38.0±40.8, P =0.047). The lobar cerebellar group had a higher Aβ positivity (75% versus 28.6%, P =0.011) and lower lacune number (2.3±3.7 versus 8.6±1.2, P =0.041) than the dentate group., Conclusions: Strictly lobar cerebral and cerebellar microbleeds are related to cerebral amyloid angiopathy, whereas any combination of concurrent lobar and deep microbleeds suggest hypertensive angiopathy regardless of cerebral or cerebellar compartments.

We aimed to quantitatively and qualitatively assess whether there is a discrepancy in detecting amyloid beta (Aβ) positivity between 18F-florbetaben (FBB) and 18F-flutemetamol (FMM) positron emission tomography (PET). We obtained paired FBB and FMM PET images from 107 participants. Three experts visually quantified the Aβ deposition as positive or negative. Quantitative assessment was performed using global cortical standardized uptake value ratio (SUVR) with the whole cerebellum as the reference region. Inter-rater agreement was excellent for FBB and FMM. The concordance rates between FBB and FMM were 94.4% (101/107) for visual assessment and 98.1% (105/107) for SUVR cut-off categorization. Both FBB and FMM showed high agreement rates between visual assessment and SUVR positive or negative categorization (93.5% in FBB and 91.2% in FMM). When the two ligands were compared based on SUVR cut-off categorization as standard of truth, although not statistically significant, the false-positive rate was higher in FMM (9.1%) than in FBB (1.8%) (p = 0.13). Our findings suggested that both FBB and FMM had excellent agreement when used to quantitatively and qualitatively evaluate Aβ deposits, thus, combining amyloid PET data associated with the use of different ligands from multi-centers is feasible.

Here, we report a tannic acid-Fe 3+ coordination complex coating that confers magnetic resonance imaging (MRI) theranostic properties to inert nanomaterials. Boron nitride nanosheets (BNS), which lack magnetic field and light responsiveness, were used as a model nonfunctional nanomaterial. Among various catechol derivatives tested (i.e., dopamine, 3,4-dihydroxyphenylacetic acid, gallic acid, and tannic acid), a coating of tannic acid-Fe 3+ coordination complex provided the highest magnetic field relaxivity and near infrared (NIR) laser light responsiveness. An in vitro study showed that KB tumor cells treated with tannic acid-Fe 3+ coordination complex adsorbed on BNS (TA-Fe/BNS) exhibited higher T1-weighted magnetic resonance contrast compared with plain BNS, and BNS coated with tannic acid or Fe alone. NIR irradiation at 808 nm caused a significant increase in KB tumor cell death after treatment with TA-Fe/BNS compared with other treatments. In vivo MRI imaging revealed tumor accumulation of intravenously administered TA-Fe/BNS. Guided by MRI information, application of focused laser irradiation onto tumor tissues resulted in complete tumor ablation. These results support the potential of TA-Fe/BNS for MRI theranostics. Moreover, this study suggests the wide applicability of TA-Fe noncovalent coating as biocompatible and facile tool for converting nonfunctional early-generation nanomaterials into functional new nanomaterials, opening new opportunities for their use in translational biomedical applications such as MRI theranostics., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The Centiloid (CL) is a method for standardizing amyloid beta (Aβ) quantification through different ligands and methods. To find the most appropriate reference region to reduce the variance in the Aβ CL unit between 18 F-florbetaben (FBB) and 18 F-flutemetamol (FMM), we conducted head-to-head comparisons from 56 participants using the direct comparison of FBB-FMM CL (dcCL) method with four reference regions: cerebellar gray (CG), whole cerebellum (WC), WC with brainstem (WC + B), and pons. The FBB and FMM dcCL units were highly correlated in four reference regions: WC (R 2  = 0.97), WC + B (R 2  = 0.98), CG (R 2  = 0.92), and pons (R 2  = 0.98). WC showed the largest effect size in both FBB and FMM. Comparison of the variance of the dcCL values within the young control group showed that with FBB, WC + B had the smallest variance and with FMM, the WC had the smallest variance. Additionally, WC + B showed the smallest absolute difference between FBB and FMM, followed by the WC, pons, and CG. We found that it would be reasonable to use the WC or WC + B as the reference region when converting FBB and FMM SUVRs into dcCL, which can increase the accuracy of standardizing FBB and FMM PET results.

Background: We sought to investigate the possible associations of rest-activity patterns with cortical amyloid burden, medial temporal lobe (MTL) neurodegeneration, and cognitive function in patients in the early stage of cognitive impairment., Methods: Rest-activity patterns were assessed in 100 participants (70 with mild cognitive impairment and 30 with mild dementia) using wrist actigraphy. All participants underwent 18 F-flutemetamol positron emission tomography (PET) imaging to quantify cortical amyloid burden, structural brain magnetic resonance imaging (MRI) to quantify MTL grey matter volume, neuropsychological testing, and clinical diagnosis. We used multiple linear regression models adjusted for covariates, including demographics, diabetes, hypertension, depressive symptom, psychotropic medication, sleep medication, weekend effect, and apolipoprotein-ε allele status., Findings: After adjusting for possible confounders, we found that the midline estimation of statistic of rhythm (MESOR) associated positively with frontal/executive function (estimate = 1.17, standard error [SE] = 0.37, p = 0.002). The least active 5-h (L5) onset time associated positively with MTL grey matter volume and memory function (estimate = 1.24, SE = 0.33, p = 0.001, and estimate = 3.77, SE = 1.22, p = 0.003, respectively), particularly in amyloid-negative participants. Additional path analysis revealed that MTL grey matter volume partially mediated the association between L5 onset time and memory function in amyloid-negative participants., Interpretation: Decreased MESOR and advanced L5 onset time may be useful as early signs of cognitive decline or MTL neurodegeneration. Furthermore, amyloid pathology may act as a moderator of the relationships between rest-activity patterns, neurodegeneration, and cognitive function., Funding: Korea Centres for Disease Control and Prevention (#4845-303); National Research Foundation of Korea (2019M3C7A1031905, 2019R1A5A2026045)., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: We developed a new method to directly calculate Centiloid (CL) units of 18 F-florbetaben (FBB) and 18 F-flutemetamol (FMM) without conversion to the PiB standardized uptake value ratio (SUVR)., Methods: Paired FBB and FMM PET scans were obtained from 20 Alzheimer's disease-related cognitive impairment patients, 16 old controls, and 20 young controls. We investigated the correlations between the FBB and FMM CL units using the direct comparison of FBB-FMM CL (dcCL) method and the standard CL method and compare differences in FBB and FMM CL units between dcCL method and the standard method., Results: Following the conversion of FBB or FMM SUVRs into CL units, a direct relationship was formed between the FBB or FMM SUVRs and the CL units using dcCL method (FBB dcCL = 151.42 × FBB dcSUVR - 142.24 and FMM dcCL = 148.52 × FMM dcSUVR - 137.09). The FBB and FMM CL units were highly correlated in both our method (R 2 = 0.97, FMM dcCL = 0.97 × FBB dcCL + 1.64) and the standard method (R 2 = 0.97, FMM CLstandard = 0.79 × FBB CLstandard + 1.36). However, the CL variations between FBB and FMM were smaller when calculated by dcCL method (6.15) than when calculated by the previous method (10.22; P = 0.01)., Conclusions: Our findings suggest that our direct comparison of FBB-FMM method, rather than the standard method, is a reasonable way to convert FBB or FMM SUVRs into CL units, at least in environments where FBB or FMM ligands are used frequently.

Background: 18F-florbetaben (FBB) and 18F-flutemetamol (FMM) amyloid PET have been developed and approved for clinical use. It is important to understand the distinct features of these ligands to compare and correctly interpret the results of different amyloid PET studies., Objective: We performed a head-to-head comparison of FBB and FMM to compare with regard to imaging characteristics, including dynamic range of retention, and differences in quantitative measurements between the two ligands in cortical, striatal, and white matter (WM) regions., Methods: Paired FBB and FMM PET images were acquired in 107 participants. Correlations of FBB and FMM amyloid deposition in the cortex, striatum, and WM were investigated and compared in different reference regions (cerebellar gray matter (CG), whole cerebellum (WC), WC with brainstem (WC + B), and pons)., Results: The cortical SUVR (R2 = 0.97) and striatal SUVR (R2 = 0.95) demonstrated an excellent linear correlation between FBB and FMM using a WC as reference region. There was no difference in the cortical SUVR ratio between the two ligands (p = 0.90), but the striatal SUVR ratio was higher in FMM than in FBB (p < 0.001). Also, the effect size of differences in striatal SUVR seemed to be higher with FMM (2.61) than with FBB (2.34). These trends were similarly observed according to four different reference regions (CG, WC, WC + B, and pons)., Conclusion: Our findings suggest that FMM might be better than FBB to detect amyloid burden in the striatum, although both ligands are comparable for imaging AD pathology in vivo.

It was previously reported that tetraiodothyroacetic acid (tetrac) inhibits angiogenesis by binding to the cell surface receptor for thyroid hormone on integrin α V β 3 . Therefore, we synthesized and evaluated two 64 Cu-labeled tetrac derivatives and a Cy5.5-labeled tetrac derivative for tumor angiogenesis imaging. Tetrac was structurally modified to conjugate with 1,4,7,10-tetraazacyclododecane-N,N',N″,N″'-tetraacetic acid (DOTA) via its hydroxy or carboxylic acid end, and the resulting DOTA-conjugated tetrac derivatives were then labeled with 64 Cu. Tetrac was also conjugated with Cy5.5 via its carboxylic acid end. All three tetrac derivatives (1-3) exhibited greater inhibitory activity than tetrac against endothelial cell tube formation. The U87MG cell binding of [ 64 Cu]2 showed a time-dependent increase over 24 h and it was inhibited by 38% at 4 h in the presence of tetrac, indicating specificity of [ 64 Cu]2 to the thyroid hormone receptor site on integrin α V β 3 . Positron emission tomography (PET) images of U87MG tumor-bearing mice injected with [ 64 Cu]1 and [ 64 Cu]2 revealed that high radioactivity accumulated in the tumors, and that the tumor uptake and tumor-to-nontarget uptake ratio were higher in small tumors than in large tumors. In addition, the Cy5.5-labeled tetrac derivative (3) displayed a strong near-infrared (NIR) signal in the tumors. Taken together, these results suggest that these ligands hold promise as imaging agents for visualization of tumor angiogenesis., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: As Alzheimer's disease (AD) and cerebral small vessel disease (CSVD) commonly coexist, the interaction between two has been of the considerable interest., Objective: We determined whether the association of Aβ and tau with cognitive decline differs by the presence of significant CSVD., Methods: We included 60 subcortical vascular cognitive impairment (SVCI) from Samsung Medical Center and 82 Alzheimer's disease-related cognitive impairment (ADCI) from ADNI, who underwent Aβ (florbetaben or florbetapir) and tau (flortaucipir, FTP) PET imaging. They were retrospectively assessed for 5.0±3.9 and 5.6±1.9 years with Clinical Dementia Rating-sum of boxes (CDR-SB)/Mini-Mental State Examination (MMSE). Mixed effects models were used to investigate the interaction between Aβ/tau and group on CDR-SB/MMSE changes., Results: The frequency of Aβ positivity (45% versus 54.9%, p = 0.556) and mean global FTP SUVR (1.17±0.21 versus 1.16±0.17, p = 0.702) were not different between the two groups. We found a significant interaction effect of Aβ positivity and SVCI group on CDR-SB increase/MMSE decrease (p = 0.013/p < 0.001), and a significant interaction effect of global FTP uptake and SVCI group on CDR-SB increase/MMSE decrease (p < 0.001 and p = 0.030). Finally, the interaction effects of regional tau and group were prominent in the Braak III/IV (p = 0.001) and V/VI (p = 0.003) not in Braak I/II region (p = 0.398)., Conclusion: The association between Aβ/tau and cognitive decline is stronger in SVCI than in ADCI. Therefore, our findings suggested that Aβ positivity or tau burden (particularly in the Braak III/IV or V/VI regions) and CSVD might synergistically affect cognitive decline.