Gait Analysis with Wearable Sensors in Isolated REM Sleep Behavior Disorder Associated with Phenoconversion: An Explorative Study.

Background: Gait disturbance is a vital characteristic of motor manifestation in α- synucleinopathies, especially Parkinson's disease. Subtle gait alterations are present in isolated rapid eye movement sleep behavior disorder (iRBD) patients before phenoconversion; it is yet unclear, if gait analysis may predict phenoconversion. Objective: To investigate subtle gait alterations and explore whether gait analysis using wearable sensors is associated with phenoconversion of iRBD to α-synucleinopathies. Methods: Thirty-one polysomnography-confirmed iRBD patients and 33 healthy controls (HCs) were enrolled at baseline. All participants walked for a minute while wearing 6 inertial sensors on bilateral wrists, ankles, and the trunk (sternal and lumbar region). Three conditions were tested: (i) normal walking, (ii) fast walking, and (iii) dual-task walking. Results: Decreased arm range of motion and increased gait variation (stride length, stride time and stride velocity) discriminate converters from HCs at baseline. After an average of 5.40 years of follow-up, 10 patients converted to neurodegenerative diseases (converters). Cox regression analysis showed higher value of stride length asymmetry under normal walking condition to be associated with an early conversion of iRBD to α- synucleinopathies (adjusted HR 4.468, 95% CI 1.088- 18.349, p = 0.038). Conclusions: Stride length asymmetry is associated with progression to α- synucleinopathies in patients with iRBD. Gait analysis with wearable sensors may be useful for screening, monitoring, and risk stratification for disease-modifying therapy trials in patients with iRBD.

MCP-1 levels in astrocyte-derived exosomes are changed in preclinical stage of Alzheimer's disease.

Background: Alzheimer's disease (AD) is the most common form of dementia in older adults. There is accumulating evidence that inflammatory processes play a critical role in AD pathogenesis. In this study, we investigated whether inflammatory factors in plasma and astrocyte-derived exosomes (ADEs) from plasma are differentially expressed in the early stages of AD and their potential role in pathological processes in the AD continuum. Method: We included 39 normal controls (NCs), 43 participants with subjective cognitive decline (SCD), and 43 participants with amnestic mild cognitive impairment (aMCI)/AD. IL-6, IL-8, and MCP-1 in plasma and ADEs from plasma were evaluated using a commercial multiplex Luminex-based kit. Results: Pairwise comparisons between the groups showed no significant differences in plasma levels of IL-6, IL-8, or MCP-1. However, ADEs in the SCD group showed an increase in MCP-1 levels compared to the NC group. To differentiate the preclinical group, discriminant analysis was performed using sex, age, years of education, and genotype. This revealed a difference between the SCD and NC groups (area under the curve: 0.664). A Spearman correlation analysis of MCP-1 in plasma and ADEs showed no or weak correlation in the SCD (R = 0.150, p = 0.350) and aMCI/AD (R = 0.310, p = 0.041) groups, while a positive correlation in the NC group (R = 0.360, p = 0.026). Conclusion: Plasma IL-6, IL-8, and MCP-1 levels were not significantly different. However, the concentration of MCP-1 in ADEs is slightly altered during the preclinical phase of AD, which could be a potential role of the central neuron system (CNS) immune response in the AD continuum. Clinical trial registration: www.ClinicalTrials.gov, identifier: NCT03370744.

Associations Between Levels of Peripheral NCAPH2 Promoter Methylation and Different Stages of Alzheimer's Disease: A Cross-Sectional Study.

BACKGROUND: Several studies have examined NCAPH2 methylation in amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD), but little is known of NCAPH2 methylation in subjective cognitive decline (SCD). OBJECTIVE: To examine whether methylation of peripheral NCAPH2 are differentially changed at various phases of AD, and whether it could serve as a diagnostic biomarker for SCD. METHODS: A total of 40 AD patients, 52 aMCI patients, 148 SCD patients, and 193 cognitively normal controls (NCs) were recruited in the current case-control study. Besides, 54 cognitively normal individuals have received amyloid positron emission tomography (amyloid PET) scans. Using bisulfite pyrosequencing method, we measured blood DNA methylation in the NCAPH2 gene promoter. RESULTS: The main outcomes were: 1) For SCD, there was no significant difference between SCD and NC regarding NCAPH2 methylation; 2) For aMCI, NCAPH2 methylation at CpG2 were significantly lower in aMCI compared with NC and SCD in the entire population and male subgroup; 3) For AD, NCAPH2 methylation at CpG1 were significantly lower in AD compared with NC among females; 4) A relationship with apolipoprotein E (APOE) ɛ4 status was shown. Receiver operating characteristic (ROC) analysis by combining NCAPH2 methylation, age, education, and APOEɛ4 status could distinguish between patients with aMCI (area under the curve (AUC): 0.742) and AD (AUC: 0.873) from NCs. CONCLUSION: NCAPH2 methylation levels were altered at the aMCI and AD stage and may be convenient and cost-effective biomarkers of AD and aMCI.

Association of plasma BDNF levels with different stages of Alzheimer's disease: a cross-sectional study.

BACKGROUND: Growing evidence shows that the expression of brain-derived neurotrophic factor (BDNF) is altered in the peripheral blood of participants with Alzheimer's disease (AD). It is unclear, however, whether altered BDNF expression is also observed in the early stages of AD. METHODS: In the present study, 138 normal controls (NC), 57 participants with subjective cognitive decline (SCD), and 37 participants with amnestic mild cognitive impairment (aMCI) and AD were included. Plasma BDNF protein levels were assessed using a commercial multiplex Luminex-based kit. Patient samples were also probed for the presence of BDNF gene variant rs6265. RESULTS: Pairwise comparisons between the groups showed that there was not a significant difference in BDNF levels when comparing SCD with NC and when comparing SCD with aMCI/AD, but BDNF levels in aMCI/AD samples were increased when compared with NC samples. For models differentiating clinical groups, discriminant analysis was performed by including education, APOE genotype, and BDNF levels in the model. This approach distinguishes participants with SCD (AUC = 0.630) and aMCI/AD (AUC = 0.665) from NC. CONCLUSION: Our results suggest that expression of BDNF in plasma is altered at the clinical stage of AD.

The clinico-pathological characterisation of focal cortical dysplasia type IIb genetically defined by MTOR mosaicism.

AIMS: Focal cortical dysplasia (FCD) is a major cause of drug-resistant paediatric epilepsy and is amenable to successful neurosurgical resection. FCD ILAE Type IIb is the most common FCD subtype, and brain somatic mutations affecting the mTOR pathway play a major pathogenic role. The aim of this study was to comprehensively describe the genotype-phenotype association of 20 patients with histopathologically confirmed FCDIIb using next generation sequencing (NGS) of paired blood-brain samples. METHODS: Clinical and neuropathological data were retrospectively reviewed from the hospital archive. The NGS panel included 11 mTOR-pathway-related genes with maximum coverage of 2000×. The detected variants were validated by digital droplet PCR. RESULTS: Pathogenic MTOR variants were identified in 10 patients (50%). Further comparison with MTOR-wildtype FCDIIb suggested a profound genotype-phenotype association characterised by (1) a non-temporal lobe lesion on MRI, (2) a larger lesion volume occupying grey and white matter (3.032 ± 1.859 cm3 vs 1.110 ± 0.856 cm3 , p = 0.014), (3) more balloon cells (50.20 ± 14.40 BC/mm2 vs 31.64 ± 30.56 BC/mm2 , p = 0.099) and dysmorphic neurons (48.72 ± 19.47DN/mm2 vs 15.28 ± 13.95DN/mm2 , p = 0.000) and (4) a positive correlation between VAF and the lesion volume (r = 0.802, p = 0.017). CONCLUSIONS: Our study identified frequent MTOR mutations in the cell-rich FCDIIb phenotype, clinically characterised by a non-temporal location and large lesion volume. Comprehensive genotype-phenotype associations will help us further explore and define the broad spectrum of FCD lesions to make more targeted therapies available in the realm of epileptology.

Fatigue in Patients with Idiopathic/Isolated REM Sleep Behavior Disorder.

Introduction: Fatigue is one of the most common and disabling symptoms of Parkinson's Disease (PD). The occurrence and clinical features of fatigue in patients with prodromal PD remain largely elusive. This study aimed to investigate the prevalence and clinical characteristics of fatigue in patients with idiopathic/isolated REM sleep behavior disorders (iRBD). Methods: A total of 97 polysomnography-confirmed iRBD patients were enrolled in this study. A comprehensive neurological assessment (including motor and non-motor assessment) was performed. Fatigue was assessed using the Fatigue Severity Scale (FSS). Motor and non-motor characteristics were compared between iRBD patients with and without fatigue. Logistic regression was used to identify the factors associated with fatigue. Results: The prevalence of fatigue was 35.05%. Compared to the non-fatigue patients, patients with fatigue had higher non-motor symptom scale (NMSS) score (p = 0.009), higher Hamilton Depression Rating Scale (HAMD) score (p = 0.002), and a higher prevalence of orthostatic hypotension (p = 0.021). Multivariate regression analysis showed that depression (OR 4.17, 95% CI 1.13−15.49, p = 0.033) and orthostatic hypotension (OR 2.80, 95% CI 1.09−7.18, p = 0.032) were significantly associated with fatigue in iRBD patients. Additionally, both NMSS (rs = 0.310, p = 0.002) and HAMD (rs = 0.385, p < 0.001) scores were mildly correlated with fatigue severity. Conclusion: Our study showed that fatigue is common in patients with iRBD. In addition, depression and orthostatic hypotension were independently associated with fatigue in iRBD patients.

Brain microglia activation and peripheral adaptive immunity in Parkinson's disease: a multimodal PET study.

BACKGROUND: Abnormal activation of immune system is an important pathogenesis of Parkinson's disease, but the relationship between peripheral inflammation, central microglia activation and dopaminergic degeneration remains unclear. OBJECTIVES: To evaluate the brain regional microglia activation and its relationship with clinical severity, dopaminergic presynaptic function, and peripheral inflammatory biomarkers related to adaptive immunity. METHODS: In this case-control study, we recruited 23 healthy participants and 24 participants with early-stage Parkinson's disease. 18F-PBR06 PET/MR for microglia activation, 18F-FP-DTBZ for dopaminergic denervation, total account of T cells and subpopulations of T helper (Th1/Th2/Th17) cells, and the levels of serum inflammatory cytokines were assessed. Sanger sequencing was used to exclude the mix-affinity binders of 18F-PBR06-PET. RESULTS: Compared to healthy controls, patients with Parkinson's disease had an increased 18F-PBR06-PET standardized uptake value ratio (SUVR) in the putamen, particularly in the ipsilateral side of the motor onset. 18F-PBR06-PET SUVR was positively associated with 18F-FP-DTBZ-PET SUVR in the brainstem and not associated with disease severity measured by Hoehn and Yahr stage, MDS-UPDRS III scores. Patients with Parkinson's disease had elevated frequencies of Th1 cells and serum levels of IL10 and IL17A as compared to healthy controls. No significant association between peripheral inflammation markers and microglia activation in the brain of PD was observed. CONCLUSION: Parkinson's disease is associated with early putaminal microglial activation and peripheral phenotypic Th1 bias. Peripheral adaptive immunity might be involved in microglia activation in the process of neurodegeneration in PD indirectly, which may be a potential biomarker for the early detection and the target for immunomodulating therapy.

ß-Amyloid in blood neuronal-derived extracellular vesicles is elevated in cognitively normal adults at risk of Alzheimer's disease and predicts cerebral amyloidosis.

BACKGROUND: Blood biomarkers that can be used for preclinical Alzheimer's disease (AD) diagnosis would enable trial enrollment at a time when the disease is potentially reversible. Here, we investigated plasma neuronal-derived extracellular vesicle (nEV) cargo in patients along the Alzheimer's continuum, focusing on cognitively normal controls (NCs) with high brain ß-amyloid (Aß) loads (Aß+). METHODS: The study was based on the Sino Longitudinal Study on Cognitive Decline project. We enrolled 246 participants, including 156 NCs, 45 amnestic mild cognitive impairment (aMCI) patients, and 45 AD dementia (ADD) patients. Brain Aß loads were determined using positron emission tomography. NCs were classified into 84 Aß- NCs and 72 Aß+ NCs. Baseline plasma nEVs were isolated by immunoprecipitation with an anti-CD171 antibody. After verification, their cargos, including Aß, tau phosphorylated at threonine 181, and neurofilament light, were quantified using a single-molecule array. Concentrations of these cargos were compared among the groups, and their receiver operating characteristic (ROC) curves were constructed. A subset of participants underwent follow-up cognitive assessment and magnetic resonance imaging. The relationships of nEV cargo levels with amyloid deposition, longitudinal changes in cognition, and brain regional volume were explored using correlation analysis. Additionally, 458 subjects in the project had previously undergone plasma Aß quantification. RESULTS: Only nEV Aß was included in the subsequent analysis. We focused on Aß42 in the current study. After normalization of nEVs, the levels of Aß42 were found to increase gradually across the cognitive continuum, with the lowest in the Aß- NC group, an increase in the Aß+ NC group, a further increase in the aMCI group, and the highest in the ADD group, contributing to their diagnoses (Aß- NCs vs. Aß+ NCs, area under the ROC curve values of 0.663; vs. aMCI, 0.857; vs. ADD, 0.957). Furthermore, nEV Aß42 was significantly correlated with amyloid deposition, as well as longitudinal changes in cognition and entorhinal volume. There were no differences in plasma Aß levels among NCs, aMCI, and ADD individuals. CONCLUSIONS: Our findings suggest the potential use of plasma nEV Aß42 levels in diagnosing AD-induced cognitive impairment and Aß+ NCs. This biomarker reflects cortical amyloid deposition and predicts cognitive decline and entorhinal atrophy.

Association of plasma apolipoproteins and levels of inflammation-related factors with different stages of Alzheimer's disease: a cross-sectional study.

OBJECTIVE: Blood-based biomarkers for the early diagnosis of Alzheimer's disease (AD) are a 'Holy Grail' of AD research. Growing evidence shows that levels of apolipoproteins and various inflammation-related factors are altered in the peripheral blood of patients with AD. The purpose of this study was to clear and definite whether these biomarkers are differentially expressed at the early stages of AD, and could be a biomarker as an early diagnosis of the disease. DESIGN: Observation study. SETTING: This study was a part of the Sino Longitudinal Study on Cognitive Decline, an ongoing prospective cohort study (ClinicalTrials.gov identifier: NCT03370744) that centres on Xuanwu Hospital (Beijing, China) in cooperation with an alliance of 94 hospitals from 50 cities across China. PARTICIPANTS: In the present study, 416 right-handed Chinese Han subjects were recruited through standardised public advertisements from 2014 to 2019. OUTCOME MEASURES: Concentrations of plasma apolipoprotein A1, apolipoprotein CIII (ApoCIII), apolipoprotein E (ApoE), A-2-macroglobulin (A2M), complement C3 (C3) and complement factor H (FH) were determined using a commercial multiplex Luminex-based panel in normal controls (NC), subjective cognitive decline (SCD), mild cognitive impairment and AD groups. RESULTS: For individual analysis, pairwise comparisons showed that: (1) For SCD versus NC, no biomarker showed significant difference; (2) For amnestic mild cognitive impairment (aMCI) versus NC, levels of ApoCIII, ApoE, A2M, C3 and FH increased significantly; and (3) For AD versus NC, amounts of C3 increased. For models differentiating clinical groups, discriminant analysis was performed by including all protein markers, age, sex, genotype and education level in the model. This approach could distinguish between patients with aMCI (area under the curve (AUC): 0.743) and AD (AUC: 0.837) from NC. CONCLUSION: Our results suggest that concentrations of certain apolipoproteins and inflammation-related factors are altered at the early stage of AD, and could be useful biomarkers for early diagnosis. TRIAL REGISTRATION NUMBER: NCT03370744.

SAAED: Embedding and Deep Learning Enhance Accurate Prediction of Association Between circRNA and Disease.

Emerging evidence indicates that circRNA can regulate various diseases. However, the mechanisms of circRNA in these diseases have not been fully understood. Therefore, detecting potential circRNA-disease associations has far-reaching significance for pathological development and treatment of these diseases. In recent years, deep learning models are used in association analysis of circRNA-disease, but a lack of circRNA-disease association data limits further improvement. Therefore, there is an urgent need to mine more semantic information from data. In this paper, we propose a novel method called Semantic Association Analysis by Embedding and Deep learning (SAAED), which consists of two parts, a neural network embedding model called Entity Relation Network (ERN) and a Pseudo-Siamese network (PSN) for analysis. ERN can fuse multiple sources of data and express the information with low-dimensional embedding vectors. PSN can extract the feature between circRNA and disease for the association analysis. CircRNA-disease, circRNA-miRNA, disease-gene, disease-miRNA, disease-lncRNA, and disease-drug association information are used in this paper. More association data can be introduced for analysis without restriction. Based on the CircR2Disease benchmark dataset for evaluation, a fivefold cross-validation experiment showed an AUC of 98.92%, an accuracy of 95.39%, and a sensitivity of 93.06%. Compared with other state-of-the-art models, SAAED achieves the best overall performance. SAAED can expand the expression of the biological related information and is an efficient method for predicting potential circRNA-disease association.

Combination of gut microbiota and plasma amyloid-ß as a potential index for identifying preclinical Alzheimer's disease: a cross-sectional analysis from the SILCODE study.

BACKGROUND: Plasma amyloid-ß (Aß) may facilitate identification of individuals with brain amyloidosis. Gut microbial dysbiosis in Alzheimer's disease (AD) is increasingly being recognized. However, knowledge about alterations of gut microbiota in preclinical AD, as well as whether the combination of plasma Aß and gut microbiota could identify preclinical AD, remains largely unknown. METHODS: This study recruited 34 Aß-negative cognitively normal (CN-) participants, 32 Aß-positive cognitively normal (CN+) participants, and 22 patients with cognitive impairment (CI), including 11 patients with mild cognitive impairment (MCI) and 11 AD dementia patients. All participants underwent neuropsychological assessments and fecal microbiota analysis through 16S ribosomal RNA (rRNA) Illumina Miseq sequencing technique. Meso Scale Discovery (MSD) kits were used to quantify the plasma Aß40, Aß42, and Aß42/Aß40 in CN- and CN+ participants. Using Spearman's correlation analysis, the associations of global standard uptake value rate (SUVR) with altered gut microbiota and plasma Aß markers were separately evaluated. Furthermore, the discriminative power of the combination of gut microbiota and plasma Aß markers for identifying CN+ individuals was investigated. RESULTS: Compared with the CN- group, the CN+ group showed significantly reduced plasma Aß42 (p = 0.011) and Aß42/Aß40 (p = 0.003). The relative abundance of phylum Bacteroidetes was significantly enriched, whereas phylum Firmicutes and class Deltaproteobacteria were significantly decreased in CN+ individuals in comparison with that in CN- individuals. Particularly, the relative abundance of phylum Firmicutes and its corresponding SCFA-producing bacteria exhibited a progressive decline tendency from CN- to CN+ and CI. Besides, the global brain Aß burden was negatively associated with the plasma Aß42/Aß40 (r = -0.298, p = 0.015), family Desulfovibrionaceae (r = -0.331, p = 0.007), genus Bilophila (r = -0.247, p = 0.046), and genus Faecalibacterium (r = -0.291, p = 0.018) for all CN participants. Finally, the combination of plasma Aß markers, altered gut microbiota, and cognitive performance reached a relatively good discriminative power in identifying individuals with CN+ from CN- (AUC = 0.869, 95% CI 0.782 ~ 0.955). CONCLUSIONS: This study provided the evidence that the gut microbial composition was altered in preclinical AD. The combination of plasma Aß and gut microbiota may serve as a non-invasive, cost-effective diagnostic tool for early AD screening. Targeting the gut microbiota may be a novel therapeutic strategy for AD. TRIAL REGISTRATION: This study has been registered in ClinicalTrials.gov (NCT03370744, https://www.clinicaltrials.gov ) in November 15, 2017.

Alterations of Erythrocytic Phosphorylated Alpha-Synuclein in Different Subtypes and Stages of Parkinson's Disease.

Serine 129-phosphorylated alpha-synuclein (pS-α-syn) is a major form of α-syn relevant to the pathogenesis of Parkinson's disease (PD), which has been recently detected in red blood cells (RBCs). However, alterations of RBC-derived pS-α-syn (pS-α-syn-RBC) in different subtypes and stages of PD remains to be investigated. In the present study, by using enzyme-linked immunosorbent assay (ELISA) to measure pS-α-syn-RBC, we demonstrated significantly higher levels of pS-α-syn-RBC in PD patients than in healthy controls. pS-α-syn-RBC separated the patients well from the controls, with a sensitivity of 93.39% (95% CI: 90.17-95.81%), a specificity of 93.11% (95% CI: 89.85-95.58%), and an area under the curve (AUC) of 0.96. Considering motor subtypes, the levels of pS-α-syn-RBC were significantly higher in late-onset than young-onset PD (p = 0.013) and in those with postural instability and gait difficulty than with tremor-dominant (TD) phenotype (p = 0.029). In addition, the levels of pS-α-syn-RBC were also different in non-motor subtypes, which were significantly lower in patients with cognitive impairment (p = 0.012) and olfactory loss (p = 0.004) than in those without such symptoms. Moreover, the levels of pS-α-syn-RBC in PD patients were positively correlated with disease duration and Hoehn & Yahr stages (H&Y) (p for trend =0.02 and <0.001) as well as UPDRS III (R 2 = 0.031, p = 0.0042) and MoCA scores (R 2 = 0.048, p = 0.0004). The results obtained suggest that pS-α-syn-RBC can be used as a potential biomarker for not only separating PD patients from healthy controls but also predicting the subtypes and stages of PD.

Identifying Biomarkers Associated with Venous Infarction in Acute/Subacute Cerebral Venous Thrombosis.

Among cerebral venous thrombosis (CVT) patients, those with venous infarction have more severe clinical presentations and worse outcomes. Identifying biomarkers associated with venous infarction in CVT may help understand the pathogenesis and provide potentially useful therapeutic markers. Fifty-two CVT patients were prospectively recruited and divided into three groups: acute/subacute CVT with venous infarction (ASVI, n=30), without venous infarction (ASOVI, n=13), and chronic CVT (n=9). Blood brain barrier (BBB) permeability-related proteins, including claudin-5, occludin, matrix metalloproteinase-9, glial fibrillary acidic protein, and S100B, and inflammation-related factor high-sensitivity C-reactive protein (hs-CRP), were tested in serum and/or cerebrospinal fluid upon admission. We compared these biomarkers between the three groups and investigated their associations with venous infarction and clinical symptom severity in acute/subacute CVT patients on admission using the NIH Stroke Scale (NIHSS). Serum hs-CRP was significantly higher in acute/subacute CVT patients than chronic CVT patients. For acute/subacute CVT patients, levels were significantly higher in the ASVI group than the ASOVI group for serum claudin-5 (medians 2.80 vs. 2.50 mg/I, respectively, P = 0.039) and hs-CRP (medians 17.25 vs. 2.27 mg/l, respectively, P = 0.003). Both these biomarkers, analyzed as categorical or continuous variables, were also significantly associated with venous infarction in acute/subacute CVT patients after logistic regression analysis. Additionally, hs-CRP was positively correlated with the NIHSS (r = 0.710, P < 0.001) on admission in acute/subacute CVT patients. In CVT patients, venous infarction was associated with BBB disruption and potentially inflammation. Hs-CRP might serve as a biomarker reflecting the clinical severity of CVT in the acute/subacute stages.

Blood NCAPH2 Methylation Is Associated With Hippocampal Volume in Subjective Cognitive Decline With Apolipoprotein E ε4 Non-carriers.

Objective: This study assessed the methylation of peripheral NCAPH2 in individuals with subjective cognitive decline (SCD), identified its correlation with the hippocampal volume, and explored whether the correlation is influenced by apolipoprotein E ε4 (APOE ε4) status. Methods: Cognitively normal controls (NCs, n = 56), individuals with SCD (n = 81), and patients with objective cognitive impairment (OCI, n = 51) were included from the Sino Longitudinal Study on Cognitive Decline (NCT03370744). All participants completed neuropsychological assessments, blood tests, and structural MRI. NCAPH2 methylation was compared according to the diagnostic and APOE ε4 status. Partial correlation analysis was conducted to assess the correlations between the hippocampal volume, cognitive tests, and the NCAPH2 methylation levels. Results: Individuals with SCD and patients with OCI showed significantly lower levels of NCAPH2 methylation than NCs, which were independent of the APOE ε4 status. The NCAPH2 methylation levels and the hippocampal volumes were positively correlated in the SCD APOE ε4 non-carriers but not in the OCI group. No association was found between the NCAPH2 methylation levels and the cognitive function. Conclusion: Abnormal changes in blood NCAPH2 methylation were found to occur in SCD, indicating its potential to be used as a useful peripheral biomarker in the early stage of Alzheimer's disease screening.

Hypomethylation of SNCA in Idiopathic REM Sleep Behavior Disorder Associated With Phenoconversion.

BACKGROUND: Hypomethylation of intron 1 of the α-synuclein (SNCA) gene has been extensively reported in the blood of patients with α-synucleinopathies. Idiopathic rapid eye movement sleep behavior disorder represents a prodromal stage of α-synucleinopathies. Methylation of α-synuclein intron 1 in idiopathic rapid eye movement sleep behavior disorder patients is largely unexplored. The objective of the current study was to assess blood α-synuclein intron 1 methylation in patients and to explore it as a potential biomarker to predict phenoconversion and monitor disease progression. METHODS: Seventy-eight polysomnography-confirmed patients and 74 healthy controls were enrolled. After an average of 3.75 years of follow up, 16 patients converted to neurodegenerative diseases (converters), whereas 59 did not (nonconverters). Blood DNA was obtained at baseline from all participants, as well as at the follow-up visit for 27 patients. DNA methylation levels were determined using bisulfite pyrosequencing methods and were compared between patients and healthy controls, converters and nonconverters, and baseline and follow-up visits. RESULTS: Hypomethylation at cytosine-phosphate-guanine 10, 11, 12, 13, and 17 was found in patients compared with healthy controls. Hypomethylation at cytosine-phosphate-guanine 17 was associated with an increased risk of clinical phenoconversion, which was further enhanced with the presence of subtle motor abnormalities. In addition, it appeared that later reduction in methylation levels at cytosine-phosphate-guanine 14, 15, and 16 was associated with disease progression. CONCLUSIONS: Peripheral blood α-synuclein intron 1 was hypomethylated in idiopathic rapid eye movement sleep behavior disorder patients. α-Synuclein methylation levels may be useful biomarkers to screen patients, predict phenoconversion, and monitor disease progression. © 2020 International Parkinson and Movement Disorder Society.

Serum factor(s) from lung adenocarcinoma patients regulates the molecular clock expression.

Lung cancer is a leading cause of cancer-associated deaths worldwide. Lung cancer may lead to circadian disruption, which could contribute to the development of lung cancer. Recently, several studies using animal models indicated that tumors influence systemic circadian homeostasis in remote tissues. However, it is unclear whether carcinoma of the lungs influences remote circadian rhythm, whether this effect exists in humans, and whether signals from the tumor travel through the blood. In this study, we used a cell-based assay to determine whether serum from patients with lung adenocarcinoma could modulate the molecular clock. We found that the daily oscillation period of Bmal1 was significantly lengthened following treatment with serum from untreated lung adenocarcinoma patients. In addition, heat inactivation of this serum abolished the effect, suggesting that a heat-sensitive circulating factor(s) is present in the serum of untreated lung adenocarcinoma patients. Using real-time PCR, we also examined the mRNA abundance of Bmal1, Cry1, and Per1 in human osteosarcoma u2os cell line, HUVECs and A549 cell lines. The expression of Bmal1 was changed in A549 cells in the presence of sera from lung adenocarcinoma patients. Our study revealed a direct effect of serum from lung adenocarcinoma patients on the molecular clock.

Stabilization of heterochromatin by CLOCK promotes stem cell rejuvenation and cartilage regeneration.

Accumulating evidence indicates an association between the circadian clock and the aging process. However, it remains elusive whether the deregulation of circadian clock proteins underlies stem cell aging and whether they are targetable for the alleviation of aging-associated syndromes. Here, we identified a transcription factor-independent role of CLOCK, a core component of the molecular circadian clock machinery, in counteracting human mesenchymal stem cell (hMSC) decay. CLOCK expression was decreased during hMSC aging. In addition, CLOCK deficiency accelerated hMSC senescence, whereas the overexpression of CLOCK, even as a transcriptionally inactive form, rejuvenated physiologically and pathologically aged hMSCs. Mechanistic studies revealed that CLOCK formed complexes with nuclear lamina proteins and KAP1, thus maintaining heterochromatin architecture and stabilizing repetitive genomic sequences. Finally, gene therapy with lentiviral vectors encoding CLOCK promoted cartilage regeneration and attenuated age-related articular degeneration in mice. These findings demonstrate a noncanonical role of CLOCK in stabilizing heterochromatin, promoting tissue regeneration, and mitigating aging-associated chronic diseases.

Risk factors for possible REM sleep behavior disorders: A community-based study in Beijing.

OBJECTIVE: To explore the risk factors for idiopathic REM sleep behavior disorder (RBD) in a community population in Beijing. METHODS: Participants aged 55 years and above were recruited from the Beijing Longitudinal Study on Aging II cohort. We identified individuals with possible RBD (pRBD) using the validated RBD Questionnaire-Hong Kong in 2010. A series of environmental, lifestyle, and other potential risk factors were assessed via standardized questionnaires in 2009. Multivariable logistic regression analysis was performed to investigate the association between the studied factors and pRBD. RESULTS: Of 7,225 participants who were free of parkinsonism and dementia, 219 (3.0%) individuals were considered as having pRBD. Participants with pRBD reported more nonmotor and motor symptoms of Parkinson disease (PD) with adjusted odds ratios (ORs) ranging from 1.10 to 4.40. Participants with pRBD were more likely to report a family history of parkinsonism or dementia (OR 3.03, 95% confidence interval [CI] 1.23-7.46). There was a significant association between pRBD and self-reported hyperlipidemia (OR 1.51, 95% CI 1.09-2.10), ever smoking (OR 1.79, 95% CI 1.20-2.65), prior carbon monoxide (CO) poisoning (OR 2.30, 95% CI 1.39-3.83), and nonoccupational exposure to pesticides (OR 2.21, 95% CI 1.40-3.50). CONCLUSION: Our study replicated previously reported associations between pRBD and hyperlipidemia, smoking, pesticide exposure, and several prodromal PD symptoms. We also found previously unreported links with a positive family history of parkinsonism or dementia and CO poisoning. Risk factor profiles for pRBD partially resemble those defined for PD, but also differ in distinct ways.

Plasma immune markers in an idiopathic REM sleep behavior disorder cohort.

INTRODUCTION: Increasing evidence shows a strong association between idiopathic REM sleep behavior disorder (iRBD) and α-synucleinopathies. Recent studies have indicated an inflammatory mechanism in the pathogenesis of α-synucleinopathies. Whether peripheral inflammatory cytokines are altered in iRBD and can be biomarkers for predicting phenoconversion remains unclear. METHODS: We collected baseline plasma samples from 77 consecutive iRBD patients and 64 age- and sex-matched healthy controls. Ten cytokines were measured: Interferon (IFN)-γ, interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, and tumor necrosis factor (TNF)-α. All iRBD patients underwent clinical assessment tests at baseline, and 75 were prospectively followed and received assessments for parkinsonism or dementia. Cox regression analyses were used to evaluate the predictive value of plasma cytokines in a follow-up period of 6.0 years. RESULTS: TNF-α and IL-10 were significantly elevated in iRBD compared with controls (both p < 0.001). IL-6/IL-10 and IL-8/IL-10 were significantly reduced in iRBD than in controls (p = 0.001, p < 0.001, respectively). After a median follow-up of 3.7 years, 16 iRBD patients developed neurodegenerative synucleinopathies. iRBD patients with higher TNF-α/IL-10 levels were more likely to develop neurodegenerative diseases (adjusted HR 1.07, 95% CI 1.01-1.14). The coexistence of elevated TNF-α/IL-10 and possible mild cognitive impairment predicted an early conversion of iRBD to neurodegenerative synucleinopathies (adjusted HR 4.17, 95% CI 1.47-11.81). CONCLUSIONS: Our study supported the early involvement of peripheral inflammation in prodromal α-synucleinopathy. Plasma cytokines may be predictive of disease conversion in iRBD, while large-scale longitudinal studies are warranted to validate the assumption.