A Pathogenic Variant p.Phe177Val in PSEN1 Causes Early-Onset Alzheimer's Disease in a Chinese Family.

Familial Alzheimer's disease (FAD) present as a positive family history of cognitive decline, with early onset and an autosomal dominant inheritance pattern. FAD is mainly caused by the mutations in the genes encoding for amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2). In the present study, we identified a variant (c.529T > G, p.Phe177Val) in PSEN1 across three generations in a Chinese family with FAD using whole-exome sequencing. The mean age of onset was 39 years (range: 37 to 40 years) in this family. In cell transfection studies, the mutant PSEN1 protein carrying p.Phe177Val increased both the production of Aß42 and the ratio of Aß42 over Aß40, as compared to wild-type PSEN1. Our results confirm the pathogenicity of PSEN1 p.Phe177Val variant in FAD and broaden the clinical phenotype spectrum of FAD patients with PSEN1 p.Phe177Val variant.

Decentralized Privacy-Preserving Platform for Clinical Data Sharing and Analysis.

Collection and management of clinical data for administration and analysis is a time-consuming and complex task, especially when multiple data providers been involved. Even if people are willing to take on the burden for it, there is still no mature solution to protect data privacy for distributed data providers. Distributed ledger is an emerging technology that supports decentralized data sharing and management. Based on this, we present a platform which enables distributed and truthful data collection and serves privacy-preserving needs in clinical data management. Our system, built on Hyperledger Fabric, used smart contract to execute data aggregation and provide basic analysis methods. The system used ledger and world status to record data access history and other metadata. This decentralized platform enables data providers to proactively share and protect their data, Thus can simplify clinical data collection procedure and promote efficient collaboration between providers.

The Associations of PMF1, ICAM1, AGT, TRIM65, FBF1, and ACOX1 Variants With Leukoaraiosis in Chinese Population.

Background: Leukoaraiosis (LA) is shown as white matter hyperintensities on T2-weighted magnetic resonance imaging brain scans. Together with candidate gene association studies (CGAS), multiple genome-wide association studies (GWAS) have reported large numbers of single nucleotide polymorphisms (SNPs) to be associated with LA in European populations. To date, no replication studies have been reported in independent Chinese samples. Methods: Here, we performed a candidate gene association study comprising 220 Chinese subjects with LA and 50 controls. Thirty-nine polymorphisms on 32 risk genes were selected from previous studies, and they were genotyped through matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Genetic association analysis was firstly performed in all subjects with LA. Then, the same analysis was conducted in the six random sampling cohorts of 50 LA patients, respectively. Data analyses on the associations of SNPs with LA risk were evaluated through Pearson's χ2 and multivariate logistic regression tests. Results: We found that eight polymorphisms in six genes (PMF1, ICAM1, TRIM65, AGT, FBF1, and ACOX1) were significantly associated with LA in the genetic association tests. Except for those eight gene variants, 24 other polymorphisms were not found to be significantly associated with LA in general genetic model, dominant model, recessive model, or multiplicative model. Among those eight polymorphisms, rs2984613 in PMF1 showed significant association with LA in the cohort of 220 LA subjects, and such significant association remained in both general genetic model (OR: 0.262, 95% CI: 0.091-0.752, p adj = 0.030) and recessive model (OR: 0.323, 95% CI: 0.119-0.881, p adj = 0.038) when controlling for clinical variables. Seven other significant variants (rs5498 in ICAM1, rs699 in AGT, rs2305913 in FBF1, rs1135640 in ACOX1, and rs3760128, rs7214628, and rs7222757 in TRIM65) were identified in those six random sampling tests that were conducted in the adjusted cohorts of 50 LA patients. In addition, except for rs699 which showed detrimental effect and represented a risk variant for LA, seven other polymorphisms seemed to exert protective effects on LA and to reduce the risk of LA. It is necessary to confirm these associations in an independent cohort. Conclusions: This first replication study on multiple genes in an independent Chinese population did not replicate any risk polymorphisms for LA other than rs 699 in AGT but revealed the significantly negative associations of PMF1, ICAM1, TRIM65, FBF1, and ACOX1 polymorphisms with LA. It not only supported the strong ethnic differences in the genetics of LA but also indicated that those six identified genes may be involved in Chinese white matter lesions. Larger scales of CGAS and GWAS are necessary to confirm and decipher those ethnic-Han specific risk genes for LA in China.

Incidence and risk factors of leukoaraiosis from 4683 hospitalized patients: A cross-sectional study.

Leukoaraiosis (LA) refers to white matter hyperintensities or white matter lesions (WMLs) on magnetic resonance imaging (MRI) scans of the brain; this disease is associated with an increased risk of stroke, dementia, and cognitive decline. The aims of the study are to assess the incidence of LA and its associated risk factors in a Chinese population.A hospital-based cross-sectional study was conducted that included 4683 patients who were 40 years or older. Data collected included age, sex, hypertension, diabetes, smoking, drinking, homocysteine (HCY), and low-density lipoprotein cholesterol (LDL-C) levels in the blood in addition to brain MRI information. We examined the relationship of those putative risk factors with LA, LA occurrence, and LA progression through single-factor and multivariate analyses.Of the total subjects, 58.3% (2731/4683 cases) suffered from LA. LA was more frequent amongst elderly females, particularly in those older than 60, compared to men. The incidence of LA increased with age. Age, sex, hypertension, diabetes, smoking, and HCY levels all were risk factors for LA. Amongst those risk factors, both smoking and high HCY levels were associated with the onset process of LA. Moreover, the multivariate logistic analysis revealed that both drinking and abnormal LDL-C levels were positive regulators in the progression process of LA.This study revealed that the incidence of LA is high in hospitalized patients in China; moreover, age, sex, hypertension, diabetes mellitus, smoking, drinking, and abnormal HCY and LDL-C levels were found to be associated with overall LA risk, LA onset, or LA progression. These results provide insight into strategies for the prevention and treatment of LA.

The CELSR1 polymorphisms rs6007897 and rs4044210 are associated with ischaemic stroke in Chinese Han population.

BACKGROUND: Recently, CELSR1 was identified by genome-wide association studies (GWAS) as a susceptibility gene for ischaemic stroke (IS) in Japanese individuals. AIM: The goal was to examine whether CELSR1 variants are associated with IS in the Chinese Han population. SUBJECTS AND METHODS: This study genotyped two single nucleotide polymorphisms (SNPs) of CELSR1, rs6007897 and rs4044210, in a Chinese sample of 569 IS cases and 581 controls and assessed their genotype and allele associations with IS. RESULTS: The results showed that rs6007897 and rs4044210 variants of CELSR1 were significantly (p < 0.01) associated with IS. These associations remained after adjustment for age, gender, smoking status, hypertension, diabetes mellitus and hypercholesterolemia. In addition, a significant association was observed of rs6007897 and rs4044210 of CELSR1 with large artery atherosclerosis (LAA), a sub-type of IS (p < 0.01). CONCLUSION: Taken together, the present study has proven for the first time that CELSR1 is a susceptibility gene for IS in the Chinese Han population, especially for LAA.

Can baseline magnetic resonance angiography (MRA) status become a foremost factor in selecting optimal acute stroke patients for recombinant tissue plasminogen activator (rt-PA) thrombolysis beyond 3 hours?

OBJECTIVE: We investigated whether baseline vessel status evaluated by magnetic resonance angiography (MRA) can be the foremost factor to classify acute ischemic stroke patients into subgroups for thrombolytic therapy within 3-6 hours of symptom onset. METHODS: Acute ischemic stroke patients beyond 3 hours after symptom onset were examined by stroke magnetic resonance imaging (MRI) (diffusion- and perfusion-weighted imaging, and MRA) before and after thrombolysis treatment within 24-48 hours. Stroke MRI was used to classify acute ischemic stroke patients into subgroups and select optimal patients for thrombolytic treatment. Clinical scores were compared to determine whether there were significant differences among subgroups. RESULTS: The difference in day 90 modified Rankin scale (mRS) between treated salvageable and untreated salvageable patients with recombinant tissue plasminogen activator (rt-PA) was remarkably statistically significant (p=0.02). Treated salvageable patients had more favorable clinical outcomes as compared with the untreated salvageable patients. Patients who did not have baseline artery occlusion were associated with more favorable clinical outcomes than untreated salvageable patients (p<0.001). The difference between treated salvageable and patients without artery occlusion in 90 day mRS score was not statistically significant (p=0.058). CONCLUSION: Baseline vessel status evaluated by MRA may be used as the first factor ahead of mismatch to categorize acute ischemic stroke patients into subgroups. Patients who do not have initial vessel occlusion may not need thrombolytic therapy.