Ruwei Ou

Large C9orf72 repeat expansions are seen in Chinese patients with sporadic amyotrophic lateral sclerosis

An intronic GGGGCC hexanucleotide repeat expansion in the chromosome 9 open reading frame 72 (C9orf72) gene was considered as the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia in Caucasian populations. Using repeat-primed polymerase chain reaction analysis and Southern blotting methods, we assessed the frequency and size of hexanucleotide repeat expansion in a cohort of 918 sporadic ALS (SALS) patients and 632 control individuals of Han Chinese origin. We identified 8 (0.87%) of the SALS patients and none of control individuals as carriers of C9orf72 expansions with 700-3500 repeats. A comprehensive neuropsychological battery was conducted on 4 expansion-positive ALS patients, where 3 patients were found to have cognitive impairment. All expansion-positive patients were genotyped for the previously reported 20 single-nucleotide polymorphism (SNP) risk haplotypes on chromosome 9p21. Among them, 13 SNP risk haplotypes were shared in all expansion carriers, suggesting a common founder from European ancestry. Further meta-analysis demonstrated that the intermediate expansion size with 24-30 repeats, rare in both patients and controls, were significantly associated with the risk for ALS. To our knowledge, this is the first study to identify a proportion of Chinese SALS patients carrying this pathologic expansion of up to ∼3500 repeats and to completely elaborate the 20-SNP risk haplotypes in Chinese expansion-positive patients, providing indispensable evidence for the origin, geographical range, and population prevalence of the C9orf72-associated ALS.

Non-motor symptoms and quality of life in tremor dominant vs postural instability gait disorder Parkinson's disease patients.

To explore the differences in the features and impact on quality of life (QOL) of non‐motor symptoms (NMS) of tremor dominant (TD) and postural instability gait disorder (PIGD) phenotypes early Parkinsons disease (PD), as well as the determinants of poor QOL for TD and PIGD phenotypes.

Genetic Variants of SNCA Are Associated with Susceptibility to Parkinson's Disease but Not Amyotrophic Lateral Sclerosis or Multiple System Atrophy in a Chinese Population.

Background The polymorphisms of α-synuclein (SNCA), rs3775444, rs3822086 and rs11931074 that are strongly associated with Parkinson’s disease (PD) in Caucasian populations, were examined in this study to elucidate the role of polymorphisms in different ethnic backgrounds. The possible associations of these three polymorphisms were also investigated in PD, amyotrophic lateral sclerosis (ALS), and multiple system atrophy (MSA) in a Chinese population based on the overlapping of clinical manifestations and pathological characteristics of these three neurodegenerative diseases. Methods A total of 1276 PD, 885 sporadic ALS (SALS), 364 MSA patients, and 846 healthy controls (HCs) were included. All subjects were genotyped for the three polymorphisms using Sequenom iPLEX Assay technology. Results Significant differences in the genotype distributions (p = 5.99E-06 and p = 4.98E-06, respectively) and the minor allele frequency (MAF) (p = 2.16E-06 and p = 2.15E-06, respectively) of SNCA rs3822086 (C) and rs11931074 (G) were observed between PD and HCs. However, no differences were found in the genotype distributions and MAF of SNCA rs3775444 (T) between PD and HCs. Haplotype that incorporated the three SNPs further strengthened the association with PD (best haplotype, p = 9.62E-005). No significant differences in the genotype distributions and MAF of the SNPs were found between SALS and HCs, MSA and HCs, and subgroups of PD and SALS. However, the MAF of SNCA rs3775444 (T) was significantly higher in MSA patients with frontal lobe dysfunction than MSA patients without dysfunction (p = 0.0002, OR 2.53, 95%CI: 1.55-4.15). Conclusion Our results suggest that the rs3822086 (C) allele and rs11931074 (G) allele in SNCA decrease the risk for PD, and SNCA rs11931074 may affect frontal lobe dysfunction of MSA in the Chinese population. However, these SNCA polymorphisms are not likely a common cause of SALS or MSA.

An association analysis of the rs1572931 polymorphism of the RAB7L1 gene in Parkinson's disease, amyotrophic lateral sclerosis and multiple system atrophy in China

Recently, the rs1572931 single‐nucleotide polymorphism (SNP) of the putative promoter of the member RAS oncogene family‐like 1 (RAB7L1) gene was reported to be associated with reduced risk for Parkinsons disease (PD) in the Ashkenazi Jewish population. Ethnic‐specific effects are an important consideration in genome‐wide association studies. Considering that the clinical manifestations and pathological characteristics overlap between PD, amyotrophic lateral sclerosis (ALS) and multiple system atrophy (MSA), the possible associations between the rs1572931 SNP and these three diseases were studied in the Chinese population.

Prevalence and clinical correlates of drooling in Parkinson disease: A study on 518 Chinese patients

BACKGROUND The prevalence and clinical correlates of drooling in Chinese patients with Parkinson disease (PD) are unknown. METHODS A cross-sectional analysis of 518 Chinese patients with PD was conducted. Assessments included Unified PD Rating Scale (UPDRS), Non-Motor Symptoms Scale (NMSS), Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), PD Questionnaire-39 (PDQ-39), Frontal assessment battery (FAB) and Montreal Cognitive Assessment (MoCA). RESULTS Two hundred and seventy-three PD patients (52.7%) reported drooling (droolers). Drooling occurred more frequently in the late-onset PD patients than the early-onset PD patients (p < 0.05). Droolers had higher levodopa equivalent daily doses, higher incidences of dysarthria, dysphagia and fluctuation, higher scores for the UPDRS part III, NMSS, HAMD and HAMA, and higher scores for the mobility, activities of daily life, stigma and communication subdomains of the PDQ-39 than the non-droolers (p < 0.05). The percentage of benzhexol use in the non-droolers was significantly higher than the droolers (p < 0.05). The FAB and MoCA scores between the droolers and non-droolers were not different. The binary logistic regression analysis indicated that dysarthria, dysphagia, benzhexol use, and a lower score for the naming domain of the MoCA were associated with drooling. CONCLUSIONS Drooling is a relatively common disabling symptom in Chinese PD patients. Patients with dysarthria, dysphagia and naming disorder are likely to experience drooling. Drooling is not correlated with disease duration and motor severity of PD.

Aberration of miRNAs Expression in Leukocytes from Sporadic Amyotrophic Lateral Sclerosis

Background: Accumulating evidence indicates that miRNAs play an important role in the development of amyotrophic lateral sclerosis (ALS). Most of previous studies on miRNA dysregulation in ALS focused on the alterative expression in ALS animal model or in limited samples from European patients with ALS. In the present study, the miRNA expression profiles were investigated in Chinese ALS patients to explore leukocytes miRNAs as a potential biomarker for the diagnosis of ALS. Methods: We analyzed the expression profiles of 1733 human mature miRNAs using microarray technology in leukocytes obtained from 5 patients with sporadic ALS (SALS) and 5 healthy controls. An independent group of 83 SALS patients, 24 Parkinsons disease (PD) patients and 61 controls was used for validation by real-time polymerase chain reaction assay. Area under the receiver operating characteristic curve (AUC) was used to evaluate diagnostic accuracy. In addition, target genes and signaling information of validated differential expression miRNAs were predicted using Bioinformatics. Results: Eleven miRNAs, including four over-expressed and seven under-expressed miRNAs detected in SALS patients compared to healthy controls were selected for validation. Four under-expressed microRNAs, including hsa-miR-183, hsa-miR-193b, hsa-miR-451, and hsa-miR-3935, were confirmed in validation stage by comparison of 83 SALS patients and 61 HCs. Moreover, we identified a miRNA panel (hsa-miR-183, hsa-miR-193b, hsa-miR-451, and hsa-miR-3935) having a high diagnostic accuracy of SALS (AUC 0.857 for the validation group). However, only hsa-miR-183 was significantly lower in SALS patients than that in PD patients and in HCs, while no differences were found between PD patients and HCs. By bioinformatics analysis, we obtained a large number of target genes and signaling information that are linked to neurodegeneration. Conclusion: This study provided evidence of abnormal miRNA expression patterns in the peripheral blood leukocytes of SALS patients. Leukocytes miRNAs provide a promising opportunity for detection of SALS. The specificity of under-expression of hsa-miR-183 in SALS needs to be confirmed by further miRNA studies on other neurodegenerative diseases.

Replication analysis of genetic variants on 17q11.2 and 9p21.2 with sporadic amyotrophic lateral sclerosis and Parkinson's disease in a Chinese population.

We performed a replication study of the 2 genetic variants, rs34517613 on 17q11.2 and rs3849942 on 9p21.2 in patients with sporadic amyotrophic lateral sclerosis (ALS) and Parkinsons disease in a Chinese population. These 2 variants are identified to be associated with increased risk of ALS in European-descended populations by genome-wide association studies. Both rs34517613 and rs3849942 showed no evidence of association in Chinese. These loci are not risk factors for sporadic ALS and Parkinsons disease in the western Han Chinese population.

The Global Cognition, Frontal Lobe Dysfunction and Behavior Changes in Chinese Patients with Multiple System Atrophy.

Background Studies on cognition in multiple system atrophy (MSA) patients are limited. Methods A total of 110 MSA patients were evaluated using Addenbrookes Cognitive Examination-Revised (ACE-R), Frontal Assessment Battery (FAB), Frontal Behavioral Inventory (FBI), and Unified MSA Rating Scale (UMSARS) tests. Fifty-five age-, sex-, education- and domicile-matched healthy controls were recruited to perform the FAB and ACE-R scales. Results Approximately 32.7% of the patients had global cognitive deficits with the most impaired domain being verbal fluency and visuospatial ability (26.4%), followed by memory (24.5%), language (20%) and orientation/attention (20%) based on a cut-off score of ACE-R ≤ 70. A total of 41.6% of the patients had frontal lobe dysfunction, with inhibitory control (60.9%) as the most impaired domain based on a cut-off score of FAB ≤14. Most patients (57.2%) showed moderate frontal behavior changes (FBI score 4–15), with incontinence (64.5%) as the most impaired domain. The binary logistic regression model revealed that an education level < 9 years (OR:13.312, 95% CI:2.931–60.469, P = 0.001) and UMSARS ≥ 40 (OR: 2.444, 95%CI: 1.002–5.962, P< 0.049) were potential determinants of abnormal ACE-R, while MSA-C (OR: 4.326, 95%CI: 1.631–11.477, P = 0.003), an education level < 9 years (OR:2.809 95% CI:1.060–7.444, P = 0.038) and UMSARS ≥ 40 (OR:5.396, 95%CI: 2.103–13.846, P < 0.0001) were potential determinants of abnormal FAB. Conclusions Cognitive impairment is common in Chinese MSA patients. MSA-C patients with low education levels and severe motor symptoms are likely to experience frontal lobe dysfunction, while MSA patients with low education levels and severe motor symptoms are likely to experience global cognitive deficits. These findings strongly suggest that cognitive impairment should not be an exclusion criterion for the diagnosis of MSA.

No association of GPNMB rs156429 polymorphism with Parkinson's disease, amyotrophic lateral sclerosis and multiple system atrophy in Chinese population.

BACKGROUND The rs156429 polymorphism in the glycoprotein nonmetastatic melanoma protein B (GPNMB) gene was found to be associated with the risk for Parkinson disease (PD) in Caucasian population by genome-wide association studies (GWAS). Recently, encoded protein, GPNMB, was identified as a novel neuro-protective factor in amyotrophic lateral sclerosis (ALS). The overlapping of clinical manifestations and pathologic characteristics among PD, ALS, and multiple system atrophy (MSA) are observed. OBJECT This study aimed at investigating the possible associations of the polymorphism and the three neurodegenerative diseases: PD, ALS and MSA in a Chinese population. METHODS All of the subjects, including PD (n=1096), sporadic ALS (SALS) (n=876) and MSA (n=356) patients, and 829 health controls (HCs) were included. All subjects were genotyped for this polymorphism using Sequenom iPLEX Assay technology. RESULTS No differences were found in the genotype distributions and minor allele frequency of GPNMB rs156429 between PD patients and HCs, between SALS patients and HCs, between MSA patients and HCs, and between subgroups of PD, ALS and MSA patients with regard to clinical features such as sex, age of onset, presence or absence of cognitive abnormality, depression and anxiety. CONCLUSION Lack of association identified in our study suggests that it may be premature to conclude associations between GPNMB rs156429 and SALS, PD and MSA. More studies on such an association involving a larger number of participants are needed to confirm the present findings.

Correlative factors of cognitive dysfunction in PD patients: a cross-sectional study from Southwest China.

Background: Cognitive dysfunction is common in Parkinson’s disease (PD). A comprehensive understanding of cognitive dysfunction and its correlative factors in Chinese PD patients were not available. Methods: This cross-sectional study included 454 PD patients. Cognitive function was evaluated using the Montreal Cognitive Assessment. Non-motor symptoms were assessed using the Non-Motor Symptoms Scale (NMSS), and depression and anxiety were assessed using the Hamilton Depression Rating Scale and the Hamilton Anxiety Rating Scale, respectively. Results: Cognitive dysfunction was observed in 58.1% of the patients. The mean age, age of onset, scores of rigidity, bradykinesia, axial impairment, tremor, speech and facial expression, total Unified PD Rating Scale part III and H&Y stage, and NMSS scores were significantly higher in PD patients with cognitive dysfunction than in those without cognitive dysfunction. The prevalence of sleep/fatigue domain with the item ‘difficulty falling asleep’, mood/apathy domain with the item ‘feelings of nervousness’, perceptual problems/hallucinations domain with the item ‘delusions’, attention/memory domain with the items ‘concentration’ and ‘forget to do things’, gastrointestinal domain with the items ‘dribbling saliva’ and ‘swallowing’, urinary domain with the item ‘nocturia’, and the item ‘taste or smell’ in the miscellaneous domain were significantly higher in PD patients with cognitive dysfunction. Logistic regression indicated that female sex, older age, lower education level, higher bradykinesia score, and presence of the urinary domain were associated with cognitive dysfunction in PD. Conclusions: Age, sex, education level, bradykinesia score, and presence of urinary symptoms are correlative factors of cognitive dysfunction in Chinese PD patients.