Candidate biomarkers of EV-microRNA in detecting REM sleep behavior disorder and Parkinson's disease.

Parkinson's disease (PD) lacks reliable, non-invasive biomarker tests for early intervention and management. Thus, a minimally invasive test for the early detection and monitoring of PD and REM sleep behavior disorder (iRBD) is a highly unmet need for developing drugs and planning patient care. Extracellular vehicles (EVs) are found in a wide variety of biofluids, including plasma. EV-mediated functional transfer of microRNAs (miRNAs) may be viable candidates as biomarkers for PD and iRBD. Next-generation sequencing (NGS) of EV-derived small RNAs was performed in 60 normal controls, 56 iRBD patients and 53 PD patients to profile small non-coding RNAs (sncRNAs). Moreover, prospective follow-up was performed for these 56 iRBD patients for an average of 3.3 years. Full-scale miRNA profiles of plasma EVs were evaluated by machine-learning methods. After optimizing the library construction method for low RNA inputs (named EVsmall-seq), we built a machine learning algorithm that identified diagnostic miRNA signatures for distinguishing iRBD patients (AUC 0.969) and PD patients (AUC 0.916) from healthy individuals; and PD patients (AUC 0.929) from iRBD patients. We illustrated all the possible expression patterns across healthy-iRBD-PD hierarchy. We also showed 20 examples of miRNAs with consistently increasing or decreasing expression levels from controls to iRBD to PD. In addition, four miRNAs were found to be correlated with iRBD conversion. Distinct characteristics of the miRNA profiles among normal, iRBD and PD samples were discovered, which provides a panel of promising biomarkers for the identification of PD patients and those in the prodromal stage iRBD.

Cortical gray to white matter signal intensity ratio as a sign of neurodegeneration and cognition independent of ß-amyloid in dementia.

Cortical gray to white matter signal intensity ratio (GWR) measured from T1-weighted magnetic resonance (MR) images was associated with neurodegeneration and dementia. We characterized topological patterns of GWR during AD pathogenesis and investigated its association with cognitive decline. The study included a cross-sectional dataset and a longitudinal dataset. The cross-sectional dataset included 60 cognitively healthy controls, 61 mild cognitive impairment (MCI), and 63 patients with dementia. The longitudinal dataset included 26 participants who progressed from cognitively normal to dementia and 26 controls that remained cognitively normal. GWR was compared across the cross-sectional groups, adjusted for amyloid PET. The correlation between GWR and cognition performance was also evaluated. The longitudinal dataset was used to investigate GWR alteration during the AD pathogenesis. Dementia with ß-amyloid deposition group exhibited the largest area of increased GWR, followed by MCI with ß-amyloid deposition, MCI without ß-amyloid deposition, and controls. The spatial pattern of GWR-increased regions was not influenced by ß-amyloid deposits. Correlation between regional GWR alteration and cognitive decline was only detected among individuals with ß-amyloid deposition. GWR showed positive correlation with tau PET in the left supramarginal, lateral occipital gyrus, and right middle frontal cortex. The longitudinal study showed that GWR increased around the fusiform, inferior/superior temporal lobe, and entorhinal cortex in MCI and progressed to larger cortical regions after progression to AD. The spatial pattern of GWR-increased regions was independent of ß-amyloid deposits but overlapped with tauopathy. The GWR can serve as a promising biomarker of neurodegeneration in AD.

Relationship Between FERMT2, CELF1, COPI, CHRNA2, and ABCA7 Genetic Polymorphisms and Alzheimer's Disease Risk in the Southern Chinese Population.

Background: Alzheimer's disease (AD) is a multi-gene inherited disease, and apolipoprotein E (APOE) ɛ4 is a strong risk factor. Other genetic factors are important but limited. Objective: This study aimed to investigate the relationship between 17 single-nucleotide polymorphisms (SNPs) and AD in the Southern Chinese populations. Methods: We recruited 242 AD patients and 208 controls. The SNaPshot technique was used to detect the SNPs. Results: Adjusted for sex and age, we found rs6572869 (FERMT2), rs11604680 (CELF1), and rs1317149 (CELF1) were associated with AD risk in the dominant (rs6572869: p = 0.022, OR = 1.55; rs11604680: p = 0.007, OR = 1.68; rs1317149: p = 0.033, OR = 1.50) and overdominant models (rs6572869: p = 0.001, OR = 1.96; rs11604680: p = 0.002, OR = 1.82; rs1317149: p = 0.003, OR = 1.80). rs9898218 (COPI) was associated with AD risk in the overdominant model (p = 0.004, OR = 1.81). Further, rs2741342 (CHRNA2) was associated with AD protection in the dominant (p = 0.002, OR = 0.5) and additive models (p = 0.002, OR = 0.64). Mutations in rs10742814 (CELF1), rs11039280 (CELF1), and rs3752242 (ABCA7) contributed to AD protection. Among them, rs10742814 (CELF1), rs3752242 (ABCA7), and rs11039280 (CELF1) were more significantly associated with AD carrying APOE ɛ4, whereas rs1317149 (CELF1) showed an opposite trend. Interestingly, rs4147912 (ABCA7) and rs2516049 (HLA-DRB1) were identified to be relevant with AD carrying APOE ɛ4. Using expression quantitative trait locus analysis, we found polymorphisms in CELF1 (rs10742814 and rs11039280), ABCA7 (rs4147912), HLA-DRB1 (rs2516049), and ADGRF4 (rs1109581) correlated with their corresponding gene expression in the brain. Conclusions: We identified four risk and four protective SNPs associated with AD in the Southern Chinese population, with different correlations between APOE ɛ4 carriers and non-carriers. rs4147912 (ABCA7) and rs2516049 (HLA-DRB1) were associated with AD carrying APOE ɛ4.

Collaborative plasma biomarkers for Parkinson disease development and progression: A cross-sectional and longitudinal study.

BACKGROUND AND PURPOSE: Relying on a single biomarker for early diagnosis of Parkinson disease (PD) may not yield accurate results. We aimed to assess the combined diagnostic value of multiple biomarkers, including plasma CCL2, plasma CXCL12, and plasma neuronal exosomal α-synuclein (α-syn) for early stage PD diagnosis and their predictive value in PD progression. METHODS: This study included both cross-sectional and longitudinal designs. The CCL2, CXCL12, and neuronal exosomal α-syn levels were analyzed in 50 healthy controls (HCs) and 50 early stage PD patients. Then, a prospective follow-up of 30 early stage PD patients was performed. RESULTS: In early stage PD, we observed a significant increase in CCL2, CXCL12, and plasma neuronal exosomal α-syn compared to HCs (p < 0.05). Utilizing a combined diagnostic approach of CCL2, CXCL12, and α-syn significantly improved the area under the curve (AUC = 0.89, p < 0.001). Spearman correlation analysis revealed that CCL2 levels were correlated with PD clinical stage and autonomic symptoms (p < 0.05). CXCL12 levels were associated with nonmotor symptoms (p < 0.05). Plasma neuronal exosomal α-syn levels were connected to the clinical stage, motor symptoms, and nonmotor symptoms in early stage PD (p < 0.01). In the longitudinal cohort, the Cox regression analysis showed that high CCL2 levels were associated with motor progression after a mean follow-up of 24 months. CONCLUSIONS: Our study suggested that the combined measurement of plasma CCL2, CXCL12, and neuronal exosomal α-syn can improve early stage PD diagnosis, and CCL2 may serve as a prognostic marker for PD progression.

Soluble TREM2 levels associate with conversion from mild cognitive impairment to Alzheimer's disease.

BACKGROUNDSoluble triggering receptor expressed on myeloid cells 2 (sTREM2) plays an important role in the clearance of pathological amyloid-ß (Aß) in Alzheimer's disease (AD). This study aimed to explore sTREM2 as a central and peripheral predictor of the conversion from mild cognitive impairment (MCI) to AD.METHODSsTREM2 and Aß1-42 levels in cerebrospinal fluid (CSF) and florbetapir-PET (AV45) images were analyzed for healthy control (HCs), patients with MCI, and patients with AD from the ADNI database. Peripheral plasma sTREM2 and Aß1-42 levels were determined for our Neurology database of Ruijin Hospital for Alzheimer's Disease (NRHAD) cohort, and patients with MCI were reevaluated at follow-up visits to assess for progression to AD. The association between CSF and plasma sTREM2 levels was analyzed in data from the Chinese Alzheimer's Biomarker and Lifestyle (CABLE) database.RESULTSThe results showed that patients with MCI who had low levels of CSF sTREM2 and Aß1-42 were more likely to develop AD. Among participants with positive Aß deposition, as assessed by AV45 imaging, elevated CSF sTREM2 levels were associated with a decreased risk of MCI-to-AD conversion. Meanwhile, in the NRHAD cohort, individuals in the MCI group with high sTREM2 levels in plasma were at a greater risk for AD, whereas low Aß1-42 with high sTREM2 levels in plasma were associated with a faster cognitive decline. In addition, CSF sTREM2 levels were highly correlated with plasma sTREM2 levels in the CABLE database.CONCLUSIONThese findings suggest that sTREM2 may be useful as a potential predictive biomarker of MCI-to-AD conversion.FUNDINGThis study was supported by grants from the National Natural Science Foundation of China (grant nos. 82001341, 82071415, 81873778, and 82201392); the Shanghai Sailing Program (grant no. 22YF1425100); and the China Postdoctoral Science Foundation funded project (grant no. 2021M702169).

Analysis of Genetic Association Between ABCA7 Polymorphism and Alzheimer's Disease Risk in the Southern Chinese Population.

Objective: The study aimed to clarify the association of the 21 single nucleotide polymorphisms (SNPs) with Alzheimer's disease (AD) in the population of southern China. Methods: A case-control study was conducted with a total sample size of 490 subjects (246 patients with AD and 244 age- and gender-matched healthy controls) enrolled in this study. Twenty-one selected SNPs were detected using SNaPshot assay and polymerase chain reaction (PCR) technique. Then, we assessed how these SNPs correlated with AD susceptibility. Results: The results showed that rs3764650 of ABCA7 was closely correlated with risen AD morbidity in the allele [P = 0.010, odds ratio (OR) = 1.43, 95% confidence interval (CI) 1.09-1.89], dominant (P = 0.004, OR = 1.71, 95% CI 1.19-2.46), and additive (P = 0.012, OR = 1.42, 95% CI 1.08-1.86) models. However, rs4147929 of ABCA7 was related to higher AD risk in the allele (P = 0.006, OR = 1.45, 95% CI 1.11-1.89), dominant (P = 0.012, OR = 1.59, 95% CI 1.11-2.27), and additive (P = 0.010, OR = 1.40, 95% CI 1.08-1.81) models. In addition, the frequencies of the G-allele at rs3764650 (P = 0.030) and the A-allele at rs4147929 (P = 0.001) in AD were statistically higher in APOE ε4 carriers in comparison to non-carriers. Conclusion: This study demonstrated that the G-allele at rs3764650 and the A-allele at rs4147929 appeared at higher risk for developing AD, particularly in APOE ε4 carriers. Moreover, it was observed that rs3764650 and rs4147929 of ABCA7 were linked to AD. More in-depth research with a relatively large sample is needed to make the results more convincing.

Parkinson's disease peripheral immune biomarker profile: a multicentre, cross-sectional and longitudinal study.

BACKGROUND: Inflammations play crucial role in the pathogenesis of Parkinson's disease (PD), however, their possible value in the diagnosis or tracking of the progress of PD is still limited, because of discordant results in the literature and a lack of information regarding its reproducibility. Thus, overall longitudinal and cross-sectional studies are needed. This multicentre study was designed to investigate the association between multiple peripheral immune biomarkers and the development and progression of PD. METHODS: This was a longitudinal and multicentre study. First, we measured the levels of five typical cytokines and five focused chemokines in 76 PD patients and 76 healthy controls (HCs) in a discovery cohort. Then, a validation cohort of 80 PD and 80 HC participants was recruited from four multicentre locations. In addition, a prospective follow-up of early-stage PD patients was performed with significant biomarkers. Finally, we performed further verification in an exploratory set of patients with idiopathic REM sleep behaviour disorder (iRBD). RESULTS: In the discovery set, CXCL12, CX3CL1 and IL-8 levels were significantly higher in PD patients than in HCs (p < 0.05). The receiver-operating characteristic (ROC) curve for a combination of these three biomarkers produced a high area under the curve (AUC) of 0.89 (p < 0.001). Moreover, four biomarkers (the previous three and CCL15) were significantly associated with PD in the discovery and validation cohorts. Furthermore, in the prospective follow-up cohort, CX3CL1 levels were associated with motor progression after a mean interval of 43 months. In addition, CX3CL1 and IL-8 levels were higher in iRBD patients than in HCs. CONCLUSION: We showed a correlation between a profile of four peripheral immune biomarkers and PD development and progression. Our findings may provide a basis whereby PD patients with abnormal inflammatory profiles can be identified and receive timely therapeutic interventions.

Evolution patterns of probable REM sleep behavior disorder predicts Parkinson's disease progression.

The course of REM sleep behavior disorder (RBD) variates in the early stage of Parkinson's disease. We aimed to delineate the association between the evolution pattern of probable RBD (pRBD) and the progression of Parkinson's disease (PD). 281 de novo PD patients from the Parkinson's Progression Markers Initiative database were included. Patients were followed up for a mean of 6.8 years and were classified into different groups according to the evolution patterns of pRBD. Disease progression was compared among groups using survival analysis, where the endpoint was defined as progression to Hoehn-Yahr stage 3 or higher for motor progression and progression to mild cognitive impairment for cognitive decline. At the 4th year of follow-up, four types of pRBD evolution patterns were identified: (1) non-RBD-stable (55.5%): patients persistently free of pRBD; (2) late-RBD (12.1%): patients developed pRBD during follow-up; (3) RBD-stable (24.9%): patients showed persistent pRBD, and (4) RBD-reversion (7.5%): patients showed pRBD at baseline which disappeared during follow-up. The RBD-reversion type showed the fastest motor progression while the RBD-stable type showed the fastest cognitive decline. At baseline, the RBD-reversion type showed the most severe gray matter atrophy in the middle frontal gyrus, while the RBD-stable type showed gray matter atrophy mainly in the para-hippocampal gyrus. Four types of early pRBD evolution patterns featured different brain lesions and predicted different courses of motor and cognitive decline in PD.

Functional Connectivity Alterations Based on the Weighted Phase Lag Index: An Exploratory Electroencephalography Study on Alzheimer's Disease.

OBJECTIVE: Numerous electroencephalography (EEG) studies focus on the alteration of electrical activity in patients with Alzheimer's Disease (AD), but there are no consistent results especially regarding functional connectivity. We supposed that the weighted Phase Lag Index (w- PLI), as phase-based measures of functional connectivity, may be used as an auxiliary diagnostic method for AD. METHODS: We enrolled 30 patients with AD, 30 patients with Mild Cognitive Impairment (MCI), and 30 Healthy Controls (HC). EEGs were recorded in all participants at baseline during relaxed wakefulness. Following EEG preprocessing, Power Spectral Density (PSD) and wPLI parameters were determined to further analyze whether they were correlated to cognitive scores. RESULTS: In the patients with AD, the increased PSD in theta band was presented compared with MCI and HC groups, which was associated with disturbances of the directional, computational, and delayed memory capacity. Furthermore, the wPLI revealed a distinctly lower connection strength between frontal and distant areas in the delta band and a higher connection strength of the central and temporo-occipital region in the theta band for AD patients. Moreover,we found a significant negative correlation between theta functional connectivity and cognitive scores. CONCLUSION: Increased theta PSD and decreased delta wPLI may be one of the earliest changes in AD and associated with disease severity. The parameter wPLI is a novel measurement of phase synchronization and has potentials in understanding underlying functional connectivity and aiding in the diagnostics of AD.

Altered structure and functional connectivity of the central autonomic network in idiopathic rapid eye movement sleep behaviour disorder.

Evidence suggests peripheral autonomic structures may contribute to autonomic dysfunction in idiopathic rapid eye movement sleep behaviour disorder (iRBD). However, whether the central autonomic network (CAN) is affected in iRBD remains unclear. Magnetic resonance imaging data were acquired from 65 participants (32 patients with iRBD and 33 matched healthy controls). We investigated the CAN in patients with iRBD using a combined voxel-based morphometry and resting-state functional connectivity analysis and characterised the relationships between alterations of the CAN and autonomic symptoms. Patients with iRBD had significantly reduced grey matter volume in the brainstem, anterior cingulate and insula compared with healthy controls. Functional connectivity analysis revealed reduced functional connectivity between the brainstem and the cerebellum posterior lobe, temporal lobe and anterior cingulate in patients with iRBD. In patients with iRBD, both reduced grey matter volume and decreased functional connectivity of the CAN were negatively correlated with the Scales for Outcomes in Parkinson's Disease-Autonomic scores. The present study demonstrated that both the structure and the functional connectivity of the CAN were abnormal in patients with iRBD. In addition, correlation analysis suggested that CAN abnormalities may also play a role in the development of autonomic symptoms in iRBD.

Predictors of Conversion to α-Synucleinopathy Diseases in Idiopathic Rapid Eye Movement Sleep Behavior Disorder.

BACKGROUND: Idiopathic rapid eye movement sleep behavior disorder (iRBD) often precedes the development of α-synucleinopathy diseases. OBJECTIVE: We aimed to assess the predictive value of clinical variables and biomarkers for the early development of α-synucleinopathy diseases in subjects with iRBD. METHODS: 56 patients with RBD Screening Questionnaire (RBDSQ) scores ≥5 at baseline and subsequent visit were enrolled as probable iRBD from the Parkinson's Progression Markers Initiative (PPMI) database. Baseline clinical data and biomarkers were analyzed. The endpoint was defined as disease progression to α-synucleinopathy diseases. Cox proportional hazard and Kaplan-Meier analyses were used to evaluate the predictive values of the indicators. RESULTS: During a mean follow-up duration of 5.1 years, 15 of 56 patients (26.8%) developed α-synucleinopathy diseases. Baseline clinical variables, including University of Pennsylvania Smell Identification Test (UPSIT, HR = 26.18, p = 0.004), 15-item Geriatric Depression Scale (GDS, HR = 14.26, p = 0.001), Montreal Cognitive Assessment (MoCA, HR = 3.56, p = 0.025), and Hopkins Verbal Learning Test Total recall (HVLT-TR, HR = 3.70, p = 0.014); genotype status of TMEM175 (HR = 3.74, p = 0.017), SCN3A (HR = 5.81, p = 0.022) and NUCKS1 (HR = 0.342, p = 0.049); ratio of phosphorylated tau to total tau (p-tau/t-tau, HR = 8.36, p = 0.001) in cerebrospinal fluid; and gray matter atrophy in inferior frontal gyrus (IFG, HR = 15.49, p = 0.001) were associated with phenoconversion to α-synucleinopathy diseases. A model combined the three independent variables (UPSIT, TMEM175 and gray matter atrophy in IFG) exhibited significantly improved predictive performance. CONCLUSION: For patients with iRBD, progression to α-synucleinopathy diseases can be predicted with good accuracy using a model combining clinical variables and biomarkers, which could form a basis for future disease prevention.

TNF receptors are associated with tau pathology and conversion to Alzheimer's dementia in subjects with mild cognitive impairment.

BACKGROUND: Tumor necrosis factor-a (TNF-α) signaling pathway plays a significant role in Alzheimer's disease (AD). This study aimed to explore the relationship between TNF-α related inflammatory proteins and pathological markers of AD, and examine their possibility as a predictor of the conversion of mild cognitive impairment (MCI) to AD. METHODS: This study included both cross-sectional and longitudinal designs. The levels of TNF-α related inflammatory proteins, Aß1-42, total-tau(t-tau), phosphorylated tau (p-tau) from cerebrospinal fluid (CSF) were analyzed in healthy controls (HC, n = 90), MCI (n = 116), and AD participants (n = 75) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Kaplan-Meier analyses were used to evaluate the predictive value of the examined putative AD markers after follow-up visits. RESULTS: In the cross-sectional cohort, we observed higher CSF levels of TNF-α related inflammatory proteins in the MCI and AD patients with positive tau pathology. TNF receptors (TNFR) were more closely associated with t-tau and p-tau than Aß1-42, in HC, MCI and AD subjects. In the longitudinal cohort with a mean follow-up of 30.2 months, MCI patients with high levels of CSF TNFR1 (p = 0.001) and low levels of TNFR2 (p < 0.001) were more likely to develop into AD. CONCLUSION: TNFR-signaling might be involved in the early pathogenesis of AD and TNF receptors may serve as potential predictive biomarkers for MCI.

Increased prediction value of biomarker combinations for the conversion of mild cognitive impairment to Alzheimer's dementia.

BACKGROUND: Progression of mild cognitive impairment (MCI) to Alzheimer's disease (AD) dementia can be predicted by clinical features and a combination of biomarkers may increase the predictive power. In the present study, we investigated whether the combination of olfactory function and plasma neuronal-derived exosome (NDE) Aß1-42 can best predict progression to AD dementia. METHODS: 87 MCI patients were enrolled and received the cognitive assessment at 2-year and 3-year follow-up to reevaluate cognition. In the meanwhile, 80 healthy controls and 88 AD dementia patients were enrolled at baseline as well to evaluate the diagnose value in cross-section. Olfactory function was evaluated with the sniffin sticks (SS-16) and Aß1-42 levels in NDEs were determined by ELISA. Logistic regression was performed to evaluate the risk factors for cognitive decline in MCI at 2-year and 3-year revisits. RESULTS: In the cross cohort, lower SS-16 scores and higher Aß1-42 levels in NDEs were found in MCI and AD dementia compared to healthy controls. For the longitudinal set, 8 MCI individuals developed AD dementia within 2 years, and 16 MCI individuals developed AD dementia within 3 years. The two parameter-combination of SS-16 scores and Aß1-42 level in NDEs showed better prediction in the conversion of MCI to AD dementia at 2-year and 3-year revisit. Moreover, after a 3-year follow-up, SS-16 scores also significantly predicted the conversion to AD dementia, where lower scores were associated with a 10-fold increased risk of developing AD dementia (p = 0.006). Similarly, higher Aß1-42 levels in NDEs in patients with MCI increased the risk of developing AD dementia by 8.5-fold (p = 0.002). CONCLUSION: A combination of two biomarkers of NDEs (Aß1-42) and SS-16 predicted the conversion of MCI to AD dementia more accurately in combination. These findings have critical implications for understanding the pathophysiology of AD dementia and for developing preventative treatments for cognitive decline.

SNPs in SNCA, MCCC1, DLG2, GBF1 and MBNL2 are associated with Parkinson's disease in southern Chinese population.

Numerous single nucleotide polymorphisms (SNPs), which have been identified as susceptibility factors for Parkinson's disease (PD) as per genome-wide association studies, have not been fully characterized for PD patients in China. This study aimed to replicate the relationship between 12 novel SNPs of 12 genes and PD risk in southern Chinese population. Twelve SNPs of 12 genes were detected in 231 PD patients and 249 controls, using the SNaPshot technique. Meta-analysis was used to assess heterogeneity of effect sizes between this study and published data. The impact of SNPs on gene expression was investigated by analysing the SNP-gene association in the expression quantitative trait loci (eQTL) data sets. rs8180209 of SNCA (allele model: P = .047, OR = 0.77; additive model: P = .047, OR = 0.77), rs2270968 of MCCC1 (dominant model: P = .024, OR = 1.52), rs7479949 of DLG2 (recessive model; P = .019, OR = 1.52), rs10748818 of GBF1 (additive model: P < .001, OR = 0.37), and rs4771268 of MBNL2 (recessive model: P = .003, OR = 0.48) were replicated to be significantly associated with the increased risk of PD. Noteworthy, a meta-analysis of previous studies suggested rs8180209, rs2270968, rs7479949 and rs4771268 were in line with those of our cohort. Our study replicated five novel functional SNPs in SNCA, MCCC1, DLG2, GBF1 and MBNL2 could be associated with increased risk of PD in southern Chinese population.

SNCA Hypomethylation in Rapid Eye Movement Sleep Behavior Disorder Is a Potential Biomarker for Parkinson's Disease.

BACKGROUND: α-Synuclein has been related to the pathogenesis of Parkinson's disease (PD), but it has not thoroughly been investigated in idiopathic rapid eye movement sleep behavior disorder (iRBD). OBJECTIVE: We aimed to explore whether there were different distributions of α-synuclein at a genetic and/or protein level in patients with iRBD. METHODS: We included 30 patients with iRBD, 30 patients with PD, and 30 age- and sex-matched healthy controls (HCs) in this study. The SNCA methylation and mRNA levels were determined using bisulfite sequencing and quantitative reverse transcription polymerase chain reaction. The plasma levels of exosome α-synuclein were measured using Meso Scale Discovery. RESULTS: SNCA methylation showed different distribution among HC, iRBD and PD groups (HC vs RBD: p = 0.011; HC vs PD: p < 0.001; RBD vs PD: p = 0.027). However, plasma exosomal α-synuclein levels were only elevated in patients with PD compared to those in HCs (p = 0.027), and were associated with the SNCA methylation only in the PD group (p = 0.030, r = -0.397). CONCLUSION: SNCA hypomethylation in leukocytes existed both in patients with iRBD and those with PD, indicating that SNCA methylation could be a potential biomarker for early PD diagnosis.

Establishment of SIAISi002-A, an induced pluripotent stem cell (iPSC) line from 39-year old healthy female donor with a family history of Alzheimer's disease (AD) and two copies of APOE4 gene.

A 39-year old healthy female with a family history of Alzheimer's disease (AD) and two copies of apolipoprotein E(APOE) ε4 allele donated her Peripheral blood mononuclear cells (PBMC). The non-integrative Sendai viral vectors used to reprogram PBMCs with the human OKSM transcription factors. The pluripotency of iPSCs was confirmed by immunocytochemistry and ability of differentiation spontaneously into 3 germ layers. Furthermore, the iPSC line displayed a normal karyotype. The APOE gene is currently considered to be the most relevant gene for sporadic AD. Our model might offer a platform to study the pathological mechanisms and drug testing studies in AD.

Genetic Association of FERMT2, HLA-DRB1, CD2AP, and PTK2B Polymorphisms With Alzheimer's Disease Risk in the Southern Chinese Population.

OBJECTIVES: This study aimed to explore the relationship between 18 single nucleotide polymorphisms (SNPs) and Alzheimer's disease (AD) within the southern Chinese population. METHODS: A total of 420 participants, consisting of 215 AD patients and 205 sex- and age-matched controls, were recruited. The SNaPshot technique and polymer chain reaction (PCR) were used to detect the 18 SNPs. Combined with the apolipoprotein E (APOE) ε4 allele and age at onset, we performed an association analysis between these SNPs and AD susceptibility. Furthermore, we analyzed SNP-associated gene expression using the expression quantitative trait loci analysis. RESULTS: Our study found that rs17125924 of FERMT2 was associated with the risk of developing AD in the dominant (P = 0.022, odds ratio [OR] = 1.57, 95% confidence interval [CI]: 1.07-2.32) and overdominant (P = 0.005, OR = 1.76, 95% CI: 1.18-2.61) models. Moreover, compared with APOE ε4 non-carriers, the frequency of the G-allele at rs17125924 was significantly higher among AD patients in APOE ε4 allele carriers (P = 0.029). The rs9271058 of HLA-DRB1 (dominant, overdominant, and additive models), rs9473117 of CD2AP (dominant and additive models), and rs73223431 of PTK2B (dominant, overdominant, and additive models) were associated with early onset AD (EOAD). Using the genotype-tissue expression (GTEx) and Braineac database, we found a significant association between rs9271058 genotypes and HLA-DRB1 expression levels, while the CC genotype at rs9473117 and the TT genotype of rs73223431 increased CD2AP and PTK2B gene expression, respectively. CONCLUSION: Our study identifies the G-allele at rs17125924 as a risk factor for developing AD, especially in APOE ε4 carriers. In addition, we found that rs9271058 of HLA-DRB1, rs9473117 of CD2AP, and rs73223431 of PTK2B were associated with EOAD. Further studies with larger sample sizes are needed to confirm our results.

Establishment of SIAISi001-A, an induced pluripotent stem cell (iPSC) line from 66-year old mild cognitive impairment (MCI) with two copies of APOE4 gene.

A 66-year old mild cognitive impairment (MCI) female patient donated her Peripheral blood mononuclear cells (PBMC). PBMC was reprogrammed using non-integrative Sendai viral vectors containing reprogramming factors OCT4, KLF4, SOX2 and C-MYC. The pluripotency of transgene-free iPSCs was confirmed by immunocytochemistry and ability of differentiation spontaneously into 3 germ layers in vitro. Moreover, the iPSC line displayed a normal karyotype. The apolipoprotein E (APOE) ε4 allele, is considered to be the strongest genetic risk factor for Sporadic Alzheimer's disease (AD). Our model might offer a good platform to study the pathological mechanisms and drug testing studies in AD and MCI.