Publications by authors named "Dong Young Lee"

216 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

A 9-Year Comparison of Dementia Prevalence in Korea: Results of NaSDEK 2008 and 2017.

J Alzheimers Dis 2021 ;81(2):821-831

Department of Psychiatry, Gachon University, School of Medicine, Incheon, Korea.

Background: In many high-income Western countries, the prevalence of dementia had been reduced over the past decades.

Objective: We investigated whether the prevalence of all-cause dementia, Alzheimer's disease, vascular dementia, and mild cognitive impairment (MCI) had changed in Korea from 2008 to 2017.

Methods: Nationwide Survey on Dementia Epidemiology of Korea (NaSDEK) in 2008 and 2017 was conducted on representative elderly populations that were randomly sampled across South Korea. Both surveys employed a two-stage design (screening and diagnostic phases) and diagnosed dementia and MCI according to the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders and the consensus criteria from the International Working Group, respectively. The numbers of participants aged 65 years or older in the screening and diagnostic phases were 6,141 and 1,673 in the NaSDEK 2008 and 2,972 and 474 in the NaSDEK 2017, respectively.

Results: The age- and sex-standardized prevalence of all-cause dementia and Alzheimer's disease showed nonsignificant decrease (12.3% to 9.8%, odds ratio [OR] = 0.89, 95% confidence interval [CI] = 0.54-1.48 for all-cause dementia; 7.6% to 6.8%, OR [95% CI] = 0.91 [0.58-1.42] for Alzheimer's disease). Vascular dementia decreased in the young-old population aged less than 75 years (2.7% to 0.001%, OR [95% CI] = 0.04 [0.01-0.15]) and in women (1.9% to 0.5%, OR [95% CI] = 0.27 [0.10-0.72]) while MCI remained stable (25.3% to 26.2%, OR [95% CI] = 1.08 [0.67-1.73]).

Conclusion: We found that the prevalence of dementia in Korea showed a nonsignificant decrease between 2008 and 2017.
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http://dx.doi.org/10.3233/JAD-201588DOI Listing
January 2021

Dual Sensory Impairment and Cognitive Impairment in the Korean Longitudinal Elderly Cohort.

Neurology 2021 05 7;96(18):e2284-e2295. Epub 2021 Apr 7.

From the Departments of Psychiatry (G.B., J.H.J.) and Neurology (J.-W.J.), Kangwon National University Hospital, Chuncheon; Public Health Medical Service (G.H.O.) and Department of Neuropsychiatry (D.Y.L.), Seoul National University Hospital; Department of Neuropsychiatry (J.B.B., J.W.H., K.W.K.), Seoul National University Bundang Hospital, Seongnam; Department of Psychiatry (T.H.K.), Yonsei University Wonju Severance Christian Hospital; Department of Psychiatry (K.P.K.), Dongguk University Gyeonju Hospital; Department of Psychiatry (B.J.K.), Gyeongsang National University School of Medicine, Jinju; Department of Neuropsychiatry (S.G.K.), Soonchunhyang University Bucheon Hospital; Department of Psychiatry, School of Medicine (J.L.K.), Chungnam National University, Daejeon; Department of Psychiatry, School of Medicine (S.W.M., S.-H.R.), Konkuk University, Konkuk University Chungju Hospital; Department of Neuropsychiatry (J.H.P.), Jeju National University Hospital; Department of Neuropsychiatry (J.C.Y.), Kyunggi Provincial Hospital for the Elderly, Yongin; Department of Neuropsychiatry (D.W.L.), Inje University Sanggye Paik Hospital, Seoul; Department of Psychiatry (S.B.L., J.J.L.), Dankook University Hospital, Cheonan; and Department of Psychiatry, College of Medicine (D.Y.L., K.W.K.), and Department of Brain and Cognitive Science, College of Natural Sciences (K.W.K.), Seoul, Korea.

Objective: To investigate the effects of single sensory impairment (SSI; visual or auditory) or dual sensory impairment (DSI; visual and auditory) on dementia and longitudinal changes of neuropsychological test scores.

Methods: In this nationwide, prospective, community-based elderly cohort study, KLOSCAD (the Korean Longitudinal Study on Cognitive Aging and Dementia), 6,520 elderly individuals (58-101 years) representing the general population were included. We defined visual and auditory sensory impairment via self-report questionnaire: 932 had normal sensory function, 2,957 had an SSI, and 2,631 had a DSI. Demographic and clinical variables including cognitive outcomes were evaluated every 2 years over 6 years. Through logistic regression, Cox regression, and linear mixed model analysis, the relationship between SSI or DSI and dementia prevalence, dementia incidence, and change in neuropsychological scores were evaluated.

Results: At baseline, DSI was significantly associated with increased dementia prevalence compared to normal sensory function (odds ratio [OR] 2.17, 95% confidence interval [CI] 1.17-4.02), but SSI was not (OR 1.27, 95% CI 0.66-2.41). During the 6-year follow-up, the incidence of dementia was significantly higher in the DSI group than in the normal sensory function group (hazard ratio 1.9, 95% CI 1.04-3.46) and neuropsychological scores significantly decreased (β -0.87, 95% CI [-1.17 to -0.58]).

Conclusions: Our results suggest that coexisting visual and hearing impairments facilitate dementia prevalence, dementia incidence, and cognitive decline, but visual or hearing impairment alone do not. Visual and hearing impairment may lead to dementia or cognitive decline independent of Alzheimer pathology.
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http://dx.doi.org/10.1212/WNL.0000000000011845DOI 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

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

Aberrant role of ALK in tau proteinopathy through autophagosomal dysregulation.

Mol Psychiatry 2021 Jan 15. Epub 2021 Jan 15.

School of Biological Science, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea.

Proteinopathy in neurodegenerative diseases is typically characterized by deteriorating activity of specific protein aggregates. In tauopathies, including Alzheimer's disease (AD), tau protein abnormally accumulates and induces dysfunction of the affected neurons. Despite active identification of tau modifications responsible for tau aggregation, a critical modulator inducing tau proteinopathy by affecting its protein degradation flux is not known. Here, we report that anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase, is crucial for the tau-mediated AD pathology. ALK caused abnormal accumulation of highly phosphorylated tau in the somatodendritic region of neurons through its tyrosine kinase activity. ALK-induced LC3-positive axon swelling and loss of spine density, leading to tau-dependent neuronal degeneration. Notably, ALK activation in neurons impaired Stx17-dependent autophagosome maturation and this defect was reversed by a dominant-negative Grb2. In a Drosophila melanogaster model, transgenic flies neuronally expressing active Drosophila Alk exhibited the aggravated tau rough eye phenotype with retinal degeneration and shortened lifespan. In contrast, expression of kinase-dead Alk blocked these phenotypes. Consistent with the previous RNAseq analysis showing upregulation of ALK expression in AD [1], ALK levels were significantly elevated in the brains of AD patients showing autophagosomal defects. Injection of an ALK.Fc-lentivirus exacerbated memory impairment in 3xTg-AD mice. Conversely, pharmacologic inhibition of ALK activity with inhibitors reversed the memory impairment and tau accumulation in both 3xTg-AD and tauC3 (caspase-cleaved tau) transgenic mice. Together, we propose that aberrantly activated ALK is a bona fide mediator of tau proteinopathy that disrupts autophagosome maturation and causes tau accumulation and aggregation, leading to neuronal dysfunction in AD.
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http://dx.doi.org/10.1038/s41380-020-01003-yDOI Listing
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

Plasma Endocan as a Predictor of Cardiovascular Event in Patients with End-Stage Renal Disease on Hemodialysis.

J Clin Med 2020 Dec 18;9(12). Epub 2020 Dec 18.

Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul 02453, Korea.

Endocan, a potential biomarker of endothelial dysfunction, is associated with increased cardiovascular risk. We investigated the utility of plasma endocan for predicting cardiovascular risk in end-stage renal disease (ESRD) patients undergoing hemodialysis. Of the 452 patients in the K-cohort, 354 with available plasma endocan levels were enrolled. The correlation between plasma endocan levels and the clinical characteristics of a study population were analyzed. We divided patients into two groups, according to plasma endocan levels, and investigated the predictive value of endocan for the occurrence of cardiovascular events. In a multiple linear regression analysis, plasma endocan levels were positively correlated with previous cardiovascular events and negatively correlated with body mass index, albumin, and triglyceride. Patients with higher plasma endocan levels experienced more frequent cardiovascular events than those with lower plasma endocan levels (12.9% in the lower group vs. 22.7% in the higher group, = 0.016). Cox proportional hazard models showed that higher plasma endocan levels were an independent predictor of cardiovascular events in ESRD patients on hemodialysis ((hazard ration) HR 1.949, 95% (confidence interval) CI 1.144-3.319, = 0.014). Our results suggest that plasma endocan level might be a useful biomarker for predicting cardiovascular events in ESRD patients on hemodialysis.
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http://dx.doi.org/10.3390/jcm9124086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766985PMC
December 2020

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

Chronic subsyndromal depression and risk of dementia in older adults.

Aust N Z J Psychiatry 2020 Nov 16:4867420972763. Epub 2020 Nov 16.

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

Objectives: Subsyndromal depression is prevalent and associated with poor outcomes in late life, but its effect on the risk of dementia has barely been investigated. This study is aimed to investigate the effect of subsyndromal depression on dementia risk in cognitively normal older adults and patients with mild cognitive impairment.

Methods: Data were collected from a nationwide, population-based, prospective cohort study on a randomly sampled Korean elderly population aged 60 years or older, which has been followed every 2 years. Using 6-year follow-up data of 4456 non-demented elderly, the authors examined the risk of dementia associated with late-onset subsyndromal depression using multivariate Cox proportional hazard models. After standardized diagnostic interviews, subsyndromal depression and dementia were diagnosed by the operational diagnostic criteria and , 4th edition criteria, respectively.

Results: Subsyndromal depression tripled the risk of dementia in non-demented elderly individuals (hazard ratio = 3.02, 95% confidence interval = [1.56, 5.85],  < 0.001). In subgroup analyses, subsyndromal depression was associated with the risk of dementia in cognitively normal participants only (hazard ratio = 4.59, 95% confidence interval = [1.20, 17.54],  = 0.026); chronic/recurrent subsyndromal depression with increasing severity during the follow-up period was associated with the risk of dementia (hazard ratio = 15.34, 95% confidence interval = [4.19, 56.18],  < 0.001).

Conclusion: Late-onset subsyndromal depression is a potential predictor of incident dementia when it is chronic or recurrent with increasing severity in cognitively normal older adults.
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http://dx.doi.org/10.1177/0004867420972763DOI Listing
November 2020

Sex differences in subjective age-associated changes in sleep: a prospective elderly cohort study.

Aging (Albany NY) 2020 11 7;12(21):21942-21958. Epub 2020 Nov 7.

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

Subjective age-associated changes in sleep (AACS) and sex differences in AACS have never been prospectively investigated in elderly populations. We compared the AACS every 2 years over a total of 6 years between 4,686 community-dwelling healthy men and women aged 60 years or older who participated in the Korean Longitudinal Study on Cognitive Aging and Dementia. Sleep parameters including sleep duration, latency, and efficiency, mid-sleep time, daytime dysfunction, and overall subjective sleep quality were measured using the Pittsburgh Sleep Quality Index at baseline and at each follow-up. The effects of time and sex on subjective sleep parameters were analyzed using linear mixed-effects models. During the 6 years of follow-up, we observed that overall, sleep latency increased, while daytime dysfunction and sleep quality worsened. Significant sex differences in AACS was found, with women showing shortened sleep duration, delayed mid-sleep time, and decreased sleep efficiency over 6 years. Sleep quality worsened in both groups but a more pronounced change was observed in women. Clinicians should be cautious in determining when to treat declared sleep disturbances in this population.
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http://dx.doi.org/10.18632/aging.104016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695390PMC
November 2020

Olanzapine-induced Concurrent Tardive Dystonia and Tardive Dyskinesia in Schizophrenia with Intellectual Disability: A Case Report.

Clin Psychopharmacol Neurosci 2020 Nov;18(4):627-630

Department of Neuropsychiatry, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, Korea.

Tardive dystonia and tardive dyskinesia (TDs) are rare extrapyramidal side effects that develop after long-term use of antipsychotics, but they are different syndromes and rarely occur at the same time. Olanzapine is an atypical antipsychotic drug associated with a low risk of extrapyramidal side effects in schizophrenia, but its associations with tardive movements are not clear. We present a case of a 19-year-old Asian female patient with schizophrenia and intellectual disabilities who developed concurrent TDs after long-term use of olanzapine. At her 10-month follow-up examination, her concurrent TDs had been treated successfully with clozapine. This case demonstrates that although the use of olanzapine to treat psychosis and behavioral disturbances is increasing due to its high efficacy and low rate of extrapyramidal side effects, concurrent TDs should be carefully assessed after long-term use of this antipsychotic, especially in patients with schizophrenia and intellectual disabilities. Clozapine, by preventing or reversing the debilitating consequences of concurrent TDs, may be an effective treatment for these patients.
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http://dx.doi.org/10.9758/cpn.2020.18.4.627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609210PMC
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

Visual interpretation of [F]Florbetaben PET supported by deep learning-based estimation of amyloid burden.

Eur J Nucl Med Mol Imaging 2021 04 29;48(4):1116-1123. Epub 2020 Sep 29.

Department of Nuclear Medicine, Seoul National University Hospital, Seoul, Republic of Korea.

Purpose: Amyloid PET which has been widely used for noninvasive assessment of cortical amyloid burden is visually interpreted in the clinical setting. As a fast and easy-to-use visual interpretation support system, we analyze whether the deep learning-based end-to-end estimation of amyloid burden improves inter-reader agreement as well as the confidence of the visual reading.

Methods: A total of 121 clinical routines [F]Florbetaben PET images were collected for the randomized blind-reader study. The amyloid PET images were visually interpreted by three experts independently blind to other information. The readers qualitatively interpreted images without quantification at the first reading session. After more than 2-week interval, the readers additionally interpreted images with the quantification results provided by the deep learning system. The qualitative assessment was based on a 3-point BAPL score (1: no amyloid load, 2: minor amyloid load, and 3: significant amyloid load). The confidence score for each session was evaluated by a 3-point score (0: ambiguous, 1: probably, and 2: definite to decide).

Results: Inter-reader agreements for the visual reading based on a 3-point scale (BAPL score) calculated by Fleiss kappa coefficients were 0.46 and 0.76 for the visual reading without and with the deep learning system, respectively. For the two reading sessions, the confidence score of visual reading was improved at the visual reading session with the output (1.27 ± 0.078 for visual reading-only session vs. 1.66 ± 0.63 for a visual reading session with the deep learning system).

Conclusion: Our results highlight the impact of deep learning-based one-step amyloid burden estimation system on inter-reader agreement and confidence of reading when applied to clinical routine amyloid PET reading.
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http://dx.doi.org/10.1007/s00259-020-05044-xDOI Listing
April 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

Associations between Cell-Free Mitochondrial DNA and Inflammation, and Their Clinical Implications for Patients on Hemodialysis: A Prospective Multicenter Cohort Study.

Blood Purif 2021 28;50(2):214-221. Epub 2020 Aug 28.

Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Republic of Korea,

Background: Cell-free mitochondrial DNA (cf-mtDNA) has recently been in the spotlight as an endogenously produced danger molecule that can potentially elicit inflammation. However, its clinical and prognostic implications are uncertain in patients undergoing hemodialysis.

Methods: We examined the association of baseline cf-mtDNA categorized as tertiles with health-related quality of life (HRQOL), inflammatory cytokines, and mortality in a multicenter prospective cohort of 334 patients on hemodialysis. To better understand cf-mtDNA-mediated inflammation, we measured cytokine production after in vitro stimulation of bone marrow-derived macrophages (BMDMs) with mtDNA.

Results: The higher cf-mtDNA tertile had a longer dialysis vintage, a greater comorbidity burden, and increased levels of inflammatory markers, including high-sensitivity-C-reactive protein, tumor necrosis factor-alpha, CXCL16, and osteoprotegerin. In particular, mtDNA augmented inflammatory cytokine release from BMDMs by lipopolysaccharide, the levels of which are reported to be increased in hemodialysis patients. Although the patients with higher levels of cf-mtDNA generally had lower (poorer) scores for HRQOL, cf-mtDNA was not associated with all-cause mortality in hemodialysis patients.

Conclusion: cf-mtDNA was correlated with poor clinical status and modestly associated with impaired quality of life in patients on hemodialysis. In proinflammatory milieu in end-stage renal disease, these associations may be attributed to the boosting effects of cf-mtDNA on inflammation.
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http://dx.doi.org/10.1159/000510088DOI Listing
August 2020

Online Clinical Consensus Diagnosis of Dementia: Development and Validation.

J Am Geriatr Soc 2020 08;68 Suppl 3:S54-S59

Department of Geriatric Medicine, All India Institute of Medical Sciences, New Delhi, India.

Objectives: To introduce cost-effective expert clinical diagnoses of dementia into population-based research using an online platform and to demonstrate their validity against in-person clinical assessment and diagnosis.

Design: The online platform provides standardized data necessary for clinicians to rate participants on the Clinical Dementia Rating (CDR ). Using this platform, clinicians diagnosed 60 patients at a range of CDR levels at two clinical sites. The online consensus diagnosis was compared with in-person clinical consensus diagnosis.

Setting: All India Institute of Medical Sciences (AIIMS), Delhi, and National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, India.

Participants: Thirty patients each at AIIMS and NIMHANS with equal numbers of patients previously independently rated in person by experts as CDR is 0 (cognitively normal), CDR is 0.5 (mild cognitive impairment), and CDR is 1 or greater (dementia).

Measurements: Multiple clinicians independently rate each participant on each CDR domain using standardized data and expert clinical judgment. The overall summary CDR is calculated by algorithm. When there are discrepancies among clinician ratings, clinicians discuss the case through a virtual consensus conference and arrive at a consensus overall rating.

Results: Online clinical consensus diagnosis based on standardized interview data provides consistent clinical diagnosis with in-person clinical assessment and consensus diagnosis (κ coefficient = 0.76).

Conclusion: A web-based clinical consensus platform built on the Harmonized Diagnostic Assessment of Dementia for the Longitudinal Aging Study in India interview data is a cost-effective way to obtain reliable expert clinical judgments. A similar approach can be used for other epidemiological studies of dementia. J Am Geriatr Soc 68:S54-S59, 2020.
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http://dx.doi.org/10.1111/jgs.16736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513553PMC
August 2020

MMSE Subscale Scores as Useful Predictors of AD Conversion in Mild Cognitive Impairment.

Neuropsychiatr Dis Treat 2020 24;16:1767-1775. Epub 2020 Jul 24.

Department of Neuropsychiatry, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, Gyeonggi, Republic of Korea.

Purpose: This study was performed to examine the usefulness of subscores on the Mini-Mental State Examination (MMSE) for predicting the progression of Alzheimer's disease (AD) dementia in individuals with mild cognitive impairment (MCI).

Patients And Methods: A total of 306 MCI individuals in the Alzheimer's Disease Neuroimaging Initiative database were included in the study. Standardized clinical and neuropsychological tests were performed at baseline and at 2-year follow-up. Logistic regression analysis was conducted to examine the MMSE total and subscale scores to predict progression to AD dementia in MCI individuals.

Results: The MMSE total score and the MMSE memory, orientation, and construction subscores were inversely associated with AD progression after controlling for all potential confounders; MMSE attention and language subscores were not correlated with AD progression. The MMSE delayed recall score among the MMSE memory subscores and the MMSE time score among the orientation subscores, especially week and day, were inversely associated with AD progression; the MMSE immediate recall and place scores were not correlated with progression.

Conclusion: Our findings suggest that the MMSE memory, orientation, and construction subscores, which are simple and readily available clinical measures, could provide useful information to predict AD dementia progression in MCI individuals in practical clinical settings.
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http://dx.doi.org/10.2147/NDT.S263702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399468PMC
July 2020