Detection of Motor Dysfunction With Wearable Sensors in Patients With Idiopathic Rapid Eye Movement Disorder.

Patients with idiopathic rapid eye movement sleep behavior disorder (iRBD) are at high risk for conversion to synucleinopathy and Parkinson disease (PD). This can potentially be monitored by measuring gait characteristics of iRBD patients, although quantitative data are scarce and previous studies have reported inconsistent findings. This study investigated subclinical gait changes in polysomnography-proven iRBD patients compared to healthy controls (HCs) during 3 different walking conditions using wearable motor sensors in order to determine whether gait changes can be detected in iRBD patients that could reflect early symptoms of movement disorder. A total 31 iRBD patients and 20 HCs were asked to walk in a 10-m corridor at their usual pace, their fastest pace, and a normal pace while performing an arithmetic operation (dual-task condition) for 1 min each while using a wearable gait analysis system. General gait measurements including stride length, stride velocity, stride time, gait length asymmetry, and gait variability did not differ between iRBD patients and HCs; however, the patients showed decreases in range of motion (P = 0.004) and peak angular velocity of the trunk (P = 0.001) that were significant in all 3 walking conditions. iRBD patients also had a longer step time before turning compared to HCs (P = 0.035), and the difference between groups remained significant after adjusting for age, sex, and height. The decreased trunk motion while walking and increased step time before turning observed in iRBD may be early manifestations of body rigidity and freezing of gait and are possible prodromal symptoms of PD.

Endophilin-A2-mediated endocytic pathway is critical for enterovirus 71 entry into caco-2 cells.

Enterovirus 71 (EV71) is typically transmitted by the oral-faecal route and initiates infection upon crossing the intestinal mucosa. Our limited understanding of the mechanisms by which it crosses the intestinal mucosa has hampered the development of effective therapeutic options. Here, using an RNA interference screen combined with chemical inhibitors or the overexpression of dominant negative proteins, we found that EV71 entry into Caco-2 cells, a polarized human intestinal epithelial cell line, does not involve clathrin- and caveolae-dependent endocytic pathways or macropinocytosis but requires GTP-binding protein dynamin 2 and cytoskeleton remodelling. The use of siRNAs targeting endophilin family members revealed that endophlin-A2 is essential for the uptake of EV71 particles by Caco-2 cells. Subcellular analysis revealed that internalized EV71 virions largely colocalized with endophilin-A2 at cytomembrane ruffles and in the perinuclear area. Combined with viral entry kinetics, these data suggest that EV71 enters Caco-2 cells mainly via an endophilin-A2-mediated endocytic (EME) pathway. Finally, we showed that internalized EV71 virions were transported to endosomal sorting complex required for transport (ESCRT)-related multivesicular bodies (MVBs). These data provide attractive therapeutic targets to block EV71 infection.

Prevalence of pre-diagnostic symptoms did not differ between LRRK2-related, GBA-related and idiopathic patients with Parkinson's disease.

INTRODUCTION: Glucocerebrosidase (GBA) mutations and leucine-rich repeat kinase 2 (LRRK2) variants are the most common genetic risk factors for late-onset Parkinson's disease (PD). In this study, we aimed to investigate the differences in pre-diagnostic symptoms of PD associated with the variants. METHODS: The participants were recruited from 24 centers across China and genotyped for LRRK2 G2385R and R1628P variants and GBA L444P mutation. Participants were surveyed with structural questionnaires for history of environmental exposure and living habits and interviewed to collect the time at onset of each symptoms before diagnosis. We compared the cumulative prevalence and manifestation pattern of symptoms between groups using multiple logistic regression, adjusting age and gender. RESULTS: Total 1799 PD patients were recruited, including 226 patients with LRRK2 G2385R or R1628P variant, 44 with GBA L444P mutation, three with both LRRK2 and GBA mutation, and 1526 idiopathic patients. The cumulative prevalence of non-motor and typical motor symptoms did not differ between groups before diagnosis (P > 0.05). The manifestation sequences of non-motor symptoms were indistinguishable between the LRRK2-carriers, GBA-carriers, and idiopathic PD subjects, and followed the sequence of constipation, hyposmia, sleep disorders, anxiety and depression, sexual dysfunction, urinary incontinency, dizziness and cognition. Slightly higher prevalence of hypomimia and micrographia were detected in the GBA-carriers. CONCLUSIONS: The prevalence of pre-diagnostic symptoms is almost indistinguishable between the LRRK2-carriers, GBA-carriers, and idiopathic PD before diagnosis; the sequence of the manifestation of non-motor symptoms largely conforms to the Braak stage for both genetic-related and idiopathic late-onset PD.

Fibrinogen­like­protein 1 promotes the invasion and metastasis of gastric cancer and is associated with poor prognosis.

The protective role of fibrinogen­like­protein 1 (FGL1) in liver injury has been reported previously. However, there are few studies on FGL1 expression in gastric cancer (GC) tissues, and the role of FGL1 in GC remains unclear. The aim of the present study was to investigate the correlation between FGL1 expression and prognosis in GC patients. Data was downloaded from The Cancer Genome Atlas database, and 50 pairs of GC tissues and the corresponding non­tumor tissues were collected between 2008 to 2011. Furthermore, FGL1 expression was silenced in order to explore its role in SGC­7901 cell proliferation, invasion and migration using Cell Counting Kit­8, wound healing, Transwell invasion and migration assays, respectively. Finally, whether FGL1 is involved in epithelial­mesenchymal transition (EMT) regulation in SGC­7901 cells was determined by western blotting. The results revealed that FGL1 expression was upregulated in GC tissues, and the overall survival time of GC patients with high FGL1 expression levels was markedly shorter than that of GC patients with low FGL1 expression levels (P=0.005). In addition, silencing FGL1 significantly inhibited SGC­7901 cell proliferation, invasion and migration in vitro. Finally, western blot analyses indicated that knockdown of FGL1 markedly increased E­cadherin expression levels (P<0.01), and significantly decreased N­cadherin (P<0.01) and vimentin expression levels (P<0.01), thereby suggesting that FGL1 may promote EMT. These results indicated that FGL1 has the potential to be a predictor in GC patients as well as a target for the treatment of GC.

Gain-of-function mutation p.Arg225Cys in SCN11A causes familial episodic pain and contributes to essential tremor.

Familial episodic pain is a rare autosomal-dominant disorder characterized by recurrent attacks of pain. The pathogenesis of familial episodic pain is not very clear so far. Essential tremor is the most common movement disorder, but the identification of essential tremor genes has remained elusive. We studied a four-generation Chinese family with early-onset familial episodic pain and adult onset familial essential tremor. All essential tremor diagnoses were confirmed based on a review of the questionnaires, videotaped neurological examinations and was then reconfirmed by a senior neurologist specializing in movement disorders using published criteria. SCN11A analysis was performed by whole-exome sequencing or Sanger sequencing. We confirmed the presence of the SCN11A (c.673C>T) mutation in family members with episodic pain and essential tremor. We identified a missense mutation of p.Arg225Cys in SCN11A in a four-generation Chinese family with early-onset familial episodic pain and adult onset familial essential tremor syndrome. This may belong to a rare hereditary syndrome that has not been reported up to now. For the first time, we associated the genetic variability of SCN11A with the development of essential tremor, and further confirmed essential tremor is one of the neurological channelopathies.

An intronic CYP46A1 polymorphism is associated with Alzheimer disease in a Chinese Han population.

Excess cholesterol is removed from the brain via hydroxylation mediated by cholesterol 24S-hydroxylase (CYP46), which is a mechanism of maintaining cholesterol homeostasis in the brain. The CYP46A1 gene has been suggested as a genetic risk factor for sporadic late-onset Alzheimer's disease (AD). In this report, we analyzed an intronic CYP46A1 single nucleotide polymorphism (SNP) in 508 sporadic AD patients and 549 controls in a Chinese Han population. Our results indicated that the distribution of CYP46A1 SNP rs754203 genotypes was significantly different in AD patients compared to controls (χ(2) = 6.59, P = 0.037). The frequency of at least one of CYP46A1 T allele (C/T or T/T) was higher in AD patients compared to controls (χ(2) = 6.58, P = 0.01). The age- and sex-adjusted odds ratio for the risk of AD in carriers of CYP46A1 T allele (C/T + T/T) was 1.69 (95 % confidence interval, 1.12-2.56). We conclude that this intronic polymorphism in CYP46A1 gene is associated with AD in a Chinese Han population, and the CYP46A1 T allele might be a risk factor for AD.

Protective role of interlekin-1 alpha gene polymorphism in Chinese Han population with sporadic Parkinson's disease.

Parkinson's disease is the second most common neurodegenerative disorders after Alzheimer's disease in the elderly. Abundant evidence showed that proinflammatory factors were involved in the pathogenesis of sporadic Parkinson's disease (SPD). Interleukin-1 (IL-1) is a cytokine that plays an important role in neurodegenerative disease. Previous association studies between genetic polymorphisms of IL-1 alpha and PD have showed conflicting results and no such study was done in Chinese. We recruited 533 SPD patients and 530 controls in Chinese Han population to investigate the association of IL-1alpha C-899T allele and risk for PD. Real-time PCR was used to detect the polymorphism, and multiple logistic regression, Chi square test and survival analysis were performed to explore the association. The distribution of IL-1alpha alleles was significantly different between the cases and controls, and the T allele was associated with a reduced risk of PD (OR: 0.72, 95%CI: 0.54-0.97, rho = 0.033). However, survival analysis showed that the T allele did not delay the onset age of PD (T allele vs. non-T allele log rank: chi2 = 0.14, p = 0.70). Our data suggest that the T allele carriers have less inclination to have PD in Chinese Han population.

Genetic association between low-density lipoprotein receptor-related protein gene polymorphisms and Alzheimer's disease in Chinese Han population.

Alzheimer's disease (AD) is the most common neurodegenerative disorders in the elderly. Low-density lipoprotein receptor-related protein (LRP), as a receptor of apolipoprotein E (APOE), APP, and alpha2 macroglobulin (alpha2-M), keeps the balance between degeneration and production of beta-amyloid protein (Abeta) clearance. Its gene had been defined as a candidate gene for AD, but the results were not universal. Total 496 AD patients and 478 controls were recruited in Chinese Han population and real-time PCR was used to detect the polymorphism of LRP C766T. Multiple logistic regression, Chi-square test and survival analysis were performed to explore the association. The distribution of LRP genotypes and alleles was significantly different between cases and controls, and T allele could reduce the risk for developing AD (OR of CT genotype: 0.57; 95% CI: 0.38-0.85, rho=0.003; OR of T allele: 0.57; 95% CI: 0.39-0.83, rho=0.003). TT genotype carriers had 5 years later for developing AD compared with CC genotype carriers, but survival analysis did not conform this (LRP TT vs. CT and CC log rank chi(2)=2.71, rho=0.26). The distribution of LRP C766T genotypes and alleles was different among different severity stratified by MMSE yet (rho=0.26). Our data suggested that the polymorphism of LRP C766T was strongly associated with AD and T allele might be a protective factor for AD in Chinese Han population.

Lack of association between the BDNF gene Val66Met polymorphism and Alzheimer disease in a Chinese Han population.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by excessive neuronal loss in specific regions of the brain. Among the areas most severely affected are the basal forebrain cholinergic neurons and their projection regions, the hippocampus and the cortex. Several lines of evidence have made brain-derived neurotrophic factor (BDNF) an important candidate gene conferring risk for AD. Recently, several reports investigated the association between a single nucleotide polymorphism (Val66Met, rs6265) of the BDNF gene and AD but yielded ambiguous results. To figure out the association of this single nucleotide polymorphism in the BDNF gene with sporadic AD in a Chinese Han population, we analyzed 513 patients with AD and 575 controls for the genetic association studies. Our results indicated that the distribution of the BDNF genotypes and alleles did not differ significantly. Similar results were observed when the AD and control groups were stratified by age/age at onset and sex. Our data also showed that in the Chinese Han population, the frequencies of the BDNF Met allele (46.5%) and Val allele (53.5%) were significantly different from ethnic groups from Italy, Japan and the USA. The present data revealed no significant effect of the genotypes on the age at onset for developing AD, and no significant association between the genotypes and the severity of the disease.

Gln192Arg polymorphism in paraoxonase 1 gene is associated with Alzheimer disease in a Chinese Han ethnic population.

BACKGROUND: Oxidative stress such as low-density lipoprotein (LDL) oxidation is thought to be an important mechanism in Alzheimer's disease (AD). Paraoxonase 1 (PON1), an enzyme located on high-density lipoprotein, can prevent LDL from oxidation to some extent. It is also a potent cholinesterase inhibitor and an arylesterase, combating organophosphate poisoning and metabolization of environmental neurotoxins which might be responsible for neurodegeneration with aging. We evaluated the association of Gln192Arg polymorphism in the PON1 gene with AD in a Chinese Han ethnic population. METHODS: Patients and age-matched controls were recruited from outpatient clinics and a population-based epidemiological survey, respectively. Gln192Arg polymorphism in the PON1 gene was detected by allele-specific PCR technique in 521 patients with AD and 578 healthy controls. RESULTS: The presence of at least one of PON1 R alleles (Q/R or R/R) was lower in AD patients than in the controls (82.7% vs 87.4%; chi(2) = 4.68, P = 0.03). PON1 gene R allele frequency was lower in AD patients than in the controls (60.7% vs 64.7%; chi(2) = 3.85, P = 0.05). One-way ANOVA showed that PON1 genotype had no effect on the age of onset for developing AD. Logistic regression analysis demonstrated the age and sex-adjusted odds ratio (OR) for the risk of AD in PON1 of PON1 R allele carriers was 0.71 (P = 0.044, 95% CI, 0.51 - 0.99). CONCLUSION: Our results indicate that Gln192Arg polymorphism in the PON1 gene is associated with AD, and PON1 R allele might be a protective factor for AD in a Chinese Han ethnic population.

[Association between interleukin-1 alpha-889 C/T polymorphism and Alzheimer's disease in Chinese Han population].

OBJECTIVE: To explore the possible association between interleukin-1 alpha-889C/T (IL-1 alpha-889 C/T) polymorphism and Alzheimer's disease (AD) in Chinese Han population. METHODS: A total of 520 AD patients and 505 normal controls were enrolled. The polymorphism of IL-1 alpha-889C/T was detected with real-time polymerase chain reaction. Multiple logistic regression and chi square test were performed for statistical analysis. RESULTS: The frequencies of C/C, C/T, and T/T genotypes were 70.96%, 25.77%, and 3.27%, respectively, among AD patients, and 80.59%, 18.22%, and 1.19%, respectively, among non-dementia controls. In multivariate analysis, T/T and C/T genotypes of IL-1 alpha-889, age > or =65 years, and female were risk factors for AD. Adjusted for the age and sex, T/T and C/T genotypes were still associated with AD. The odds ratio for AD were 3.57 and 1.74 for individuals with T/T and C/T genotypes compared with individuals with C/C genotype. P value was 0. 019 and 0. 001, respectively. CONCLUSION: The IL-1 alpha-889 T/T and C/T genotypes are likely to be susceptible factors for the development of AD in Chinese Han population. The susceptibility genotype, female, and age > or =65 years are risk factors for AD.

[Paraoxonase 1 gene Gln192Arg polymorphism in and Alzheimer disease].

OBJECTIVE: The aim of this study was to evaluate the association of Gln192Arg polymorphism in paraoxonase 1 (PON1) gene with Alzheimer's disease (AD) in Chinese Han population. METHODS: Gln192Arg polymorphism in PON1 gene was detected with real-time PCR (RT-PCR) technique in 521 patients with AD and 578 healthy controls. RESULTS: The presence of at least one of PON1 R allele (Q/R or R/R) was lower in AD patients as compared with the controls (82.7% vs 87.4%; chi(2) = 4.68, P = 0.03). PON1 gene R allele frequency was lower in AD patients as compared with the controls (60.7% vs 64.7%; chi(2) = 3.85, P = 0.05). One-Way ANOVA showed that PON1 genotype had no effect on the age of onset of AD. Logistic regression analysis demonstrated that the age and sex-adjusted OR for the risk of AD in PON1 R allele carriers was 0.71 (P = 0.044, 95% CI = 0.51 - 0.99). CONCLUSION: Our results indicate that Gln192Arg polymorphism in PON1 gene is associated with AD and PON1 R allele might be a protective factor for AD in Chinese Han population.

The Fas gene A-670G polymorphism is not associated with sporadic Alzheimer disease in a Chinese Han population.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by excessive neuronal loss, intracellular neurofibrillary tangles and extracellular deposition of amyloid beta-peptide (Abeta). The Fas antigen is a cell surface receptor-mediating cell apoptosis. Several lines of evidence have made Fas/Fas ligand induced apoptosis play an important role in the pathogenesis of AD. Moreover, the Fas gene is located on chromosome 10q24.1, a region of linkage to late-onset AD. Several reports have investigated the association between a single nucleotide polymorphism (SNP) that is located at position -670 of Fas gene and AD, but yielded ambiguous results. To figure out the association of this SNP with sporadic AD in Chinese Han population, we have analyzed 509 patients with AD and 561 controls for the genetic association studies. Our results indicate that the distribution of the Fas genotypes (chi(2) = 0.66, P = 0.72) and alleles (chi(2) = 0.70, P = 0.40) did not differ significantly. The similar results were observed when AD and control groups were stratified by age/age at onset and sex (P > 0.10). The present data revealed no significant effect of the genotypes on the age of onset for developing AD, and no significant association between the genotypes and the severity of the disease.