Publications by authors named "Min Soo Byun"

89 Publications

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
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. 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
June 2021

Novel Alzheimer's disease risk variants identified based on whole-genome sequencing of APOE ε4 carriers.

Transl Psychiatry 2021 May 19;11(1):296. Epub 2021 May 19.

Clinical Genomics Center, Samsung Medical Center, Seoul, South Korea.

Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with a complex genetic etiology. Besides the apolipoprotein E ε4 (APOE ε4) allele, a few dozen other genetic loci associated with AD have been identified through genome-wide association studies (GWAS) conducted mainly in individuals of European ancestry. Recently, several GWAS performed in other ethnic groups have shown the importance of replicating studies that identify previously established risk loci and searching for novel risk loci. APOE-stratified GWAS have yielded novel AD risk loci that might be masked by, or be dependent on, APOE alleles. We performed whole-genome sequencing (WGS) on DNA from blood samples of 331 AD patients and 169 elderly controls of Korean ethnicity who were APOE ε4 carriers. Based on WGS data, we designed a customized AD chip (cAD chip) for further analysis on an independent set of 543 AD patients and 894 elderly controls of the same ethnicity, regardless of their APOE ε4 allele status. Combined analysis of WGS and cAD chip data revealed that SNPs rs1890078 (P = 6.64E-07) and rs12594991 (P = 2.03E-07) in SORCS1 and CHD2 genes, respectively, are novel genetic variants among APOE ε4 carriers in the Korean population. In addition, nine possible novel variants that were rare in individuals of European ancestry but common in East Asia were identified. This study demonstrates that APOE-stratified analysis is important for understanding the genetic background of AD in different populations.
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http://dx.doi.org/10.1038/s41398-021-01412-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134477PMC
May 2021

Validation of the Korean Version of the Anosognosia Questionnaire for Dementia.

Psychiatry Investig 2021 Apr 25;18(4):324-331. Epub 2021 Apr 25.

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

Objective: Anosognosia is a common phenomenon in individuals with dementia. Anosognosia Questionnaire for dementia (AQ-D) is a well-known scale for evaluating anosognosia. This study aimed to establish a Korean version of the AQ-D (AQ-D-K) and to evaluate the reliability and validity of the AQ-D-K in patients with Alzheimer's disease (AD) dementia.

Methods: We translated the original English version of AQ-D into Korean (AQ-D-K). Eighty-four subjects with very mild or mild AD dementia and their caregivers participated. Reliability of AQ-D-K was assessed by internal consistency and one-month test-retest reliability. Construct validity and concurrent validity were also evaluated.

Results: Internal consistencies of the AQ-D-K patient form and caregiver form were high (Cronbach alpha 0.95 and 0.93, respectively). The test-retest reliability of AQ-D-K measured by intra-class correlation coefficient was 0.84. Three factors were identified: 1) anosognosia of instrumental activity of daily living; 2) anosognosia basic activity of daily living; and 3) anosognosia of depression and disinhibition. AQ-D-K score was significantly correlated with the clinician-rated anosognosia rating scale (ARS), center for epidemiological studies-depression scale (CES-D) and state-trait anxiety inventory (STAI).

Conclusion: The findings suggest that the AQ-D-K is a reliable and valid scale for evaluating anosognosia for AD dementia patients using Korean language.
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http://dx.doi.org/10.30773/pi.2020.0364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103024PMC
April 2021

Functional Neural Correlates of the WAIS-IV Block Design Test in Older Adult with Mild Cognitive Impairment and Alzheimer's Disease.

Neuroscience 2021 05 15;463:197-203. Epub 2021 Apr 15.

Department of Neuropsychiatry, Seoul National University Hospital, Seoul, Republic of Korea; Institute of Human Behavioral Medicine, Medical Research Center Seoul National University, Seoul, Republic of Korea; Department of Psychiatry, Seoul National University College of Medicine, Seoul, Republic of Korea. Electronic address:

The Wechsler Adult intelligence scale-Revised (WAIS-R) Block design test (BDT) is a neuropsychological test widely used to assess cognitive declines in aging population. Previous studies suggest parietal lobe is the key region to influence the performance on the BDT; yet, it has not been clearly identified. The aim of the current study, therefore, is to identify the functional neural correlates of the BDT in older adults with mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia patients. The current study includes 213 cognitively impaired mid to old-aged community dwelling Korean. All participants underwent comprehensive clinical and neuropsychological assessments and 18F-fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) scans. Performance on the BDT was assessed using the WAIS-IV Korean version. Voxel-wise analyses were used to investigate the correlation between regional cerebral glucose metabolism and BDT performance. The same analyses were conducted on the subgroups categorized by clinical severity based on the Clinical Dementia Rating (CDR). Significant positive correlations between performance on the BDT and regional cerebral glucose metabolism were found bilaterally in the inferior parietal lobules, right thalamus and right middle frontal gyrus. Our results suggest that performance on the BDT in MCI and AD patients functionally relies on the brain regions known to be associated with motor and executive functions in addition to visuospatial function.
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http://dx.doi.org/10.1016/j.neuroscience.2021.04.001DOI Listing
May 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
January 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 May 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 Jan 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

A logical network-based drug-screening platform for Alzheimer's disease representing pathological features of human brain organoids.

Nat Commun 2021 01 12;12(1):280. Epub 2021 Jan 12.

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

Developing effective drugs for Alzheimer's disease (AD), the most common cause of dementia, has been difficult because of complicated pathogenesis. Here, we report an efficient, network-based drug-screening platform developed by integrating mathematical modeling and the pathological features of AD with human iPSC-derived cerebral organoids (iCOs), including CRISPR-Cas9-edited isogenic lines. We use 1300 organoids from 11 participants to build a high-content screening (HCS) system and test blood-brain barrier-permeable FDA-approved drugs. Our study provides a strategy for precision medicine through the convergence of mathematical modeling and a miniature pathological brain model using iCOs.
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http://dx.doi.org/10.1038/s41467-020-20440-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804132PMC
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

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

Long-Term Exposure to PM10 and in vivo Alzheimer's Disease Pathologies.

J Alzheimers Dis 2020 ;78(2):745-756

Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul, Republic of Korea.

Background: Previous studies indicated an association between Alzheimer's disease (AD) dementia and air particulate matter (PM) with aerodynamic diameter <10μm (PM10), as well as smaller PM. Limited information, however, is available for the neuropathological links underlying such association.

Objective: This study aimed to investigate the relationship between long-term PM10 exposure and in vivo pathologies of AD using multimodal neuroimaging.

Methods: The study population consisted of 309 older adults without dementia (191 cognitively normal and 118 mild cognitive impairment individuals), who lived in Republic of Korea. Participants underwent comprehensive clinical assessments, 11C-Pittsburg compound B (PiB) positron emission tomography (PET), and magnetic resonance imaging scans. A subset of 78 participants also underwent 18F-AV-1451 tau PET evaluation. The mean concentration of PM with aerodynamic diameter <10μm over the past 5 years (PM10mean) collected from air pollution surveillance stations were matched to each participant's residence.

Results: In this non-demented study population, of which 62% were cognitively normal and 38% were in mild cognitive impairment state, exposure to the highest tertile of PM10mean was associated with increased risk of amyloid-β (Aβ) positivity (odds ratio 2.19, 95% confidence interval 1.13 to 4.26) even after controlling all potential confounders. In contrast, there was no significant associations between PM10mean exposure and tau accumulation. AD signature cortical thickness and white matter hyperintensity volume were also not associated with PM10mean exposure.

Conclusion: The findings suggest that long-term exposure to PM10 may contribute to pathological Aβ deposition.
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http://dx.doi.org/10.3233/JAD-200694DOI Listing
May 2021

Regional Quantitative Magnetic Resonance Imaging Data Improve Screening Accuracy of Subjective Memory Complaints and Informant Reports of Cognitive Decline.

Psychiatry Investig 2020 Sep 17;17(9):851-857. Epub 2020 Sep 17.

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

Objective: We investigated whether the addition of Alzheimer's disease-signature region cortical thickness (AD-Ct) and hippocampal volume (Hv) obtained from brain MRI to subjective memory complaints and informant-reports of cognitive decline enhances the screening accuracy for cognitive disorders in a memory clinic setting.

Methods: 120 participants (40 cognitively normal, 40 MCI, 40 dementia) underwent clinical evaluation, neuropsychological assessment, and brain MRI. The Subjective Memory Complaints Questionnaire (SMCQ) and Seoul Informant-Report Questionnaire for Dementia (SIRQD) were applied to assess subjective memory complaints and informant-reports of cognitive decline respectively. Logistic regression and ROC curve analyses were conducted to compare the screening abilities of SMCQ+SIRQD, SMCQ+SIRQD+Hv, and SMCQ+SIRQD+AD-Ct models for cognitive disorders.

Results: SMCQ+SIRQD+Hv model indicated better screening accuracy for MCI and overall cognitive disorder (CDall) than SMCQ+ SIRQD model. SMCQ+SIRQD+AD-Ct model had superior screening accuracy for dementia in comparison to SMCQ+SIRQD model. ROC curve analyses revealed that SMCQ+SIRQD+Hv model had the greatest area under the curve (AUC) for screening MCI and CDall (AUC: 0.941 and 0.957), while SMCQ+SIRQD+AD-Ct model had the greatest AUC for screening dementia (AUC: 0.966).

Conclusion: Our results suggest that the addition of regional quantitative MRI data enhances the screening ability of subjective memory complaints and informant-reports of cognitive decline for MCI and dementia.
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http://dx.doi.org/10.30773/pi.2020.0323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538245PMC
September 2020

Decreased Alpha Reactivity from Eyes-Closed to Eyes-Open in Non-Demented Older Adults with Alzheimer's Disease: A Combined EEG and [18F]florbetaben PET Study.

J Alzheimers Dis 2020 ;77(4):1681-1692

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

Background: The degree of alpha attenuation from eyes-closed (EC) to eyes-open (EO) has been suggested as a neural marker of cognitive health, and its disruption has been reported in patients with clinically defined Alzheimer's disease (AD) dementia.

Objective: We tested if EC-to-EO alpha reactivity was related to cerebral amyloid-β (Aβ) deposition during the early stage of AD.

Methods: Non-demented participants aged ≥55 years who visited the memory clinic between March 2018 and June 2019 (N = 143; 67.8% female; mean age±standard deviation, 74.0±7.6 years) were included in the analyses. Based on the [18F]florbetaben positron emission tomography assessment, the participants were divided into Aβ+ (N = 70) and Aβ- (N = 73) groups. EEG was recorded during the 7 min EC condition followed by a 3 min EO phase, and a Fourier transform spectral analysis was performed.

Results: A significant three-way interaction was detected among Aβ positivity, eye condition, and the laterality factor on alpha-band power after adjusting for age, sex, educational years, global cognition, depression, medication use, and white matter hyperintensities on magnetic resonance imaging (F = 5.987, p = 0.016); EC-to-EO alpha reactivity in the left hemisphere was significantly reduced in Aβ+ subjects without dementia compared with the others (F = 3.984, p = 0.048).

Conclusion: Among mild cognitive impairment subjects, alpha reactivity additively contributed to predict cerebral Aβ positivity beyond the clinical predictors, including vascular risks, impaired memory function, and apolipoprotein E ɛ4. These findings support that EC-to-EO alpha reactivity acts as an early biomarker of cerebral Aβ deposition and is a useful measurement for screening early-stage AD.
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http://dx.doi.org/10.3233/JAD-200442DOI Listing
January 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

Comparison of Amyloid Positivity Rate and Accumulation Pattern between Amnestic and Non-Amnestic Type Mild Cognitive Impairment.

Psychiatry Investig 2020 Jun 11;17(6):603-607. Epub 2020 Jun 11.

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

Objective: We aimed to compare cerebral beta-amyloid protein (Aβ) positivity rate and amyloid accumulation pattern on amyloid positron emission tomography (PET) between mild cognitive impairment (MCI) subtypes, i.e. amnestic mild cognitive impairment (aMCI) and non-amnestic mild cognitive impairment (naMCI).

Methods: The study participants were 34 naMCI patients and age-, sex- and education-matched 68 aMCI patients (1:2 ratio) who visited the Dementia and Age-Associated Cognitive Decline Clinic of the Seoul National University Hospital. All participants received comprehensive clinical and neuropsychological assessments and [F] florbetaben PET.

Results: Aβ positivity rate of naMCI group (26.5%) was significantly lower than that of aMCI group (64.7%). Among Aβ positive individuals, there was no difference in Aβ accumulation pattern between naMCI and aMCI.

Conclusion: The findings suggest that MCI subtypes based on impaired cognitive domains have a differential association with brain Aβ deposition, a core pathology of AD. Amnestic subtype of MCI are more closely associated with cerebral Aβ deposition compared to nonamnestic subtype. In contrast, the pattern of amyloid deposition does not appear to have any difference between the subtypes.
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http://dx.doi.org/10.30773/pi.2020.0063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324742PMC
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

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

Resting State Glucose Utilization and Adult Reading Test Performance.

Front Aging Neurosci 2020 5;12:48. Epub 2020 Mar 5.

Interdisciplinary Program of Cognitive Science, Seoul National University, Seoul, South Korea.

Adult reading tests (ART) have been widely used in both research and clinical settings as a measure of premorbid cognitive abilities or cognitive reserve. However, the neural substrates underlying ART performance are largely unknown. Furthermore, it has not yet been examined whether the neural substrates of ART performance reflect the cortical regions associated with premorbid intelligence or cognitive reserve. The aim of the study is to identify the functional neural correlates of ART performance using 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging in the cognitively normal (CN) middle- and old-aged adults. Voxel-wise analyses revealed positive correlations between glucose metabolism and ART performance in the frontal and primary somatosensory regions, more specifically the lateral frontal cortex, anterior cingulate cortex and postcentral gyrus (PCG). When conducted again only for amyloid-β (Aβ)-negative individuals, the voxel-wise analysis showed significant correlations in broader areas of the frontal and primary somatosensory regions. This is the first neuroimaging study to directly demonstrate the cerebral resting-state glucose utilization associated with ART performance. Our findings provide important evidence at the neural level that ART predicts premorbid general intelligence and cognitive reserve, as brain areas that showed significant correlations with ART performance correspond to regions that have been associated with general intelligence and cognitive reserve.
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http://dx.doi.org/10.3389/fnagi.2020.00048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066080PMC
March 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

Deep proteome profiling of the hippocampus in the 5XFAD mouse model reveals biological process alterations and a novel biomarker of Alzheimer's disease.

Exp Mol Med 2019 11 15;51(11):1-17. Epub 2019 Nov 15.

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

Alzheimer's disease (AD), which is the most common type of dementia, is characterized by the deposition of extracellular amyloid plaques. To understand the pathophysiology of the AD brain, the assessment of global proteomic dynamics is required. Since the hippocampus is a major region affected in the AD brain, we performed hippocampal analysis and identified proteins that are differentially expressed between wild-type and 5XFAD model mice via LC-MS methods. To reveal the relationship between proteomic changes and the progression of amyloid plaque deposition in the hippocampus, we analyzed the hippocampal proteome at two ages (5 and 10 months). We identified 9,313 total proteins and 1411 differentially expressed proteins (DEPs) in 5- and 10-month-old wild-type and 5XFAD mice. We designated a group of proteins showing the same pattern of changes as amyloid beta (Aβ) as the Aβ-responsive proteome. In addition, we examined potential biomarkers by investigating secretory proteins from the Aβ-responsive proteome. Consequently, we identified vitamin K-dependent protein S (PROS1) as a novel microglia-derived biomarker candidate in the hippocampus of 5XFAD mice. Moreover, we confirmed that the PROS1 level in the serum of 5XFAD mice increases as the disease progresses. An increase in PROS1 is also observed in the sera of AD patients and shows a close correlation with AD neuroimaging markers in humans. Therefore, our quantitative proteome data obtained from 5XFAD model mice successfully predicted AD-related biological alterations and suggested a novel protein biomarker for AD.
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http://dx.doi.org/10.1038/s12276-019-0326-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856180PMC
November 2019

Normative Data for the Logical Memory Subtest of the Wechsler Memory Scale-IV in Middle-Aged and Elderly Korean People.

Psychiatry Investig 2019 Nov 28;16(11):793-799. Epub 2019 Oct 28.

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

Objective: The purpose of this study is to identify the demographic variables that are affecting performances on the Logical Memory (LM) subtest included in the Korean version of the Wechsler Memory Scale (WMS)-IV and to provide normative data on the LM subtest for the middle-age and elderly Korean people.

Methods: The participants were 435 non-demented adults aging from 50 to 90 and with the educational level ranging from 0 to 21 years.

Results: Age and education were found to be significantly associated with performance on the LM subtest, while gender effect was not statistically significant. Therefore, we stratified the norm blocks by age and education. Age was divided into three groups: 50-59, 60-74, and 75-90 years. Education was stratified into three groups: 0-8 years, 9-12 years, and 13 years or more.

Conclusion: The normative data provided in the current study are expected to be useful in clinical and research settings to detect or define subtle changes in episodic memory in Korean adults and elderly, and can also be used for cross-cultural comparison of verbal episodic memory performance among elderly populations using different languages.
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http://dx.doi.org/10.30773/pi.2019.0061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877463PMC
November 2019

Coffee intake and decreased amyloid pathology in human brain.

Transl Psychiatry 2019 10 22;9(1):270. Epub 2019 Oct 22.

Institute of Human Behavioral Medicine, Medical Research Center Seoul National University, Seoul, 03080, Republic of Korea.

Several epidemiological and preclinical studies supported the protective effect of coffee on Alzheimer's disease (AD). However, it is still unknown whether coffee is specifically related with reduced brain AD pathologies in human. Hence, this study aims to investigate relationships between coffee intake and in vivo AD pathologies, including cerebral beta-amyloid (Aβ) deposition, the neurodegeneration of AD-signature regions, and cerebral white matter hyperintensities (WMH). A total of 411 non-demented older adults were included. Participants underwent comprehensive clinical assessment and multimodal neuroimaging including [C] Pittsburgh compound B-positron emission tomography (PET), [F] fluorodeoxyglucose PET, and magnetic resonance imaging scans. Lifetime and current coffee intake were categorized as follows: no coffee or <2 cups/day (reference category) and ≥2 cups/day (higher coffee intake). Lifetime coffee intake of ≥2 cups/day was significantly associated with a lower Aβ positivity compared to coffee intake of <2 cups/day, even after controlling for potential confounders. In contrast, neither lifetime nor current coffee intake was not related to hypometabolism, atrophy of AD-signature region, and WMH volume. The findings suggest that higher lifetime coffee intake may contribute to lowering the risk of AD or related cognitive decline by reducing pathological cerebral amyloid deposition.
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http://dx.doi.org/10.1038/s41398-019-0604-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805864PMC
October 2019