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This paper examines the feasibility of extracting useful information from customer comments using a Naïve Bayes classifier. This was done for a database, obtained from a large Korean mobile telephone service provider, of 533 customer calls to call centers in 2009. After eliminating calls not containing customer complaints or comments, the remaining 383 comments were classified by an expert panel into four domains and 27 complaint categories. The four domains were Transaction-related (189 comments, 49%), Product-related (120 comments, 31%), Customer Service or Support-related (38 comments, 10%) and Customer Outreach and Marketing-related (36 comments, 9%). The comments were then randomly assigned to either a training set (257 cases, 67%) or test set (126 cases, 33%). The training set was used to develop a Naïve Bayes classifier that correctly predicted the domain 75% of the time and the specific subcategory 51% of the time for the test set. Prediction accuracy was strongly related to prediction strength for both sets of predictions, suggesting that simple filtering strategies where difficult to understand comments are flagged for expert review and easy comments are automatically classified are both technically feasible and likely to be practically valuable. Several strong predictors were also identified that corresponded to categories more detailed than those originally assigned. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Vacuolar H+-ATPases (V-ATPases) are ATP-dependent proton pumps localized at membranes of intracellular acidic organelles and plasma membranes of various cell types. By virtue of its regulation in acidification, V-ATPase is required for many intracellular processes such as receptor-mediated endocytosis and protein sorting. Here we report the molecular characterization of the E subunit of V-ATPase in Caenorhabditis elegans. This subunit is one of the most well conserved subunits sharing approximately 57% identity with the human homologue, ATP6E. Green fluorescent protein (GFP) and whole-mount immunostaining analyses showed that V-ATPase E subunit (vha-8) is abundantly expressed in the H-shaped excretory cell, consistent with the expression patterns observed for other V-ATPase subunits. Double-stranded RNAs (or RNAi) targeted to vha-8 resulted in embryonic and larval lethality for the first filial generation, indicating that vha-8 is essential during early developmental processes. In addition, accumulation of abnormal endomitotic oocytes and defects in receptor-mediated endocytosis were observed in parental animals. These findings suggest that multiple phenotypes caused by the disruption of pH homeostasis are due to the defective V-ATPase. In summary, vha-8 encoding the E subunit of V-ATPase in C. elegans is essential for embryogenesis and receptor-mediated endocytosis. [Copyright &y& Elsevier]

Variants in the APOE gene region may explain ethnic differences in the association of Alzheimer's disease (AD) with ε4. Ethnic differences in allele frequencies for three APOE region SNPs (single nucleotide polymorphisms) were identified and tested for association in 19,398 East Asians (EastA), including Koreans and Japanese, 15,836 European ancestry (EuroA) individuals, and 4985 African Americans, and with brain imaging measures of cortical atrophy in sub-samples of Koreans and EuroAs. Among ε4/ε4 individuals, AD risk increased substantially in a dose-dependent manner with the number of APOE promoter SNP rs405509 T alleles in EastAs (TT: OR (odds ratio) = 27.02, p = 8.80 × 10−94; GT: OR = 15.87, p = 2.62 × 10−9) and EuroAs (TT: OR = 18.13, p = 2.69 × 10−108; GT: OR = 12.63, p = 3.44 × 10−64), and rs405509-T homozygotes had a younger onset and more severe cortical atrophy than those with G-allele. Functional experiments using APOE promoter fragments demonstrated that TT lowered APOE expression in human brain and serum. The modifying effect of rs405509 genotype explained much of the ethnic variability in the AD/ε4 association, and increasing APOE expression might lower AD risk among ε4 homozygotes. [ABSTRACT FROM AUTHOR]

Background: We previously demonstrated the validity of a regression model that included ethnicity as a novel predictor for predicting normative brain volumes in old age. The model was optimized using brain volumes measured with a standard tool FreeSurfer. Objective: Here we further verified the prediction model using newly estimated brain volumes from Neuro I, a quantitative brain analysis system developed for Korean populations. Methods: Lobar and subcortical volumes were estimated from MRI images of 1,629 normal Korean and 786 Caucasian subjects (age range 59–89) and were predicted in linear regression from ethnicity, age, sex, intracranial volume, magnetic field strength, and scanner manufacturers. Results: In the regression model predicting the new volumes, ethnicity was again a substantial predictor in most regions. Additionally, the model-based z-scores of regions were calculated for 428 AD patients and the matched controls, and then employed for diagnostic classification. When the AD classifier adopted the z-scores adjusted for ethnicity, the diagnostic accuracy has noticeably improved (AUC = 0.85, ΔAUC = + 0.04, D = 4.10, p < 0.001). Conclusions: Our results suggest that the prediction model remains robust across different measurement tool, and ethnicity significantly contributes to the establishment of norms for brain volumes and the development of a diagnostic system for neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Alzheimer disease (AD) is a leading cause of dementia that has gained prominence in our aging society. Yet, the complexity of diagnosing AD and measuring its invasiveness poses an obstacle. To this end, blood-based biomarkers could mitigate the inconveniences that impede an accurate diagnosis. We developed models to diagnose AD and measure the severity of neurocognitive impairment using blood protein biomarkers. Multiple reaction monitoring–mass spectrometry, a highly selective and sensitive approach for quantifying targeted proteins in samples, was used to analyze blood samples from 4 AD groups: cognitive normal control, asymptomatic AD, prodromal AD), and AD dementia. Multimarker models were developed using 10 protein biomarkers and apolipoprotein E genotypes for amyloid beta and 10 biomarkers with Korean Mini-Mental Status Examination (K-MMSE) score for predicting Alzheimer disease progression. The accuracies for the AD classification model and AD progression monitoring model were 84.9% (95% CI 82.8 to 87.0) and 79.1% (95% CI 77.8 to 80.5), respectively. The models were more accurate in diagnosing AD, compared with single APOE genotypes and the K-MMSE score. Our study demonstrates the possibility of predicting AD with high accuracy by blood biomarker analysis as an alternative method of screening for AD. [ABSTRACT FROM AUTHOR]

Background: Diabetic individuals have increased circulating inflammatory mediators which are implicated as underlying causes of neuroinflammation and memory deficits. Tonicity-responsive enhancer-binding protein (TonEBP) promotes diabetic neuroinflammation. However, the precise role of TonEBP in the diabetic brain is not fully understood.Methods: We employed a high-fat diet (HFD)-only fed mice or HFD/streptozotocin (STZ)-treated mice in our diabetic mouse models. Circulating TonEBP and lipocalin-2 (LCN2) levels were measured in type 2 diabetic subjects. TonEBP haploinsufficient mice were used to investigate the role of TonEBP in HFD/STZ-induced diabetic mice. In addition, RAW 264.7 macrophages were given a lipopolysaccharide (LPS)/high glucose (HG) treatment. Using a siRNA, we examined the effects of TonEBP knockdown on RAW264 cell' medium/HG-treated mouse hippocampal HT22 cells.Results: Circulating TonEBP and LCN2 levels were higher in experimental diabetic mice or type 2 diabetic patients with cognitive impairment. TonEBP haploinsufficiency ameliorated the diabetic phenotypes including adipose tissue macrophage infiltrations, neuroinflammation, blood-brain barrier leakage, and memory deficits. Systemic and hippocampal LCN2 proteins were reduced in diabetic mice by TonEBP haploinsufficiency. TonEBP (+ / -) mice had a reduction of hippocampal heme oxygenase-1 (HO-1) expression compared to diabetic wild-type mice. In particular, we found that TonEBP bound to the LCN2 promoter in the diabetic hippocampus, and this binding was abolished by TonEBP haploinsufficiency. Furthermore, TonEBP knockdown attenuated LCN2 expression in lipopolysaccharide/high glucose-treated mouse hippocampal HT22 cells.Conclusions: These findings indicate that TonEBP may promote neuroinflammation and cognitive impairment via upregulation of LCN2 in diabetic mice. [ABSTRACT FROM AUTHOR]

Background: Given that tau accumulation, not amyloid-β (Aβ) burden, is more closely connected with cognitive impairment in Alzheimer's disease (AD), a detailed understanding of the tau-related characteristics of cognitive function is critical in both clinical and research settings. We investigated the association between phosphorylated tau (p-Tau) level and cognitive impairment across the AD continuum and the mediating role of medial temporal lobe (MTL) atrophy. We also developed a prediction model for abnormal tau accumulation. Methods: We included participants from the Gwangju Alzheimer's Disease and Related Dementia Cohort in Korea, who completed cerebrospinal fluid analysis and clinical evaluation, and corresponded to one of three groups according to the biomarkers of A and T profiles based on the National Institute on Aging and Alzheimer's Association research framework. Multiple linear and logistic regression analyses were performed to examine the association between p-Tau and cognition and to develop prediction models. Receiver operating characteristic curve analysis was performed to examine the discrimination ability of the models. Results: Among 185 participants, 93 were classified as A-T-, 23 as A+T-, and 69 as A+T+. There was an association between decreased visuospatial delayed memory performance and p-Tau level (B = − 0.754, β = − 0.363, p < 0.001), independent of other relevant variables (e.g., Aβ). MTL neurodegeneration was found to mediate the association between the two. Prediction models with visuospatial delayed memory alone (area under the curve [AUC] = 0.872) and visuospatial delayed memory and entorhinal thickness (AUC = 0.921) for abnormal tau accumulation were suggested and they were validated in an independent sample (AUC = 0.879 and 0.891, respectively). Conclusion: It is crucial to identify sensitive cognitive measures that capture subtle cognitive impairment associated with underlying pathological changes. Preliminary findings from the current study might suggest that abnormal tau accumulation underlies episodic memory impairment, particularly visuospatial modality, in the AD continuum. Suggested models are potentially useful in predicting tau pathology, and might be utilized practically in the field. [ABSTRACT FROM AUTHOR]

Meta-analyses have found a negative relationship between religiousness and IQ of around r = −0.2, including in samples of elderly Westerners. However, there have been few attempts to directly test the existence of the religion-IQ nexus in non-Western societies. We administered a cognitive test to a representative sample of elderly South Koreans who were also surveyed about their religion and tested whether elderly nonreligious people had higher mean IQ scores than elderly religious people. Using a broad cognitive test battery, we computed mean IQ scores of n = 589 non-religious, n = 494 Protestants, n = 520 Catholics, n = 347 Buddhists, and n = 17 Confucianists. Elderly South Koreans who claimed to have 'no religion' had lower mean IQs than religious Koreans. This finding is not consistent with previous findings from meta-analyses. We argue that it is explicable in terms of differences in how the concept of religion is understood when comparing Western and Northeast Asian societies. Many of the 'non-religious' category would be adherents to Korean folk religion, something expected to be associated with lower mean IQ. • There is a negative relationship between religiousness and IQ. • The relationship has not been tested in non-Western societies. • We tested a representative sample of elderly South Koreans. • Elderly non-religious persons had lower mean IQs than elderly religious persons. • The non-religious are most likely adherents to Korean folk religion. [ABSTRACT FROM AUTHOR]

The early diagnosis of Alzheimer's Disease (AD) plays a central role in the treatment of AD. Particularly, identifying the preclinical AD (pAD) stage could be crucial for timely treatment in the elderly. However, screening participants with pAD requires a series of psychological and neurological examinations. Thus, an efficient diagnostic tool is needed. Here, we recruited 91 elderly participants and collected 1 min of resting-state electroencephalography data to classify participants as normal aging or diagnosed with pAD. We used deep neural networks (Deep ConvNet, EEGNet, EEG-TCNet, and cascade CRNN) in the within- and cross-subject paradigms for classification and found individual variations of classification accuracy in the cross-subject paradigm. Further, we proposed an individualized diagnostic strategy to identify neurophysiological similarities across participants and the proposed approach considering individual characteristics improved the diagnostic performance by approximately 20%. Our findings suggest that considering individual characteristics would be a breakthrough in diagnosing AD using deep neural networks. [ABSTRACT FROM AUTHOR]

[Display omitted] • Amyloid-β increases the acetylcholine-induced intracellular calcium load in SH-SY5Y cells. • Phospholipase C-β1 expression is upregulated in amyloid-β-treated SH-SY5Y cells and 5× familiar Alzheimer's disease (5×FAD) mice brains. • Overexpression of phospholipase C-β1 elevates the calcium release from endoplasmic reticulum in SH-SY5Y cells. • Knockdown of phospholipase C-β1 abrogates the calcium overload induced by amyloid-β in SH-SY5Y cells. Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia. Amyloid-β (Aβ) has long been considered a key cause of neurodegeneration in the AD brain. Although the mechanisms underlying Aβ-induced neurodegeneration are not fully understood, a number of recent studies have suggested that intracellular calcium overload mediates this process. In this study, we focused on the cellular function of phospholipase C-β1 (PLCB1), which regulates calcium signaling by mediating hydrolysis of phosphatidylinositol 4,5-bisphosphate through G-protein coupled receptor pathways. First, we confirmed that acetylcholine-induced calcium release from intracellular stores of SH-SY5Y cells was significantly increased with Aβ 42 oligomer treatment. We further found that PLCB1 expression was upregulated in Aβ 42 -treated cells, and PLCB1 overexpression in SH-SY5Y cells elicited the calcium overload observed in Aβ-treated cells. In addition, Aβ 42 oligomer-induced calcium overload in SH-SY5Y cells was alleviated by knockdown of PLCB1, indicating that PLCB1 plays an essential role in the neurotoxic process initiated by Aβ. The elevation of PLCB1 expression was confirmed in the brain tissues from the 5× familial AD (5×FAD) model mice. These findings suggest that PLCB1 may represent a potential therapeutic target for protecting neuronal cells against excitotoxicity in AD progression. [ABSTRACT FROM AUTHOR]

Introduction: The genetic basis of Alzheimer's disease (AD) in Koreans is poorly understood., Methods: We performed an AD genome-wide association study using whole-genome sequence data from 3540 Koreans (1583 AD cases, 1957 controls) and single-nucleotide polymorphism array data from 2978 Japanese (1336 AD cases, 1642 controls). Significant findings were evaluated by pathway enrichment and differential gene expression analysis in brain tissue from controls and AD cases with and without dementia prior to death., Results: We identified genome-wide significant associations with APOE in the total sample and ROCK2 (rs76484417, p = 2.71×10 -8 ) among APOE ε4 non-carriers. A study-wide significant association was found with aggregated rare variants in MICALL1 (MICAL like 1) (p = 9.04×10 -7 ). Several novel AD-associated genes, including ROCK2 and MICALL1, were differentially expressed in AD cases compared to controls (p < 3.33×10 -3 ). ROCK2 was also differentially expressed between AD cases with and without dementia (p = 1.34×10 -4 )., Discussion: Our results provide insight into genetic mechanisms leading to AD and cognitive resilience in East Asians., Highlights: Novel genome-wide significant associations for AD identified with ROCK2 and MICALL1. ROCK2 and MICALL1 are differentially expressed between AD cases and controls in the brain. This is the largest whole-genome-sequence study of AD in an East Asian population., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Alzheimer's disease (AD) is a neurodegenerative disorder influenced by age, sex, genetic factors, immune alterations, and infections. Multiple lines of evidence suggest that changes in antibody response are linked to AD pathology., Methods: To elucidate the mechanisms underlying AD development, we investigated antibodies that target autoimmune epitopes using high-resolution epitope microarrays. Our study compared two groups: individuals with AD (n = 19) and non-demented (ND) controls (n = 19). To validate the results, we measured antibody levels in plasma samples from AD patients (n = 96), mild cognitive impairment (MCI; n = 91), and ND controls (n = 97). To further explore the invlovement of EBV, we performed epitope masking immunofluorescence microscopy analysis and tests to induce lytic replication using the B95-8 cell line., Results: In this study, we analyzed high-resolution epitope-specific serum antibody levels in AD, revealing significant disparities in antibodies targeting multiple epitopes between the AD and control groups. Particularly noteworthy was the significant down-regulation of antibody (anti-DG#29) targeting an epitope of Epstein-Barr virus nuclear antigen 1 (EBNA1). This down-regulation increased AD risk in female patients (odds ratio up to 6.6), but not in male patients. Our investigation further revealed that the down-regulation of the antibody (anti-DG#29) is associated with EBV reactivation in AD, as indicated by the analysis of EBV VCA IgG or IgM levels. Additionally, our data demonstrated that the epitope region on EBNA1 for the antibody is hidden during the EBV lytic reactivation of B95-8 cells., Conclusion: Our findings suggest a potential relationship of EBV in the development of AD in female. Moreover, we propose that antibodies targeting the epitope (DG#29) of EBNA1 could serve as valuable indicators of AD risk in female., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Alzheimer's Disease (AD) is one of the most common neurodegenerative disorders in elderly people. It is diagnosed by detecting amyloid beta (Aβ) protein in cerebrospinal fluid (CSF) obtained by lumbar puncture or through expensive positron emission tomography (PET) imaging. Although blood-based diagnosis of AD offers a less invasive and cost-effective alternative, the quantification of Aβ is technically challenging due to its low abundance in peripheral blood. To address this, we developed a compact yet highly sensitive microwell-based electrochemical sensor with a densely packed microelectrode array (20 by 20) for enhancing sensitivity. Employing microwells on the working and counter electrodes minimized the leakage current from the metallic conductors into the assay medium, refining the signal fidelity. We achieved a detection limit <10 fg/mL for Aβ by elevating the signal-to-noise ratio, thus capable of AD biomarker quantification. Moreover, the microwell structure maintained the performance irrespective of variations in bead number, indicative of the sensor's robustness. The sensor's efficacy was validated through the analysis of Aβ concentrations in plasma samples from 96 subjects, revealing a significant distinction between AD patients and healthy controls with an area under the receiver operating characteristic curve (AUC) of 0.85. Consequently, our novel microwell-based electrochemical biosensor represents a highly sensitive platform for detecting scant blood-based biomarkers, including Aβ, offering substantial potential for advancing AD diagnostics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The gut-brain axis (GBA) plays a significant role in various neurodegenerative disorders, such as Alzheimer's disease (AD), and the gut microbiome (GM) can bidirectionally communicate with the brain through the GBA. Thus, recent evidence indicates that the GM may affect the pathological features and the progression of AD in humans. The aim of our study was to elucidate the impact of probiotics on the pathological features of AD in a 5xFAD model. Probiotics ( Bifidobacterium lactis , Levilactobacillus brevis , and Limosilactobacillus fermentum ) were orally administered in 5xFAD mice to modify the GM composition. Additionally, freeze-dried food containing phosphatidylserine was used as the positive control. Behavioral pathogenesis was assessed through the cross maze and Morris water maze tests. Our findings revealed that probiotic administration resulted in significant improvements in spatial and recognition memories. Furthermore, the neuroprotective effects of probiotics were substantiated by a reduction in amyloid-β accumulation in critical brain regions. Microglial activation in 5xFAD mice was also attenuated by probiotics in the hippocampus and cerebral cortex. Moreover, elevated tau phosphorylation in 5xFAD mice was ameliorated in the probiotics-treated group. The results highlight the potential use of probiotics as a neuroprotective intervention in AD.

Amyloid-β (Aβ) oligomers are implicated in the onset of Alzheimer's disease (AD). Herein, quinoline-derived half-curcumin-dioxaborine (Q-OB) fluorescent probe was designed for detecting Aβ oligomers by finely tailoring the hydrophobicity of the biannulate donor motifs in donor-π-acceptor structure. Q-OB shows a great sensing potency in dynamically monitoring oligomerization of Aβ during amyloid fibrillogenesis in vitro. In addition, we applied this strategy to fluorometrically analyze Aβ self-assembly kinetics in the cerebrospinal fluids (CSF) of AD patients. The fluorescence intensity of Q-OB in AD patients' CSF revealed a marked change of log (I/I 0 ) value of 0.34 ± 0.13 (cognitive normal), 0.15 ± 0.12 (mild cognitive impairment), and 0.14 ± 0.10 (AD dementia), guiding to distinguish a state of AD continuum for early diagnosis of AD. These studies demonstrate the potential of our approach can expand the currently available preclinical diagnostic platform for the early stages of AD, aiding in the disruption of pathological progression and the development of appropriate treatment strategies., (© 2024. The Author(s).)

Background: We previously demonstrated the validity of a regression model that included ethnicity as a novel predictor for predicting normative brain volumes in old age. The model was optimized using brain volumes measured with a standard tool FreeSurfer., Objective: Here we further verified the prediction model using newly estimated brain volumes from Neuro I, a quantitative brain analysis system developed for Korean populations., Methods: Lobar and subcortical volumes were estimated from MRI images of 1,629 normal Korean and 786 Caucasian subjects (age range 59-89) and were predicted in linear regression from ethnicity, age, sex, intracranial volume, magnetic field strength, and scanner manufacturers., Results: In the regression model predicting the new volumes, ethnicity was again a substantial predictor in most regions. Additionally, the model-based z-scores of regions were calculated for 428 AD patients and the matched controls, and then employed for diagnostic classification. When the AD classifier adopted the z-scores adjusted for ethnicity, the diagnostic accuracy has noticeably improved (AUC = 0.85, ΔAUC = + 0.04, D = 4.10, p < 0.001)., Conclusions: Our results suggest that the prediction model remains robust across different measurement tool, and ethnicity significantly contributes to the establishment of norms for brain volumes and the development of a diagnostic system for neurodegenerative diseases.

Brain age prediction is a practical method used to quantify brain aging and detect neurodegenerative diseases such as Alzheimer's disease (AD). However, very few studies have considered brain age prediction as a biomarker for the conversion of cognitively normal (CN) to mild cognitive impairment (MCI). In this study, we developed a novel brain age prediction model using brain volume and cortical thickness features. We calculated an acceleration of brain age (ABA) derived from the suggested model to estimate different diagnostic groups (CN, MCI, and AD) and to classify CN to MCI and MCI to AD conversion groups. We observed a strong association between ABA and the 3 diagnostic groups. Additionally, the classification models for CN to MCI conversion and MCI to AD conversion exhibited acceptable and robust performances, with area under the curve values of 0.66 and 0.76, respectively. We believe that our proposed model provides a reliable estimate of brain age for elderly individuals and can identify those at risk of progressing from CN to MCI. This model has great potential to reveal a diagnosis associated with a change in cognitive decline., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The gut-brain axis encompasses a bidirectional communication pathway between the gastrointestinal microbiota and the central nervous system. There is some evidence to suggest that probiotics may have a positive effect on cognitive function, but more research is needed before any definitive conclusions can be drawn. Inflammation-induced by lipopolysaccharide (LPS) may affect cognitive function. To confirm the effect of probiotics on oxidative stress induced by LPS, the relative expression of antioxidant factors was confirmed, and it was revealed that the administration of probiotics had a positive effect on the expression of antioxidant-related factors. After oral administration of probiotics to mice, an intentional inflammatory response was induced through LPS i.p., and the effect on cognition was confirmed by the Morris water maze test, nitric oxide (NO) assay, and interleukin (IL)-1β enzyme-linked immunosorbent assay performed. Experimental results, levels of NO and IL-1 β in the blood of LPS i.p. mice were significantly decreased, and cognitive evaluation using the Morris water maze test showed significant values in the latency and target quadrant percentages in the group that received probiotics. This proves that intake of these probiotics improves cognitive impairment and memory loss through anti-inflammatory and antioxidant mechanisms., Competing Interests: The authors declare no potential conflicts of interest., (© Korean Society for Food Science of Animal Resources.)

Introduction: Basic studies suggest that olfactory dysfunction and functional near-infrared spectroscopy (fNIRS) can be used as tools for the diagnosis of mild cognitive impairment (MCI); however, real-world evidence is lacking. We investigated the potential diagnostic efficacy of olfactory-stimulated fNIRS for early detection of MCI and/or Alzheimer disease (AD)., Methods: We conducted a patient-level, single-group, diagnostic interventional trial involving elderly volunteers (age >60 years) suspected of declining cognitive function. Patients received open-label olfactory-stimulated fNIRS for measurement of oxygenation difference in the orbitofrontal cortex. All participants underwent amyloid PET, MRI, Mini-Mental State Examination (MMSE), and Seoul Neuropsychological Screening Battery (SNSB)., Results: Of 97 subjects, 28 (28.9%) were cognitively normal, 32 (33.0%) had preclinical AD, 21 (21.6%) had MCI, and 16 (16.5%) had AD. Olfactory-stimulated oxygenation differences in the orbitofrontal cortex were associated with cognitive impairment; the association was more pronounced with cognitive severity. Olfactory-stimulated oxygenation difference was associated with MMSE (adjusted β [aβ] 1.001; 95% CI 0.540-1.463), SNSB language and related function (aβ, 1.218; 95% CI, 0.020-2.417), SNSB memory (aβ, 1.963; 95% CI, 0.841-3.084), SNSB frontal/executive function (aβ, 1.715; 95% CI, 0.401-3.029) scores, standard uptake value ratio from amyloid PET (aβ, -10.083; 95% CI, -19.063 to -1.103), and hippocampal volume from MRI (aβ, 0.002; 95% CI, 0.001-0.004). Olfactory-stimulated oxygenation difference in the orbitofrontal cortex was superior in diagnosing MCI and AD (AUC, 0.909; 95% CI, 0.848-0.971), compared to amyloid PET (AUC, 0.793; 95% CI, 0.694-0.893) or MRI (AUC, 0.758; 95% CI, 0.644-0.871)., Discussion: Our trial showed that olfactory-stimulated oxygenation differences in the orbitofrontal cortex detected by fNIRS were associated with cognitive impairment and cognitive-related objectives. This novel approach may be a potential diagnostic tool for patients with MCI and/or AD., Trial Registration: CRIS number, KCT0006197 ., (© 2022. The Author(s).)

Established genetic risk factors for Alzheimer's disease (AD) account for only a portion of AD heritability. The aim of this study was to identify novel associations between genetic variants and AD-specific brain atrophy. We conducted genome-wide association studies for brain magnetic resonance imaging measures of hippocampal volume and entorhinal cortical thickness in 2643 Koreans meeting the clinical criteria for AD (n = 209), mild cognitive impairment (n = 1449) or normal cognition (n = 985). A missense variant, rs77359862 (R274W), in the SHANK-associated RH Domain Interactor (SHARPIN) gene was associated with entorhinal cortical thickness (p = 5.0 × 10 -9 ) and hippocampal volume (p = 5.1 × 10 -12 ). It revealed an increased risk of developing AD in the mediation analyses. This variant was also associated with amyloid-β accumulation (p = 0.03) and measures of memory (p = 1.0 × 10 -4 ) and executive function (p = 0.04). We also found significant association of other SHARPIN variants with hippocampal volume in the Alzheimer's Disease Neuroimaging Initiative (rs3417062, p = 4.1 × 10 -6 ) and AddNeuroMed (rs138412600, p = 5.9 × 10 -5 ) cohorts. Further, molecular dynamics simulations and co-immunoprecipitation indicated that the variant significantly reduced the binding of linear ubiquitination assembly complex proteins, SHPARIN and HOIL-1 Interacting Protein (HOIP), altering the downstream NF-κB signaling pathway. These findings suggest that SHARPIN plays an important role in the pathogenesis of AD., (© 2021. The Author(s).)

Background: The prevalence of non-tuberculous mycobacterial pulmonary disease (NTM-PD) is increasing in South Korea and many parts of the world. However, the genetic factors underlying susceptibility to this disease remain elusive., Methods: To identify genetic variants in patients with NTM-PD, we performed a genome-wide association study with 403 Korean patients with NTM-PD and 306 healthy controls from the Healthy Twin Study, Korea cohort. Candidate variants from the discovery cohort were subsequently validated in an independent cohort. The Genotype-Tissue Expression (GTEx) database was used to identify expression quantitative trait loci (eQTL) and to conduct Mendelian randomisation (MR)., Results: We identified a putatively significant locus on chromosome 7p13, rs849177 (OR, 2.34; 95% CI, 1.71 to 3.21; p=1.36×10 -7 ), as the candidate genetic variant associated with NTM-PD susceptibility. Its association was subsequently replicated and the combined p value was 4.92×10 -8 . The eQTL analysis showed that a risk allele at rs849177 was associated with lower expression levels of STK17A , a proapoptotic gene. In the MR analysis, a causal effect of STK17A on NTM-PD development was identified (β, -4.627; 95% CI, -8.768 to -0.486; p=0.029)., Conclusions: The 7p13 genetic variant might be associated with susceptibility to NTM-PD in the Korean population by altering the expression level of STK17A ., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Purpose: Although two white matter hyperintensity (WMH) probability maps of healthy older adults already exist, they have several limitations in representing the distribution of WMH in healthy older adults, especially Asian older adults. We constructed and validated a WMH probability map (WPM) of healthy older Koreans and examined the age-associated differences of WMH., Methods: We constructed WPM using development dataset that consisted of high-resolution 3D fluid-attenuated inversion recovery images of 5 age groups (60-64 years, 65-69 years, 70-74 years, 75-79 years, and 80+ years). Each age group included 30 age-matched men and women each. We tested the validity of the WPM by comparing WMH ages estimated by the WPM and the chronological ages of 30 healthy controls, 30 hypertension patients, and 30 S patients., Results: Older age groups showed a higher volume of WMH in both hemispheres (p < 0.001). About 90% of the WMH were periventricular in all age groups. With advancing age, the peak of the distance histogram from the ventricular wall of the periventricular WMH shifted away from the ventricular wall, while that of deep WMH shifted toward the ventricular wall. The estimated WMH ages were comparable to the chronological ages in the healthy controls, while being higher than the chronological ages in hypertension and stroke patients., Conclusions: This WPM may serve as a standard atlas in research on WMH of older adults, especially Asians., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In genetic analyses, the term 'batch effect' refers to systematic differences caused by batch heterogeneity. Controlling this unintended effect is the most important step in quality control (QC) processes that precede analyses. Currently, batch effects are not appropriately controlled by statistics, and newer approaches are required., Methods: In this report, we propose a new method to detect the heterogeneity of probe intensities among different batches and a procedure for calling genotypes and QC in the presence of a batch effect. First, we conducted a multivariate analysis of variance (MANOVA) to test the differences in probe intensities among batches. If heterogeneity is detected, subjects should be clustered using a K-medoid algorithm using the averages of the probe intensity measurements for each batch and the genotypes of subjects in different clusters should be called separately., Results: The proposed method was used to assess genotyping data of 3619 subjects consisting of 1074 patients with Alzheimer's disease, 296 with mild cognitive impairment (MCI), and 1153 controls. The proposed method improves the accuracy of called genotypes without the need to filter a lot of subjects and SNPs, and therefore is a reasonable approach for controlling batch effects., Conclusions: We proposed a new strategy that detects batch effects with probe intensity measurement and calls genotypes in the presence of batch effects. The application of the proposed method to real data shows that it produces a balanced approach. Furthermore, the proposed method can be extended to various scenarios with a simple modification.

Metabotropic glutamate receptors (mGluRs) are G-protein-coupled receptors that modulate excitatory neurotransmission and synaptic plasticity. The group I mGluRs (mGluR1 and mGluR5) have long intracellular C-terminal domains, which interact with many proteins. Our previous studies identified calmodulin (CaM) as a strong regulator of mGluR5 trafficking and mGluR5-induced calcium signaling. Although it has been accepted that both mGluR1 and mGluR5 interact with CaM, we now show that CaM specifically binds mGluR5 and not mGluR1. We have identified a single critical residue in mGluR5 (L896) that is required for CaM binding. In mGluR1, mutation of the corresponding residue, V909, to leucine is sufficient to confer CaM binding to mGluR1. To investigate the functional effects of CaM binding, we examined the surface expression of mGluR1 and mGluR5 in hippocampal neurons. The mutation in mGluR1 (V909L) that confers CaM binding dramatically increases mGluR1 surface expression, whereas the analogous mutation in mGluR5 that disrupts CaM binding (L896V) decreases mGluR5 surface expression. In addition, the critical residue that alters CaM binding regulates mGluR internalization. Furthermore, we find that mGluR-mediated AMPA receptor endocytosis is enhanced by CaM binding to group I mGluRs. Finally, we show that calcium responses evoked by group I mGluRs are modulated by these mutations, which regulate CaM binding. Our findings elucidate a critical mechanism that specifically affects mGluR5 trafficking and signaling, and distinguishes mGluR1 and mGluR5 regulation.

As a result of screen searching for proteins interacting with MEF-2 transcription factor, we have identified the hda-7 gene in Caenorhabditis elegans. The hda-7 locus encodes a class II histone deacetylase containing a highly conserved catalytic domain. C. elegans HDA-7 protein translated in vitro demonstrated a direct interaction with CeMEF-2, as shown in other organisms. CeHDA-7 is abundantly expressed in body-wall muscle cells, neurons, and hypodermal seam cells, similar to CeMEF-2 expression patterns. Consistent with previously known phenotypes observed in mef-2 deletion mutants [Dev. Biol. 223 (2000) 431], RNA interference targeted for hda-7 did not result in muscle function or developmental defects., ((c) 2002 Elsevier Science (USA).)