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To determine the existence of cortical thinning in subcortical vascular dementia (SVaD) with a negative 11C-Pittsburgh compound B (PiB) positron emission tomography scan and to compare the topography of cortical thinning between PiB-negative SVaD and Alzheimer's disease (AD), we enrolled 24 patients with PiB(-) SVaD, 81 clinically probable AD individuals, and 72 normal cognitive controls. Compared with controls, cortical thinning in PiB(-) SVaD was most profound in the perisylvian area, medial prefrontal area, and posterior cingulate gyri, while the precuneus and medial temporal lobes were relatively spared. When the cortical thickness of AD and PiB(-) SVaD were directly compared, PiB(-) SVaD demonstrated significant cortical thinning in the bilateral inferior frontal, superior temporal gyri, and right medial frontal and orbitofrontal lobes, while AD showed significant cortical thinning in the right medial temporal region. SVaD without amyloid burden may lead to substantial cortical atrophy. Moreover, characteristic topography of cortical thinning in PiB(-) SVaD suggests different mechanisms of cortical thinning in PiB(-) SVaD and AD. [ABSTRACT FROM AUTHOR]

Background: CSF1R-related leukoencephalopathy is a type of autosomal dominant leukodystrophy caused by mutations in the colony stimulating factor 1 receptor (CSF1R) gene. Subcortical ischemic vascular dementia (SIVaD), which is caused by cerebral small vessel disease, is similar to CSF1R-related leukoencephalopathy in that it mainly affects subcortical white matter. In this study, we compared the patterns of white matter hyperintensity (WMH) and cortical thickness in CSF1R-related leukoencephalopathy with those in SIVaD., Methods: Fourteen patients with CSF1R-related leukoencephalopathy and 129 with SIVaD were retrospectively recruited from three tertiary medical centers. We extracted and visualized WMH data using voxel-based morphometry to compare the WMH distributions between the two groups. Cortical thickness was measured using a surface-based method. Statistical maps of differences in cortical thickness between the two groups were generated using a surface model, with age, sex, education, and intracranial volume as covariates., Results: Predominant distribution of WMH in the CSF1R-related leukoencephalopathy group was in the bilateral frontal and parietal areas, whereas the SIVaD group showed diffuse WMH involvement in the bilateral frontal, parietal, and temporal areas. Compared with the SIVaD group, the CSF1R-related leukoencephalopathy group showed more severe corpus callosum atrophy (CCA) and widespread cortical thinning., Conclusions: To our knowledge, this is the first study using the automated MR measurement to capture WMH, cortical thinning, and CCA with signal changes in CSF1R-related leukoencephalopathy. It provides new evidence regarding differences in the patterns of WMH distribution and cortical thinning between CSF1R-related leukoencephalopathy and SIVaD., Competing Interests: NO authors have competing interests., (Copyright: © 2024 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: As society ages, the incidence of Alzheimer's disease and other dementias has surged, highlighting the importance of early dementia diagnosis. The Seoul Cognitive Status Test (SCST), a digital neuropsychological test, is designed for the early detection of cognitive impairment and has been standardized to establish reliability and validity. This study aims to verify whether the SCST effectively discriminates between groups based on three cognitive statuses (subjective cognitive decline [SCD], mild cognitive impairment [MCI], Dementia) in a large sample. We also seek to determine whether the SCST discriminates between individuals with three different cognitive statuses as defined by the Cognitive Dementia Rating (CDR)., Methods: We enrolled 254 participants from a dementia clinic who underwent a comprehensive neuropsychological battery (Seoul Neuropsychological Screening Battery-II) during the dementia evaluation by experienced neurologists (55 with SCD, 126 with MCI, 73 with dementia). In addition, the degree of cognitive decline in participants was classified by CDR level (186 with CDR 0.5, 52 with CDR 1, 15 with CDR 2). One-way analysis of variance was used to compare SCST scores according to each of the three cognitive status groups and CDR levels., Results: The SCST total score, cognitive domain scores (attention, language, visuospatial function, memory, executive function), and most of the subtest scores decreased significantly in the order of SCD, MCI and dementia. Likewise, the differences in SCST scores between CDR levels were significant, particularly in distinguishing between CDR 0.5 and CDR 1., Conclusion: This study reaffirmed that the SCST can significantly discriminate between groups of individuals with SCD, MCI, and dementia based on a large sample. Furthermore, differences in SCT scores were found across the levels of CDR, confirming the clinical utility of the SCST. These findings suggest that the SCST is an efficient and useful neuropsychological test for the sensitive detection of early cognitive impairment., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

Introduction: We investigated the prevalence of amyloid beta (Aβ) positivity (+) and cognitive trajectories in Koreans and non-Hispanic Whites (NHWs)., Methods: We included 5121 Koreans from multiple centers across South Korea and 929 NHWs from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants underwent Aβ positron emission tomography and were categorized into cognitively unimpaired (CU), mild cognitive impairment (MCI), and dementia stages. Age, sex, education, and apolipoprotein E. genotype were adjusted using multivariable logistic regression and stabilized inverse probability of treatment weights based on the propensity scores to mitigate imbalances in these variables., Results: The prevalence of Aβ+ was lower in CU Koreans than in CU NHWs (adjusted odds ratio 0.60). Aβ+ Koreans showed a faster cognitive decline than Aβ+ NHWs in the CU (B = -0.314, p = .004) and MCI stages (B = -0.385, p < .001)., Discussion: Ethnic characteristics of Aβ biomarkers should be considered in research and clinical application of Aβ-targeted therapies in diverse populations., Highlights: Koreans have a lower prevalence of Aβ positivity compared to NHWs in the CU stage. The effects of Alzheimer's risk factors on Aβ positivity differ between Koreans and NHWs. Aβ-positive (Aβ+) Koreans show faster cognitive decline than Aβ+ NHWs in the CU and MCI stages., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: We investigated distinctive factors associated with cognitive reserve (CR) based on education level., Methods: Among 1247 participants who underwent neuropsychological assessment, amyloid positron emission tomography, and brain magnetic resonance imaging, 336 participants with low education (≤6 years) and 697 with high education (≥12 years) were selected. CR was measured as the difference between the predicted and observed value of cognitive function based on cortical thickness. Multiple linear regression was conducted in each group after controlling for age and sex., Results: In the low-education group, low literacy, long sleep duration(>8 h/day), and diabetes were negatively associated with CR, whereas cognitive and physical activity were positively associated with CR. In the high-education group, cognitive activity was positively related to CR, whereas low literacy, long sleep duration (> 8 h/day), and depression were negatively related to CR., Discussion: This study provides insights into different strategies for enhancing CR based on educational background., Highlights: Factors associated with cognitive reserve (CR) varied according to the education level. Diabetes and physical activity were associated with CR in the low-education group. Depression was related to CR in the high-education group. Low literacy, sleep duration, and cognitive activity were associated with CR in both groups. Dementia-prevention strategies should be tailored according to educational level., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: The clinical effects of β-amyloid positivity (Aβ+) on copathologies in various dementias remain relatively underexamined. Thus, the present study was conducted to investigate the prevalence and clinical effects of Aβ+ in subcortical vascular cognitive impairment (SVCI) and frontotemporal dementia (FTD)., Patients and Methods: We enrolled SVCI (n = 583), FTD (n = 152), and cognitively unimpaired (CU) participants (n = 1,249) who underwent Aβ PET scans. The odds of having Aβ+ were subsequently compared among the diagnostic groups (CU, SVCI, and FTD) according to age and apolipoprotein E genotype. Additionally, a linear mixed-effects model was used to investigate the effects of Aβ+ on cognitive trajectories in SVCI and FTD., Results: Compared with CU, the SVCI group had a higher prevalence of Aβ+ in the 75 to 90 years age group (adjusted odds ratio, 1.97; 95% confidence interval, 1.36-2.85; P < 0.001), as well as within the apolipoprotein E ε3/ε3 group (adjusted odds ratio, 1.78; 95% confidence interval, 1.20-2.63; P = 0.001), whereas the FTD group showed no difference in Aβ+ prevalence. Aβ+ was associated with a worse cognitive trajectory in SVCI (adjusted β-coefficient = -0.6424; P < 0.001), but not in FTD., Conclusions: These findings contribute to our understanding of Aβ biomarker traits in various dementias in Korea., Competing Interests: Conflicts of interest and sources of funding: The authors have no competing interests to declare that are relevant to the content of this article. This research was supported by a grant of the Korea Dementia Research Project through the Korea Dementia Research Center, funded by the Ministry of Health and Welfare and Ministry of Science and ICT, Republic of Korea (grant number: RS-2020-KH106434 and RS-2020-KH107436); a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health and Welfare and Ministry of Science and ICT, Republic of Korea (grant number: RS-2022-KH127756 and RS-2022-KH125667); Future Medicine 20*30 Project of the Samsung Medical Center (#SMX1240561); the “Korea National Institute of Health” research project (2024-ER1003-00); Institute of Information and Communications Technology planning and evaluation grant funded by the Korea government (MSIT) (NO.RS-2021-II212068, Artificial Intelligence Innovation Hub); and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF-2019R1A5A2027340)., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background and Purpose: Amyloid β (Aβ), a major biomarker of Alzheimer's disease, leads to tau accumulation, neurodegeneration and cognitive decline. Modelling the trajectory of Aβ accumulation in cognitively unimpaired (CU) individuals is crucial, as treatments targeting Aβ are anticipated. The evolution of Aβ levels was investigated to determine whether it could lead to classification into different groups by studying longitudinal Aβ changes in older CU individuals, and differences between the groups were compared., Methods: A total of 297 CU participants were included from the Alzheimer's Disease Neuroimaging Initiative database, and these participants underwent apolipoprotein E (APOE) genotyping, neuropsychological testing, brain magnetic resonance imaging, and an average of 3.03 follow-up 18 F-florbetapir positron emission tomography scans. Distinct Aβ trajectory patterns were classified using latent class growth analysis, and longitudinal cognitive performances across these patterns were assessed with a linear mixed effects model., Results: The optimal model consisted of three classes, with a high entropy value of 0.947. The classes were designated as follows: class 1, non-accumulation group (n  = 197); class 2, late accumulation group (n  = 70); and class 3, early accumulation group (n  = 30). The late accumulation and early accumulation groups had more APOE ε4 carriers than the non-accumulation group. The longitudinal analysis of cognitive performance revealed that the early accumulation group showed the steepest decline (modified Preclinical Alzheimer's Cognitive Composite with digit symbol substitution [mPACCdigit], p < 0.001; modified Preclinical Alzheimer's Cognitive Composite with trails B [mPACCtrailsB], p < 0.001) and the late accumulation group showed a steeper decline (mPACCdigit, p = 0.014; mPACCtrailsB, p = 0.007) compared to the non-accumulation group., Conclusions: Our study showed the heterogeneity of Aβ accumulation trajectories in CU older individuals. The prognoses for cognitive decline differ according to the Aβ trajectory patterns., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Increasing evidence supports the association between body mass index (BMI), Alzheimer's disease, and vascular markers. Recently, metabolically unhealthy conditions have been reported to affect the expression of these markers. We aimed to investigate the effects of BMI status on Alzheimer's and vascular markers in relation to metabolic health status., Methods: We recruited 1,736 Asians without dementia (71.6 ± 8.0 years). Participants were categorized into underweight, normal weight, or obese groups based on their BMI. Each group was further divided into metabolically healthy (MH) and unhealthy (MU) groups based on the International Diabetes Foundation definition of metabolic syndrome. The main outcome was Aβ positivity, defined as a Centiloid value of 20.0 or above and the presence of vascular markers, defined as severe white matter hyperintensities (WMH). Logistic regression analyses were performed for Aβ positivity and severe WMH with BMI status or interaction terms between BMI and metabolic health status as predictors. Mediation analyses were performed with hippocampal volume (HV) and baseline Mini-Mental State Examination (MMSE) scores as the outcomes, and linear mixed models were performed for longitudinal change in MMSE scores., Results: Being underweight increased the risk of Aβ positivity (odds ratio [OR] = 2.37, 95% confidence interval [CI] 1.13-4.98), whereas obesity decreased Aβ positivity risk (OR = 0.63, 95% CI 0.50-0.80). Especially, obesity decreased the risk of Aβ positivity (OR = 0.38, 95% CI 0.26-0.56) in the MH group, but not in the MU group. Obesity increased the risk of severe WMH (OR = 1.69, 1.16-2.47). Decreased Aβ positivity mediate the relationship between obesity and higher HV and MMSE scores, particularly in the MH group. Obesity demonstrated a slower decline in MMSE (β = 1.423, p = 0.037) compared to being normal weight, especially in the MH group., Conclusions: Our findings provide new evidence that metabolic health has a significant effect on the relationship between obesity and Alzheimer's markers, which, in turn, lead to better clinical outcomes., (© 2024. The Author(s).)

Background: Determining brain atrophy is crucial for the diagnosis of neurodegenerative diseases. Despite detailed brain atrophy assessments using three-dimensional (3D) T1-weighted magnetic resonance imaging, their practical utility is limited by cost and time. This study introduces deep learning algorithms for quantifying brain atrophy using a more accessible two-dimensional (2D) T1, aiming to achieve cost-effective differentiation of dementia of the Alzheimer's type (DAT) from cognitively unimpaired (CU), while maintaining or exceeding the performance obtained with T1-3D individuals and to accurately predict AD-specific atrophy similarity and atrophic changes [W-scores and Brain Age Index (BAI)]., Methods: Involving 924 participants (478 CU and 446 DAT), our deep learning models were trained on cerebrospinal fluid (CSF) volumes from 2D T1 images and compared with 3D T1 images. The performance of the models in differentiating DAT from CU was assessed using receiver operating characteristic analysis. Pearson's correlation analyses were used to evaluate the relations between 3D T1 and 2D T1 measurements of cortical thickness and CSF volumes, AD-specific atrophy similarity, W-scores, and BAIs., Results: Our deep learning models demonstrated strong correlations between 2D and 3D T1-derived CSF volumes, with correlation coefficients r ranging from 0.805 to 0.971. The algorithms based on 2D T1 accurately distinguished DAT from CU with high accuracy (area under the curve values of 0.873), which were comparable to those of algorithms based on 3D T1. Algorithms based on 2D T1 image-derived CSF volumes showed high correlations in AD-specific atrophy similarity ( r  = 0.915), W-scores for brain atrophy (0.732 ≤  r  ≤ 0.976), and BAIs ( r  = 0.821) compared with those based on 3D T1 images., Conclusion: Deep learning-based analysis of 2D T1 images is a feasible and accurate alternative for assessing brain atrophy, offering diagnostic precision comparable to that of 3D T1 imaging. This approach offers the advantage of the availability of T1-2D imaging, as well as reduced time and cost, while maintaining diagnostic precision comparable to T1-3D., Competing Interests: KK, SC, DN, and SS were employed by BeauBrain Healthcare, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Park, Park, Kwak, Choi, Kim, Na, Seo and Chun.)

The frequency of the apolipoprotein E ɛ4 allele and vascular risk factors differs among ethnic groups. We aimed to assess the combined effects of apolipoprotein E ɛ4 and vascular risk factors on brain age in Korean and UK cognitively unimpaired populations. We also aimed to determine the differences in the combined effects between the two populations. We enrolled 2314 cognitively unimpaired individuals aged ≥45 years from Korea and 6942 cognitively unimpaired individuals from the UK, who were matched using propensity scores. Brain age was defined using the brain age index. The apolipoprotein E genotype (ɛ4 carriers, ɛ2 carriers and ɛ3/ɛ3 homozygotes) and vascular risk factors (age, hypertension and diabetes) were considered predictors. Apolipoprotein E ɛ4 carriers in the Korean ( β = 0.511, P = 0.012) and UK ( β = 0.302, P = 0.006) groups had higher brain age index values. The adverse effects of the apolipoprotein E genotype on brain age index values increased with age in the Korean group alone (ɛ2 carriers × age, β = 0.085, P = 0.009; ɛ4 carriers × age, β = 0.100, P < 0.001). The apolipoprotein E genotype, age and ethnicity showed a three-way interaction with the brain age index (ɛ2 carriers × age × ethnicity, β = 0.091, P = 0.022; ɛ4 carriers × age × ethnicity, β = 0.093, P = 0.003). The effects of apolipoprotein E on the brain age index values were more pronounced in individuals with hypertension in the Korean group alone (ɛ4 carriers × hypertension, β = 0.777, P = 0.038). The apolipoprotein E genotype, age and ethnicity showed a three-way interaction with the brain age index (ɛ4 carriers × hypertension × ethnicity, β =1.091, P = 0.014). We highlight the ethnic differences in the combined effects of the apolipoprotein E ɛ4 genotype and vascular risk factors on accelerated brain age. These findings emphasize the need for ethnicity-specific strategies to mitigate apolipoprotein E ɛ4-related brain aging in cognitively unimpaired individuals., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Purpose: We developed a new digital cognitive assessment called Seoul Cognitive Status Test (SCST), formerly called Inbrain Cognitive Screening Test. The purpose of this study was to validate the clinical utility of the SCST by comparing its scores of those with subjective cognitive decline (SCD), amnestic mild cognitive impairment (aMCI), and dementia diagnosed by the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease Assessment Packet (CERAD-K)., Methods: All participants (n=296) who completed the CERAD-K, SCST, and Instrumental Activities of Daily Living tests were included in this study. Total score, cognitive domain scores, and subtest scores of the SCST were compared among the 3 groups (SCD, aMCI, and dementia). Additionally, correlations between SCST and CERAD-K subtests were examined., Results: Cognitive domain scores and total score of the SCST showed significant differences among the three groups, with scores being the highest in the order of SCD, aMCI, and dementia ( p <0.001). Most subtests of the SCST also showed higher scores in the order of SCD, aMCI, and dementia ( p <0.001). However, SCD and aMCI groups showed no significant differences in scores of the Phonemic Word Fluency Test ( p =0.083) or Korean Trail Making Test-Elderly version Part A ( p =0.434). Additionally, there was no significant difference in the score of Place Recognition ( p =0.274) of the Word-Place Association Test between aMCI and dementia groups., Conclusions: In conclusion, differences in total score, cognitive domain scores, and subtest scores of the SCST among the 3 groups of participants diagnosed using CERAD-K confirm the clinical utility of the SCST for cognitive assessment., Competing Interests: Conflict of Interest: Duk L. Na is one of the scientific co-founders of BeauBrain Healthcare, a company aiming to commercialize the SCST. Joon Soo Shin is employed at BeauBrain Healthcare and participated in the development of SCST. Duk L. Na and Joon Soo Shin had no role in the analysis and interpretation of the data. The remaining authors have no conflicts of interest to declare., (© 2024 Korean Dementia Association.)

Background: Risk factors for cardiovascular disease, including elevated blood pressure, are known to increase risk of Alzheimer's disease. There has been increasing awareness of the relationship between long-term blood pressure (BP) patterns and their effects on the brain. We aimed to investigate the association of repeated BP measurements with Alzheimer's and vascular disease markers., Methods: We recruited 1,952 participants without dementia between August 2015 and February 2022. During serial clinic visits, we assessed both systolic BP (SBP) and diastolic BP (DBP), and visit-to-visit BP variability (BPV) was quantified from repeated measurements. In order to investigate the relationship of mean SBP (or DBP) with Alzheimer's and vascular markers and cognition, we performed multiple linear and logistic regression analyses after controlling for potential confounders (Model 1). Next, we investigated the relationship of with variation of SBP (or DBP) with the aforementioned variables by adding it into Model 1 (Model 2). In addition, mediation analyses were conducted to determine mediation effects of Alzheimer's and vascular makers on the relationship between BP parameters and cognitive impairment., Results: High Aβ uptake was associated with greater mean SBP (β = 1.049, 95% confidence interval 1.016-1.083). High vascular burden was positively associated with mean SBP (odds ratio = 1.293, 95% CI 1.015-1.647) and mean DBP (1.390, 1.098-1.757). High tau uptake was related to greater systolic BPV (0.094, 0.001-0.187) and diastolic BPV (0.096, 0.007-0.184). High Aβ uptake partially mediated the relationship between mean SBP and the Mini-Mental State Examination (MMSE) scores. Hippocampal atrophy mediated the relationship between diastolic BPV and MMSE scores., Conclusions: Each BP parameter affects Alzheimer's and vascular disease markers differently, which in turn leads to cognitive impairment. Therefore, it is necessary to appropriately control specific BP parameters to prevent the development of dementia. Furthermore, a better understanding of pathways from specific BP parameters to cognitive impairments might enable us to select the managements targeting the specific BP parameters to prevent dementia effectively., (© 2024. The Author(s).)

Background: Predicting conversion to probable Alzheimer&s disease (AD) from amnestic mild cognitive impairment (aMCI) is difficult but important. A nomogram was developed previously for determining the risk of 3-year probable AD conversion in aMCI., Objective: To compare the probable AD conversion rates with cognitive and neurodegenerative changes for 2 years from high- and low risk aMCI groups classified using the nomogram., Methods: This prospective, multicenter, observational study was conducted in Korea. A total of patients were classified as high- or low-risk aMCI according to the nomogram and followed-up for 2 years to compare the annual conversion rate to probable AD and brain structure changes between the two groups., Results: In total, 176 (high-risk, 85; low-risk, 91) and 160 (high-risk, 77; low-risk, 83) patients completed the 1-year and 2-year follow-up, respectively. The probable AD conversion rate was significantly higher in the high-risk (Year 1, 28.9%; Year 2, 46.1%) versus low-risk group (Year 1, 0.0%; Year 2, 4.9%, both p < 0.0001). Mean changes from baseline in Seoul Neuropsychological Screening Battery-Dementia Version, Clinical Dementia Rating-Sum of Box, and Korean version of the Instrumental Activities of Daily Living scores and cortical atrophy index at Years 1 and 2 were significantly greater in the high-risk group (p < 0.0001)., Conclusions: The high-risk aMCI group, as determined by the nomogram, had a higher conversion rate to probable AD and faster cognitive decline and neurodegeneration change than the low-risk group. These real-world results have clinical implications that help clinicians in accurately predicting patient outcomes and facilitating early decision-making.Trial Registration: ClinicalTrials.gov (NCT03448445)., Competing Interests: Jieun Kim is an employee of Eisai Korea Inc. All of the other authors have nothing to declare., (© 2024 – The authors. Published by IOS Press.)

Objectives: Accurately predicting when patients with mild cognitive impairment (MCI) will progress to dementia is a formidable challenge. This work aims to develop a predictive deep learning model to accurately predict future cognitive decline and magnetic resonance imaging (MRI) marker changes over time at the individual level for patients with MCI., Methods: We recruited 657 amnestic patients with MCI from the Samsung Medical Center who underwent cognitive tests, brain MRI scans, and amyloid-β (Aβ) positron emission tomography (PET) scans. We devised a novel deep learning architecture by leveraging an attention mechanism in a recurrent neural network. We trained a predictive model by inputting age, gender, education, apolipoprotein E genotype, neuropsychological test scores, and brain MRI and amyloid PET features. Cognitive outcomes and MRI features of an MCI subject were predicted using the proposed network., Results: The proposed predictive model demonstrated good prediction performance (AUC = 0.814 ± 0.035) in five-fold cross-validation, along with reliable prediction in cognitive decline and MRI markers over time. Faster cognitive decline and brain atrophy in larger regions were forecasted in patients with Aβ (+) than with Aβ (-)., Conclusion: The proposed method provides effective and accurate means for predicting the progression of individuals within a specific period. This model could assist clinicians in identifying subjects at a higher risk of rapid cognitive decline by predicting future cognitive decline and MRI marker changes over time for patients with MCI. Future studies should validate and refine the proposed predictive model further to improve clinical decision-making., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Jung, Kim, Kim, Jang, Park, Kim, Na, Seo and Suk.)

Background and Purpose: Early- and late-onset Alzheimer's disease (EOAD and LOAD, respectively) share the same neuropathological hallmarks of amyloid and neurofibrillary tangles but have distinct cognitive features. We compared structural brain connectivity between the EOAD and LOAD groups using structural network efficiency and evaluated the association of structural network efficiency with the cognitive profile and pathological markers of Alzheimer's disease (AD)., Methods: The structural brain connectivity networks of 80 AD patients (47 with EOAD and 33 with LOAD) and 57 healthy controls were reconstructed using diffusion-tensor imaging. Graph-theoretic indices were calculated and intergroup differences were evaluated. Correlations between network parameters and neuropsychological test results were analyzed. The correlations of the amyloid and tau burdens with network parameters were evaluated for the patients and controls., Results: Compared with the age-matched control group, the EOAD patients had increased global path length and decreased global efficiency, averaged local efficiency, and averaged clustering coefficient. In contrast, no significant differences were found in the LOAD patients. Locally, the EOAD patients showed decreases in local efficiency and the clustering coefficient over a wide area compared with the control group, whereas LOAD patients showed such decreases only within a limited area. Changes in network parameters were significantly correlated with multiple cognitive domains in EOAD patients, but only with Clinical Dementia Rating Sum-of-Boxes scores in LOAD patients. Finally, the tau burden was correlated with changes in network parameters in AD signature areas in both patient groups, while there was no correlation with the amyloid burden., Conclusions: The impairment of structural network efficiency and its effects on cognition may differ between EOAD and LOAD., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2024 Korean Neurological Association.)

Importance: Repetitive transcranial magnetic stimulation (rTMS) has emerged as a safe and promising intervention for Alzheimer disease (AD)., Objective: To investigate the effect of a 4-week personalized hippocampal network-targeted rTMS on cognitive and functional performance, as well as functional connectivity in AD., Design, Setting, and Participants: This randomized clinical trial, which was sham-controlled and masked to participants and evaluators, was conducted between May 2020 and April 2022 at a single Korean memory clinic. Eligible participants were between ages 55 and 90 years and had confirmed early AD with evidence of an amyloid biomarker. Participants who met the inclusion criteria were randomly assigned to receive hippocampal network-targeted rTMS or sham stimulation. Participants received 4-week rTMS treatment, with assessment conducted at weeks 4 and 8. Data were analyzed between April 2022 and January 2024., Interventions: Each patient received 20 sessions of personalized rTMS targeting the left parietal area, functionally connected to the hippocampus, based on fMRI connectivity analysis over 4 weeks. The sham group underwent the same procedure, excluding actual magnetic stimulation. A personalized 3-dimensional printed frame to fix the TMS coil to the optimal target site was produced., Main Outcomes and Measures: The primary outcome was the change in the AD Assessment Scale-Cognitive Subscale test (ADAS-Cog) after 8 weeks from baseline. Secondary outcomes included changes in the Clinical Dementia Rating-Sum of Boxes (CDR-SOB) and Seoul-Instrumental Activity Daily Living (S-IADL) scales, as well as resting-state fMRI connectivity between the hippocampus and cortical areas., Results: Among 30 participants (18 in the rTMS group; 12 in the sham group) who completed the 8-week trial, the mean (SD) age was 69.8 (9.1) years; 18 (60%) were female. As the primary outcome, the change in ADAS-Cog at the eighth week was significantly different between the rTMS and sham groups (coefficient [SE], -5.2 [1.6]; P = .002). The change in CDR-SOB (-4.5 [1.4]; P = .007) and S-IADL (1.7 [0.7]; P = .004) were significantly different between the groups favoring rTMS groups. The fMRI connectivity analysis revealed that rTMS increased the functional connectivity between the hippocampus and precuneus, with its changes associated with improvements in ADAS-Cog (r = -0.57; P = .005)., Conclusions and Relevance: This randomized clinical trial demonstrated the positive effects of rTMS on cognitive and functional performance, and the plastic changes in the hippocampal-cortical network. Our results support the consideration of rTMS as a potential treatment for AD., Trial Registration: ClinicalTrials.gov Identifier: NCT04260724.

Background: Early-onset dementia (EOD, onset age < 65) and late-onset dementia (LOD, onset age ≥ 65) exhibit distinct features. Understanding the risk factors for dementia development and mortality in EOD and LOD respectively is crucial for personalized care. While risk factors are known for LOD development and mortality, their impact on EOD remains unclear. We aimed to investigate how hypertension, diabetes mellitus, hyperlipidemia, atrial fibrillation, and osteoporosis influence the development and mortality of EOD and LOD, respectively., Methods: Using the Korean National Health Insurance Service (NHIS) database, we collected 546,709 dementia-free individuals and followed up for 11 years. In the two study groups, the Younger group (< 65 years old) and the Older group (≥ 65 years old), we applied Cox proportional hazard models to assess risk factors for development of EOD and LOD, respectively. Then, we assessed risk factors for mortality among EOD and LOD., Results: Diabetes mellitus and osteoporosis increased the risk of EOD and LOD development. Hypertension increased the risk of EOD, while atrial fibrillation increased the risk of LOD. Conversely, hyperlipidemia exhibited a protective effect against LOD development. Additionally, diabetes mellitus increased mortality in EOD and LOD. Hypertension and atrial fibrillation increased mortality in LOD, while hyperlipidemia decreased mortality in EOD and LOD., Conclusions: Risk factors influencing dementia development and mortality differed in EOD and LOD. Targeted public health interventions addressing age-related risk factors may reduce dementia incidence and mortality., (© 2024. The Author(s).)

Early detection and intervention in individuals in the pre-clinical stage of dementia are crucial. This study aimed to examine whether there are significant differences in (1) word retrieval, (2) subjective communication ability, (3) intervention satisfaction through the 'Fill-in-the-blanks in editorial and newspaper articles' training in patients with subjective cognitive decline and mild cognitive impairment corresponding to the pre-clinical stage of dementia. Ninety-nine patients (50 in the intervention group and 49 in the control group) aged 50-84 years were administered pre- and post-test after 6 weeks of intervention (30 sessions). Regarding word retrieval, there were significant intervention effects on confrontation naming, semantic fluency, and phonemic fluency. The majority of participants in the intervention group were highly satisfied with the training. In terms of intervention satisfaction, the majority of the participants in the intervention group showed high satisfaction with all the questions. This result confirmed the improvement of word retrieval ability through mass communication content-based 'Fill-in-the-blanks' training, and ultimately helps to provide a clinical basis for applying this intervention to prevent dementia., (© 2024. The Author(s).)

We propose a hybrid technique that employs artificial intelligence (AI)-based segmentation and machine learning classification using multiple features extracted from the foveal avascular zone (FAZ)-a retinal biomarker for Alzheimer's disease-to improve the disease diagnostic performance. Imaging data of optical coherence tomography angiography from 37 patients with Alzheimer's disease and 48 healthy controls were investigated. The presence or absence of brain amyloids was confirmed using amyloid positron emission tomography. In the superficial capillary plexus of the angiography scans, the FAZ was automatically segmented using an AI method to extract multiple biomarkers (area, solidity, compactness, roundness, and eccentricity), which were paired with clinical data (age and sex) as common correction variables. We used a light-gradient boosting machine (a light-gradient boosting machine is a machine learning algorithm based on trees utilizing gradient boosting) to diagnose Alzheimer's disease by integrating the corresponding multiple radiomic biomarkers. Fivefold cross-validation was applied for analysis, and the diagnostic performance for Alzheimer's disease was determined by the area under the curve. The proposed hybrid technique achieved an area under the curve of [Formula: see text]%, outperforming the existing single-feature (area) criteria by over 13%. Furthermore, in the holdout test set, the proposed technique exhibited a 14% improvement compared to single features, achieving an area under the curve of 72.0± 4.8%. Based on these facts, we have demonstrated the effectiveness of our technology in achieving significant performance improvements in FAZ-based Alzheimer's diagnosis research through the use of multiple radiomic biomarkers (area, solidity, compactness, roundness, and eccentricity)., (© 2024. The Author(s).)

Background and Objective: We aimed to investigate the association between glycemic variability (GV) and neuroimaging markers of white matter hyperintensities (WMH), beta-amyloid (Aβ), brain atrophy, and cognitive impairment., Methods: This was a retrospective cohort study that included participants without dementia from a memory clinic. They all had Aβ PET, brain MRI, and standardized neuropsychological tests and had fasting glucose (FG) levels tested more than twice during the study period. We defined GV as the intraindividual visit-to-visit variability in FG levels. Multivariable linear regression and logistic regression were used to identify whether GV was associated with the presence of severe WMH and Aβ uptake with DM, mean FG levels, age, sex, hypertension, and presence of APOE4 allele as covariates. Mediation analyses were used to investigate the mediating effect of WMH and Aβ uptake on the relationship between GV and brain atrophy and cognition., Results: Among the 688 participants, the mean age was 72.2 years, and the proportion of female participants was 51.9%. Increase in GV was predictive of the presence of severe WMH (coefficient [95% CI] 1.032 [1.012-1.054]; p = 0.002) and increased Aβ uptake (1.005 [1.001-1.008]; p = 0.007). Both WMH and increased Aβ uptake partially mediated the relationship between GV and frontal-executive dysfunction (GV → WMH → frontal-executive; direct effect, -0.319 [-0.557 to -0.080]; indirect effect, -0.050 [-0.091 to -0.008]) and memory dysfunction (GV → Aβ → memory; direct effect, -0.182 [-0.338 to -0.026]; indirect effect, -0.067 [-0.119 to -0.015]), respectively. In addition, increased Aβ uptake completely mediated the relationship between GV and hippocampal volume (indirect effect, -1.091 [-2.078 to -0.103]) and partially mediated the relationship between GV and parietal thickness (direct effect, -0.00101 [-0.00185 to -0.00016]; indirect effect, -0.00016 [-0.00032 to -0.000002])., Discussion: Our findings suggest that increased GV is related to vascular and Alzheimer risk factors and neurodegenerative markers, which in turn leads to subsequent cognitive impairment. Furthermore, GV can be considered a potentially modifiable risk factor for dementia prevention.

Background: Amyloid-β (Aβ) commonly coexists and impacts prognosis in subcortical vascular cognitive impairment (SVCI)., Objective: This study aimed to examine the differences in clinical and neuroimaging variables between Aβ-positive and Aβ-negative SVCI and to propose a prediction model for Aβ positivity in clinically diagnosed SVCI patients., Methods: A total of 130 patients with SVCI were included in model development, and a separate cohort of 70 SVCI patients was used in external validation. The variables for the prediction model were selected by comparing the characteristics of the Aβ-negative and Aβ-positive SVCI groups. The final model was determined using a stepwise method. The model performance was evaluated using the receiver operating characteristic (ROC) curve and a calibration curve. A nomogram was used for visualization., Results: Among 130 SVCI patients, 70 (53.8%) were Aβ-positive. The Aβ-positive SVCI group was characterized by older age, tendency to be in the dementia stage, a higher prevalence of APOEɛ4, a lower prevalence of lacune, and more severe medial temporal atrophy (MTA). The final prediction model, which excluded MTA grade following the stepwise method for variable selection, demonstrated good accuracy in distinguishing between Aβ-positive and Aβ-negative SVCI, with an area under the curve (AUC) of 0.80. The external validation demonstrated an AUC of 0.71., Conclusions: The findings suggest that older age, dementia stage, APOEɛ4 carrier, and absence of lacunes may be predictive of Aβ positivity in clinically diagnosed SVCI patients.

Purpose: The CT-based regional direct comparison Centiloid (dcCL) method was developed to harmonize and quantify regional β-amyloid (Aβ) burden. In the present study, we aimed to investigate correlations between the CT-based regional dcCL scales and Aβ pathological burdens and to validate the clinical utility using thresholds derived from pathological assessment., Patients and Methods: We included a pathological cohort of 63 cases and a clinical cohort of 4062 participants, and obtained modified Consortium to Establish a Registry for Alzheimer's Disease criteria (mCERAD) scores by assessment of neuritic plaque burdens in multiple areas of each cortical region. PET and CT images were processed using the CT-based regional dcCL method to calculate scales in 6 distinct regions., Results: The CT-based regional dcCL scales were correlated with neuritic plaque burdens represented by mCERAD scores, globally and regionally ( r = 0.56~0.76). In addition, striatum dcCL scales reflected Aβ involvement in the striatum ( P < 0.001). The regional dcCL scales could predict significant Aβ deposition in specific brain regions with high accuracy: area under the receiver operating characteristic curve of 0.81-0.97 with an mCERAD cutoff of 1.5 and area under the receiver operating characteristic curve of 0.88-0.93 with an mCERAD cutoff of 0.5. When applying the dcCL thresholds of 1.5 mCERAD scores, the G(-)R(+) group showed lower performances in memory and global cognitive functions and had less hippocampal volume compared with the G(-)R(-) group ( P < 0.001). However, when applying the dcCL thresholds of 0.5 mCERAD scores, there were no differences in the global cognitive functions between the 2 groups., Conclusions: The thresholds of regional dcCL scales derived from pathological assessments might provide clinicians with a better understanding of biomarker-guided diagnosis and distinguishable clinical phenotypes, which are particularly useful when harmonizing different PET ligands with only PET/CT., Competing Interests: Conflicts of interest and sources of funding: The authors declare that they have no conflicts of interest. This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare and Ministry of science and ICT, Republic of Korea (grant number: HU20C0111, HU22C0170); the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF-2019R1A5A2027340); partly supported by Institute of Information & communications Technology Planning & Evaluation (IITP) grant funded by the Korea government (MSIT) (No.2021-0-02068, Artificial Intelligence Innovation Hub); Future Medicine 20*30 Project of the Samsung Medical Center [#SMX1230081]; the “Korea National Institute of Health” research project (2021-ER1006-02); the “Korea National Institute of Health” research project (2023-ER1001-00); the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF-2020R1A2C1009778); grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare and Ministry of science and ICT, Republic of Korea (grant number: HU20C0414). This work was supported by GE Healthcare and DuchemBio, Co, Ltd., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

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

Background: As the population ages and the prevalence of dementia increases, there is a growing emphasis on the importance of cognitive training to prevent dementia. A smartphone application-based cognitive training software program, BeauBrain Trainer (BBT), has been developed to provide better access to cognitive training for older adults. Numerous studies have revealed the effectiveness of cognitive training using a cognitive assessment tool. However, relatively few studies have evaluated brain activation using brain imaging as a result of improved cognitive function., Methods: All participants were required to download the BBT, an Android-based application for cognitive training, onto their own smartphone or tablet computer and to engage in cognitive training at home. Older adults without dementia were enrolled in this study, including 51 participants in the intervention group and 50 participants in the control group. The BBT comprised a set of 12 cognitive tasks, including two tasks in each of the following six cognitive domains: attention, language, calculation, visuospatial function, memory, and frontal/executive function. Each cognitive task was divided into four blocks based on its level of difficulty. A 16-week cognitive training was designed to carry out cognitive tasks using a total of 48 blocks (12 tasks × 4 levels) for at least 1.5 h per day, 5 days per week. All participants in the intervention group were given BBT tasks that gradually increased in difficulty level, which they submitted through a smartphone application daily for 16 weeks. The researchers monitored the participants' task performance records on the website and encouraged participants to engage in cognitive training through regular contact. This study was conducted to investigate the improvement in cognitive function and the activation pattern of the frontal cortex in older adults participating in smartphone application-based cognitive training. The cognitive assessment tool was the BeauBrain cognitive screening test (CST), a tablet-based computerized cognitive screening test. The activation pattern of the frontal cortex was measured using functional near-infrared spectroscopy (fNIRS). Additionally, this study aimed to determine the positive effects of cognitive training on everyday functioning and psychological states using a questionnaire., Results: Of 101 participants, 85 older adults without dementia (84.1%) who completed the study protocol were included in the statistical analysis. There were 41 participants (80.3%) in the intervention group and 44 participants (88.0%) in the control group. A two-way repeated-measures analysis of variance (ANOVA) was used to compare the cognitive scores over a 16-week period between the intervention and control groups. According to the CST results, the intervention group exhibited a statistically significant increase in the language subtest scores, specifically the phonemic word fluency test, compared to those of the control group. The fNIRS results revealed greater activation in the dorsolateral prefrontal cortex during the STROOP incongruent task in the intervention group than did the control group. However, the effectiveness of cognitive training was not observed across a variety of rating scales, including everyday functioning, depression, self-efficacy, attention, and subjective memory complaints., Conclusion: This study revealed that a smartphone-based cognitive training application led to improvements in phonemic generative naming ability and activation of the prefrontal cortex in older adults without dementia. This study is meaningful because it confirmed that cognitive training is partially effective in enhancing frontal lobe function. It also provided information on the brain mechanisms related to the effects of cognitive training using fNIRS., Competing Interests: IC, JihC, and JoC are employed at OBELAB, which is the company that produces fNIRS. JinC and DN were employed as co-researchers at BeauBrain Healthcare company, which is the company that produces the BeauBrain Trainer used in this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Cho, An, Cho, Kim, Choi, Cha, Choi, Na, Jang and Chin.)

Background: Visuospatial memory impairment is a common symptom of Alzheimer's disease; however, conventional visuospatial memory tests are insufficient to fully reflect visuospatial memory impairment in daily life., Methods: To address patients' difficulties in locating and recalling misplaced objects, we introduced a novel visuospatial memory test, the Hidden Objects Test (HOT), conducted in a virtual environment. We categorized HOT scores into prospective memory, item free-recall, place free-recall, item recognition, and place-item matching scores. To validate the VR memory test, we compared HOT scores among individuals with Alzheimer's disease (AD), amnestic mild cognitive impairment (aMCI), and normal controls (NC), and also compared these scores with those of conventional neuropsychological tests. We tracked the participants' movement paths in the virtual environment and assessed basic features, such as total distance, duration, and speed. Additionally, we performed walking trajectory pattern mining such as outlier and stay-point detection., Results: We designed and implemented the HOT to simulate a house's living room and assess participants' ability to locate hidden objects. Our preliminary results showed that the total HOT score differed among 17 patients with AD, 14 with aMCI, and 15 NC ( p  < 0.001). The total HOT score correlated positively with conventional memory test scores ( p  < 0.001). Walking trajectories showed that patients with AD and aMCI wandered rather than going straight to the hidden objects. In terms of basic features, the total duration was significantly greater in AD than in NC ( p  = 0.008). In terms of trajectory pattern mining, the number of outliers, which were over 95% of the estimated trajectory, was significantly higher in AD than in NC ( p  = 0.002). The number of stay points, an index in which participants stayed in the same position for more than 2 s, was significantly higher in patients with AD and aMCI compared with NC (AD vs. NC: p  = 0.003, aMCI vs. NC: p  = 0.019)., Conclusion: The HOT simulating real life showed potential as an ecologically valid test for assessing visuospatial memory function in daily life. Walking trajectory analysis suggested that patients with AD and aMCI wandered rather than going straight toward the hidden objects., Competing Interests: JDC is employed by Seers Technology Company Ltd. (Seongnam-si, Republic of Korea). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kim, Choi, Chin, Lee, Choi and Na.)

Background: Cholesterol plays important roles in β-amyloid (Aβ) metabolism and atherosclerosis. However, the relationships of plasma cholesterol levels with Aβ and cerebral small vessel disease (CSVD) burdens are not fully understood in Asians. Herein, we investigated the relationships between plasma cholesterol profile components and Aβ and CSVD burdens in a large, non-demented Korean cohort., Methods: We enrolled 1,175 non-demented participants (456 with unimpaired cognition [CU] and 719 with mild cognitive impairment [MCI]) aged ≥ 45 years who underwent Aβ PET at the Samsung Medical Center in Korea. We performed linear regression analyses with each cholesterol (low-density lipoprotein cholesterol [LDL-c], high-density lipoprotein cholesterol [HDL-c], and triglyceride) level as a predictor and each image marker (Aβ uptake on PET, white matter hyperintensity [WMH] volume, and hippocampal volume) as an outcome after controlling for potential confounders., Results: Increased LDL-c levels (β = 0.014 to 0.115, p = 0.013) were associated with greater Aβ uptake, independent of the APOE e4 allele genotype and lipid-lowering medication. Decreased HDL-c levels (β =  - 0.133 to - 0.006, p = 0.032) were predictive of higher WMH volumes. Increased LDL-c levels were also associated with decreased hippocampal volume (direct effect β =  - 0.053, p = 0.040), which was partially mediated by Aβ uptake (indirect effect β =  - 0.018, p = 0.006)., Conclusions: Our findings highlight that increased LDL-c and decreased HDL-c levels are important risk factors for Aβ and CSVD burdens, respectively. Furthermore, considering that plasma cholesterol profile components are potentially modified by diet, exercise, and pharmacological agents, our results provide evidence that regulating LDL-c and HDL-c levels is a potential strategy to prevent dementia., (© 2023. The Author(s).)

Background: Non-alcoholic fatty liver disease (NAFLD) is known to be associated with a high risk of clinically diagnosed Alzheimer's disease (AD). Additionally, the prevalence of NAFLD and AD is higher in elderly females than in males. However, a sex-specific association between NAFLD and amyloid-beta (Aβ) deposition remains unclear. Therefore, we investigated the sex-specific relationship between NAFLD and Aβ deposition in a large-sized cohort of cognitively unimpaired (CU) individuals., Methods: We enrolled 673 (410 [60.9%] females and 263 [39.1%] males) CU individuals aged ≥45 years who underwent Aβ positron emission tomography (PET). The presence of NAFLD, assessed using the hepatic steatosis index, and the severity of NAFLD, assessed using the Fibrosis-4 index, were considered predictors. Aβ deposition on PET was considered as an outcome., Results: Females had a higher frequency of NAFLD than males (48 and 23.2%, p  < 0.001). Among females, the presence of NAFLD (β = 0.216, p  < 0.001) was predictive of increased Aβ deposition, whereas among males, the presence of NAFLD (β = 0.191, p  = 0.064) was not associated with Aβ deposition. Among females, the presence of NAFLD with low (β = 0.254, p  = 0.039), intermediate (β = 0.201, p  = 0.006), and high fibrosis (β = 0.257, p  = 0.027) was predictive of increased Aβ deposition. Aβ deposition also increased as the severity of NAFLD increased in females ( p for trend = 0.001)., Conclusion: We highlight the marked influence of NAFLD and its severity on the risk of Aβ deposition in relation to sex. Furthermore, our findings suggest that sex-specific strategies regarding the management of NAFLD are necessary for the prevention of Aβ deposition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kang, Yoo, Cheon, Kim, Jang, Kim, Kang, Oh, Koh, Na, Chang and Seo.)

Introduction: Beta-amyloid (Aβ) deposition, a hallmark of Alzheimer's disease (AD), begins before dementia and is an important factor in mild cognitive impairment (MCI). Aβ deposition is a recognized risk factor for various cognitive impairments and has been reported to affect motor performance as well. This study aimed to identify the linguistic, visuospatial, and kinematic characteristics evident in the writing performance of patients with cognitive impairment (CI) who exhibit Aβ deposition., Methods: A total of 31 patients diagnosed with amnestic mild cognitive impairment (aMCI) with Aβ deposition, 26 patients with Alzheimer's-type dementia, and 33 healthy control (HC) participants without deposition were administered tasks involving dictation of 60 regular words, irregular words, and non-words consisting of 1-4 syllables. Responses from all participants were collected and analyzed through digitized writing tests and analysis tools., Results: In terms of linguistic aspects, as cognitive decline progressed, performance in the dictation of irregular words decreased, with errors observed in substituting the target grapheme with other graphemes. The aMCI group frequently exhibited corrective aspects involving letter rewriting during the task. In terms of visuospatial aspects, the AD group displayed more errors in grapheme combination compared to the HC group. Lastly, in the kinematic aspects, both the aMCI group and the AD group exhibited slower writing speeds compared to the HC group., Discussion: The findings suggest that individuals in the CI group exhibited lower performance in word dictation tasks than those in the HC group, and these results possibly indicate complex cognitive-language-motor deficits resulting from temporal-parietal lobe damage, particularly affecting spelling processing. These results provide valuable clinical insights into understanding linguistic-visuospatial-kinematic aspects that contribute to the early diagnosis of CI with Aβ deposition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 An, Jang, Kim, Na and Yoon.)

Background: Preclinical studies showed that mesenchymal stem cells (MSCs) ameliorate tau phosphorylation, amyloid-beta accumulation, and inflammation in Alzheimer's disease (AD) mouse models via secretion of neurotrophic factors and cytokines. We aimed to identify CSF biomarkers that can be used to predict or monitor the response to MSCs in patients with AD., Methods: AD patients were injected with human umbilical cord blood-MSCs (n = 22) or placebo (n = 12). The cerebrospinal fluid (CSF) samples were collected at baseline, one day after the first injection, and one day after the third injection. The patients injected with MSCs were classified into good responder (GR) or poor responder (PR) groups based on the rate of changes in the ratio of total-tau and phosphorylated-tau in the CSF. We selected three typical participants in each group, and their CSF protein levels were analyzed using liquid chromatography/tandem mass spectrometry (LC-MS/MS)., Results: In the LC-MS/MS analysis, 1,667 proteins were identified. Eleven proteins showed significant differences between the typical GR and PR at baseline. Based on their significance level and known functions, two proteins, reticulocalbin-3 (RCN3) and follistatin-related protein 3 (FSTL3), were selected as potential biomarkers to predict MSC response. A total of 173 proteins showed significant change one day after the third injection compared to the baseline in typical GR. We excluded 45 proteins that showed significant change after the third injection compared to the baseline in the typical PR. Based on their significance level and known function, four proteins, scrapie-responsive protein 1 (SCRG1), neural proliferation differentiation and control protein (NPDC1), apolipoprotein E (ApoE), and cystatin C (CysC), were selected as potential biomarker to monitor MSC response. Additionally, functional analysis revealed that the increased CSF proteins after the third injection compared to the baseline in the typical GR were associated with synaptogenesis., Conclusions: This study identified two proteins (RCN3 and FSTL3) that may be potential biomarkers for predicting MSC response and four proteins (SCRG1, NPDC1, ApoE, CysC) that may be potential biomarkers for monitoring MSC response in patients with AD. Further studies are needed to validate our results. Trial registration Clinical Trials.gov, NCT02054208. Registered on 4 February 2014. Samsung Medical Center IRB File No.2017-04-025. Registered on 20 June 2017., (© 2023. The Author(s).)

Background: We aimed to investigate the incidence of dementia by age and year as well as the population-attributable fractions (PAFs) for known dementia risk factors in Republic of Korea., Methods: A 12-year, nationwide, population-based, retrospective cohort study was conducted. We used customized health information from the National Health Insurance Service (NHIS) data from 2002 to 2017. We analyzed age- and sex-adjusted incidence rates and PAF of dementia for each risk factor such as depression, diabetes, hemorrhagic stroke, ischemic stroke, hypertension, osteoporosis and physical inactivity using Levin's formula., Results: Of the 794,448 subjects in the dementia-free cohort, 49,524 (6.2%) developed dementia. Dementia incidence showed annual growth from 1.56 per 1,000 person-years in 2006 to 6.94 per 1,000 person-years in 2017. Of all dementia cases, 34,544 subjects (69.8%) were female and 2,479 subjects (5.0%) were early onset dementia. AD dementia accounted for 66.5% of the total dementia incidence. Considering relative risk and prevalence, physical inactivity attributed the greatest to dementia (PAF, 8.1%), followed by diabetes (PAF, 4.2%), and hypertension (PAF, 2.9%). Altogether, the significant risk factors increased the risk of dementia by 18.0% (overall PAF)., Conclusion: We provided the incidence of dementia and PAFs for dementia risk factors in Republic of Korea using a 12-year, nationwide cohort. Encouraging lifestyle modifications and more aggressive control of risk factors may effectively prevent dementia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hwangbo, Lee, Han, Chun, Jang, Seo, Na, Won, Kim and Lim.)

Objective: Phosphodiesterase-5 inhibitors (PDE5Is) enhance vasodilation. We investigated the effects of PDE5I on cerebral hemodynamics during cognitive tasks using functional near-infrared spectroscopy (fNIRS)., Methods: This study used a crossover design. Twelve cognitively healthy men participants (mean age, 59 ± 3 years; range, 55-65 years) were recruited and randomly assigned to the experimental or control arm, then the experimental and control arm were exchanged after 1 week. Udenafil 100 mg was administered to participants in the experimental arm once daily for 3 days. We measured the fNIRS signal during the resting state and four cognitive tasks three times for each participant: at baseline, in the experimental arm, and in the control arm., Results: Behavioral data did not show a significant difference between the experimental and control arms. The fNIRS signal showed significant decreases in the experimental arm compared to the control arm during several cognitive tests: verbal fluency test (left dorsolateral prefrontal cortex, T = -3.02, p = 0.014; left frontopolar cortex, T = -4.37, p = 0.002; right dorsolateral prefrontal cortex, T = -2.59, p = 0.027), Korean-color word Stroop test (left orbitofrontal cortex, T = -3.61, p = 0.009), and social event memory test (left dorsolateral prefrontal cortex, T = -2.35, p = 0.043; left frontopolar cortex, T = -3.35, p = 0.01)., Interpretation: Our results showed a paradoxical effect of udenafil on cerebral hemodynamics in older adults. This contradicts our hypothesis, but it suggests that fNIRS is sensitive to changes in cerebral hemodynamics in response to PDE5Is., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: The genetic basis of amyloid β (Aβ) deposition in subcortical vascular cognitive impairment (SVCI) is still unknown. Here, we investigated genetic variants involved in Aβ deposition in patients with SVCI., Methods: We recruited a total of 110 patients with SVCI and 424 patients with Alzheimer's disease-related cognitive impairment (ADCI), who underwent Aβ positron emission tomography and genetic testing. Using candidate AD-associated single nucleotide polymorphisms (SNPs) that were previously identified, we investigated Aβ-associated SNPs that were shared or distinct between patients with SVCI and those with ADCI. Replication analyses were performed using the Alzheimer's Disease Neuroimaging Initiative (ADNI) and Religious Orders Study and Rush Memory and Aging Project cohorts (ROS/MAP)., Results: We identified a novel SNP, rs4732728, which showed distinct associations with Aβ positivity in patients with SVCI ( P interaction = 1.49 × 10 -5 ); rs4732728 was associated with increased Aβ positivity in SVCI but decreased Aβ positivity in ADCI. This pattern was also observed in ADNI and ROS/MAP cohorts. Prediction performance for Aβ positivity in patients with SVCI increased (area under the receiver operating characteristic curve = 0.780; 95% confidence interval = 0.757-0.803) when rs4732728 was included. Cis-expression quantitative trait loci analysis demonstrated that rs4732728 was associated with EPHX2 expression in the brain (normalized effect size = -0.182, P = 0.005)., Conclusion: The novel genetic variants associated with EPHX2 showed a distinct effect on Aβ deposition between SVCI and ADCI. This finding may provide a potential pre-screening marker for Aβ positivity and a candidate therapeutic target for SVCI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kim, Jung, Kim, Kim, Jang, Kim, Kim, Na, Kim, Nho, Won and Seo.)

The spatiotemporal pattern of the spread of pathologically modified tau through brain regions in Alzheimer's disease (AD) can be explained by prion-like cell-to-cell seeding and propagation of misfolded tau aggregates. Hence, to develop targeted therapeutic antibodies, it is important to identify the seeding- and propagation-competent tau species. The hexapeptide 275VQIINK280 of tau is a critical region for tau aggregation, and K280 is acetylated in various tauopathies, including AD. However, the mechanism that links tau acetylated on lysine 280 (tau-acK280) to subsequent progression to neurodegenerative disease remains unclear. Here, we demonstrate that tau-acK280 is critical for tau propagation processes including secretion, aggregation, and seeding. We developed an antibody, Y01, that specifically targets tau-acK280 and solved the crystal structure of Y01 in complex with an acK280 peptide. The structure confirmed that Y01 directly recognizes acK280 and the surrounding residues. Strikingly, upon interaction with acetylated tau aggregates, Y01 prevented tauopathy progression and increased neuronal viability in neuron cultures and in tau-Tg mice through antibody-mediated neutralization and phagocytosis, respectively. Based on our observations that tau-acK280 is a core species involved in seeding and propagation activities, the Y01 antibody that specifically recognizes acK280 represents a promising therapeutic candidate for AD and other neurodegenerative diseases associated with tauopathy.

Background: A growing body of evidence shows differences in the prevalence of cardiometabolic syndrome (CMS) and dementia based on gender and ethnicity. However, there is a paucity of information about ethnic- and gender-specific CMS effects on brain age. We investigated the different effects of CMS on brain age by gender in Korean and British cognitively unimpaired (CU) populations. We also determined whether the gender-specific difference in the effects of CMS on brain age changes depending on ethnicity., Methods: These analyses used de-identified, cross-sectional data on CU populations from Korea and United Kingdom (UK) that underwent brain MRI. After propensity score matching to balance the age and gender between the Korean and UK populations, 5759 Korean individuals (3042 males and 2717 females) and 9903 individuals from the UK (4736 males and 5167 females) were included in this study. Brain age index (BAI), calculated by the difference between the predicted brain age by the algorithm and the chronological age, was considered as main outcome and presence of CMS, including type 2 diabetes mellitus (T2DM), hypertension, obesity, and underweight was considered as a predictor. Gender (males and females) and ethnicity (Korean and UK) were considered as effect modifiers., Results: The presence of T2DM and hypertension was associated with a higher BAI regardless of gender and ethnicity (p < 0.001), except for hypertension in Korean males (p = 0.309). Among Koreans, there were interaction effects of gender and the presence of T2DM (p for T2DM*gender = 0.035) and hypertension (p for hypertension*gender = 0.046) on BAI in Koreans, suggesting that T2DM and hypertension are each associated with a higher BAI in females than in males. In contrast, among individuals from the UK, there were no differences in the effects of T2DM (p for T2DM*gender = 0.098) and hypertension (p for hypertension*gender = 0.203) on BAI between males and females., Conclusions: Our results highlight gender and ethnic differences as important factors in mediating the effects of CMS on brain age. Furthermore, these results suggest that ethnic- and gender-specific prevention strategies may be needed to protect against accelerated brain aging., (© 2023. The Author(s).)

Background: Early detection of β-amyloid (Aβ) accumulation, a major biomarker for Alzheimer's disease (AD), has become important. As fluid biomarkers, the accuracy of cerebrospinal fluid (CSF) Aβ for predicting Aβ deposition on positron emission tomography (PET) has been extensively studied, and the development of plasma Aβ is beginning to receive increased attention recently. In the present study, we aimed to determine whether APOE genotypes, age, and cognitive status increase the predictive performance of plasma Aβ and CSF Aβ levels for Aβ PET positivity., Methods: We recruited 488 participants who underwent both plasma Aβ and Aβ PET studies (Cohort 1) and 217 participants who underwent both cerebrospinal fluid (CSF) Aβ and Aβ PET studies (Cohort 2). Plasma and CSF samples were analyzed using ABtest-MS, an antibody-free liquid chromatography-differential mobility spectrometry-triple quadrupole mass spectrometry method and INNOTEST enzyme-linked immunosorbent assay kits, respectively. To evaluate the predictive performance of plasma Aβ and CSF Aβ, respectively, logistic regression and receiver operating characteristic analyses were performed., Results: When predicting Aβ PET status, both plasma Aβ42/40 ratio and CSF Aβ42 showed high accuracy (plasma Aβ area under the curve (AUC) 0.814; CSF Aβ AUC 0.848). In the plasma Aβ models, the AUC values were higher than plasma Aβ alone model, when the models were combined with either cognitive stage ( p  < 0.001) or APOE genotype ( p  = 0.011). On the other hand, there was no difference between the CSF Aβ models, when these variables were added., Conclusion: Plasma Aβ might be a useful predictor of Aβ deposition on PET status as much as CSF Aβ, particularly when considered with clinical information such as APOE genotype and cognitive stag e ., Competing Interests: JA, LS, SC, and MP-L are full-time employees of Araclon Biotech-Grifols, the manufacturer of the mass spectrometry test (ABtest-MS). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chun, Jang, Kim, Kim, Gallacher, Allué, Sarasa, Castillo, Pascual-Lucas, Na, Seo and on behalf of DPUK.)