Publications by authors named "Yu Kyeong Kim"

147 Publications

Seasonal Trends of Viral Prevalence and Incidence of Kawasaki Disease: A Korea Public Health Data Analysis.

J Clin Med 2021 Jul 27;10(15). Epub 2021 Jul 27.

Department of Pediatrics, College of Medicine, Yeungnam University, Daegu 42415, Korea.

Kawasaki disease (KD) is a systemic vasculitis that occurs mainly in children under 5 years of age and is often accompanied by coronary artery lesions. The cause of the disease remains undetermined, but it is estimated to result from viral or bacterial infections. Certain studies have shown infection as a leading cause of KD. The purpose of this study was to investigate the relationship between KD incidence and viral infections in different pediatric age groups, using the Health Insurance Review and Assessment (HIRA) Open Access Big Data Platform, to confirm seasonal trends by analyzing monthly patterns. We investigated the HIRA data of KD patients (M30.3) who were treated with intravenous immunoglobulin from 2015 to 2018. Weekly virus positive detection rate data (PDR) for this period was obtained from the Korea Disease Control and Prevention Agency for human adenovirus (HAdV), human parainfluenza virus (HPIV), human respiratory syncytial virus (HRSV), influenza virus (IFV), human coronavirus (HCoV), human rhinovirus (HRV), human bocavirus (HBoV), human metapneumovirus (HMPV), rotavirus, norovirus, and astrovirus. We then analyzed the weekly/monthly virus PDR and its association with KD incidence, including monthly incidence patterns, and seasonal trends. Seasonal trend analysis of the virus PDR was performed using the time series analysis method through ARIMA (Autoregressive Integrated Moving Average). Correlations between KD incidence and PDR at 1- and 2-month intervals were analyzed using the Granger test. A total of 16,740 patients were diagnosed with KD during the study period, mainly young children, with a male-to-female ratio of 1.35. Specifically, 15,635 (93%) patients were under 5 years of age, with an incidence rate of 172.4/100,000 person-years. Annually, the cumulative number of cases per month was the highest in January, with an average of 469 cases, and was the lowest in September, with an average of 291 cases, although most were diagnosed with KD in winter (29.3%). Granger tests showed that PDR for HRSV, rotavirus, and norovirus were related with KD incidence by 1 month, while PDR for HRSV, HRV, rotavirus, and norovirus by 2 months. This study found that detection rates of respiratory and enteric viruses preceded KD by 1-2 months. Further research is needed to confirm the association between these viruses and KD.
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http://dx.doi.org/10.3390/jcm10153301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8347058PMC
July 2021

Mild cognitive impairment and abnormal brain metabolic expression in idiopathic REM sleep behavior disorder.

Parkinsonism Relat Disord 2021 Jul 22;90:1-7. Epub 2021 Jul 22.

Department of Neurology and Movement Disorder Center, Parkinson Study Group, Neuroscience Research Institute, College of Medicine, Seoul National University Hospital, Seoul, 03080, Republic of Korea. Electronic address:

Background: Mild cognitive impairment (MCI) is a common feature of isolated rapid-eye-movement sleep behavior disorder (iRBD). Here, we assessed cognitive functions and MCI in a prospective iRBD cohort and investigated their association with disease-specific brain metabolic patterns.

Methods: Forty-four patients with polysomnography-confirmed iRBD performed a standardized battery of neuropsychological examinations every two years. We used previously established spatial covariance patterns from de novo drug-naïve Parkinson's disease with concomitant RBD (PDRBD-RP) and iRBD (iRBD-RP) using F-fluorodeoxyglucose PET scan. We compared those expressions between iRBD with normal cognition (iRBD-NC) and with mild cognitive impairment (iRBD-MCI), and evaluated whether they predict progressive cognitive deterioration.

Results: Twenty iRBD patients (45 %) had MCI at baseline and 12 patients (27 %, about 7 % per year) had clinically significant cognitive deterioration after 4 years. The iRBD-MCI and iRBD-NC groups showed similar rates of cognitive change, but iRBD-MCI consistently performed worse in the domains of verbal memory and executive function. Elevated PDRBD-RP expression predicted cognitive deterioration (hazard ratio = 5.98 [1.70-21.06]), whereas iRBD-RP did not.

Conclusions: Increased disease-specific brain metabolic patterns are associated with iRBD-MCI and impending cognitive deterioration with the risk of progression to Lewy body dementia.
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http://dx.doi.org/10.1016/j.parkreldis.2021.07.022DOI Listing
July 2021

Differences in Brain Morphology between Hydrocephalus Ex Vacuo and Idiopathic Normal Pressure Hydrocephalus.

Psychiatry Investig 2021 Jul 16;18(7):628-635. Epub 2021 Jul 16.

Department of Neurosurgery, Seoul National University College of Medicine & SMG-SNU Boramae Medical Center, Seoul, Republic of Korea.

Objective: The distinction between idiopathic normal pressure hydrocephalus (iNPH) and hydrocephalus ex vacuo caused by encephalic volume loss remains to be established. This study aims to investigate radiological parameters as clinically useful tools to discriminate iNPH from hydrocephalus ex vacuo caused by Alzheimer's disease (AD).

Methods: A total of 54 patients with ventriculomegaly (iNPH, 25; hydrocephalus ex vacuo, 29) were recruited in this study. Consequently, nine radiological parameters were compared between iNPH and hydrocephalus ex vacuo using magnetic resonance imaging (MRI).

Results: A small callosal angle (CA), the Sylvian fissure dilatation, and absence of narrowing of superior parietal sulci discriminated the iNPH group from the hydrocephalus ex vacuo group (p<0.05). The final binary logistic regression model included narrowing of superior parietal sulci, degrees of the CA, and height of the Sylvian fissure after controlling for age and global Clinical Dementia Rating (CDR). The composite score made from these three indicators (narrowing of superior parietal sulci, degrees of the CA, and height of the Sylvian fissure) was statistically different between iNPH and hydrocephalus ex vacuo.

Conclusion: The narrowing of the CA, dilatation of the Sylvain fissure, and narrowing of superior parietal sulci may be used as radiological key indices and noninvasive tools for the differential diagnosis of iNPH from hydrocephalus ex vacuo.
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http://dx.doi.org/10.30773/pi.2020.0352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328827PMC
July 2021

Deep learning-based amyloid PET positivity classification model in the Alzheimer's disease continuum by using 2-[F]FDG PET.

EJNMMI Res 2021 Jun 10;11(1):56. Epub 2021 Jun 10.

Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.

Background: Considering the limited accessibility of amyloid position emission tomography (PET) in patients with dementia, we proposed a deep learning (DL)-based amyloid PET positivity classification model from PET images with 2-deoxy-2-[fluorine-18]fluoro-D-glucose (2-[F]FDG).

Methods: We used 2-[F]FDG PET datasets from the Alzheimer's Disease Neuroimaging Initiative and Korean Brain Aging Study for the Early diagnosis and prediction of Alzheimer's disease for model development. Moreover, we used an independent dataset from another hospital. A 2.5-D deep learning architecture was constructed using 291 submodules and three axes images as the input. We conducted the voxel-wise analysis to assess the regions with substantial differences in glucose metabolism between the amyloid PET-positive and PET-negative participants. This facilitated an understanding of the deep model classification. In addition, we compared these regions with the classification probability from the submodules.

Results: There were 686 out of 1433 (47.9%) and 50 out of 100 (50%) amyloid PET-positive participants in the training and internal validation datasets and the external validation datasets, respectively. With 50 times iterations of model training and validation, the model achieved an AUC of 0.811 (95% confidence interval (CI) of 0.803-0.819) and 0.798 (95% CI, 0.789-0.807) on the internal and external validation datasets, respectively. The area under the curve (AUC) was 0.860 when tested with the model with the highest value (0.864) on the external validation dataset. Moreover, it had 75.0% accuracy, 76.0% sensitivity, 74.0% specificity, and 75.0% F1-score. We found an overlap between the regions within the default mode network, thus generating high classification values.

Conclusion: The proposed model based on the 2-[F]FDG PET imaging data and a DL framework might successfully classify amyloid PET positivity in clinical practice, without performing amyloid PET, which have limited accessibility.
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http://dx.doi.org/10.1186/s13550-021-00798-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192639PMC
June 2021

The clinical use of blood-test factors for Alzheimer's disease: improving the prediction of cerebral amyloid deposition by the QPLEX Alz plus assay kit.

Exp Mol Med 2021 Jun 9;53(6):1046-1054. Epub 2021 Jun 9.

Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea.

Alzheimer's disease (AD) is the leading cause of dementia, and many studies have focused on finding effective blood biomarkers for the accurate diagnosis of this disease. Predicting cerebral amyloid deposition is considered the key for AD diagnosis because a cerebral amyloid deposition is the hallmark of AD pathogenesis. Previously, blood biomarkers were discovered to predict cerebral amyloid deposition, and further efforts have been made to increase their sensitivity and specificity. In this study, we analyzed blood-test factors (BTFs) that can be commonly measured in medical health check-ups from 149 participants with cognitively normal, 87 patients with mild cognitive impairment, and 64 patients with clinically diagnosed AD dementia with brain amyloid imaging data available. We demonstrated that four factors among regular health check-up blood tests, cortisol, triglyceride/high-density lipoprotein cholesterol ratio, alanine aminotransferase, and free triiodothyronine, showed either a significant difference by or correlation with cerebral amyloid deposition. Furthermore, we made a prediction model for Pittsburgh compound B-positron emission tomography positivity, using BTFs and the previously discovered blood biomarkers, the QPLEX Alz plus assay kit biomarker panel, and the area under the curve was significantly increased up to 0.845% with 69.4% sensitivity and 90.6% specificity. These results show that BTFs could be used as co-biomarkers and that a highly advanced prediction model for amyloid plaque deposition could be achieved by the combinational use of diverse biomarkers.
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http://dx.doi.org/10.1038/s12276-021-00638-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257730PMC
June 2021

Parkinson Disease-Related Brain Metabolic Patterns and Neurodegeneration in Isolated REM Sleep Behavior Disorder.

Neurology 2021 07 19;97(4):e378-e388. Epub 2021 May 19.

From the Department of Neurology (J.H.S., J.-Y.L., H.N.), Seoul Metropolitan Government--Seoul National University Boramae Medical Center and Seoul National University College of Medicine; Department of Nuclear Medicine (Y.-K.K., E.J.Y., H.K.), Seoul Metropolitan Government--Seoul National University Boramae Medical Center; Institute of Radiation Medicine (H.K.), Medical Research Center, Seoul National University; and Department of Neurology (B.J.), Seoul National University Hospital and Seoul National University College of Medicine, South Korea.

Objective: To elucidate the role of Parkinson disease (PD)-related brain metabolic patterns as a biomarker in isolated REM sleep behavior disorder (iRBD) for future disease conversion.

Methods: This is a prospective cohort study consisting of 30 patients with iRBD, 25 patients with de novo PD with a premorbid history of RBD, 21 patients with longstanding PD on stable treatment, and 24 healthy controls. The iRBD group was longitudinally followed up. All participants underwent F-fluorodeoxyglucose (FDG) PET and were evaluated with olfaction, cognition, and the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) at baseline. From FDG-PET scans, we derived metabolic patterns from the longstanding PD group (PD-RP) and de novo PD group with RBD (dnPDRBD-RP). Subsequently, we calculated the PD-RP and dnPDRBD-RP scores in patients with iRBD. We validated the metabolic patterns in each PD group and separate iRBD cohort (n = 14).

Results: The 2 patterns significantly correlated with each other and were spatially overlapping yet distinct. The MDS-UPDRS motor scores significantly correlated with PD-RP ( = 0.013) but not with dnPDRBD-RP ( = 0.076). In contrast, dnPDRBD-RP correlated with olfaction in butanol threshold test ( = 0.018) in patients with iRBD, but PD-RP did not ( = 0.21). High dnPDRBD-RP in patients with iRBD predicted future phenoconversion with all cutoff ranges from 1.5 to 3 SD of the control value, whereas predictability of PD-RP was only significant in a partial range of cutoff.

Conclusion: The dnPDRBD-RP is an efficient neuroimaging biomarker that reflects prodromal features of PD and predicts phenoconversion in iRBD that can be applied individually.

Classification Of Evidence: This study provides Class IV evidence that a de novo PD pattern on FDG-PET predicts future conversion to neurodegenerative disease in patients with iRBD.
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http://dx.doi.org/10.1212/WNL.0000000000012228DOI Listing
July 2021

Epidemiology and Viral Etiology of Pediatric Immune Thrombocytopenia through Korean Public Health Data Analysis.

J Clin Med 2021 Mar 25;10(7). Epub 2021 Mar 25.

Department of Pediatrics, College of Medicine, Yeungnam University, Daegu 42415, Korea.

Immune thrombocytopenic purpura (ITP) is prevalent in children aged 2-5 years but may occur in all pediatric age groups. In 50-60% of pediatric patients, ITP is preceded by an upper respiratory tract infection 1-4 weeks before its onset. In this study, the relationship between the development of ITP and viral infections in children was assessed. We analyzed data of 6487 patients aged < 18 years with incident ITP from the Health Insurance Review and Assessment Open Access Big Data Platform (2015 to 2018) and the Korea Disease Control and Prevention Agency. The monthly positive detection rate (PDR) of seven respiratory and four acute diarrhea viruses was calculated. The virus PDR seasonal trend data was analyzed through ARIMA modeling. The ITP diagnostic data and prevalence of viral infection 1 and 2 months prior were analyzed using the Granger test. The overall male to female (M/F) ratio was 1.2, whereas it was 1.4 in the youngest age group (< 1 year). The overall ITP incidence rate was 18.1 per 100,000 person-years. Respiratory syncytial virus, rhinovirus, rotavirus, and astrovirus infections influenced ITP occurrence in children. However, rotavirus infection is positively associated with the etiology of ITP after 1-2 months.
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http://dx.doi.org/10.3390/jcm10071356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037772PMC
March 2021

Longitudinal Changes in Isolated Rapid Eye Movement Sleep Behavior Disorder-Related Metabolic Pattern Expression.

Mov Disord 2021 08 31;36(8):1889-1898. Epub 2021 Mar 31.

Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.

Background: It remains unclear whether and how the isolated rapid eye movement (REM) sleep behavior disorder (iRBD)-related metabolic pattern (RBDRP) changes with disease progression in iRBD.

Objective: To examine longitudinal changes in RBDRP expression in iRBD patients and to explore trajectories of relative metabolic activities of individual brain regions constituting RBDRP.

Methods: In this cohort study, 25 iRBD patients (mean age [±standard deviation], 69.2 ± 5.3 years; 12 [48%] patients were men) and 24 age-matched healthy controls were included. The patients underwent at least two F-fluorodeoxyglucose positron emission tomography scans at baseline and at the 2-year and/or 4-year follow-ups. We measured the RBDRP expression of the patients and controls which was validated by reproduction in a separate iRBD cohort (n = 13).

Results: At baseline, the RBDRP expression discriminated iRBD patients from healthy controls. However, the RBDRP expression z scores tended to decrease over time in the patients, especially with longer follow-ups, and this tendency was observed even in patients with high-risk of phenoconversion. Furthermore, the degree of RBDRP expression at baseline did not predict the disease conversion. The RBDRP breakdown was mainly provoked by the attenuation of relative hypermetabolism in the frontal cortex including premotor areas and relative hypometabolism in the occipital cortex. The putaminal metabolic activity increased steadily with the disease progression.

Conclusions: The RBDRP expression in iRBD patients was altered significantly over time. Some of the brain metabolic changes seem to represent attempted functional compensation against ongoing neurodegeneration. The RBDRP expression measurement at one time point may not be a reliable biomarker for predicting disease conversion. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28592DOI Listing
August 2021

Association of Retinal Changes With Alzheimer Disease Neuroimaging Biomarkers in Cognitively Normal Individuals.

JAMA Ophthalmol 2021 May;139(5):548-556

Institute of Human Behavioral Medicine, Medical Research Center Seoul National University, Seoul, Republic of Korea.

Importance: Retinal biomarkers reflecting in vivo brain Alzheimer disease (AD) pathologic abnormalities could be a useful tool for screening cognitively normal (CN) individuals at the preclinical stage of AD.

Objectives: To investigate the association of both functional and structural alterations of the retina with in vivo AD pathologic abnormalities in CN older adults and model a screening tool for detection of preclinical AD.

Design, Setting, And Participants: This cross-sectional study included a total of 49 CN individuals, and all assessment was done at the Seoul National University Hospital, Seoul, South Korea. All participants underwent complete ophthalmic examination, including swept-source optical coherence tomography (SS-OCT) and multifocal electroretinogram as well as amyloid-β (Aβ) positron emission tomography and magnetic resonance imaging. Data were collected from January 1, 2016, through October 31, 2017, and analyzed from February 1, 2018, through June 30, 2020.

Main Outcomes And Measures: For structural parameters of the retina, the thickness of the macula and layer-specific thicknesses, including peripapillary retinal nerve fiber layer and ganglion cell-inner plexiform layer measured by SS-OCT, were used for analysis. For functional parameters of the retina, implicit time and amplitude of rings 1 to 6 measured by multifocal electroretinogram were used.

Results: Of the 49 participants, 25 were women (51.0%); mean (SD) age was 70.6 (9.4) years. Compared with 33 CN individuals without Aβ deposition (Aβ-CN), the 16 participants with Aβ (Aβ+CN) showed reduced inner nasal macular thickness (mean [SD], 308.9 [18.4] vs 286.1 [22.5] μm; P = .007) and retinal nerve fiber layer thickness, particularly in the inferior quadrant (133.8 [17.9] vs 103.8 [43.5] μm; P = .003). In addition, the Aβ+CN group showed prolonged implicit time compared with the Aβ-CN group, particularly in ring 5 (41.3 [4.0] vs 38.2 [1.3] milliseconds; P = .002). AD-related neurodegeneration was correlated with the thickness of the ganglion cell-inner plexiform layer only (r = 0.41, P = .005). The model to differentiate the Aβ+CN vs Aβ-CN groups derived from the results showed 90% accuracy.

Conclusions And Relevance: The findings of this study showing both functional as well as structural changes of retina measured by multifocal electroretinogram and SS-OCT in preclinical AD suggest the potential use of retinal biomarkers as a tool for early detection of in vivo AD pathologic abnormalities in CN older adults.
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http://dx.doi.org/10.1001/jamaophthalmol.2021.0320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995126PMC
May 2021

Synergistic Effect of Serum Homocysteine and Diabetes Mellitus on Brain Alterations.

J Alzheimers Dis 2021 ;81(1):287-295

Institute of Human Behavioral Medicine, Medical Research Center Seoul National University, Seoul, Republic of Korea.

Background: Both elevated blood homocysteine and diabetes mellitus (DM) are related to cognitive impairments or dementia. A previous study also demonstrated that the association between homocysteine and cognitive decline was much stronger in individuals with DM than in those without DM.

Objective: This study aimed to examine the interactive effect of blood homocysteine and DM on brain pathological changes including brain atrophy, amyloid-β and tau deposition, and small vessel disease (SVD) related to cognitive impairments.

Methods: A total of 430 non-demented older adults underwent comprehensive clinical assessment, measurement of serum homocysteine level, [11C] Pittsburgh Compound B (PiB) PET, [18F] AV-1451 PET, and brain MRI.

Results: The interactive effect of homocysteine with the presence of DM on brain atrophy, especially in aging-related brain regions, was significant. Higher homocysteine concentration was associated with more prominent brain atrophy in individuals with DM, but not in those without DM. In contrast, interaction effect of homocysteine and DM was found neither on Alzheimer's disease (AD) pathologies, including amyloid-β and tau deposition, nor white matter hyperintensity volume as a measure of SVD.

Conclusion: The present findings suggest that high blood homocysteine level and DM synergistically aggravate brain damage independently of AD and cerebrovascular disease. With regard to preventing dementia or cognitive decline in older adults, these results support the importance of strictly controlling blood glucose in individuals with hyperhomocysteinemia and lowering blood homocysteine level in those with DM.
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http://dx.doi.org/10.3233/JAD-210036DOI Listing
September 2021

Blood Hemoglobin, Alzheimer Pathologies, and Cognitive Impairment: A Cross-Sectional Study.

Front Aging Neurosci 2021 24;13:625511. Epub 2021 Feb 24.

Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, South Korea.

Despite known associations between low blood hemoglobin level and Alzheimer's disease (AD) or cognitive impairment, the underlying neuropathological links are poorly understood. We aimed to examine the relationships of blood hemoglobin levels with AD pathologies (i.e., cerebral beta-amyloid [Aβ] deposition, tau deposition, and AD-signature degeneration) and white matter hyperintensities (WMHs), which are a measure of cerebrovascular injury. We also investigated the association between hemoglobin level and cognitive performance, and then assessed whether such an association is mediated by brain pathologies. A total of 428 non-demented older adults underwent comprehensive clinical assessments, hemoglobin level measurement, and multimodal brain imaging, including Pittsburgh compound B-positron emission tomography (PET), AV-1451 PET, fluorodeoxyglucose (FDG)-PET, and magnetic resonance imaging. Episodic memory score and global cognition scores were also measured. A lower hemoglobin level was significantly associated with reduced AD-signature cerebral glucose metabolism (AD-CM), but not Aβ deposition, tau deposition, or WMH volume. A lower hemoglobin level was also significantly associated with poorer episodic memory and global cognition scores, but such associations disappeared when AD-CM was controlled as a covariate, indicating that AD-CM has a moderating effect. The present findings suggest that low blood hemoglobin in older adults is associated with cognitive decline via reduced brain metabolism, which seems to be independent of those aspects of AD-specific protein pathologies and cerebrovascular injury that are reflected in PET and MRI measures.
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http://dx.doi.org/10.3389/fnagi.2021.625511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943867PMC
February 2021

Differential associations of age and Alzheimer's disease with sleep and rest-activity rhythms across the adult lifespan.

Neurobiol Aging 2021 05 22;101:141-149. Epub 2021 Jan 22.

Department of Psychiatry, Seoul National University College of Medicine, Seoul, South Korea; Department of Neuropsychiatry, Seoul National University Hospital, Seoul, South Korea; Medical Research Center, Institute of Human Behavioral Medicine, Seoul National University Hospital, Seoul, South Korea; Interdisiplinary Program in Cognitive science, Seoul National University, Seoul, South Korea. Electronic address:

This study aimed to identify differences between physiological age-related and Alzheimer's disease (AD)-related alterations in sleep and rest-activity rhythm. All participants (n = 280; 20-90 years) underwent clinical assessments, [C] Pittsburgh compound B-positron emission tomography, and actigraphic monitoring. In cognitively normal adults without cerebral amyloid-β, older age was associated with earlier timing of circadian phase and robust rest-activity rhythm, but sleep quantity and quality were mostly unaffected by age. While preclinical AD was associated with earlier circadian timing, clinical AD exhibited later timing of daily rhythm and increased sleep duration. In conclusion, our findings suggest that older age itself leads to a more regular daily activity rhythm, but does not affect sleep duration. While preclinical AD made the effects of age-related phase advance more prominent, clinical AD was related to later circadian timing and increased sleep duration.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.01.006DOI Listing
May 2021

Deep learning-Based 3D inpainting of brain MR images.

Sci Rep 2021 01 18;11(1):1673. Epub 2021 Jan 18.

Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.

The detailed anatomical information of the brain provided by 3D magnetic resonance imaging (MRI) enables various neuroscience research. However, due to the long scan time for 3D MR images, 2D images are mainly obtained in clinical environments. The purpose of this study is to generate 3D images from a sparsely sampled 2D images using an inpainting deep neural network that has a U-net-like structure and DenseNet sub-blocks. To train the network, not only fidelity loss but also perceptual loss based on the VGG network were considered. Various methods were used to assess the overall similarity between the inpainted and original 3D data. In addition, morphological analyzes were performed to investigate whether the inpainted data produced local features similar to the original 3D data. The diagnostic ability using the inpainted data was also evaluated by investigating the pattern of morphological changes in disease groups. Brain anatomy details were efficiently recovered by the proposed neural network. In voxel-based analysis to assess gray matter volume and cortical thickness, differences between the inpainted data and the original 3D data were observed only in small clusters. The proposed method will be useful for utilizing advanced neuroimaging techniques with 2D MRI data.
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http://dx.doi.org/10.1038/s41598-020-80930-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814079PMC
January 2021

Retrospective study of relationship between vastus medialis volume on SPECT-CT and outcome of unilateral total knee arthroplasty.

Medicine (Baltimore) 2021 Jan;100(1):e24138

Department of Orthopedic Surgery, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.

Abstract: Although the importance of quadriceps femoris function was reported previously, little is known about volume-related factors and their effects on clinical outcomes after total knee arthroplasty (TKA). We sought to determine whether there was a bilateral difference in vastus medialis muscle volume measured on single-photon emission computed tomography-computed tomography (SPECT-CT) in patients who underwent unilateral TKA. We also aimed to determine whether vastus medialis volume was related to osteoarthritis (OA) severity or scintigraphic uptake degree around the knee joint on SPECT-CT. And finally, we attempted to investigate the factors, such as vastus medialis volume and scintigraphic uptake degree, associated with the functional outcomes of TKA.This retrospective study included 50 patients (41 female, 9 male) undergone unilateral TKA due to primary OA. The maximal cross-sectional area of the vastus medialis was measured on axial SPECT-CT images. Scintigraphic uptake degrees and Kellgren-Lawrence (K-L) grade at the tibiofemoral joints were assessed. We compared maximal cross-sectional area of the vastus medialis on SPECT-CT for difference of bilateral lower limbs. We also analyzed the relationship between volume of vastus medialis and scintigraphic uptake measured on SPECT-CT and the severity of OA on conventional radiographs. The clinical outcomes were evaluated using the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index at baseline and at 1 and 2 years after surgery. The relationship between preoperative muscle volume and scintigraphic uptake on SPECT-CT and WOMAC index was analyzed.The amount of muscle volume measured on SPECT-CT was smaller in operated limb in patients who underwent unilateral TKA. Preoperative vastus medialis muscle volume was not related to preoperative OA severity measured on conventional radiographs and scintigraphic uptake on SPECT-CT. However, a decreased vastus medialis muscle volume was related to worse clinical outcomes after TKA (P = .045), whereas the degree of scintigraphic uptake on SPECT-CT was not associated with postoperative clinical outcomes.Muscle volume of vastus medialis was decreased in the operated knee than in the nonoperated knee, and that was correlated with worse postoperative results. Even if the preoperative volume of vastus medialis were not related to OA severity on conventional radiographs and scintigraphic uptake on SPECT-CT, preservation and improvement of the muscle mass of the knee undergoing TKA is important.
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http://dx.doi.org/10.1097/MD.0000000000024138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793406PMC
January 2021

Performance of the QPLEX™ Alz plus assay, a novel multiplex kit for screening cerebral amyloid deposition.

Alzheimers Res Ther 2021 01 6;13(1):12. Epub 2021 Jan 6.

Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea.

Background: Alzheimer's disease (AD) is an irreversible neurodegenerative disease characterized by the hallmark finding of cerebral amyloid deposition. Many researchers have tried to predict the existence of cerebral amyloid deposition by using easily accessible blood plasma samples, but the effectiveness of such strategies remains controversial.

Methods: We developed a new multiplex kit, the QPLEX™ Alz plus assay kit, which uses proteomics-based blood biomarkers to prescreen for cerebral amyloid deposition. A total of 300 participants who underwent Pittsburgh compound B (PiB)-positron emission tomography (PET) which allows imaging of cerebral amyloid deposition were included in this study. We compared the levels of QPLEX™ biomarkers between patients who were classified as PiB-negative or PiB-positive, regardless of their cognitive function. Logistic regression analysis followed by receiver operating characteristic (ROC) curve analysis was performed. The kit accuracy was tested using a randomized sample selection method.

Results: The results obtained using our assay kit reached 89.1% area under curve (AUC) with 80.0% sensitivity and 83.0% specificity. Further validation of the QPLEX™ Alz plus assay kit using a randomized sample selection method showed an average accuracy of 81.5%.

Conclusions: Our QPLEX™ Alz plus assay kit provides preliminary evidence that it can be used as blood marker to predict cerebral amyloid deposition but independent validation is needed.
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http://dx.doi.org/10.1186/s13195-020-00751-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786945PMC
January 2021

Effects of Chronic Tinnitus on Metabolic and Structural Changes in Subjects With Mild Cognitive Impairment.

Front Aging Neurosci 2020 19;12:594282. Epub 2020 Nov 19.

Department of Nuclear Medicine, Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, South Korea.

Tinnitus is a conscious auditory perception in the absence of an external stimulus. Despite previous reports of a recognized association between tinnitus and cognitive deficits, the effects of tinnitus on functional and structural brain changes associated with cognitive deficits remain unknown. We aimed to investigate the changes in glucose metabolism and gray matter (GM) volume in subjects diagnosed with mild cognitive impairment (MCI) depending on tinnitus. Twenty-three subjects were subclassified into MCI with the chronic tinnitus (MCI_T) and MCI without tinnitus (MCI_NT) groups. Encouraged by the identification of neural substrates associated with tinnitus and cognitive deficits, we correlated the extent of tinnitus severity with the changes in glucose metabolism and GM volume and conducted a glucose metabolic connectivity study. Compared to the MCI_NT group, the MCI_T group showed significantly lower metabolism in the right superior temporal pole and left fusiform gyrus. Additionally, the GM volume in the right insula was markedly lower in the MCI_T group compared to the MCI_NT group. Moreover, correlation analyses in metabolism or GM volumes revealed specific brain regions associated with the cognitive decline with increasing tinnitus severity. Metabolic connectivity analysis revealed that MCI_NT had markedly strengthened intra-hemispheric connectivity in the frontal, parietal, and occipital regions than did MCI_T. Furthermore, MCI_NT showed a strong negative association between the parietal and temporal and parietal and limbic regions, but the association was not observed in MCI_T. These findings indicate that tinnitus may cause metabolic and structural changes in the brain and alters complex inter- or intra-hemispheric networks in MCI. Considering the impact of MCI on accelerating dementia, these results provide a valuable basis on which yet-to-be-identified neurodegenerative markers of tinnitus can be refined.
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http://dx.doi.org/10.3389/fnagi.2020.594282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710517PMC
November 2020

Genetic associations of in vivo pathology influence Alzheimer's disease susceptibility.

Alzheimers Res Ther 2020 11 19;12(1):156. Epub 2020 Nov 19.

Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.

Introduction: Although the heritability of sporadic Alzheimer's disease (AD) is estimated to be 60-80%, addressing the genetic contribution to AD risk still remains elusive. More specifically, it remains unclear whether genetic variants are able to affect neurodegenerative brain features that can be addressed by in vivo imaging techniques.

Methods: Targeted sequencing analysis of the coding and UTR regions of 132 AD susceptibility genes was performed. Neuroimaging data using C-Pittsburgh Compound B positron emission tomography (PET), F-fluorodeoxyglucose PET, and MRI that are available from the KBASE (Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's disease) cohort were acquired. A total of 557 participants consisted of 336 cognitively normal (CN) adults, 137 mild cognitive impairment (MCI), and 84 AD dementia (ADD) groups.

Results: We called 5391 high-quality single nucleotide variants (SNVs) on AD susceptibility genes and selected significant associations between variants and five in vivo AD pathologies: (1) amyloid β (Aβ) deposition, (2) AD-signature region cerebral glucose metabolism (AD-Cm), (3) posterior cingulate cortex (PCC) cerebral glucose metabolism (PCC-Cm), (4) AD-signature region cortical thickness (AD-Ct), and (5) hippocampal volume (Hv). The association analysis for common variants (allele frequency (AF) > 0.05) yielded several novel loci associated with Aβ deposition (PIWIL1-rs10848087), AD-Cm (NME8-rs2722372 and PSEN2-rs75733498), AD-Ct (PSEN1-rs7523) and, Hv (CASS4-rs3746625). Meanwhile, in a gene-based analysis for rare variants (AF < 0.05), cases carrying rare variants in LPL, FERMT2, NFAT5, DSG2, and ITPR1 displayed associations with the neuroimaging features. Exploratory voxel-based brain morphometry between the variant carriers and non-carriers was performed subsequently. Finally, we document a strong association of previously reported APOE variants with the in vivo AD pathologies and demonstrate that the variants exert a causal effect on AD susceptibility via neuroimaging features.

Conclusions: This study provides novel associations of genetic factors to Aβ accumulation and AD-related neurodegeneration to influence AD susceptibility.
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http://dx.doi.org/10.1186/s13195-020-00722-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678113PMC
November 2020

Serum TNF-α and neurodegeneration in isolated REM sleep behavior disorder.

Parkinsonism Relat Disord 2020 12 30;81:1-7. Epub 2020 Sep 30.

Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.

Objective: To investigate serum inflammatory cytokine profiles in patients with isolated REM sleep behavior disorder (iRBD) and to explore whether these markers are associated with phenoconversion risk to α-synucleinopathies.

Methods: In this prospective cohort study, we analyzed serum samples from patients with polysomnography-confirmed iRBD (n = 30) and healthy controls (n = 12). We measured the following cytokines: interleukin (IL)-1β, IL-2, IL-6, IL-10, and tumor necrosis factor-α (TNF-α). All patients underwent motor and non-motor evaluations and dopamine transporter imaging at baseline for predicting the phenoconversion risk. We followed the patients quarterly over up to 6 years to identify disease conversion. We also assessed longitudinal changes in cytokine levels from baseline at the 2- and 4-year follow-up visits.

Results: The baseline cytokine levels did not differ between the patients and controls. However, the TNF-α levels were significantly increased in a subgroup of the patients with multiple markers (≥3) for phenoconversion risk compared to those without (p = 0.008) and controls (p = 0.003). At longitudinal analyses, patients with TNF-α levels above the median showed a higher incidence of phenoconversion than those with lower TNF-α levels (47% vs. 7%; p = 0.008), and this significant association persisted after adjusting for covariates (p = 0.026). The cytokine levels over 4 years of follow-up period did not change significantly.

Conclusions: Our data suggest a possible link between serum TNF-α and phenoconversion risk in iRBD. Further studies are warranted to confirm the role of peripheral TNF-α in the pathogenesis of neurodegeneration in this disorder.
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http://dx.doi.org/10.1016/j.parkreldis.2020.09.041DOI Listing
December 2020

Longitudinal change in dopamine transporter availability in idiopathic REM sleep behavior disorder.

Neurology 2020 12 28;95(23):e3081-e3092. Epub 2020 Sep 28.

From the Department of Neurology (J.H.S., J.-Y.L., H.N.), Seoul Metropolitan Government-Seoul National University Boramae Medical Center and Seoul National University College of Medicine; Department of Nuclear Medicine (Y.-K.K., S.-A.S., H.K.), Seoul Metropolitan Government-Seoul National University Boramae Medical Center; and Department of Neurology (B.J.), Seoul National University Hospital and Seoul National University College of Medicine, South Korea.

Objective: To elucidate longitudinal changes in the dopamine transporter (DAT) availability in association with the prodromal markers in idiopathic REM sleep behavior disorder (iRBD), we analyzed a longitudinal prospective iRBD cohort data.

Method: The study cohort consisted of patients with iRBD, individuals with Parkinson disease (PD), and healthy controls. All participants were evaluated for olfaction, neuropsychological tests, and the Movement Disorders Society-Unified Parkinson's Disease Rating Scale and underwent F-FP-CIT PET scans every 2 years. We calculated the DAT pattern by performing the principal component analysis of tracer uptakes in 6 striatal regions.

Result: DAT patterns in patients with iRBD with baseline hyposmia, constipation, and mild parkinsonian signs distributed toward the PD pattern and clearly distinguished from the healthy control pattern. The DAT pattern moved toward the PD pattern over time in some patients with iRBD during the follow-up, and baseline hyposmia was the only biomarker significantly associated with this change. Baseline PD pattern of DAT predicted 58% of disease converters (hazard ratio 4.95 [95% confidence interval 1.16-21.08]). The combination of hyposmia and baseline PD pattern of DAT predicted 67% of the conversion (hazard ratio 7.89 [confidence interval 1.85-33.69]). The estimated sample size required for a simulated neuroprotective clinical trial was 63 per group when the annual change of DAT pattern was used as an outcome in the subgroup with baseline DAT PD pattern and hyposmia, which is the smallest number reported so far.

Conclusion: Baseline and longitudinal monitoring of the DAT pattern can be a useful biomarker in identifying individuals with a high risk of disease conversion and in selecting the potential population for clinical trials in iRBD.
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http://dx.doi.org/10.1212/WNL.0000000000010942DOI Listing
December 2020

Persistent Activity of Metabotropic Glutamate Receptor 5 in the Periaqueductal Gray Constrains Emergence of Chronic Neuropathic Pain.

Curr Biol 2020 12 24;30(23):4631-4642.e6. Epub 2020 Sep 24.

Department of Physiology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea; Department of Brain and Cognitive Sciences, Seoul National University College of Natural Sciences, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea; Neuroscience Research Institute, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea. Electronic address:

Pain sensation is powerfully modulated by signal processing in the brain, and pain becomes chronic with the dysfunction of the pain modulatory system; however, the underlying mechanisms are unclear. We found that the metabotropic glutamate receptor 5 (mGluR5) in the periaqueductal gray (PAG), the key area of endogenous pain modulation, is persistently active in normal conditions to maintain an appropriate sensory perception. In the neuropathic pain condition, Homer1a, an activity-dependent immediate early gene product, disrupted the persistent mGluR5 activity resulting in chronic pain. Remarkably a single-time blockage of the mGluR5 resulted in chronic neuropathic pain-like symptoms even in the absence of nerve injury. The decline of mGluR5 activity induced the pain modulatory dysfunction with a profound reduction of excitability of PAG neurons. These findings uncover the role of the persistent mGluR5 activity in vivo and provide new insight into how pain becomes chronic with the maladaptive coping of the PAG to pain sensation.
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http://dx.doi.org/10.1016/j.cub.2020.09.008DOI Listing
December 2020

Association of carotid and intracranial stenosis with Alzheimer's disease biomarkers.

Alzheimers Res Ther 2020 09 10;12(1):106. Epub 2020 Sep 10.

Institute of Human Behavioral Medicine, Medical Research Center Seoul National University, Seoul, Republic of Korea.

Background: To clarify whether atherosclerosis of the carotid and intracranial arteries is related to Alzheimer's disease (AD) pathology in vivo, we investigated the associations of carotid and intracranial artery stenosis with cerebral beta-amyloid (Aβ) deposition and neurodegeneration in middle- and old-aged individuals. Given different variations of the pathologies between cognitive groups, we focused separately on cognitively normal (CN) and cognitively impaired (CI) groups.

Methods: A total of 281 CN and 199 CI (mild cognitive impairment and AD dementia) subjects underwent comprehensive clinical assessment, [C] Pittsburgh compound B-positron emission tomography, and magnetic resonance (MR) imaging including MR angiography. We evaluated extracranial carotid and intracranial arteries for the overall presence, severity (i.e., number and degree of narrowing), and location of stenosis.

Results: We found no associations between carotid and intracranial artery stenosis and cerebral Aβ burden in either the CN or the CI group. In terms of neurodegeneration, exploratory univariable analyses showed associations between the presence and severity of stenosis and regional neurodegeneration biomarkers (i.e., reduced hippocampal volume [HV] and cortical thickness in the AD-signature regions) in both the CN and CI groups. In confirmatory multivariable analyses controlling for demographic covariates and diagnosis, the association between number of stenotic intracranial arteries ≥ 2 and reduced HV in the CI group remained significant.

Conclusions: Neither carotid nor intracranial artery stenosis appears to be associated with brain Aβ burden, while intracranial artery stenosis is related to amyloid-independent neurodegeneration, particularly hippocampal atrophy.
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http://dx.doi.org/10.1186/s13195-020-00675-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488394PMC
September 2020

Prediction of Amyloid Positivity in Mild Cognitive Impairment Using Fully Automated Brain Segmentation Software.

Neuropsychiatr Dis Treat 2020 22;16:1745-1754. Epub 2020 Jul 22.

Department of Neuropsychiatry, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.

Objective: To assess the predictive ability of regional volume information provided by fully automated brain segmentation software for cerebral amyloid positivity in mild cognitive impairment (MCI).

Methods: This study included 130 subjects with amnestic MCI who participated in the Korean brain aging study of early diagnosis and prediction of Alzheimer's disease, an ongoing prospective cohort. All participants underwent comprehensive clinical assessment as well as C-labeled Pittsburgh compound PET/MRI scans. The predictive ability of volumetric results provided by automated brain segmentation software was evaluated using binary logistic regression and receiver operating characteristic curve analysis.

Results: Subjects were divided into two groups: one with Aβ deposition (58 subjects) and one without Aβ deposition (72 subjects). Among the varied volumetric information provided, the hippocampal volume percentage of intracranial volume (%HC/ICV), normative percentiles of hippocampal volume (HC), and gray matter volume were associated with amyloid-β (Aβ) positivity (all < 0.01). Multivariate analyses revealed that both %HC/ICV and HC were independent significant predictors of Aβ positivity (all < 0.001). In addition, prediction scores derived from %HC/ICV with age and HC showed moderate accuracy in predicting Aβ positivity in MCI subjects (the areas under the curve: 0.739 and 0.723, respectively).

Conclusion: Relative hippocampal volume measures provided by automated brain segmentation software can be useful for screening cerebral Aβ positivity in clinical practice for patients with amnestic MCI. The information may also help clinicians interpret structural MRI to predict outcomes and determine early intervention for delaying the progression to Alzheimer's disease dementia.
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http://dx.doi.org/10.2147/NDT.S252293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383107PMC
July 2020

Serum albumin and beta-amyloid deposition in the human brain.

Neurology 2020 08 20;95(7):e815-e826. Epub 2020 Jul 20.

From the Department of Neuropsychiatry (J.W.K.), Hallym University Dongtan Sacred Heart Hospital, Hwaseong-si, Gyeonggi-do; Department of Psychiatry (J.W.K.), Hallym University College of Medicine, Chuncheon, Gangwan-do; Institute of Human Behavioral Medicine (M.S.B., D.Y., D.Y.L.), Medical Research Center Seoul National University; Departments of Neuropsychiatry (J.H.L., D.Y.L.) and Radiology (K.M.K., C.-H.S.), Seoul National University Hospital; Department of Psychiatry (S.Y.J.), Chungnam National University Hospital, Daejeon; Sanggye Paik Hospital (B.K.S.), Department of Psychiatry, Inje University College of Medicine; Departments of Neuropsychiatry (J.-Y.L.) and Nuclear Medicine (S.A.S., Y.K.K.), SMG-SNU Boramae Medical Center; and Department of Psychiatry (J.-Y.L., D.Y.L.), Seoul National University College of Medicine, Republic of Korea.

Objectives: To investigate the relationships of serum albumin with in vivo Alzheimer disease (AD) pathologies, including cerebral β-amyloid (Aβ) protein deposition, neurodegeneration of AD-signature regions, and cerebral white matter hyperintensities (WMH), in the human brain.

Methods: A total of 396 older adults without dementia underwent comprehensive clinical assessments, measurement of serum albumin level, and multimodal brain imaging, including [C] Pittsburgh compound B-PET, F-fluorodeoxyglucose-PET, and MRI. Serum albumin was categorized as follows: <4.4 g/dL (low albumin), 4.4 to 4.5 g/dL (middle albumin), and >4.5 g/dL (high albumin; used as a reference category). Aβ positivity, AD-signature region cerebral glucose metabolism (AD-CM), AD-signature region cortical thickness (AD-CT), and WMH volume were used as outcome measures.

Results: Serum albumin level (as a continuous variable) was inversely associated with Aβ deposition and Aβ positivity. The low albumin group showed a significantly higher Aβ positivity rate compared to the high albumin group (odds ratio 3.40, 95% confidence interval 1.67-6.92, = 0.001), while the middle albumin group showed no difference (odds ratio 1.74, 95% confidence interval 0.80-3.77, = 0.162). Neither serum albumin level (as a continuous variable) nor albumin categories were related to AD-CM, AD-CT, or WMH volume.

Conclusions: Low serum albumin may increase the risk of AD dementia by elevating amyloid accumulation. In terms of AD prevention, more attention needs to be paid to avoid a low serum albumin level, even within the clinical normal range, by clinicians.
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http://dx.doi.org/10.1212/WNL.0000000000010005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605506PMC
August 2020

Serum Uric Acid, Alzheimer-Related Brain Changes, and Cognitive Impairment.

Front Aging Neurosci 2020 5;12:160. Epub 2020 Jun 5.

Institute of Human Behavioral Medicine, Medical Research Center Seoul National University, Seoul, South Korea.

Background: Despite known associations of lower serum uric acid (UA) with Alzheimer's disease (AD) dementia or AD-related cognitive impairment, little is known regarding the underlying patho-mechanisms. We aimed to examine the relationships of serum UA with in vivo AD pathologies including cerebral beta-amyloid (Aβ) and tau deposition, AD-signature region cerebral glucose metabolism (AD-CM), and white matter hyperintensities (WMH). We also investigated the association between serum UA and cognitive performance, and then assessed whether such an association is mediated by the brain pathologies.

Methods: A total of 430 non-demented older adults underwent comprehensive clinical assessments, measurement of serum UA level, and multimodal brain imaging, including Pittsburgh compound B-positron emission tomography (PET), AV-1451 PET, fluorodeoxyglucose (FDG)-PET, and magnetic resonance imaging scans. Mini-Mental State Examination (MMSE) and word list recall (WLR) test scores were used to measure cognitive performance.

Results: Serum UA level was significantly associated with AD-CM, but not with Aβ deposition, tau deposition, or WMH volume. Serum UA levels also had significant association with WLR and marginal association with MMSE; such associations disappeared when AD-CM was controlled as a covariate, indicating that AD-CM has a mediating effect.

Conclusion: The findings of the present study indicate that there is an association of low serum UA with AD-related cerebral hypometabolism, and whether this represents a causal relationship remains to be determined.
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http://dx.doi.org/10.3389/fnagi.2020.00160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291838PMC
June 2020

Multiparity, Brain Atrophy, and Cognitive Decline.

Front Aging Neurosci 2020 3;12:159. Epub 2020 Jun 3.

Department of Psychiatry, Seoul National University College of Medicine, Seoul, South Korea.

Background: Multiparity - grand multiparity (i.e., five or more childbirths) in particular - has been reported to have an association with increased risk of Alzheimer's disease (AD) dementia or related cognitive decline in women. However, the pathological links underlying this relationship are still unknown. This study was conducted to examine the relationships of multiparity with cerebral amyloid-beta (Aβ) deposition, brain atrophy, and white matter hyperintensities (WMHs).

Methods: In this study, total of 237 older women with 148 cognitively normal and 89 mild cognitive impairment from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease (KBASE) were included. Participants underwent clinical and neuropsychological assessments in addition to C-labeled Pittsburgh Compound B positron emission tomography, and magnetic resonance imaging. The associations of parity with Aβ deposition, hippocampal volume, cortical volume, WMH volume and mini-mental status examination (MMSE) score were examined.

Results: Participants with grand multiparity showed significantly reduced adjusted hippocampal volume, spatial pattern of atrophy for recognition of AD volume and spatial pattern of atrophy for recognition of brain aging volume even after controlling for potential confounders. Furthermore, MMSE score was also significantly lower in this group. In contrast, grand multiparity did not show any association with global Aβ retention, Aβ positivity rate, or WMH volume, regardless of covariates.

Conclusion: Our findings suggest that grand multiparity contributes to cognitive decline or increased dementia risk in older women by aggravating amyloid-independent hippocampal or cortical atrophy.
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http://dx.doi.org/10.3389/fnagi.2020.00159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291884PMC
June 2020

Sex-Specific Association of Lifetime Body Mass Index with Alzheimer's Disease Neuroimaging Biomarkers.

J Alzheimers Dis 2020 ;75(3):767-777

Institute of Human Behavioral Medicine, Medical Research Center, Seoul National University, Seoul, Republic of Korea.

Background: Although recent studies indicate that the relationship between body mass index (BMI) and Alzheimer's disease (AD) may differ by both sex and age of BMI measurement, little information is available on sex- or age-specific associations between BMI and AD neuropathologies.

Objective: To examined whether sex-specific BMIs measured at different life-stages (in early adulthood, midlife, and late life) were associated with cerebral amyloid-β (Aβ) deposition and AD-signature region cortical thickness (AD-CT) in cognitively normal (CN) older adults.

Methods: A total of 212 CN subjects aged 60-90 years (females 108, males 104), who participated in the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease (KBASE), an ongoing prospective cohort study, were included. All participants underwent comprehensive clinical and neuropsychological assessments, [11C] Pittsburgh Compound B positron emission tomography, and brain magnetic resonance imaging. BMIs at different life stages were calculated. Multiple regression analyses were performed separately for either sex.

Results: In males, lower early adulthood or midlife BMI was associated with greater cerebral Aβ deposition, but late life BMI was not. Lower midlife BMI was associated with reduced AD-CT, but the BMI in early adulthood and late life was not. In females, no significant association was observed between any lifetime BMI and Aβ deposition or AD-CT.

Conclusion: Our results support a male-specific association between BMI prior to late life, and in vivo AD pathologies. Avoiding underweight status early in life may be important to prevent AD dementia in males, but not females.
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http://dx.doi.org/10.3233/JAD-191216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369081PMC
May 2021

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

Medicine (Baltimore) 2020 Apr;99(16):e19620

Department of Neurology.

For the diagnosis of mild cognitive impairment (MCI) and Alzheimer disease (AD), variable neuroimaging and neuropsychological tests have been used. We aimed to evaluate the correlation of neuropsychological domain with new amyloid positron emission tomography (PET) study and to validate the availability of new PET tracer.We enrolled 20 patients who underwent C-PiB-PET/CT, new PET tracer F-FC119S PET/CT from November, 2014 to July, 2015. Among them, 10 patients were diagnosed with AD and 10 patients with MCI. The current version of Seoul Neuropsychological Screening Battery (SNSB) II was performed for cognitive evaluation. Each parameter of SNSB was compared between 2 patient groups. Spearman correlation analysis between value of SNSB domain and standardized uptake value ratio (SUVR) of PET was also performed.The AD group presented significant poor z-score in Korean-Boston Naming Test(K-BNT) (P = .01),copy score of Rey Complex Figure Test (RCFT) (P = .049), immediate (P = .028)and delayed memory of Seoul Verbal Learning Test (SVLT) (P = .028), recognition of RCFT (P = .004), "animal" of Controlled Oral Word Association Test (COWAT) (P = .041), color reading of Korean-Color Word Stroop test (K-CWST) (P = .014), and Digit Symbol Coding (DSC) (P = .007) compared with MCI group. That means, except attention domain, all other cognitive domains were relatively impaired in AD compared with MCI. In correlation analysis, we found that poor performances on copy score of RCFT in MCI groups were associated with great beta amyloid burden in frontal area in both C-PiB-PET/CT and F-FC119S PET/CT. In AD group, F-FC119S PET presented more extensive correlation in each cognitive domain with multiple cortical areas compared with C-PiB-PET.The degree of amyloid burden assessed on F-FC119S PET was significantly correlated with neuropsychological test in AD, and also MCI patients. The combination of neuropsychological evaluation with novel F-FC119S PET/CT can be used for valid biomarker for MCI and AD.
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http://dx.doi.org/10.1097/MD.0000000000019620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220040PMC
April 2020

Midlife Lifestyle Activities Moderate APOE ε4 Effect on Alzheimer's Disease Pathologies.

Front Aging Neurosci 2020 27;12:42. Epub 2020 Feb 27.

Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, South Korea.

This study aimed to investigate whether the midlife cognitive activity and physical activity moderate the relationship between apolipoprotein Eε4 (APOE4) and Alzheimer's disease (AD) pathologies. In total, 287 non-demented older adults (mean age 72 years) from the Korean Brain Aging Study for the Early diagnosis and prediction of Alzheimer's disease cohort were included. Participants underwent a comprehensive clinical assessment including the evaluation for midlife CA and physical activity, [C]-Pittsburgh-Compound-B-positron emission tomography (PET), [F]-fluorodeoxyglucose PET, structural magnetic resonance imaging (MRI), and APOE genotyping. We used linear regression and regression-based mediated-moderation models for statistical analyses. Neither midlife cognitive activity nor physical activity moderated the effect of APOE4 on β-amyloid (Aβ) retention itself. Midlife cognitive activity significantly moderated the effect of APOE4 on hippocampal volume [ (SE) = - 627.580 (252.327), = -2.488, = 0.014]: APOE4 carriers had smaller hippocampal volume than non-carriers at relatively high cognitive activity state ( = 0.004), but not at relatively low cognitive activity condition ( = 0.937). Midlife physical activity significantly moderated the effect of Aβ retention, which was closely related to APOE4, on AD-signature region cerebral glucose metabolism [AD-CM; (SE) = 0.004 (0.002), = 2.030, = 0.043]: higher Aβ accumulation was associated with lower AD-CM in relatively low physical activity condition ( < 0.001), whereas no such association was observed in relatively high physical activity state ( = 0.791). The findings suggest that high midlife cognitive activity may accelerate hippocampal atrophy induced by APOE4, whereas high midlife physical activity may delay AD-related cerebral hypometabolism by weakening the influence of APOE4-associated Aβ retention.
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http://dx.doi.org/10.3389/fnagi.2020.00042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093017PMC
February 2020

Association of moderate alcohol intake with in vivo amyloid-beta deposition in human brain: A cross-sectional study.

PLoS Med 2020 02 25;17(2):e1003022. Epub 2020 Feb 25.

Institute of Human Behavioral Medicine, Medical Research Center, Seoul National University, Seoul, Republic of Korea.

Background: An emerging body of literature has indicated that moderate alcohol intake may be protective against Alzheimer disease (AD) dementia. However, little information is available regarding whether moderate alcohol intake is related to reductions in amyloid-beta (Aβ) deposition, or is protective via amyloid-independent mechanisms in the living human brain. Here we examined the associations of moderate alcohol intake with in vivo AD pathologies, including cerebral Aβ deposition, neurodegeneration of AD-signature regions, and cerebral white matter hyperintensities (WMHs) in the living human brain.

Methods And Findings: The present study was part of the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease (KBASE), an ongoing prospective cohort study that started in 2014. As of November 2016, 414 community-dwelling individuals with neither dementia nor alcohol-related disorders (280 cognitively normal [CN] individuals and 134 individuals with mild cognitive impairment [MCI]) between 56 and 90 years of age (mean age 70.9 years ± standard deviation 7.8; male, n [%] = 180 [43.5]) were recruited from 4 sites (i.e., 2 university hospitals and 2 public centers for dementia prevention and management) around Seoul, South Korea. All the participants underwent comprehensive clinical assessments comprising lifetime and current histories of alcohol intake and multimodal brain imaging, including [11C] Pittsburgh compound B positron emission tomography (PET), [18F] fluorodeoxyglucose (FDG) PET, and magnetic resonance imaging (MRI) scans. Lifetime and current alcohol intake were categorized as follows: no drinking, <1 standard drink (SD)/week, 1-13 SDs/week, and 14+ SDs/week. A moderate lifetime alcohol intake (1-13 SDs/week) was significantly associated with a lower Aβ positivity rate compared to the no drinking group, even after controlling for potential confounders (odds ratio 0.341, 95% confidence interval 0.163-0.714, p = 0.004). In contrast, current alcohol intake was not associated with amyloid deposition. Additionally, alcohol intake was not related to neurodegeneration of AD-signature regions or cerebral WMH volume. The present study had some limitations in that it had a cross-sectional design and depended on retrospective recall for alcohol drinking history.

Conclusions: In this study, we observed in middle- and old-aged individuals with neither dementia nor alcohol-related disorders that moderate lifetime alcohol intake was associated with lower cerebral Aβ deposition compared to a lifetime history of not drinking. Moderate lifetime alcohol intake may have a beneficial influence on AD by reducing pathological amyloid deposition rather than amyloid-independent neurodegeneration or cerebrovascular injury.
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http://dx.doi.org/10.1371/journal.pmed.1003022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041799PMC
February 2020

Neuroticism, conscientiousness, and in vivo Alzheimer pathologies measured by amyloid PET and MRI.

Psychiatry Clin Neurosci 2020 May 23;74(5):303-310. Epub 2020 Feb 23.

Department of Psychiatry, Seoul National University College of Medicine, Seoul, Republic of Korea.

Aim: It has been suggested that personality traits, particularly neuroticism and conscientiousness, are risk factors for Alzheimer's disease (AD) and related cognitive decline. However, the underlying pathological links between personality traits and AD-related cognitive impairments remain unclear. Thus, the present study investigated associations of neuroticism and conscientiousness with in vivo cerebral amyloid-beta (Aβ) burden, AD-signature regional neurodegeneration, and white matter hyperintensities (WMH) in non-demented middle- and old-aged adults.

Methods: A total of 397 non-demented participants underwent comprehensive clinical and neuropsychological assessments, C-labeled Pittsburgh Compound B positron emission tomography, and magnetic resonance imaging. Additionally, the NEO Five-Factor Inventory was administered to both the participants and their informants to measure neuroticism and conscientiousness.

Results: Neither neuroticism nor conscientiousness was associated with cerebral Aβ deposition or WMH. In contrast, higher neuroticism and lower conscientiousness, reported by informants in particular, were significantly associated with reduced AD-signature region cortical thickness. In regards to the direct and indirect effect of each personality on AD-signature region cortical thickness, only the direct effects were found, whereas indirect effects via Aβ deposition or WMH were not.

Conclusion: The present findings suggest that amyloid-independent regional neurodegeneration might underlie relations of neuroticism and conscientiousness with AD.
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http://dx.doi.org/10.1111/pcn.12983DOI Listing
May 2020
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