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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.

Heart failure is a leading cause of death and is often accompanied by activation of quiescent cardiac myofibroblasts, which results in cardiac fibrosis. In this study, we aimed to identify novel circular RNAs that regulate cardiac fibrosis. We applied transverse aortic constriction (TAC) for 1, 4, and 8 weeks in mice. RNA sequencing datasets were obtained from cardiac fibroblasts isolated by use of a Langendorff apparatus and then further processed by use of selection criteria such as differential expression and conservation in species. CircSMAD4 was upregulated by TAC in mice or by transforming growth factor (TGF)-β1 in primarily cultured human cardiac fibroblasts. Delivery of si-circSMAD4 attenuated myofibroblast activation and cardiac fibrosis in mice treated with isoproterenol (ISP). si-circSmad4 significantly reduced cardiac fibrosis and remodeling at 8 weeks. Mechanistically, circSMAD4 acted as a sponge against the microRNA miR-671-5p in a sequence-specific manner. miR-671-5p was downregulated during myofibroblast activation and its mimic form attenuated cardiac fibrosis. miR-671-5p mimic destabilized fibroblast growth factor receptor 2 (FGFR2) mRNA in a sequence-specific manner and interfered with the fibrotic action of FGFR2. The circSMAD4-miR-671-5p-FGFR2 pathway is involved in the differentiation of cardiac myofibroblasts and thereby the development of cardiac fibrosis.

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.

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.

Vascular calcification (VC), or calcium deposition inside the blood vessels, is common in patients with atherosclerosis, cardiovascular disease, and chronic kidney disease. Although several treatments are available to reduce calcification, the incidence of VC continues to rise. Recently, there have been several reports describing the regulation of circular RNAs (circRNAs) in various diseases. However, the role of circRNAs in VC has not yet been fully explored. Here, we investigated the function of circSmoc1-2, one of the circRNAs generated from the Smoc1 gene, which is downregulated in response to VC. CircSmoc1-2 is localized primarily to the cytoplasm and is resistant to exonuclease digestion. Inhibition of circSmoc1-2 worsens VC, while overexpression of circSmoc1-2 reduces VC, suggesting that circSmoc1-2 can prevent calcification. We went on to investigate the mechanism of circSmoc1-2 as a microRNA sponge and noted that miR-874-3p, the predicted target of circSmoc1-2, promotes VC, while overexpression of circSmoc1-2 reduces VC by suppressing miR-874-3p. Additionally, we identified the potential mRNA target of miR-874-3p as Adam19. In conclusion, we revealed that the circSmoc1-2/miR-874-3p/Adam19 axis regulates VC, suggesting that circSmoc1-2 may be a novel therapeutic target in the treatment of VC.

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.

Macrophages are the major primary immune cells that mediate the inflammatory response. In this process, long non-coding RNAs (lncRNAs) play an important, yet largely unknown role. Therefore, utilizing several publicly available RNA sequencing datasets, we predicted and selected lncRNAs that are differentially expressed in M1 or M2 macrophages and involved in the inflammatory response. We identified SUGCT-AS1, which is a human macrophage-specific lncRNA whose expression is increased upon M1 macrophage stimulation. Conditioned media of SUGCT-AS1-depleted M1 macrophages induced an inflammatory phenotype of vascular smooth muscle cells, which included increased expression of inflammatory genes (IL1B and IL6), decreased contractile marker proteins (ACTA2 and SM22α), and increased cell migration. Depletion of SUGCT-AS1 promoted the expression and secretion of proinflammatory cytokines, such as TNF, IL1B, and IL6, in M1 macrophages, and transcriptomic analysis showed that SUGCT-AS1 has functions related to inflammatory responses and cytokines. Furthermore, we found that SUGCT-AS1 directly binds to hnRNPU and regulates its nuclear–cytoplasmic translocation. This translocation of hnRNPU altered the proportion of the MALT1 isoforms by regulating the alternative splicing of MALT1, a mediator of NF-κB signaling. Overall, our findings suggest that lncRNAs can be used for future studies on macrophage regulation. Moreover, they establish the SUGCT-AS1/hnRNPU/MALT1 axis, which is a novel inflammatory regulatory mechanism in macrophages.

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.

Vascular disease: Driver of deposition of calcium salts identified The identification of a signaling pathway involved in triggering vascular calcification, the deposition of calcium phosphate crystals in blood vessels, could inform new therapeutic interventions for related cardiovascular complications. Vascular calcification causes significant complications in patients with metabolic syndrome, renal failure, or cardiovascular disease. In their previous work, Hyun Kook and Duk-Hwa Kwon at Chonnam National University Medical School, Jeollanamdo, Republic of Korea, and coworkers demonstrated that the E3 ligase activity of a protein called MDM2 induces calcification. Now, following further mouse trials, the team have identified an upstream signaling pathway involving several development proteins such as MSX1 and MSX2 which activate MDM2. The activation of this signaling axis leads to the degradation of a key protein that would otherwise prevent calcification. The results may provide a platform for novel therapies targeting the condition.

Abstract Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to dementia and behavioral changes. Extracellular deposition of amyloid plaques (Aβ) and intracellular deposition of neurofibrillary tangles in neurons are the major pathogenicities of AD. However, drugs targeting these therapeutic targets are not effective. Therefore, novel targets for the treatment of AD urgently need to be identified. Expression of the mesoderm-specific transcript (Mest) is regulated by genomic imprinting, where only the paternal allele is active for transcription. We identified hypermethylation on the Mest promoter, which led to a reduction in Mest mRNA levels and activation of Wnt signaling in brain tissues of AD patients. Mest knockout (KO) using the CRIPSR/Cas9 system in mouse embryonic stem cells and P19 embryonic carcinoma cells leads to neuronal differentiation arrest. Depletion of Mest in primary hippocampal neurons via lentivirus expressing shMest or inducible KO system causes neurodegeneration. Notably, depletion of Mest in primary cortical neurons of rats leads to tau phosphorylation at the S199 and T231 sites. Overall, our data suggest that hypermethylation of the Mest promoter may cause or facilitate the progression of AD.

Abstract Background Stem cell transplantation is a fascinating therapeutic approach for the treatment of many neurodegenerative disorders; however, clinical trials using stem cells have not been as effective as expected based on preclinical studies. The aim of this study is to validate the hypothesis that human neural crest-derived nasal turbinate stem cells (hNTSCs) are a clinically promising therapeutic source of adult stem cells for the treatment of Alzheimer’s disease (AD). Methods hNTSCs were evaluated in comparison with human bone marrow-derived mesenchymal stem cells (hBM-MSCs) according to the effect of transplantation on AD pathology, including PET/CT neuroimaging, immune status indicated by microglial numbers and autophagic capacity, neuronal survival, and cognition, in a 5 × FAD transgenic mouse model of AD. Results We demonstrated that hNTSCs showed a high proliferative capacity and great neurogenic properties in vitro. Compared with hBM-MSC transplantation, hNTSC transplantation markedly reduced Aβ42 levels and plaque formation in the brains of the 5 × FAD transgenic AD mice on neuroimaging, concomitant with increased survival of hippocampal and cortex neurons. Moreover, hNTSCs strongly modulated immune status by reducing the number of microglia and the expression of the inflammatory cytokine IL-6 and upregulating autophagic capacity at 7 weeks after transplantation in AD models. Notably, compared with transplantation of hBM-MSCs, transplantation of hNTSCs significantly enhanced performance on the Morris water maze, with an increased level of TIMP2, which is necessary for spatial memory in young mice and neurons; this difference could be explained by the high engraftment of hNTSCs after transplantation. Conclusion The reliable evidence provided by these findings reveals a promising therapeutic effect of hNTSCs and indicates a step forward the clinical application of hNTSCs in patients with AD.

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.

Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by progressive muscle degeneration due to dystrophin gene mutations. Patients with DMD initially experience muscle weakness in their limbs during adolescence. With age, patients develop fatal respiratory and cardiac dysfunctions. During the later stages of the disease, severe cardiac fibrosis occurs, compromising cardiac function. Previously, our research showed that the matricellular protein CCN5 has antifibrotic properties. Therefore, we hypothesized that CCN5 gene transfer would ameliorate cardiac fibrosis and thus improve cardiac function in DMD-induced cardiomyopathy. We utilized mdx/utrn (±) haploinsufficient mice that recapitulated the DMD-disease phenotypes and used an adeno-associated virus serotype-9 viral vector for CCN5 gene transfer. We evaluated the onset of cardiac dysfunction using echocardiography and determined the experimental starting point in 13-month-old mice. Two months after CCN5 gene transfer, cardiac function was significantly enhanced, and cardiac fibrosis was ameliorated. Additionally, running performance was improved in CCN5 gene-transfected mice. Furthermore, in silico gene profiling analysis identified utrophin as a novel transcriptional target of CCN5. This was supplemented by a utrophin promoter assay and RNA-seq analysis, which confirmed that CCN5 was directly associated with utrophin expression. Our results showed that CCN5 may be a promising therapeutic molecule for DMD-induced cardiac and skeletal dysfunction.

A NAND flash memory senses a cell current in the range of tens of nA, which is smaller than other nonvolatile memories in the read operation. Because of the small cell current, it is difficult to improve the latency and accuracy of the read operation. The improvement of read latency has been a major challenge for the all-bit-line (ABL) sensing architecture because the BL coupling capacitance caused by the off cell limits the BL pre-charge time. In this paper, a high-speed BL pre-charge scheme with an off-cell-like BL locking (OCBLL) is proposed to reduce the BL coupling capacitance between the off-cell BL and the adjacent BL. The deviation of the latch trip voltage caused by the variations in process, voltage, and temperature (PVT) presents another challenge because the deviation increases the read error owing to the small cell current. A sense-out-node amplification (SOA) scheme is proposed to amplify the voltage of the sense-out-node according to the cell current. The SOA scheme generates a large voltage difference despite the small cell current difference. In the simulation with HSPICE models under the same BL-to-BL coupling ratio, it is found that the proposed schemes improve the speed of the BL pre-charge operation by 75% and reduce the read error by 57%.

Long noncoding RNAs (lncRNAs) have recently been implicated in many pathophysiological cardiovascular processes, including vascular remodeling and atherosclerosis. However, the functional role of lncRNAs in the differentiation, proliferation, and apoptosis of vascular smooth muscle cells (VSMCs) is largely unknown. In this study, differentially expressed lncRNAs in synthetic and contractile human VSMCs were screened using RNA sequencing. Among the seven selected lncRNAs, the expression of MSC-AS1, MBNL1-AS1, and GAS6-AS2 was upregulated, whereas the expression of NR2F1-AS1, FUT8-AS1, FOXC2-AS1, and CTD-2207P18.2 was reduced upon VSMC differentiation. We focused on the NR2F1-AS1 and FOXC2-AS1 lncRNAs and showed that their knockdown significantly reduced the expression of smooth muscle contractile marker genes (ACTA2, CNN1, and TAGLN). Furthermore, FOXC2-AS1 was found to regulate cell proliferation and apoptosis through Akt/mTOR signaling, and affect Notch signaling, which is a key regulator of the contractile phenotype of VSMCs. Taken together, we identified novel lncRNAs involved in VSMC proliferation and differentiation and FOXC2-AS1 as a multifunctional regulator for vascular homeostasis and associated diseases.

Vascular calcification, the ectopic deposition of calcium in blood vessels, develops in association with various metabolic diseases and atherosclerosis and is an independent predictor of morbidity and mortality associated with these diseases. Herein, we report that reduction of microRNA-27a-3p (miR-27a-3p) causes an increase in activating transcription factor 3 (ATF3), a novel osteogenic transcription factor, in vascular smooth muscle cells. Both microRNA (miRNA) and mRNA microarrays were performed with rat vascular smooth muscle cells, and reciprocally regulated pairs of miRNA and mRNA were selected after bioinformatics analysis. Inorganic phosphate significantly reduced the expression of miR-27a-3p in A10 cells. The transcript level was also reduced in vitamin D3-administered mouse aortas. miR-27a-3p mimic reduced calcium deposition, whereas miR-27a-3p inhibitor increased it. The Atf3 mRNA level was upregulated in a cellular vascular calcification model, and miR-27a-3p reduced the Atf3 mRNA and protein levels. Transfection with Atf3 could recover the miR-27a-3p-induced reduction of calcium deposition. Our results suggest that reduction of miR-27a-3p may contribute to the development of vascular calcification by de-repression of ATF3.

Comorbid psychiatric disorders in adults with ADHD are important because these comorbidities might complicate the diagnosis of ADHD and also worsen the prognosis. However, the prevalence of comorbid psychiatric disorders in adult ADHD varies according to the diagnostic tools used and the characteristics of target populations. The purpose of this review was to describe the prevalence of comorbid psychiatric disorders in adults with ADHD compared with adults without ADHD. Thirty-two studies published before August 2022 were identified and classified according to diagnosis of other psychiatric disorder in those with ADHD. The most frequent comorbid psychiatric disorder in the ADHD group was substance use disorder (SUD), followed by mood disorders, anxiety disorders, and personality disorders. The prevalence of these four disorders was higher in the ADHD group, whether or not subjects were diagnosed with other psychiatric disorders. In addition, the diversity of ADHD diagnostic tools was observed. This also might have affected the variability in prevalence of comorbidities. Standardization of ADHD diagnostic tools is necessary in the future.

We previously showed that the matricellular protein CCN5 reverses established cardiac fibrosis (CF) through inducing apoptosis in myofibroblasts (MyoFBs) but not in cardiomyocytes or fibroblasts (FBs). In this study, we set out to elucidate the molecular mechanisms underlying CCN5-mediated selective apoptosis of MyoFBs. We first observed that the apoptotic protein p53 and the anti-apoptotic protein NFκB are simultaneously induced in MyoFBs. When the expression level of p53 was suppressed using a siRNA, CCN5 did not induce apoptosis in MyoFBs. By contrast, when NFκB signaling was inhibited using IKK VII, an IκB inhibitor, MyoFBs underwent apoptosis even in the absence of CCN5. SMAD7 is one of the downstream targets of CCN5 and it was previously shown to potentiate apoptosis in epithelial cells through inhibition of NFκB. In accordance with these reports, when the expression of SMAD7 was suppressed using a siRNA, NFκB signaling was enhanced, and CCN5 did not induce apoptosis. Lastly, we used a luciferase reporter construct to show that CCN5 positively regulated SMAD7 expression at the transcriptional level. Collectively, our data suggest that a delicate balance between the two mutually antagonistic proteins p53 and NFκB is maintained for MyoFBs to survive, and CCN5 tips the balance in favor of the apoptotic protein p53. This study provides insight into the anti-fibrotic activity of CCN5 during the regression of CF.

The matricellular protein CCN5 exerts anti-fibrotic activity in hearts partly by inducing reverse trans-differentiation of myofibroblasts (MyoFBs) to fibroblasts (FBs). CCN5 consists of three structural domains: an insulin-like growth factor binding protein (IGFBP), a von Willebrand factor type C (VWC), and a thrombospondin type 1 (TSP-1). In this study, we set out to elucidate the roles of these domains in the context of the reverse trans-differentiation of MyoFBs to FBs. First, human cardiac FBs were trans-differentiated to MyoFBs by treatment with TGF-β; this was then reversed by treatment with recombinant human CCN5 protein or various recombinant proteins comprising individual or paired CCN5 domains. Subcellular localization of these recombinant proteins was analyzed by immunocytochemistry, cellular fractionation, and western blotting. Anti-fibrotic activity was also evaluated by examining expression of MyoFB-specific markers, α-SMA and fibronectin. Our data show that CCN5 is taken up by FBs and MyoFBs mainly via clathrin-mediated endocytosis, which is essential for the function of CCN5 during the reverse trans-differentiation of MyoFBs. Furthermore, we showed that the TSP-1 domain is essential and sufficient for endocytosis and nuclear localization of CCN5. However, the TSP-1 domain alone is not sufficient for the anti-fibrotic function of CCN5; either the IGFBP or VWC domain is needed in addition to the TSP-1 domain.

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.

Non-specific histone deacetylase (HDAC) inhibition reduces high blood pressure in essential hypertensive animal models. However, the exact HDAC isoforms that play a critical role in controlling hypertension are not known. Here, we investigated the role of HDAC5 in vascular contraction, hypertrophy, and oxidative stress in the context of angiotensin II (Ang II)-induced hypertension.Genetic deletion of HDAC5 and treatment with class IIa HDAC inhibitors (TMP269 and TMP195) prevented Ang II-induced increases in blood pressure and arterial wall thickness. Hdac5-knockout mice were also resistant to the thromboxane A2 agonist (U46619)-induced vascular contractile response. Furthermore, the expression of Rho-associated protein kinase (ROCK) 2 was downregulated in the aortas of Ang II-treated Hdac5-knockout mice. Knockdown of HDAC5, RhoA, or ROCK2 reduced collagen gel contraction, whereas silencing of ROCK1 increased it. VSMC hypertrophy reduced on knocking down HDAC5, ROCK1, and ROCK2. Here we showed that genetic deletion of HDAC5 and pharmacological inhibition of class IIa HDACs ameliorated Ang II-induced ROS generation. Moreover, ROCK1 and ROCK2, the downstream targets of HDAC5, influenced ROS generation. The relative protein levels of HDAC5, ROCK1, and ROCK2 were increased both in the cytoplasm and nuclear fraction in response to Ang II stimulation in vascular smooth muscle cells. Inhibition of HDAC5 expression or activity reduced vascular hypertrophy, vasoconstriction, and oxidative stress in the Ang II-induced hypertension model. These findings indicate that HDAC5 may serve as a potential target in the treatment of hypertension.

ObjectiveLate-life depression and subjective cognitive decline (SCD) are significant risk factors for dementia. However, studies with a large sample size are needed to clarify their independent and combined risks for subsequent dementia.MethodsThis nationwide population-based cohort study included all individuals aged 66 years who participated in the National Screening Program between 2009 and 2013 (N = 939,099). Subjects were followed from the day they underwent screening to the diagnosis of dementia, death, or the last follow-up day (December 31, 2017).ResultsDepressive symptom presentation, recent depressive disorder, and SCD independently increased dementia incidence with adjusted hazard ratio (aHR) of 1.286 (95% CI:1.255-1.318), 1.697 (95% CI:1.621-1.776), and 1.748 (95% CI: 689-1.808) respectively. Subjects having both SCD and depression had a higher risk (aHR = 2.466, 95% CI:2.383-2.551) of dementia than having depression (aHR = 1.402, 95% CI:1.364-1.441) or SCD (aHR = 1.748, 95% CI:1.689-1.808) alone.ConclusionsDepressive symptoms, depressive disorder, and SCD are independent risk factors for dementia. Co-occurring depression and SCD have an additive effect on the risk of dementia; thus, early intervention and close follow up are necessary for patients with co-occurring SCD and depression.

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.

Amyloid positron emission tomography (PET) scan is clinically essential for the non-invasive assessment of the presence and spatial distribution of amyloid-beta deposition in subjects with cognitive impairment suspected to have been a result of Alzheimer’s disease. Quantitative assessment can enhance the interpretation reliability of PET scan; however, its clinical application has been limited due to the complexity of preprocessing. This study introduces a novel deep-learning-based approach for SUVR quantification that simplifies the preprocessing step and significantly reduces the analysis time. Using two heterogeneous amyloid ligands, our proposed method successfully distinguished standardized uptake value ratio (SUVR) between amyloidosis-positive and negative groups. The proposed method’s intra-class correlation coefficients were 0.97 and 0.99 against PETSurfer and PMOD, respectively. The difference of global SUVRs between the proposed method and PETSurfer or PMOD were 0.04 and −0.02, which are clinically acceptable. The AUC-ROC exceeded 0.95 for three tools in the amyloid positive assessment. Moreover, the proposed method had the fastest processing time and had a low registration failure rate (1%). In conclusion, our proposed method calculates SUVR that is consistent with PETSurfer and PMOD, and has advantages of fast processing time and low registration failure rate. Therefore, PET quantification provided by our proposed method can be used in clinical practice.

Cardiovascular disease: A brake for heart muscle growth A regulatory mechanism that controls how cardiac muscle responds to stress could inform development of new therapies for preventing heart failure. Physiological stimuli ranging from heavy exercise to heart attack can induce hypertrophy, an increase in cardiac muscle mass that is initially beneficial but can lead to organ failure. Researchers led by Gwang Hyeon Eom and Hyun Kook at the Chonnam National University Biomedical Research Center, Hwasungun, South Korea have found that an enzyme called protein phosphatase 2A (PP2A) keeps cardiac hypertrophy in check. PP2A binds to and inhibits a second protein known as HDAC2, which would otherwise stimulate the hypertrophic response to stress. The researchers have identified the biochemical mechanism by which PP2A inactivates HDAC2, and demonstrate that this inhibition effectively protects against hypertrophic cardiac damage in mice, revealing a possible avenue for clinical intervention.

Various heart diseases cause cardiac remodeling, which in turn leads to ineffective contraction. Although it is an adaptive response to injury, cardiac fibrosis contributes to this remodeling, for which the reactivation of quiescent myofibroblasts is a key feature. In the present study, we investigated the role of the p300/CBP-associated factor (PCAF), a histone acetyltransferase, in the activation of cardiac fibroblasts. An intraperitoneal (i.p.) injection of a high dose (160 mg/kg) of isoproterenol (ISP) induced cardiac fibrosis and reduced the amount of the PCAF in cardiac fibroblasts in the mouse heart. However, the PCAF activity was significantly increased in cardiac fibroblasts, but not in cardiomyocytes, obtained from ISP-administered mice. An in vitro study using human cardiac fibroblast cells recapitulated the in vivo results; an treatment with transforming growth factor-β1 (TGF-β1) reduced the PCAF, whereas it activated the PCAF in the fibroblasts. PCAF siRNA attenuated the TGF-β1-induced increase in and translocation of fibrosis marker proteins. PCAF siRNA blocked TGF-β1-mediated gel contraction and cell migration. The PCAF directly interacted with and acetylated mothers against decapentaplegic homolog 2 (SMAD2). PCAF siRNA prevented TGF-β1-induced phosphorylation and the nuclear localization of SMAD2. These results suggest that the increase in PCAF activity during cardiac fibrosis may participate in SMAD2 acetylation and thereby in its activation.

Coupled signaling between bone-forming osteoblasts and bone-resorbing osteoclasts is crucial to the maintenance of bone homeostasis. We previously reported that v-crk avian sarcoma virus CT10 oncogene homolog-like (CrkL), which belongs to the Crk family of adaptors, inhibits bone morphogenetic protein 2 (BMP2)-mediated osteoblast differentiation, while enhancing receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation. In this study, we investigated whether CrkL can also regulate the coupling signals between osteoblasts and osteoclasts, facilitating bone homeostasis. Osteoblastic CrkL strongly decreased RANKL expression through its inhibition of runt-related transcription factor 2 (Runx2) transcription. Reduction in RANKL expression by CrkL in osteoblasts resulted in the inhibition of not only osteoblast-dependent osteoclast differentiation but also osteoclast-dependent osteoblast differentiation, suggesting that CrkL participates in the coupling signals between osteoblasts and osteoclasts via its regulation of RANKL expression. Therefore, CrkL bifunctionally regulates osteoclast differentiation through both a direct and indirect mechanism while it inhibits osteoblast differentiation through its blockade of both BMP2 and RANKL reverse signaling pathways. Collectively, these data suggest that CrkL is involved in bone homeostasis, where it helps to regulate the complex interactions of the osteoblasts, osteoclasts, and their coupling signals.

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.

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).

Background: It has been suggested that maintaining the efficient organization of the brain’s functional connectivity (FC) supports neuroflexibility under neurogenerative stress. This study examined psychological resilience-related FC in 112 older adults with mild cognitive impairment (MCI).Methods: Using a resting-state functional magnetic resonance imaging (fMRI) approach, we investigated reorganization of the orbitofrontal gyrus (OFG)/amygdala (AMG)/hippocampus (HP)/parahippocampal gyrus (PHG) FC according to the different levels of resilience scale.Results: Compared with the low resilient group, the high resilient group had greater connectivity strengths between the left inferior OFG and right superior OFG (P < 0.05, Bonferroni corrected), between the right inferior OFG and left PHG (P < 0.05, Bonferroni corrected), and between the right middle OFG and left PHG (false discovery rate < 0.05).Conclusion: Psychological resilience may be associated with enhancement of the orbitofrontal network in the elderly with MCI.

Blockchain technology has recently inspired remarkable attention due to its unique features, such as privacy, accountability, immutability, and anonymity, to name of the few. In contrast, core functionalities of most Internet of Things (IoT) resources make them vulnerable to security threats. The IoT devices, such as smartphones and tablets, have limited capacity in terms of network, computing, and storage, which make them easier for vulnerable threats. Furthermore, a massive amount of data produced by the IoT devices, which is still an open challenge for the existing platforms to process, analyze, and unearth underlying patterns to provide convenience environment. Therefore, a new solution is required to ensure data accountability, improve data privacy and accessibility, and extract hidden patterns and useful knowledge to provide adequate services. In this paper, we present a secure fitness framework that is based on an IoT-enabled blockchain network integrated with machine learning approaches. The proposed framework consists of two modules: a blockchain-based IoT network to provide security and integrity to sensing data as well as an enhanced smart contract enabled relationship and inference engine to discover hidden insights and useful knowledge from IoT and user device network data. The enhanced smart contract aims to support users with a practical application that provides real-time monitoring, control, easy access, and immutable logs of multiple devices that are deployed in several domains. The inference engine module aims to unearth underlying patterns and useful knowledge from IoT environment data, which helps in effective decision making to provide convenient services. For experimental analysis, we implement an intelligent fitness service that is based on an enhanced smart contract enabled relationship and inference engine as a case study where several IoT fitness devices are used to securely acquire user personalized fitness data. Furthermore, a real-time inference engine investigates user personalized data to discover useful knowledge and hidden insights. Based on inference engine knowledge, a recommendation model is developed to recommend a daily and monthly diet, as well as a workout plan for better and improved body shape. The recommendation model aims to facilitate a trainer formulating effective future decisions of trainee’s health in terms of a diet and workout plan. Lastly, for performance analysis, we have used Hyperledger Caliper to access the system performance in terms of latency, throughput, resource utilization, and varying orderer and peers nodes. The analysis results imply that the design architecture is applicable for resource-constrained IoT blockchain platform and it is extensible for different IoT scenarios.

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.

Vascular calcification (VC) increases morbidity and mortality in cardiovascular and metabolic diseases. Here, Kwon et al.show that calcification stimuli induce MDM2- mediated ubiquitination and proteasomal degradation of HDAC1, suggesting a possible therapeutic strategy for treatment of VC patients.

Close connections between depression and type 2 diabetes (T2DM) have been suggested by many epidemiological and experimental studies. Disturbances in insulin sensitivity due to the disruption of various molecular pathways cause insulin resistance, which underpins many metabolic disorders, including diabetes, as well as depression. Several anti-hyperglycemic agents have demonstrated antidepressant properties in clinical trials, probably due to their action on brain targets based on the shared pathophysiology of depression and T2DM. In this article, we review reports of clinical trials examining the antidepressant effect of these medications, including insulin, metformin, glucagon like peptide-1 receptor agonists (GLP-1RA), and peroxisome proliferator-activated receptor (PPAR)-γ agonists, and briefly consider possible molecular mechanisms underlying the associations between amelioration of insulin resistance and improvement of depressive symptoms. In doing so, we intend to suggest an integrative perspective for understanding the pathophysiology of depression.

Vascular calcification (VC) is characterized by calcium deposition inside arteries and is closely associated with the morbidity and mortality of atherosclerosis, chronic kidney disease, diabetes, and other cardiovascular diseases (CVDs). VC is now widely known to be an active process occurring in vascular smooth muscle cells (VSMCs) involving multiple mechanisms and factors. These mechanisms share features with the process of bone formation, since the phenotype switching from the contractile to the osteochondrogenic phenotype also occurs in VSMCs during VC. In addition, VC can be regulated by epigenetic factors, including DNA methylation, histone modification, and noncoding RNAs. Although VC is commonly observed in patients with chronic kidney disease and CVD, specific drugs for VC have not been developed. Thus, discovering novel therapeutic targets may be necessary. In this review, we summarize the current experimental evidence regarding the role of epigenetic regulators including histone deacetylases and propose the therapeutic implication of these regulators in the treatment of VC.

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.