Comparison of elasticity changes in the paraspinal muscles of adolescent patients with scoliosis treated with surgery and bracing.

Scoliosis is a three-dimensional spinal deformity, and paraspinal muscles play an important role as stabilizers of the spinal curve. In this prospective study, we compared elasticity changes in the paraspinal muscles of adolescent patients with scoliosis after surgery or bracing. Elasticity was measured on the concave and convex sides of the paraspinal muscles at the apex of the curve at the beginning of treatment and 6 and 12 months after treatment. Twenty-six patients with correction surgery (n = 15) or bracing (n = 11) were included. At initial evaluation, the Cobb angle was larger in the surgery group (72.3 ± 20.2° in surgery vs. 30.6 ± 5.1° in brace, p < 0.001). The estimated mean elasticity value of the paraspinal muscles was lower in the surgery group at baseline on the convex side (15.8 vs. 22.8 kPa, p = 0.037) and 6 months on both the concave (12.1 vs. 22.7 kPa, p = 0.004) and convex (13.4 vs. 23.8 kPa, p = 0.005) sides. There was a significant stiffness decrease from baseline to 6 months on the concave side in the surgery group (5.9 kPa, p = 0.025). However, the elasticity change recovered at 12 months without significant differences between the two groups.

Vitamin D Reduces GABA-Positive Astrocytes in the 5xFAD Mouse Model of Alzheimer's Disease.

Background: Vitamin D has neuroprotective and immunomodulating functions that may impact glial cell function in the brain. Previously, we reported molecular and behavioral changes caused by deficiency and supplementation of vitamin D in an Alzheimer's disease (AD) mouse model. Recent studies have highlighted reactive astrocytes as a new therapeutic target for AD treatment. However, the mechanisms underlying the therapeutic effects of vitamin D on the glial cells of AD remain unclear. Objective: To investigate the potential association between vitamin D deficiency/supplementation and the pathological progression of AD, including amyloid-ß (Aß) pathology and reactive astrogliosis. Methods: Transgenic hemizygous 5XFAD male mice were subjected to different dietary interventions and intraperitoneal vitamin D injections to examine the effects of vitamin D deficiency and supplementation on AD. Brain tissue was then analyzed using immunohistochemistry for Aß plaques, microglia, and astrocytes, with quantifications performed via ImageJ software. Results: Our results demonstrated that vitamin D deficiency exacerbated Aß plaque formation and increased GABA-positive reactive astrocytes in AD model mice, while vitamin D supplementation ameliorated these effects, leading to a reduction in Aß plaques and GABA-positive astrocytes. Conclusions: Our findings highlight the significant impact of vitamin D status on Aß pathology and reactive astrogliosis, underscoring its potential role in the prevention and treatment of AD. This study provides the first in vivo evidence of the association between vitamin D and reactive astrogliosis in AD model mice, indicating the potential for targeting vitamin D levels as a novel therapeutic approach for AD.

Development and Validation of a Screening Questionnaire for Dementia With Lewy Bodies (DLB): the DLB Screening Questionnaire (DLBSQ).

Background and Purpose: Although dementia with Lewy bodies (DLB) is the second most common cause of neurodegenerative dementia, its clinical prevalence is low. We developed a short and easy-to-complete DLB screening questionnaire (DLBSQ) to raise diagnostic sensitivity in routine clinical settings. Methods: A total of 501 participants were retrospectively enrolled, including 71 controls, 184 patients without DLB, and 246 patients with probable DLB. All patients underwent clinical evaluation, including core features of DLB, the DLBSQ, brain magnetic resonance imaging, and detailed neuropsychological assessments. The diagnostic performance of the DLBSQ for probable DLB was investigated using a receiver operating characteristic curve analysis. Results: Total DLBSQ score was associated with visuospatial and frontal/executive dysfunction and the diagnosis of probable DLB. The area under the receiver operating characteristic curve for total DLBSQ score was 0.727. Youden's method revealed an optimal cutoff value of 3. The sensitivity and specificity of the DLBSQ were 68.7% and 62.4%, respectively. Its discriminating performance improved when cognitive test profiles were additionally considered (area under the curve: 0.822, sensitivity: 80.6%, and specificity: 70.4%). Conclusions: The DLBSQ might be a useful screening tool for DLB in routine clinical practice with good sensitivity and specificity.

Association of Family History and Polygenic Risk Score With Longitudinal Prognosis in Parkinson Disease.

Background and Objectives: Evidence suggests that either family history or polygenic risk score (PRS) is associated with developing Parkinson disease (PD). However, little is known about the longitudinal prognosis of PD according to family history and higher PRS. Methods: From the Parkinson's Progression Markers Initiative database, 395 patients with PD who followed up for more than 2 years were grouped into those with family history within first-degree, second-degree, and third-degree relatives (N = 127 [32.2%]) vs those without (N = 268 [67.8%]). The PRS of 386 patients was computed using whole-genome sequencing data. Longitudinal assessment of motor, cognition, and imaging based on dopaminergic degeneration was conducted during the regular follow-up period. Effects of family history, PRS, or both on longitudinal changes of cognition, motor severity, and nigrostriatal degeneration were tested using a linear mixed model. The risk of freezing of gait (FOG) according to family history was assessed using the Kaplan-Meier analysis and Cox regression models. Results: During a median follow-up of 9.1 years, PD with positive family history showed a slower decline of caudate dopamine transporter uptake (ß estimate of family history × time = 0.02, 95% CI = 0.002-0.036, p = 0.027). Family history of PD and higher PRS were independently associated with a slower decline of Montreal Cognitive Assessment (ß estimate of family history × time = 0.12, 95% CI = 0.02-0.22, p = 0.017; ß estimate of PRS × time = 0.09, 95% CI = 0.03-0.16, p = 0.006). In those 364 patients without FOG at baseline, PD with positive family history had a lower risk of FOG (hazard ratio of family history = 0.57, 95% CI = 0.38-0.84, p = 0.005). Discussion: Having a family history of PD predicts slower progression of cognitive decline and caudate dopaminergic degeneration, and less FOG compared with those without a family history independent of PRS. Taken together, information on family history could be used as a proxy for the clinical heterogeneity of PD. Trial Registration Information: The study was registered at clinicaltrials.gov (NCT01141023), and the enrollment began June 1, 2010.

Functional Brain Networks of Minor and Well-Structured Major Hallucinations in Parkinson's Disease.

BACKGROUND: Minor hallucinations (mHs) and well-structured major hallucinations (MHs) are common symptoms of Parkinson's disease (PD) psychosis. OBJECTIVES: To investigate the resting-state networks (RSNs) in patients with PD without hallucinations (PD-nH), with mH (PD-mH), and with MH (PD-MH). METHODS: A total of 73 patients with PD were enrolled (27 PD-nH, 23 PD-mH, and 23 PD-MH). Using seed-based functional connectivity analyses, we investigated the RSNs supposedly related to hallucinations in PD: the default mode network (DMN), executive control network (ECN), dorsal attention network (DAN), ventral attention network (VAN), and visual network (VN). We compared the cognitive function and RSN connectivity among the three groups. In addition, we performed a seed-to-seed analysis to examine the inter-network connectivity within each group using the corresponding RSN seeds. RESULTS: PD-MH group had lower test scores for attention and visuospatial functions compared with those in the other groups. The connectivity of the right intracalcarine cortex within the DAN was lower in the PD-MH group than in the others. The PD-mH and PD-MH groups showed higher connectivity in the left orbitofrontal cortex within DMN compared with the PD-nH group, whereas the connectivity was lower in the right middle frontal gyrus (MFG) within ECN, precuneus cortex within VAN, right middle temporal gyrus and precuneus cortex within DAN, and left MFG within VN. The PD-mH and PD-MH groups showed different inter-network connectivity between the five RSNs, especially regarding DAN connectivity. CONCLUSIONS: DAN dysfunction may be a key factor in the progression from mH to MH in patients with PD. © 2023 International Parkinson and Movement Disorder Society.

Slow gut transit increases the risk of Alzheimer's disease: An integrated study of the bi-national cohort in South Korea and Japan and Alzheimer's disease model mice.

INTRODUCTION: Although the association between Alzheimer's disease (AD) and constipation is controversial, its causality and underlying mechanisms remain unknown. OBJECTIVES: To investigate the potential association between slow gut transit and AD using epidemiological data and a murine model. METHODS: We conducted a bi-national cohort study in South Korea (discovery cohort, N=3,130,193) and Japan (validation cohort, N=4,379,285) during the pre-observation period to determine the previous diagnostic history (2009-2010) and the follow-up period (2011-2021). To evaluate the causality, we induced slow gut transit using loperamide in 5xFAD transgenic mice. Changes in amyloid-beta (Aß) and other markers were examined using ELISA, qRT-PCR, RNA-seq, and behavioral tests. RESULTS: Constipation was associated with an increased risk of AD in the discovery cohort (hazard ratio, 2.04; 95% confidence interval [CI], 2.01-2.07) and the validation cohort (hazard ratio; 2.82; 95% CI, 2.61-3.05). We found that loperamide induced slower gut transit in 5xFAD mice, increased Aß and microglia levels in the brain, increased transcription of genes related to norepinephrine secretion and immune responses, and decreased the transcription of defense against bacteria in the colonic tissue. CONCLUSION: Impaired gut transit may contribute to AD pathogenesis via the gut-brain axis, thus suggesting a cyclical relationship between intestinal barrier disruption and Aß accumulation in the brain. We propose that gut transit or motility may be a modifiable lifestyle factor in the prevention of AD, and further clinical investigations are warranted.

Nanoporous MoS2 Field-Effect Transistor Based Artificial Olfaction: Achieving Enhanced Volatile Organic Compound Detection Inspired by the Drosophila Olfactory System.

Olfaction, a primal and effective sense, profoundly impacts our emotions and instincts. This sensory system plays a crucial role in detecting volatile organic compounds (VOCs) and realizing the chemical environment. Animals possess superior olfactory systems compared to humans. Thus, taking inspiration from nature, artificial olfaction aims to achieve a similar level of excellence in VOC detection. In this study, we present the development of an artificial olfaction sensor utilizing a nanostructured bio-field-effect transistor (bio-FET) based on transition metal dichalcogenides and the Drosophila odor-binding protein LUSH. To create an effective sensing platform, we prepared a hexagonal nanoporous structure of molybdenum disulfide (MoS2) using block copolymer lithography and selective etching techniques. This structure provides plenty of active sites for the integration of the LUSH protein, enabling enhanced binding with ethanol (EtOH) for detection purposes. The coupling of the biomolecule with EtOH influences the bio-FETs potential, which generates indicative electrical signals. By mimicking the sniffing techniques observed in Drosophila, these bio-FETs exhibit an impressive limit of detection of 10-6% for EtOH, with high selectivity, sensitivity, and detection ability even in realistic environments. This bioelectric sensor demonstrates substantial potential in the field of artificial olfaction, offering advancements in VOC detection.

Chronic Atopic Dermatitis with Eosinophilia Improved by Daesiho-Tang: A Case Report.

Purpose: This study is to report a case of chronic atopic dermatitis (AD) with eosinophilia, which did not respond to conventional therapy and was improved by Daesiho-tang (DSHT). Patients and Methods: The patient visited our clinic with symptoms of atopic dermatitis including skin lesions and pruritus. Based on her symptoms, DSHT was prescribed. At each visit, the Scoring Atopic Dermatitis (SCORAD), Dermatology Life Quality Index (DLQI), and accompanying systemic symptoms (ASS) were measured. Multiple Allergen Simultaneous Test (MAST) was initially performed for 108 allergens and analyzed by Western blotting using an Alternate Scoring Method (ASM) according to the specific IgE concentration. Also, peripheral blood laboratory (Lab) tests were performed three times during the patient's visit. Results: After taking DSHT, the total SCORAD score improved from 62.9 to 23.5, while the patient's ASS also improved. The DLQI score improved from 19 to 5. The total number of eosinophils in the peripheral blood, which showed a mild increase, recovered from 17.2% (0.98 x103/µL) to 4.5% (0.24 x103/µL). The total IgE slightly decreased, while AST and ALT were also restored to normal ranges. Conclusion: Based on this case, DSHT is considered a potential alternative treatment for AD.

Distinct amyloid-dependent patterns of nigra dopamine depletion in Lewy body diseases.

Introduction: Concomitant amyloid pathology is not uncommon and contributes to the clinical characteristics of Lewy body disease (LBD). We investigated the effect of amyloid on striatal18F-FP-CIT uptake patterns in LBD, including Parkinson's disease (PD) and dementia with Lewy bodies. Methods: We enrolled 125 patients with LBD who underwent18F-florbetaben positron emission tomography (PET) and18F-FP-CIT PET. Patients were divided into amyloid-positive and amyloid-negative groups. We investigated the effect of amyloid on striatal dopamine transporter (DAT) availability, depending on the type of LBD, using general linear models with interaction analysis after controlling for age, sex, education, deep white matter hyperintensity (WMH), periventricular WMH, and cognitive status. Results: There was a significant interaction effect between the disease group and the presence of amyloid on DAT availability in the anterior putamen, posterior putamen, caudate, and ventral striatum. In the presence of amyloid, only the PD group exhibited decreased DAT availability in the anterior and posterior putamen. In both groups, the presence of amyloid was not associated with DAT availability in the caudate and ventral striatum. The presence of amyloid was not directly related to the worse parkinsonian motor symptoms in both groups. However, there was a significant indirect effect of amyloid on parkinsonian motor symptoms, which was mediated by anterior and posterior putaminal DAT availability in the PD group alone. Discussion: This study demonstrates different amyloid-dependent or amyloid-independent18F-FP-CIT PET patterns in patients with LBD, suggesting distinctive interactions between α-synuclein and amyloid pathology based on the type of LBD.

High-fat diet-induced dopaminergic dysregulation induces REM sleep fragmentation and ADHD-like behaviors.

Consumption of a high-fat diet (HFD) has been associated with reduced wakefulness and various behavioral deficits, including anxiety, depression, and anhedonia. The dopaminergic system, which plays a crucial role in sleep and ADHD, is known to be vulnerable to chronic HFD. However, the association between HFD-induced behavioral and molecular changes remains unclear. Therefore, we investigated the effects of a HFD on the dopaminergic system and its association with behavioral deficits in male mice. The mice were divided into normal diet and HFD groups and were analyzed for sleep patterns, behavior tests, and transcription levels of dopamine-related genes in the brain. The HFD group showed decreased wakefulness, increased REM sleep with fragmented patterns, decreased time spent in the center zone of the open field test, shorter immobile time in the tail suspension test, impaired visuospatial memory, and reduced sucrose preference. Additionally, the HFD group had decreased mRNA levels of D1R, COMT, and DAT in the nucleus accumbens, which negatively correlated with REM sleep proportion and REM sleep bout count. The results suggest that HFD-induced behavioral deficits were resemblance to ADHD-like behavioral phenotypes and disturbs REM sleep by dysregulating the dopaminergic system.

Visible-Light-Mediated TiO2-Catalyzed Aerobic Dehydrogenation of N-Heterocycles in Batch and Flow.

We report a simple and environmentally friendly method for synthesizing N-containing heterocycles via a visible-light-mediated aerobic dehydrogenation reaction. Using a nontoxic, stable, and inexpensive titanium dioxide catalyst, a variety of substituted quinoline, indole, quinoxaline, and 3,4-dihydroisoquinoline derivatives could be synthesized using the green oxidant molecular oxygen. Improved reactivity and scalability of this reaction were demonstrated by adapting the photochemical multiphasic reaction to a continuous flow system. To gain insight into the mechanism, we also conducted several mechanistic studies, including absorption analysis, light on-off testing, and NMR analysis. Especially, oxygen is reduced to hydrogen peroxide, and dimethyl sulfoxide is a critical scavenger of the oxidant byproduct for ensuring high yields.

Association of Neuropsychiatric Symptom Profiles With Cognitive Decline in Patients With Parkinson Disease and Mild Cognitive Impairment.

BACKGROUND AND OBJECTIVES: Neuropsychiatric symptoms (NPS) are closely associated with cognitive decline in patients with Parkinson disease (PD). We investigated which profiles of NPS are associated with the risk of dementia in PD with mild cognitive impairment (PD-MCI). METHODS: We retrospectively assessed 338 patients with PD-MCI from a single tertiary hospital, who underwent neuropsychological tests and a neuropsychiatric inventory (NPI) questionnaire. We conducted a factor analysis of the dichotomized presence of 12 NPI symptoms, yielding 3 NPI factors: factor 1, mood symptoms; factor 2, hyperactivity-related symptoms; and factor 3, psychotic symptoms. Factor analysis of the severity of NPI symptoms also identified similar NPI factors. The neuropsychiatric correlates of NPI factors were evaluated using general linear models for cognitive tests. Subsequently, we evaluated the hazard ratio (HR) of NPI factors on conversion to dementia. RESULTS: A higher prevalence factor 1 score was associated with lower scores in the verbal memory (ß = -0.15; 95% CI -0.24 to -0.06; p = 0.001) and executive domains (ß = -0.16; 95% CI -0.28 to -0.04; p = 0.007), whereas higher severity factor 2 scores were associated with lower scores in the naming (ß = -0.16; 95% CI -0.28 to -0.03; p = 0.012), visuospatial (ß = -0.24; 95% CI -0.41 to -0.07; p = 0.005), and verbal memory domains (ß = -0.15; 95% CI -0.24 to -0.05; p = 0.005). A higher severity factor 3 score was associated with lower scores in the visuospatial domain (ß = -0.25; 95% CI -0.46 to -0.07; p = 0.007). Cox regression models demonstrated that the risk of dementia was increased in those with higher prevalence factor 1 (HR = 1.48, 95% CI 1.17-1.88, p = 0.001) and factor 2 scores (HR = 1.27, 95% CI 1.07-1.51, p = 0.007) and severity factor 3 score (HR = 1.52, 95% CI 1.29-1.80, p < 0.001) after adjusting for age, sex, education, disease duration, scores for cognition and parkinsonism, and levodopa equivalent dose. DISCUSSION: This study demonstrated that a higher burden of NPS is associated with dementia conversion in patients with PD-MCI.

Clinical relevance of deep learning models in predicting the onset timing of cancer pain exacerbation.

Cancer pain is a challenging clinical problem that is encountered in the management of cancer pain. We aimed to investigate the clinical relevance of deep learning models that predict the onset of cancer pain exacerbation in hospitalized patients. We defined cancer pain exacerbation (CPE) as the pain with a numerical rating scale (NRS) score of ≥ 4. We investigated the performance of the deep learning models using the Matthews correlation coefficient (MCC) with different input lengths and time binning. All the pain records were obtained from the electronic medical records of the hematology-oncology wards in a Samsung Medical Center between July 2016 and February 2020. The model was externally validated using the holdout method with 20% of the datasets. The most common type of cancer was lung cancer (n = 745, 21.7%), and the median CPE per day was 1.01. The NRS pain records showed circadian patterns that correlated with NRS pain patterns of the previous days. The correlation of the NRS scores showed a positive association with the closeness of the NRS pattern of the day with forecast date and size of time binning. The long short-term memory-based model exhibited a good performance by demonstrating 9 times the best performance and 8 times the second-best performance among 21 different settings. The best performance was achieved with 120 h input and 12 h bin lengths (MCC: 0.4927). Our study demonstrated the possibility of predicting CPE using deep learning models, thereby suggesting that preemptive cancer pain management using deep learning could potentially improve patients' daily life.

GABA-Positive Astrogliosis in Sleep-Promoting Areas Associated with Sleep Disturbance in 5XFAD Mice.

Sleep disturbances, a debilitating symptom of Alzheimer's disease (AD), are associated with neuropathological changes. However, the relationship between these disturbances and regional neuron and astrocyte pathologies remains unclear. This study examined whether sleep disturbances in AD result from pathological changes in sleep-promoting brain areas. Male 5XFAD mice underwent electroencephalography (EEG) recordings at 3, 6, and 10 months, followed by an immunohistochemical analysis of three brain regions associated with sleep promotion. The findings showed that 5XFAD mice demonstrated reduced duration and bout counts of nonrapid eye movement (NREM) sleep by 6 months and reduced duration and bout counts of rapid eye movement (REM) sleep by 10 months. Additionally, peak theta EEG power frequency during REM sleep decreased by 10 months. Sleep disturbances correlated with the total number of GFAP-positive astrocytes and the ratio of GFAP- and GABA-positive astrocytes across all three sleep-associated regions corresponding to their roles in sleep promotion. The presence of GABRD in sleep-promoting neurons indicated their susceptibility to inhibition by extrasynaptic GABA. This study reveals that neurotoxic reactive astrogliosis in NREM and REM sleep-promoting areas is linked to sleep disturbances in 5XFAD mice, which suggests a potential target for the treatment of sleep disorders in AD.

Controlling Local Thermalization Dynamics in a Floquet-Engineered Dipolar Ensemble.

Understanding the microscopic mechanisms of thermalization in closed quantum systems is among the key challenges in modern quantum many-body physics. We demonstrate a method to probe local thermalization in a large-scale many-body system by exploiting its inherent disorder and use this to uncover the thermalization mechanisms in a three-dimensional, dipolar-interacting spin system with tunable interactions. Utilizing advanced Hamiltonian engineering techniques to explore a range of spin Hamiltonians, we observe a striking change in the characteristic shape and timescale of local correlation decay as we vary the engineered exchange anisotropy. We show that these observations originate from the system's intrinsic many-body dynamics and reveal the signatures of conservation laws within localized clusters of spins, which do not readily manifest using global probes. Our method provides an exquisite lens into the tunable nature of local thermalization dynamics and enables detailed studies of scrambling, thermalization, and hydrodynamics in strongly interacting quantum systems.

Comparison Between 18F-Florapronol and 18F-Florbetaben Imaging in Patients With Cognitive Impairment.

BACKGROUND AND PURPOSE: To determine the imaging characteristics and cutoff value of 18F-florapronol (FC119S) quantitative analysis for detecting ß-amyloid positivity and Alzheimer's disease (AD), we compared the findings of FC119S and 18F-florbetaben (FBB) positron-emission tomography (PET) in patients with cognitive impairment. METHODS: We prospectively enrolled 35 patients with cognitive impairment who underwent FBB-PET, FC119S-PET, and brain magnetic resonance imaging. We measured global and vertex-wise standardized uptake value ratios (SUVRs) using a surface-based method with the cerebellar gray matter as reference. Optimal global FC119S SUVR cutoffs were determined using receiver operating characteristic curves for ß-amyloid positivity based on the global FBB SUVR of 1.478 and presence of AD, respectively. We evaluated the global and vertex-wise SUVR correlations between the two tracers. In addition, we performed correlation analysis for global or vertex-wise SUVR of each tracer with the vertex-wise cortical thicknesses. RESULTS: The optimal global FC119S SUVR cutoff value was 1.385 both for detecting ß-amyloid positivity and for detecting AD. Based on the global SUVR cutoff value of each tracer, 32 (91.4%) patients had concordant ß-amyloid positivity. The SUVRs of FC119S and FBB had strong global (r=0.72) and vertex-wise (r>0.7) correlations in the overall cortices, except for the parietal and temporal cortices (0.4

Effect of Amyloid on Cognitive Performance in Parkinson's Disease and Dementia with Lewy Bodies.

BACKGROUND: Concomitant amyloid pathology contributes to the clinical heterogeneity of Lewy body diseases (LBDs). OBJECTIVE: The objective of this study was to investigate the pattern and effect of amyloid accumulation on cognitive dysfunction in Parkinson's disease (PD) and dementia with Lewy bodies (DLB). METHODS: We retrospectively assessed 205 patients with LBD (91 with DLB and 114 with PD) who underwent 18 F-florbetaben positron emission tomography and divided them into amyloid-positive and amyloid-negative groups depending on global standardized uptake value ratios (SUVRs). We investigated the effect of group on the regional and global SUVRs using general linear models (GLMs) after controlling for age, sex, cognitive status, and score on the Korean version of the Mini-Mental State Examination. Moreover, the effect of amyloid on cognitive function, depending on the type of LBD, was evaluated using GLMs with interaction analysis. RESULTS: In all evaluated regions including the striatum, the DLB group showed a higher SUVR than the PD group. Among amyloid-positive patients, the DLB group had a higher regional SUVR than the PD group in the frontal and parietal cortices. There was a significant interaction effect between amyloid and disease groups in language and memory function. In patients with PD, global amyloid load was negatively associated with language (B = -2.03; P = 0.010) and memory functions (B = -1.96; P < 0.001). However, amyloid load was not significantly associated with cognitive performance in the DLB group. CONCLUSIONS: Although the burden of amyloid was higher in the DLB group, amyloid accumulation was negatively associated with the memory and language functions in the PD group only. © 2022 International Parkinson and Movement Disorder Society.

Poria cocos Extract from Mushrooms Stimulates Aquaporin-3 via the PI3K/Akt/mTOR Signaling Pathway.

Background: Poria cocos (PC), a fungus, has been used for more than 2000 years as a food and medicine in China. PC and its components have various pharmacological effects on the skin, including immunomodulatory activities, barrier function improvement, and anti-tumor effects. However, the effect of PC in aquaporin-3 (AQP3) expression, which is essential for epidermal water permeability barrier maintenance, was not reported. Methods: This study examined the mechanism through which the ethanol extract of the sclerotium of PC (EPC) promoted the expression of AQP3 in cultured human keratinocytes. Western blotting was used to investigate the expression of AQPs and the activation of phosphoinositide 3-kinase (PI3K)/Akt-related signaling molecules in HaCaT cells. Cells were treated with inhibitors of PI3K/Akt and mechanistic target of rapamycin (mTOR) prior to EPC treatment. Results: EPC promoted the expression of AQP3 in HaCaT cells without affecting AQP1 and AQP2 expression. Phosphorylated Akt levels were increased by EPC treatment, and the inhibition of PI3K by LY2940002 resulted in a reduction in EPC-induced AQP3 expression. Furthermore, EPC stimulated the phosphorylation of p70S6K and AktSer473, which are downstream targets of mTORC1 and mTORC2, respectively. The mTOR complex inhibitors, rapamycin and Torin 1, partially reduced EPC-induced AQP3 expression. Conclusion: These results suggest that EPC increased expression of AQP3, which is important for skin moisturization, by activating the PI3K/Akt/mTOR signaling pathway in human keratinocytes.

The Role of Vitamin D in Alzheimer's Disease: A Transcriptional Regulator of Amyloidopathy and Gliopathy.

Alzheimer's disease (AD) is characterized by amyloid-beta (Aß) accumulation and cognitive mental decline. Epidemiological studies have suggested an association between low serum vitamin D levels and an increased risk of AD. Vitamin D regulates gene expression via the vitamin D receptor, a nuclear ligand-dependent transcription factor. However, the molecular mechanism underlying the pathogenic and therapeutic effects of vitamin D on AD is not fully understood yet. To better understand how vitamin D regulates the expression of genes related to AD pathology, first, we induced vitamin D deficiency in 5xFAD mice by providing a vitamin-D-deficient diet and observed the changes in the mRNA level of genes related to Aß processing, which resulted in an increase in the Aß load in the brain. The vitamin D-deficient diet also suppressed the expression of genes for microglial Aß phagocytosis. Interestingly, vitamin D deficiency in the early stage of AD resulted in earlier memory impairment. In addition, we administered vitamin D intraperitoneally to 5xFAD mice with a normal diet and found lower Aß levels with the suppressed expression of genes for Aß generation and observed improved memory function, which may be potentially associated with reduced MAO-B expression. These findings strongly suggest the role of vitamin D as a crucial disease-modifying factor that may modulate the amyloid pathology with regard to reducing AD symptoms.

Association of Enlarged Perivascular Spaces With Amyloid Burden and Cognitive Decline in Alzheimer Disease Continuum.

BACKGROUND AND OBJECTIVES: To investigate the effects of enlarged perivascular space (EPVS) on amyloid burden and cognitive function in Alzheimer's disease (AD) continuum. METHODS: We retrospectively reviewed 208 patients with AD across the cognitive continuum (preclinical, prodromal, and AD dementia) who showed amyloid deposition on 18F-florbetaben positron emission tomography scans and 82 healthy controls. EPVSs were counted for each patient in the basal ganglia (BG), centrum semiovale (CSO), and hippocampus (HP) on axial T2-weighted images. Patients were then classified according to the number of EPVS into the EPVS+ (> 10 EPVSs) and EPVS- (0-10 EPVSs) groups for the BG and CSO, respectively. In terms of HP-EPVS, equal or more than seven EPVSs on bilateral hemisphere were regarded as the presence of HP-EPVS. After adjusting for markers of small vessel disease (SVD), multiple linear regression analyses were performed to determine the inter-group differences in global and regional amyloid deposition and cognitive function at the time of diagnosis of AD continuum. A linear mixed model was used to assess the effects of EPVSs on the longitudinal changes in the Mini-Mental State Examination (MMSE) scores. RESULTS: Amyloid burden at the time of diagnosis of AD continuum was not associated with the degree of BG-, CSO-, or HP-EPVS. BG-EPVS affected language and frontal/executive function via SVD markers and HP-EPVS was associated with general cognition via SVD markers. However, CSO-EPVS was not associated with baseline cognition. A higher number of CSO-EPVS was significantly associated with a more rapid decline in MMSE scores (ß = -0.58, SE = 0.23, p = 0.011) independent of the amyloid burden. In terms of BG and HP, there was no difference between the EPVS+ and EPVS- groups in the rate of longitudinal decreases in MMSE scores. DISCUSSION: Our findings suggest that BG-, CSO-, and HP-EPVS are not associated with baseline ß-amyloid burden or cognitive function independently of SVD at the diagnosis of AD continuum. However, CSO-EPVS appears to be associated with the progression of cognitive decline in an amyloid-independent manner. Further studies are needed to investigate whether CSO-EPVS is a potential therapeutic target in patients with AD continuum.