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Abstract Despite the growing interest in precision medicine-based therapies for Alzheimer's disease (AD), little research has been conducted on how individual AD risk factors influence changes in cognitive function following transcranial direct current stimulation (tDCS). This study evaluates the cognitive effects of sequential tDCS on 63 mild cognitive impairment (MCI) patients, considering AD risk factors such as amyloid-beta deposition, APOE ε4, BDNF polymorphism, and sex. Using both frequentist and Bayesian methods, we assessed the interaction of tDCS with these risk factors on cognitive performance. Notably, we found that amyloid-beta deposition significantly interacted with tDCS in improving executive function, specifically Stroop Word-Color scores, with strong Bayesian support for this finding. Memory enhancements were differentially influenced by BDNF Met carrier status. However, sex and APOE ε4 status did not show significant effects. Our results highlight the importance of individual AD risk factors in modulating cognitive outcomes from tDCS, suggesting that precision medicine may offer more effective tDCS treatments tailored to individual risk profiles in early AD stages.

Abstract Alzheimer’s disease (AD) accounts for 60–70% of the population with dementia. Mild cognitive impairment (MCI) is a diagnostic entity defined as an intermediate stage between subjective cognitive decline and dementia, and about 10–15% of people annually convert to AD. We aimed to investigate the most robust model and modality combination by combining multi-modality image features based on demographic characteristics in six machine learning models. A total of 196 subjects were enrolled from four hospitals and the Alzheimer’s Disease Neuroimaging Initiative dataset. During the four-year follow-up period, 47 (24%) patients progressed from MCI to AD. Volumes of the regions of interest, white matter hyperintensity, and regional Standardized Uptake Value Ratio (SUVR) were analyzed using T1, T2-weighted-Fluid-Attenuated Inversion Recovery (T2-FLAIR) MRIs, and amyloid PET (αPET), along with automatically provided hippocampal occupancy scores (HOC) and Fazekas scales. As a result of testing the robustness of the model, the GBM model was the most stable, and in modality combination, model performance was further improved in the absence of T2-FLAIR image features. Our study predicts the probability of AD conversion in MCI patients, which is expected to be useful information for clinician’s early diagnosis and treatment plan design.

BackgroundThe interrelation between infections, subjective cognitive decline (SCD), and dementia development is recognized, but not fully understood. This study explored the combined effect of specific infections and SCD on the risk of dementia.ObjectivesTo assess the influence of Helicobacter pylori, herpes simplex virus, varicella-zoster virus, and human papillomavirus on dementia risk in individuals with varying cognitive statuses, especially focusing on those with and without SCD.MethodsA cohort of 1,100,540 participants aged 66 years from the Korean National Health Insurance Service was divided into cognitively preserved (CP, n = 825,405) and SCD (n = 275,135) groups. This study analyzed the effects of single, dual, and triple infections on the risk of overall dementia, Alzheimer’s disease (AD), and vascular dementia (VaD) using incidence rates and hazard ratios.ResultsThe SCD group consistently showed a doubled risk of dementia, particularly AD, regardless of the number of infections. In the initial data, both the presence and number of infections, especially in the CP group, were associated with an increased dementia incidence and risk; however, this correlation disappeared after adjusting for covariates, hinting at a possible protective effect.ConclusionOur findings emphasize that, while SCD is a steadfast risk factor for dementia, the role of infections is layered, subject to various influences, and requires more comprehensive exploration to fully understand their impact on dementia development.

BackgroundAlzheimer’s disease (AD) encompasses a spectrum that may progress from mild cognitive impairment (MCI) to full dementia, characterized by amyloid-beta and tau accumulation. Transcranial direct current stimulation (tDCS) is being investigated as a therapeutic option, but its efficacy in relation to individual genetic and biological risk factors remains underexplored.ObjectiveTo evaluate the effects of a two-week anodal tDCS regimen on the left dorsolateral prefrontal cortex, focusing on functional connectivity changes in neural networks in MCI patients resulting from various possible underlying disorders, considering individual factors associated to AD such as amyloid-beta deposition, APOE ϵ4 allele, BDNF Val66Met polymorphism, and sex.MethodsIn a single-arm prospective study, 63 patients with MCI, including both amyloid-PET positive and negative cases, received 10 sessions of tDCS. We assessed intra- and inter-network functional connectivity (FC) using fMRI and analyzed interactions between tDCS effects and individual factors associated to AD.ResultstDCS significantly enhanced intra-network FC within the Salience Network (SN) and inter-network FC between the Central Executive Network and SN, predominantly in APOE ϵ4 carriers. We also observed significant sex*tDCS interactions that benefited inter-network FC among females. Furthermore, the effects of multiple modifiers, particularly the interaction of the BDNF Val66Met polymorphism and sex, were evident, as demonstrated by increased intra-network FC of the SN in female Met non-carriers. Lastly, the effects of tDCS on FC did not differ between the group of 26 MCI patients with cerebral amyloid-beta deposition detected by flutemetamol PET and the group of 37 MCI patients without cerebral amyloid-beta deposition.ConclusionsThe study highlights the importance of precision medicine in tDCS applications for MCI, suggesting that individual genetic and biological profiles significantly influence therapeutic outcomes. Tailoring interventions based on these profiles may optimize treatment efficacy in early stages of AD.

Abstract Background Multimer detection system-oligomeric amyloid-β (MDS-OAβ) is a measure of plasma OAβ, which is associated with Alzheimer’s disease (AD) pathology. However, the relationship between MDS-OAβ and disease severity of AD is not clear. We aimed to investigate MDS-OAβ levels in different stages of AD and analyze the association between MDS-OAβ and cerebral Aβ deposition, cognitive function, and cortical thickness in subjects within the AD continuum. Methods In this cross-sectional study, we analyzed a total 126 participants who underwent plasma MDS-OAβ, structural magnetic resonance image of brain, and neurocognitive measures using Korean version of the Consortium to Establish a Registry for Alzheimer’s Disease, and cerebral Aβ deposition or amyloid positron emission tomography (A-PET) assessed by [18F] flutemetamol PET. Subjects were divided into 4 groups: N = 39 for normal control (NC), N = 31 for A-PET-negative mild cognitive impairment (MCI) patients, N = 30 for A-PET-positive MCI patients, and N = 22 for AD dementia patients. The severity of cerebral Aβ deposition was expressed as standard uptake value ratio (SUVR). Results Compared to the NC (0.803 ± 0.27), MDS-OAβ level was higher in the A-PET-negative MCI group (0.946 ± 0.137) and highest in the A-PET-positive MCI group (1.07 ± 0.17). MDS-OAβ level in the AD dementia group was higher than in the NC, but it fell to that of the A-PET-negative MCI group level (0.958 ± 0.103). There were negative associations between MDS-OAβ and cognitive function and both global and regional cerebral Aβ deposition (SUVR). Cortical thickness of the left fusiform gyrus showed a negative association with MDS-OAβ when we excluded the AD dementia group. Conclusions These findings suggest that MDS-OAβ is not only associated with neurocognitive staging, but also with cerebral Aβ burden in patients along the AD continuum.

IntroductionTranscranial direct current stimulation (tDCS) may effectively preserve and improve cognitive function in patients with mild cognitive impairment (MCI). Research has shown that Individual brain characteristics can influence the effects of tDCS. Computer three-dimensional brain modeling based on magnetic resonance imaging (MRI) has been suggested as an alternative for determining the most accurate tDCS electrode position based on the patients’ individual brain characteristics to enhance tDCS effects. Therefore, this study aims to determine the feasibility and safety of applying tDCS treatment using optimized and personalized tDCS electrode positions in patients with Alzheimer’s disease (AD)-induced MCI using computer modeling and compare the results with those of a sham group to improve cognitive function.MethodA prospective active-sham group feasibility study was set to recruit 40 participants, who will be randomized into Optimized-tDCS and Sham-tDCS groups. The parameters for tDCS will be 2 mA (disk electrodes R = 1.5 cm) for 30 min during two sets of 15 sessions (2 weeks of resting period in between), using two electrodes in pairs. Using computer modeling, the tDCS electrode positions of each participant will be personalized. Outcome measurements are going to be obtained at three points: baseline, first post-test, and second post-test. The AD assessment scale-cognitive subscale (ADAS-Cog) and the Korean version of Mini-Mental State Examination (K-MMSE), together with other secondary outcomes and safety tests will be used.DiscussionFor the present study, we hypothesize that compared to a sham group, the optimized personalized tDCS application would be effective in improving the cognitive function of patients with AD-induced MCI and the participants would tolerate the tDCS intervention without any significant adverse effects.Clinical trial registration: https://cris.nih.go.kr, identifier [KCT0008918].

Accurate quantification of amyloid positron emission tomography (PET) is essential for early detection of and intervention in Alzheimer’s disease (AD) but there is still a lack of studies comparing the performance of various automated methods. This study compared the PET-only method and PET-and-MRI-based method with a pre-trained deep learning segmentation model. A large sample of 1180 participants in the Catholic Aging Brain Imaging (CABI) database was analyzed to calculate the regional standardized uptake value ratio (SUVR) using both methods. The logistic regression models were employed to assess the discriminability of amyloid-positive and negative groups through 10-fold cross-validation and area under the receiver operating characteristics (AUROC) metrics. The two methods showed a high correlation in calculating SUVRs but the PET-MRI method, incorporating MRI data for anatomical accuracy, demonstrated superior performance in predicting amyloid-positivity. The parietal, frontal, and cingulate importantly contributed to the prediction. The PET-MRI method with a pre-trained deep learning model approach provides an efficient and precise method for earlier diagnosis and intervention in the AD continuum.

BackgroundEducation years, as a measure of cognitive reserve, have been shown to affect the progression of Alzheimer’s disease (AD), both pathologically and clinically. However, inconsistent results have been reported regarding the association between years of education and intermediate structural changes in AD-vulnerable brain regions, particularly when AD risk factors were not considered during the preclinical phase.ObjectiveThis study aimed to examine how Aβ deposition and APOE ε4 carrier status moderate the relationship between years of education and cortical volume in AD-vulnerable regions among cognitively normal older adults.MethodsA total of 121 participants underwent structural MRI, [18F] flutemetamol PET-CT imaging, and neuropsychological battery assessment. Multiple regression analysis was conducted to examine the interaction between years of education and the effects of potential modifiers on cortical volume. The associations between cortical volume and neuropsychological performance were further explored in subgroups categorized based on AD risk factors.ResultsThe cortical volume of the left lateral occipital cortex and bilateral fusiform gyrus demonstrated a significant differential association with years of education, depending on the presence of Aβ deposition and APOE ε4 carrier status. Furthermore, a significant relationship between the cortical volume of the bilateral fusiform gyrus and AD-nonspecific cognitive function was predominantly observed in individuals without AD risk factors.ConclusionAD risk factors exerted varying influences on the association between years of education and cortical volume during the preclinical phase. Further investigations into the long-term implications of these findings would enhance our understanding of cognitive reserves in the preclinical stages of AD.

BackgroundLittle research exists on how individual risk factors for Alzheimer’s disease (AD) affect the intermediate phenotype after transcranial direct current stimulation (tDCS), despite the importance of precision medicine-based therapeutic approaches.ObjectiveTo determine how an application of sequential tDCS (2 mA/day, left dorsolateral prefrontal cortex, 10 sessions) affects changes in white matter (WM) microstructure integrity in 63 mild cognitive impairment (MCI) patients with effect modifiers such as Aβ deposition, APOE ε4 carrier status, BDNF Val66Met polymorphism status, and sex.MethodsWe examined individual effect modifier-by-tDCS interactions and multiple effect modifiers-by-tDCS interactions for diffusion metrics. We also evaluated the association between baseline Aβ deposition and changes in WM microstructure integrity following tDCS.ResultsWe found that APOE ε4 carrier status and sex had a significant interaction with tDCS, resulting in increased fractional anisotropy (FA) in the right uncinate fasciculus (UF) after stimulation. Additionally, we observed multiple effect modifiers-by-tDCS interactions on WM integrity of the right UF, leading to a more pronounced increase in FA values in APOE ε4 carriers and females with Val66 homozygotes. Finally, baseline Aβ deposition was positively associated with a difference in FA of the left cingulum in the hippocampal area, which showed a positive association with the changes in the score for delayed memory.ConclusionOur study shows the differential impact of individual AD risk factors on changes in the early intermediate phenotype after sequential tDCS in MCI patients. This research emphasizes the importance of precision medicine approaches in tDCS for the prodromal stages of AD.

Abstract It is clear that matter is dominant in the Universe compared to antimatter. We call this problem baryon asymmetry. The baryon asymmetry is experimentally determined by both cosmic microwave background and big bang nucleosynthesis measurements. To resolve the baryon number asymmetry of the Universe as well as neutrino oscillations, we study a radiative seesaw model in a modular A 4 symmetry. Degenerate heavy Majorana neutrino masses can be naturally realized in an appropriate assignments under modular A 4 with large imaginary part of modulus τ, and it can induce measured baryon number via resonant leptogenesis that is valid in around TeV scale energy theory. We also find that the dominant contribution to the CP asymmetry arises from Re[τ] through our numerical analysis satisfying the neutrino oscillation data.

We introduce DeeLeMa, a deep learning-based network for the analysis of energy and momentum in high-energy particle collisions. This novel approach is specifically designed to address the challenge of analyzing collision events with multiple invisible particles, which are prevalent in many high-energy physics experiments. DeeLeMa is constructed based on the kinematic constraints and symmetry of the event topologies. We show that DeeLeMa can robustly estimate mass distribution even in the presence of combinatorial uncertainties and detector smearing effects. The approach is flexible and can be applied to various event topologies by leveraging the relevant kinematic symmetries. This work opens up exciting opportunities for the analysis of high-energy particle collision data, and we believe that DeeLeMa has the potential to become a valuable tool for the high-energy physics community.

Recent studies have demonstrated the pivotal role of locus coeruleus (LC) and salience network (SN) resting state functional connectivity (rsFC) changes in the early stage of Alzheimer’s disease (AD). Moreover, sex has been a crucial point of discussion in understanding AD pathology. We aimed to demonstrate the sex-related disparities in the functional connectivity (FC) of the SN and LC in preclinical AD. A total of 89 cognitively normal patients with evidence of amyloid beta (Aβ) accumulation ([18F] flutemetamol +) were recruited in the study. A seed-to-voxel analysis was conducted to measure the LC and SN rsFC differences between sexes. In addition, sex by Aβ interactive effects on FC values were analyzed with a general linear model. There were statistically significant sex by regional standardized uptake value ratio (SUVR) interactions in the LC FC with the parietal, frontal, and occipital cortices. Moreover, there was a significant sex by global SUVR interaction in the SN FC with the temporal cortex. The findings suggest that there are differential patterns of LC FC and SN FC in males and females with preclinical AD, which interact with regional Aβ deposition.

Olfactory dysfunction is consistently observed in individuals with Alzheimer’s disease (AD), but its association with beta-amyloid (Aβ) deposition remains unclear. This study aimed to investigate the relationship among olfactory function, cerebral Aβ deposition, and neuropsychological profiles in individuals with no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD dementia. A total of 164 participants were included, and olfactory function was assessed using the brief smell identification test (B-SIT). Cerebral Aβ deposition was measured using [18F]-flutemetamol PET imaging (A-PET). The results show a significant group difference in olfactory function, with the highest impairment observed in the Aβ-positive MCI and AD dementia groups, and the impairment was the lowest in Aβ-negative NCI. Olfactory dysfunction was positively associated with cognitive impairments across multiple domains. Furthermore, individuals with Aβ deposition had lower olfactory function compared to those without Aβ, even within the same neuropsychological stage. The association between olfactory dysfunction and Aβ deposition was observed globally and in specific cortical regions. These findings suggest that olfactory dysfunction is associated with both cognitive function and cerebral Aβ pathology in the trajectory of AD. Olfactory deficits may serve as an additional marker for disease progression and contribute to understanding the underlying mechanisms of AD.

Mild cognitive impairment (MCI) is an intermediate stage between normal aging and dementia, and a significant number of individuals with MCI progress to develop dementia. Depression is prevalent in MCI patients and has been found to influence the disease progression of MCI. The default mode network (DMN), a brain network associated with Alzheimer’s disease (AD), and its functional connectivity might be a neurological mechanism linking depression and AD. However, the relationship between depression, DMN functional connectivity, and cerebral beta-amyloid (Aβ) pathology remains unclear. This study aimed to investigate DMN functional connectivity differences in Aβ-positive MCI patients with depression compared to those without depression. A total of 126 Aβ-positive MCI patients were included, with 66 having depression and 60 without depression. The results revealed increased functional connectivity in the anterior DMN in the depression group compared to the non-depression group. The functional connectivity of the anterior DMN positively correlated with depression severity but not with Aβ deposition. Our findings suggest that depression influences DMN functional connectivity in Aβ-positive MCI patients, and the depression-associated DMN functional connectivity aberrance might be an important neural mechanism linking depression, Aβ pathology, and disease progression in the trajectory of AD.

The ε2 allele of apolipoprotein E (ε2) has neuroprotective effects against beta-amyloid (Aβ) pathology in Alzheimer’s disease (AD). However, its impact on the functional connectivity and hub efficiency in cognitively normal older adults (CN) with ε2 is unclear. We investigated the functional connectivity differences in the default mode network (DMN), salience network, and central executive network (CEN) between A-PET-negative (N = 29) and A-PET-positive (N = 15) CNs with ε2/ε2 or ε2/ε3 genotypes. The A-PET-positive CNs exhibited a lower anterior DMN functional connectivity, higher posterior DMN functional connectivity, and increased CEN functional connectivity compared to the A-PET-negative CNs. Cerebral Aβ retention was negatively correlated with anterior DMN functional connectivity and positively correlated with posterior DMN and anterior CEN functional connectivity. A graph theory analysis showed that the A-PET-positive CNs displayed a higher betweenness centrality in the middle frontal gyrus (left) and medial fronto-parietal regions (left). The betweenness centrality in the middle frontal gyrus (left) was positively correlated with Aβ retention. Our findings reveal a reversed anterior–posterior dissociation in the DMN functional connectivity and heightened CEN functional connectivity in A-PET-positive CNs with ε2. Hub efficiencies, measured by betweenness centrality, were increased in the DMN and CEN of the A-PET-positive CNs with ε2. These results suggest unique functional connectivity responses to Aβ pathology in CN individuals with ε2.

Abstract The inelastic dark matter model is one kind of popular models for the light dark matter (DM) below O(1) GeV. If the mass splitting between DM excited and ground states is small enough, the co-annihilation becomes the dominant channel for thermal relic density and the DM excited state can be long-lived at the collider scale. We study scalar and fermion inelastic dark matter models for O $$ \mathcal{O} $$ (1) GeV DM at Belle II with U(1) D dark gauge symmetry broken into its Z 2 subgroup. We focus on dilepton displaced vertex signatures from decays of the DM excited state. With the help of precise displaced vertex detection ability at Belle II, we can explore the DM spin, mass and mass splitting between DM excited and ground states. Especially, we show scalar and fermion DM candidates can be discriminated and the mass and mass splitting of DM sector can be determined within the percentage of deviation for some benchmark points. Furthermore, the allowed parameter space to explain the excess of muon (g − 2) μ is also studied and it can be covered in our displaced vertex analysis during the early stage of Belle II experiment.

BackgroundTransdermal trigeminal electrical neuromodulation (TTEN) is a novel treatment modality that is known for noradrenergic modulation through the trigeminal nerve and locus coeruleus (LC). This study aimed to demonstrate the alterations of LC functional connectivity (FC) in patients with insomnia after a 4-week TTEN.MethodsThe Cefaly device targeting the ophthalmic division of the trigeminal nerve was applied to a total of 12 patients with insomnia to monitor for the effects of TTEN. All the patients went through a 4-week daily 20 min TTEN sessions before bedtime. Baseline and post-TTEN demographic data, polysomnography (PSG) parameters, and insomnia severity index (ISI) were attained. Data from pre- and post-intervention resting-state functional magnetic resonance imaging (MRI) were collected. LC FC differences were measured between the pre-and post-TTEN groups through seed-to-voxel analysis. Correlation analyses were conducted between LC FC changes after TTEN, ISI score changes, and PSG parameter changes.ResultsThere was a significantly decreased LC FC with occipital and temporal cortices after a 4-week TTEN. However, there was no significant correlation between LC FC, ISI score changes, and PSG parameter changes.ConclusionBy targeting hyperarousal symptoms of insomnia, TTEN can be a promising intervention that can modulate LC FC in patients with insomnia patients. The data presented in the study are from a study exploring the effect of TTEN on insomnia (www.clinicaltrials.gov, NCT04838067).

BackgroundA growing body of evidence suggests a deteriorating effect of subthreshold amyloid-beta (Aβ) accumulation on cognition before the onset of clinical symptoms of Alzheimer's disease (AD). Despite the association between the Aβ-dependent pathway and the APOE ε4 allele, the impact of this allele on the progression from the subthreshold Aβ deposits to cognitive function impairment is unclear. Furthermore, the comparative analysis of positive Aβ accumulation in the preclinical phase is lacking.ObjectiveThis study aimed to explore the differential effect of the APOE ε4 carrier status on the association between Aβ deposition, resting-state brain function, and cognitive performance in cognitively normal (CN) older adults, depending on the Aβ burden status.MethodsOne hundred and eighty-two older CN adults underwent resting-state functional magnetic resonance imaging, [18F] flutemetamol (FMM) positron emission tomography, a neuropsychological battery, and APOE genotyping. We evaluated the resting-state brain function by measuring the local and remote functional connectivity (FC) and measured the remote FC in the default-mode network (DMN), central-executive network (CEN), and salience network (SN). In addition, the subjects were dichotomized into those with subthreshold and positive Aβ deposits using a neocortical standardized uptake value ratio with the cut-off value of 0.62, which was calculated with respect to the pons.ResultsThe present result showed that APOE ε4 carrier status moderated the relationship between Aβ deposition, local and remote resting-state brain function, and cognitive performance in each CN subthreshold and positive Aβ group. We observed the following: (i) the APOE ε4 carrier status-Aβ deposition and APOE ε4 carrier status-local FC interaction for the executive and memory function; (ii) the APOE ε4 carrier status-regional Aβ accumulation interaction for the local FC; and (iv) the APOE ε4 carrier status-local FC interaction for the remote inter-network FC between the DMN and CEN, contributing higher cognitive performance in the APOE ε4 carrier with higher inter-network FC. Finally, these results were modulated according to Aβ positivity.ConclusionThis study is the first attempt to thoroughly examine the influence of the APOE ε4 carrier status from the subthreshold to positive Aβ accumulation during the preclinical phase.

Abstract Background Histone deacetylase (HDAC) inhibitors are promising anticancer drugs but their effect on tumor treatment has been disappointing mainly due to the acquisition of HDAC inhibitor resistance. However, the mechanisms underlying such resistance remain unclear. Methods In this study, we performed Western blot, q-PCR, and promoter assay to examine the expression of HDAC inhibitor-induced phospholipase D2 (PLD2) in MDA-MB231and MDA-MB435 breast cancer cells. Apoptosis and proliferation were analyzed by flow cytometry. In addition to invasion and migration assay, angiogenesis was further measured using in vitro tube formation and chick embryo chorioallantoic membrane model. Results HDAC inhibitors including suberoylanilide hydroxamic acid (SAHA), trichostatin, and apicidin, induce expression of PLD2 in a transcriptional level. SAHA upregulates expression of PLD2 via protein kinase C-ζ in breast cancer cells and increases the enzymatic activity of PLD. The combination treatment of SAHA with PLD2 inhibitor significantly enhances cell death in breast cancer cells. Phosphatidic acid, a product of PLD activity, prevented apoptosis promoted by cotreatment with SAHA and PLD2 inhibitor, suggesting that SAHA-induced PLD2 expression and subsequent activation of PLD2 might confers resistance of breast cancer cells to HDAC inhibitor. The combinational treatment of the drugs significantly suppressed invasion, migration, and angiogenesis, compared with that of either treatment. Conclusion These findings provide further insight into elucidating the advantages of combination therapy with HDAC and PLD2 inhibitors over single-agent strategies for the treatment of cancer.

Abstract We re-examine current and future constraints on a heavy dilaton coupled to a simple dark sector consisting of a Majorana fermion or a Stückelberg vector field. We include three different treatments of dilaton-Higgs mixing, paying particular attention to a gauge-invariant formulation of the model. Moreover, we also invite readers to re-examine effective field theories of vector dark matter, which we show are missing important terms. Along with the latest Higgs coupling data, heavy scalar search results, and dark matter density/direct detection constraints, we study the LHC bounds on the model and estimate the prospects of dark matter production at the future HL-LHC and 100 TeV FCC colliders. We additionally compute novel perturbative unitarity constraints involving vector dark matter, dilaton and gluon scattering.

Abstract With the timely advent of the electric vehicle era, where battery stability has emerged as a major issue, all‐solid‐state batteries (ASSBs) have attracted significant attention as the game changer owing to their high stability. However, despite the introduction of a densely packed solid electrolyte (SE) layer, when Li is used to increase the energy density of the cell, the short‐circuit problem caused by Li protrusion is unavoidable. Furthermore, most strategies to control nonuniform Li growth are so complicated that they hinder the practical application of ASSBs. To overcome these limitations, this study proposes an Ag‐Li alloy anode via mass‐producible roll pressing method. Unlike previous studies reporting solid‐solution‐based metal alloys containing a small amount of lithiophilic Ag, the in situ formed and Ag‐enriched Ag‐Li intermetallic layer mitigates uneven Li deposition and maintains a stable SE/Ag‐Li interface, facilitating reversible Li operation. Contrary to Li cells showing frequent initial short‐circuit, the cell incorporating the Ag‐Li anode exhibits a better capacity retention of 94.3% for 140 cycles, as well as stable cycling even under 12 C. Through a facile approach enabling the fabrication of a large‐area anode with controllable Li growth, this study provides practical insight for developing ASSBs with stable cyclabilities.

Abstract A long-standing kinematic challenge in data analysis at hadron colliders is the determination of the masses of invisible particles. This issue is particularly relevant in searches for evidence of dark matter production, which remains one of the prominent targets of future collider experiments. In this paper, we show that the additional information from the precision timing measurements, provided by planned detector upgrades during the high- luminosity run of the LHC (HL-LHC), allows for previously unrealizable measurements of invisible particle kinematics. As a concrete example, we focus on the signal of pair produced long-lived particles (LLP1,2), each decaying with a displaced vertex to visible (V 1,2) and invisible (I 1,2) final state particles, pp → LLP1 + LLP2 → (V 1 + I 1) + (V 2 + I 2). We explicitly show that the complete kinematics of the invisible particles in such events can be determined with the addition of timing information, and evaluate the precision with which the masses of new long-lived and invisible particles can be determined.

Abstract Background Cancer stem cells (CSCs), the major driver of tumorigenesis, is a sub-population of tumor cells responsible for poor clinical outcomes. However, molecular mechanism to identify targets for controlling CSCs is poorly understood. Methods Gene Set Enrichment Analyses (GSEA) of Wnt/β-catenin and RAS signaling pathways in stem-like subtype of colorectal cancer (CRC) patients were performed using two gene expression data set. The therapeutic effects of destabilization of β-catenin and RAS were tested by treatment of small molecule KYA1797K using CRC patient derived cells. Results Treatment with KYA1797K, a small molecule that destabilizes both β-catenin and RAS via Axin binding, effectively suppresses the stemness of CSCs as shown in CRC spheroids and small intestinal tumors of Apc Min/+ /K-Ras G12D LA2 mice. Moreover, KYA1797K also suppresses the stemness of cells in CRC patient avatar model systems, such as patient-derived tumor organoids (PDTOs) and patient-derived tumor xenograft (PDTX). Conclusion Our results suggest that destabilization of both β-catenin and RAS is a potential therapeutic strategy for controlling stemness of CRC cells. Video abstract

We explore muon anomalous magnetic moment (muon g−2) in a scotogenic neutrino model with a gauged lepton number symmetry U(1)μ−τ. In this model, a dominant muon g−2 contribution comes not from an additional gauge sector but from a Yukawa sector. In our numerical Δχ2 analysis, we show that our model is in favor of normal hierarchy with some features. We demonstrate one benchmark point, satisfying muon g−2 at the best fit value 25.1×10−10.

BackgroundAttempts have been made to explore the biological basis of neurodegeneration in the amnestic mild cognitive impairment (MCI) stage, subdivided by memory performance. However, few studies have evaluated the differential impact of functional connectivity (FC) on memory performances in early- and late-MCI patients.ObjectiveThis study aims to explore the difference in FC of the posterior cingulate cortex (PCC) among healthy controls (HC) (n = 37), early-MCI patients (n = 30), and late-MCI patients (n = 35) and to evaluate a group-memory performance interaction against the FC of PCC.MethodsThe subjects underwent resting-state functional MRI scanning and a battery of neuropsychological tests.ResultsA significant difference among the three groups was found in FC between the PCC (seed region) and bilateral crus cerebellum, right superior medial frontal gyrus, superior temporal gyrus, and left middle cingulate gyrus (Monte Carlo simulation-corrected p < 0.01; cluster p < 0.05). Additionally, the early-MCI patients displayed higher FC values than the HC and late-MCI patients in the right superior medial frontal gyrus, cerebellum crus 1, and left cerebellum crus 2 (Bonferroni-corrected p < 0.05). Furthermore, there was a significant group-memory performance interaction (HC vs. early MCI vs. late MCI) for the FC between PCC and bilateral crus cerebellum, right superior medial frontal gyrus, superior temporal gyrus, and left middle cingulate gyrus (Bonferroni-corrected p < 0.05).ConclusionThese findings contribute to the biological implications of early- and late-MCI stages, categorized by evaluating the impairment of memory performance. Additionally, comprehensively analyzing the structural differences in the subdivided amnestic MCI (aMCI) stages could deepen our understanding of these biological meanings.

Objective: Diverse resting-state functional magnetic resonance imaging (rs-fMRI) studies showed that rs-fMRI might be able to reflect the earliest detrimental effect of cerebral beta-amyloid (Aβ) pathology. However, no previous studies specifically compared the predictive value of different rs-fMRI parameters in preclinical AD.Methods: A total of 106 cognitively normal adults (Aβ+ group = 66 and Aβ− group = 40) were included. Three different rs-fMRI parameter maps including functional connectivity (FC), fractional amplitude of low-frequency fluctuations (fALFF), and regional homogeneity (ReHo) were calculated. Receiver operating characteristic (ROC) curve analyses were utilized to compare classification performance of the three rs-fMRI parameters.Results: FC maps showed the best classifying performance in ROC curve analysis (AUC, 0.915, p < 0.001). Good but weaker performance was achieved by using ReHo maps (AUC, 0.836, p < 0.001) and fALFF maps (AUC, 0.804, p < 0.001). The brain regions showing the greatest discriminative power included the left angular gyrus for FC, left anterior cingulate for ReHo, and left middle frontal gyrus for fALFF. However, among the three measurements, ROI-based FC was the only measure showing group difference in voxel-wise analysis.Conclusion: Our results strengthen the idea that rs-fMRI might be sensitive to earlier changes in spontaneous brain activity and FC in response to cerebral Aβ retention. However, further longitudinal studies with larger sample sizes are needed to confirm their utility in predicting the risk of AD.

Background: The effect of educational status on brain structural measurements depends on demographic and clinical factors in cognitively healthy older adults.Objectives: The current study aimed to evaluate the impact of interaction between years of education and sex on gray matter volume and to investigate whether cortical volume has a differential impact on cognitive function according to sex.Methods: One hundred twenty-one subjects between 60 and 85 years old were included in this study. Gray matter volume was evaluated by whole brain surface-based morphometry. Multiple regression analysis was used to analyze the effects of sex-cortical volume interactions on cognitive functions.Results: There was a significant interaction between years of education and sex on the cortical volume of the left inferior temporal gyrus after adjusting for age, APOE ε4 allele prevalence, and total intracranial volume. In addition, we found a significant impact of the interaction between adjusted left inferior temporal volume and sex on CERAD-K total scores.Conclusion: These findings have significant implications for the understanding of how sex could affect the role of cognitive reserve for cortical atrophy in cognitively intact older adults.

Background: Previous studies have demonstrated an increased risk of fractures in subjects with various degrees of cognitive impairments. Recently, there has been growing recognition of the vital effect of physical activity (PA) on delay and prevention of fractures in older adults.Objectives: This study aimed to evaluate the optimal intensity and frequency of PA needed to prevent fractures in cognitively preserved older adults (CP), participants with subjective cognitive decline (SCD), and dementia patients using a large-scale nationwide cohort study.Methods: Data from a nationwide health screening program for individuals at the transitional age of 66 years were used in this study. A total of 968,240 subjects was enrolled, followed from 2007 to 2014, and classified as CP (n = 759,874), SCD (n = 195,365), or dementia group (n = 13,001). Adjusted hazard ratios (aHRs) by demographic and known risk factors for fractures were evaluated to identify the impact of various frequency and intensity PA on the occurrence of hip, vertebral, and limb fractures.Results: In CP participants, the most noticeable reduction of hip and vertebral fracture risk was shown in those performing vigorous-intensity PA at least three times per week. In the SCD group, the risk decrement in hip and vertebral fractures was most prominent in subjects who performed multiple-intensity PAs at least three times a week regardless of intensity. In the dementia group, only high-frequency walking and high-frequency & multiple-intensity PA decreased the risk of hip fractures compared with absence of PA.Conclusion: These findings suggest a role for various PA intensity and frequency levels to prevent hip and vertebral fractures according to cognitive status. Further study is needed to validate the effects of PA intensity and frequency proposed in this study on fractures according to cognitive status.

Purpose: Body mass index (BMI) may not be appropriate for different populations. Therefore, the World Health Organization (WHO) suggested 25 kg/m2 as a measure of obesity for Asian populations. The purpose of this report was to compare the oncologic outcomes of laparoscopic colorectal resection with BMI classified from the WHO Asia-Pacific perspective. Patients and Methods: All patients underwent laparoscopic colorectal resection from September 2006 to March 2015 at a tertiary referral hospital. A total of 2408 patients were included and classified into four groups: underweight (n = 112, BMI 25 kg/m2). Perioperative parameters and oncologic outcomes were analysed amongst groups. Results: Conversion rate was the highest in the underweight group (2.7%, P < 0.001), whereas the obese group had the fewest harvested lymph nodes (21.7, P < 0.001). Comparing oncologic outcomes except Stage IV, the underweight group was lowest for overall (P = 0.007) and cancer-specific survival (P = 0.002). The underweight group had the lowest proportion of national health insurance but the highest rate of medical care (P = 0.012). Conclusion: The obese group had the fewest harvested lymph nodes, whereas the underweight group had the highest estimated blood loss, conversion rate to open approaches and the poorest overall and cancer-specific survivals.

White-matter hyperintensity (WMH) is a primary biomarker for small-vessel cerebrovascular disease, Alzheimer’s disease (AD), and others. The association of WMH with brain structural changes has also recently been reported. Although fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) provide valuable information about WMH, FLAIR does not provide other normal tissue information. The multi-modal analysis of FLAIR and T1-weighted (T1w) MRI is thus desirable for WMH-related brain aging studies. In clinical settings, however, FLAIR is often the only available modality. In this study, we thus propose a semi-supervised learning method for full brain segmentation using FLAIR. The results of our proposed method were compared with the reference labels, which were obtained by FreeSurfer segmentation on T1w MRI. The relative volume difference between the two sets of results shows that our proposed method has high reliability. We further evaluated our proposed WMH segmentation by comparing the Dice similarity coefficients of the reference and the results of our proposed method. We believe our semi-supervised learning method has a great potential for use for other MRI sequences and will encourage others to perform brain tissue segmentation using MRI modalities other than T1w.

Abstract In models with universal extra dimensions (UED), the lightest Kaluza-Klein excitation of neutral electroweak gauge bosons is a stable, weakly interacting massive particle and thus is a candidate for dark matter thanks to Kaluza-Klein parity. We examine concrete model realizations of such dark matter in the context of non-minimal UED extensions. The boundary localized kinetic terms for the electroweak gauge bosons lead to a non-trivial mixing among the first Kaluza-Klein excitations of the SU(2) W and U(1) Y gauge bosons and the resultant low energy phenomenology is rich. We investigate implications of various experiments including low energy electroweak precision measurements, direct and indirect detection of dark matter particles and direct collider searches at the LHC. Notably, we show that the electroweak Kaluza-Klein dark matter can be as heavy as 2.4 TeV, which is significantly higher than 1.3 TeV as is indicated as an upper bound in the minimal UED model.

We study the jet activity that accompanies the production by gluon fusion of a new physics scalar particle decaying into photons at the LHC. In the considered scenarios, both the production and decay mechanisms are governed by loop-induced interactions involving a heavy colored state. We show that the presence of large new physics contributions to the inclusive diphoton invariant-mass spectrum always implies a significant production rate of non-standard diphoton events containing extra hard jets. We investigate the existence of possible handles that could provide a way to obtain information on the underlying physics behind the scalar resonance, and this in a wide mass window.

BackgroundEarly and late mild cognitive impairment (MCI) patients have been reported to have a distinctive prognosis of converting to Alzheimer’s disease.ObjectiveTo evaluate the difference in gray matter volume and assess the association between cognitive function evaluated by comprehensive cognitive function test, and cortical thickness across healthy controls (HCs) (n = 37), early (n = 30), and late MCI patients (n = 35).MethodsDifferences in gray matter volume were evaluated by whole brain voxel-based morphometry across the groups. Multiple regression analysis was used to analyze group by memory performance interactions for the normalized gray matter volume.ResultsThe early MCI group showed reduced gray matter volume in the right middle temporal gyrus in comparison to the HC group. The late MCI group displayed atrophy in the left parahippocampal gyrus in comparison to the HC group. Late MCI patients exhibited a decreased gray matter volume in the left fusiform gyrus in comparison to patients in the early MCI group (Monte Carlo simulation corrected p < 0.01, Tukey post hoc tests). Furthermore, there was a significant group (HC vs. early MCI) by memory performance interaction for the normalized cortical volume of the right middle temporal gyrus. Additionally, a significant group (early MCI vs. late MCI) by memory performance interaction was found for the normalized gray matter volume of the left fusiform gyrus (p < 0.001).ConclusionEarly and late MCI patients showed distinctive associations of gray matter volumes in compensatory brain regions with memory performances. The findings can contribute to a better understanding of the structural changes in compensatory brain regions to elucidate memory decline in the trajectory of the subdivided prodromal stages of the Alzheimer’s disease (AD).

Multi-label brain segmentation from brain magnetic resonance imaging (MRI) provides valuable structural information for most neurological analyses. Due to the complexity of the brain segmentation algorithm, it could delay the delivery of neuroimaging findings. Therefore, we introduce Split-Attention U-Net (SAU-Net), a convolutional neural network with skip pathways and a split-attention module that segments brain MRI scans. The proposed architecture employs split-attention blocks, skip pathways with pyramid levels, and evolving normalization layers. For efficient training, we performed pre-training and fine-tuning with the original and manually modified FreeSurfer labels, respectively. This learning strategy enables involvement of heterogeneous neuroimaging data in the training without the need for many manual annotations. Using nine evaluation datasets, we demonstrated that SAU-Net achieved better segmentation accuracy with better reliability that surpasses those of state-of-the-art methods. We believe that SAU-Net has excellent potential due to its robustness to neuroanatomical variability that would enable almost instantaneous access to accurate neuroimaging biomarkers and its swift processing runtime compared to other methods investigated.

Normative brain magnetic resonance imaging (MRI) is essential to interpret the state of an individual’s brain health. However, a normative study is often expensive for small research groups. Although several attempts have been made to establish brain MRI norms, the focus has been limited to certain age ranges. This study aimed to establish East Asian normative brain data using multi-site MRI and determine the robustness of these data for clinical research. Normative MRI was gathered covering a wide range of cognitively normal East Asian populations (age: 18–96 years) from two open sources and three research sites. Eight sub-regional volumes were extracted in the left and right hemispheres using an in-house deep learning-based tool. Repeated measure consistency and multicenter reliability were determined using intraclass correlation coefficients and compared to a widely used tool, FreeSurfer. Our results showed highly consistent outcomes with high reliability across sites. Our method outperformed FreeSurfer in repeated measure consistency for most structures and multicenter reliability for all structures. The normative MRI we constructed was able to identify sub-regional differences in mild cognitive impairments and dementia after covariate adjustments. Our investigation suggests it is possible to provide a sound normative reference for neurodegenerative or aging research.

Introduction: Mild cognitive impairment (MCI) is a prodromal stage of dementia. The association of body mass index (BMI) and progression to Alzheimer's disease (AD) in MCI subjects according to age, sex, and cognitive intervention remains unknown. We investigated the relationship between BMI and the risk of progression to AD in subjects with MCI, as well as the effect of BMI on progression to AD depending on age, sex, cognitive intervention, and chronic diseases.Methods: Three hundred and eighty-eight MCI subjects were followed for 36.3 ± 18.4 months, prospectively. They underwent neuropsychological testing more than twice during the follow-up period. The MCI subjects were categorized into underweight, normal weight, overweight, and obese subgroups. The associations between baseline BMI and progression to AD over the follow-up period were estimated using Cox proportional hazard regression models. Data were analyzed after stratification by age, sex, cognitive intervention, and chronic diseases.Results: After adjustment for the covariates, the underweight MCI group had a higher risk of progression to AD [hazard ratio (HR): 2.38, 95% confidence interval (CI): 1.17–4.82] relative to the normal weight group. After stratifying by age, sex, cognitive intervention, and chronic diseases, this effect remained significant among females (HR: 3.15, 95% CI: 1.40–7.10), the older elderly ≥75 years old (HR: 3.52, 95% CI: 1.42–8.72), the non-intervention group (HR: 3.06, 95%CI: 1.18–7.91), and the hypertensive group (HR: 4.71, 95% CI: 1.17–18.99).Conclusion: These data indicate that underweight could be a useful marker for identifying individuals at increased risk for AD in MCI subjects. This association is even stronger in females, older elderly subjects, the non-cognitive intervention group, and the hypertensive group.

This report describes 4 narcolepsy cases that were developed after Influenza A/H1N1 infection or vaccination. The durations from Influenza A/H1N1 infection or vaccination to the symptom onset were 10 days, 2 weeks, 3 months, 6 months respectively. Among the four, two were teenagers or younger. One of them developed symptoms after Influenza A/H1N1 infection while three of them developed after vaccination. All went through polysomnography followed by multiple sleep latency tests for accurate diagnosis. All suffered from cataplexy. However, one of them presented with negative results in the human leukocyte antigen DQB1*0602 study. These cases suggest a possibility an association between H1N1/Influenza A virus and narcolepsy development via immune mechanism.

Background and Objective It has been reported that Streptococcal infection is probably a significant environmental trigger for narcolepsy patients from recent studies. However the relationship between the streptococcal infection and narcolepsy is not clear. The aim of this study is to explore the anti-streptolysin O (ASO) titer in narcolepsy patients and healthy control, and the associations of ASO titer levels and polysomnographic findings. Methods Sixty two narcolepsy patients and Fifty six healthy controls were recruited at the Sleep Center of St. Vincent’s Hospital. The multiple sleep latency test data and polysomnographic findings from the time of their diagnosis were reviewed. Disease duration was defined as the time between the first symptom and time of blood draw. HLA typing was also performed. Participants were tested for markers of immune response to β hemolytic streptococcus. Results Results indicated that titers of anti-streptococcal antibodies were not significantly different between patients with narcolepsy and healthy controls. There was no significant difference of ASO titer between the HLA DQB1*0602 positive group and HLA DQB1*0602 negative group. In narcolepsy with cataplexy patients, rapid eye movement sleep latency was significantly shorter in the ASO > 200 group. Conclusions There is no significant difference of ASO titers between patients with narcolepsy and healthy controls. The association between streptococcal infections and narcolepsy in Asian people may be not as significant as Caucasian people.

We investigated the geometric and chemical factors of nonspherical Janus particles (i.e., Janus ellipsoids) with regard to the pinning and unpinning behaviors of the Janus boundary at the oil–water interface using attachment energy numerical calculations. The geometric factors were characterized by aspect ratio (AR) and location of the Janus boundary (α) separating the polar and apolar regions of the particle. The chemical factor indicated the supplementary wettability (β) of the two sides of the particle with identical deviations of apolarity and polarity from neutral wetting. These two factors competed with each other to determine particle configurations at the interface. In general, the critical value of β (βc) required to preserve the pinned configuration was inversely proportional to the values of α and AR. From the numerical calculations, the empirical relationship of the parameter values of Janus ellipsoids was found; that is, λ = Δ β c / Δ α ≈ 0.61 A R − 1.61 . Particularly for the Janus ellipsoids with AR > 1, the βc value is consistent with the boundary between the tilted only and the tilted equilibrium/upright metastable region in their configuration phase diagram. We believe that this work performed at the single particle level offers a fundamental understanding of the manipulation of interparticle interactions and control of the rheological properties of particle-laden interfaces when particles are used as solid surfactants.

BACKGROUND: Aberrant activation of the canonical Wnt/beta-catenin pathway occurs in almost all colorectal cancers and contributes to their growth, invasion and survival. Phopholipase D (PLD) has been implicated in progression of colorectal carcinoma However, an understanding of the targets and regulation of this important pathway remains incomplete and besides, relationship between Wnt signaling and PLD is not known. METHODOLOGY/PRINCIPAL FINDINGS: Here, we demonstrate that PLD isozymes, PLD1 and PLD2 are direct targets and positive feedback regulators of the Wnt/beta-catenin signaling. Wnt3a and Wnt mimetics significantly enhanced the expression of PLDs at a transcriptional level in HCT116 colorectal cancer cells, whereas silencing of beta-catenin gene expression or utilization of a dominant negative form of T cell factor-4 (TCF-4) inhibited expression of PLDs. Moreover, both PLD1 and PLD2 were highly induced in colon, liver and stomach tissues of mice after injection of LiCl, a Wnt mimetic. Wnt3a stimulated formation of the beta-catenin/TCF complexes to two functional TCF-4-binding elements within the PLD2 promoter as assessed by chromatin immunoprecipitation assay. Suppressing PLD using gene silencing or selective inhibitor blocked the ability of beta-catenin to transcriptionally activate PLD and other Wnt target genes by preventing formation of the beta-catenin/TCF-4 complex, whereas tactics to elevate intracellular levels of phosphatidic acid, the product of PLD activity, enhanced these effects. Here we show that PLD is necessary for Wnt3a-driven invasion and anchorage-independent growth of colon cancer cells. CONCLUSION/SIGNIFICANCE: PLD isozyme acts as a novel transcriptional target and positive feedback regulator of Wnt signaling, and then promotes Wnt-driven anchorage-independent growth of colorectal cancer cells. We propose that therapeutic interventions targeting PLD may confer a clinical benefit in Wnt/beta-catenin-driven malignancies.

Background: Skeletal muscle loss is prevalent throughout the cancer continuum and correlated with morbidity and mortality. Resistance exercise has been trialed to mitigate skeletal muscle loss. This systematic review summarizes and qualitatively synthesizes the effects of resistance exercise on muscle-related outcomes in adult cancer populations, including skeletal muscle mass, performance and muscle-related biomarkers. Methods: The systematic review protocol was developed in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). We searched electronic databases including AMED, CENTRAL, CINAHL, CIRRIE, EMBASE, MEDLINE, PEDro, REHABDATA, Scopus, and SPORTDiscus from inception to December 2021. We included randomized controlled trials that investigated the effects of resistance exercise on muscle-related outcomes in adult cancer populations. Interventions that involved any resistance exercise were included. Muscle-related outcomes were categorized as skeletal muscle mass (e.g., lean mass, appendicular muscle mass), muscle performance (e.g., muscle strength, physical function), and muscle-related biomarkers (e.g., muscle cells, metabolic/inflammatory markers). Risk of bias (RoB) was assessed using the Cochrane ROB tool. Results: A total of 102 studies from 101 randomized controlled trials were included. The majority of studies focused on breast cancer (46%) and those who completed treatment (43%). Resistance exercise interventions were largely 3-4 months long (48%), combined with aerobic exercise (56%), at a vigorous intensity (25%), and in-person/supervised settings (57%). Among the studies assessing muscle mass, performance, and biomarkers (n = 42, 83, and 22, respectively), resistance exercise interventions improved upper/lower body or appendicular muscle mass (67%-100%), muscle strength (61%-68%), and physical function (74%-100%). Most biomarkers did not show significant changes (75%-100%) or showed inconsistent results. Conclusions: Generally, resistance exercise had positive effects on skeletal muscle mass and performance with no negative effects compared to controls. Our findings demonstrated that resistance exercise may be an effective strategy to attenuate deterioration or exert improvements in muscle mass and performance outcomes. [ABSTRACT FROM AUTHOR]

Background. Suicide is a pressing global health concern, and identifying its risk factors is crucial for prevention. Body weight variability (BWV) has been increasingly recognized as a potential factor impacting physical and mental health outcomes. We aimed to explore the relationship between BWV and the risk of suicide mortality using a nationally representative database. Methods. This population-based cohort study used data from the Korean National Health Insurance Database and included a total of 1,983,701 subjects. BWV was assessed using at least three health examination datasets and validated variability indices (variability independent of the mean (VIM), average successive variability, and coefficient of variation), and patients were divided into BWV quartiles (Q1–Q4). The primary endpoint was suicide-related death. Results. During a median of 11.3 years of follow-up, 5,883 suicide deaths occurred. A higher baseline body weight was associated with a lower risk of suicide. However, greater BWV (VIM) was associated with a significantly greater risk of suicide (adjusted hazard ratio [95% confidence interval], 1.35 [1.26–1.45] in the Q4 group), even after adjusting for baseline body mass index (BMI). Similar results were observed regardless of obesity or BMI category. Consistent findings were observed when using different variability indices. Subgroup analyses according to sex, age, diabetes, and depression also supported these findings. Conclusion. Our study highlights the importance of considering BWV as a potential risk factor for suicide. [ABSTRACT FROM AUTHOR]

Objective: Cognitive reserve has emerged as a concept to explain the variable expression of clinical symptoms in the pathology of Alzheimer’s disease (AD). The association between years of education, a proxy of cognitive reserve, and resting-state functional connectivity (rFC), a representative intermediate phenotype, has not been explored in the preclinical phase, considering risk factors for AD. We aimed to evaluate whether the relationship between years of education and rFC in cognitively preserved older adults differs depending on amyloid-beta deposition and APOE ε4 carrier status as effect modifiers. Methods: A total of 121 participants underwent functional magnetic resonance imaging, [18F] flutemetamol positron emission tomography-computed tomography, APOE genotyping, and a neuropsychological battery. Potential interactions between years of education and AD risk factors for rFC of AD-vulnerable neural networks were assessed with wholebrain voxel-wise analysis. Results: We found a significant education years-by-APOE ε4 carrier status interaction for the rFC from the seed region of the central executive (CEN) and dorsal attention networks. Moreover, there was a significant interaction of rFC between right superior occipital gyrus and the CEN seed region by APOE ε4 carrier status for memory performances and overall cognitive function. Conclusion: In preclinical APOE ε4 carriers, higher years of education were associated with higher rFC of the AD vulnerable network, but this contributed to lower cognitive function. These results contribute to a deeper understanding of the impact of cognitive reserve on sensitive functional intermediate phenotypic markers in the preclinical phase of AD. [ABSTRACT FROM AUTHOR]