Lingyu Zhang

Causes of Death in Chinese Patients with Multiple System Atrophy

The objective of this study was to explore the causes of death in Chinese patients with multiple system atrophy (MSA) as well as differences in the cause of death according to sex, subtype, disease onset, and whether the disease was accompanied by nocturnal stridor. A total of 131 MSA patients were enrolled and followed up once every year until their deaths. Clinical information was collected by neurologists, and the cause of death of the MSA patients was obtained from the patients’ relatives or caregivers. The current study included 62 MSA with predominant parkinsonism (MSA-P) and 69 MSA with predominant cerebellar ataxia (MSA-C) patients. Median survival time from disease onset to death of the MSA patients was 5.59 years. The most common cause of death was respiratory infection (65.6%). The second most common cause of death was sudden death (14.5%). Other causes included nutritional disorder due to dysphagia (9.2%), urinary tract infection (3.1%), suicide (2.3%), choking (1.5%), cerebrovascular accident (1.5%), myocardial infarction (1.5%), and lymphoma (0.8%). We found that sudden death was more likely to occur in patients with nocturnal stridor than in those without (P<0.001). There were no significant differences in the cause of death according to subtype, sex, or onset symptoms (autonomic failure or motor symptoms). Sudden death is a relatively common cause of death in MSA patients, second only to respiratory infection, especially in patients with nocturnal stridor. The information provided by our study may help to provide better medical care to MSA patients.

Survival analysis and prognostic nomogram model for multiple system atrophy

OBJECTIVE The purpose of our study was to explore the factors associated with the survival of multiple system atrophy (MSA) patients and to produce a prognostic nomogram to predict survival in an individual MSA patient. METHODS 220 probable MSA patients were included from 2009 to 2013. Disease severity was measured by the Unified Multiple System Atrophy Rating Scale (UMSARS). The univariate and multivariable Cox regression analyses were used to identify factors associated with survival in MSA patients. A nomogram model predicting the probability of survival was formulated based on the results of the multivariate Cox analysis. The results were validated using bootstrap resampling and a prospective study on 80 patients included from January 2014 to August 2015 at the same institution. RESULTS Median survival from symptom onset to death was 6.4 years (95%CI = 6.1-6.7). The multivariate Cox survival model suggested that autonomic onset, higher UMSARS score, frequent falls, orthostatic hypotension(OH) and shorter diagnostic delay were associated with poor survival. The nomogram model for the multivariate Cox survival model had a concordance index of 0.677 in primary cohort, which showed a concordance index of 0.721 in validation cohort. CONCLUSION Autonomic onset, higher UMSARS score, frequent falls, OH and shorter diagnostic delay at baseline were independent markers for poor survival in MSA. The prognostic nomogram model created by the significant independent factors for longer survival provided an effective way to predict the probability of longer survival in an individual MSA patient.

No association between five new GWAS-linked loci in Parkinson’s disease and multiple system atrophy in a Chinese population

Recently, 17 new Parkinsons disease (PD) risk loci were identified in a genome-wide association studies meta-analysis in Caucasians; however, their association with PD in Chinese patients is largely unknown. Therefore, we performed a replication study of 5 of the most commonly identified candidate variants, including SORBS3 rs2280104, SCN3A rs353116, TOX3 rs4784227, GLAC rs8005172, and ZNF184 rs9468199, in a large sample of patients with PD (1506) and multiple system atrophy (MSA, 496) in a Chinese population. These 5 variants were found to not be associated with PD and MSA in the Chinese population. Our results suggest that these variants are not risk factors for PD or MSA in the Chinese population.

Analysis of GWAS-linked variants in multiple system atrophy

A recent genome-wide association study performed in European population identified 4 potentially interesting gene loci of multiple system atrophy (MSA), including the EDN1 rs16872704, MAPT rs9303521, FBXO47 rs78523330, and ELOVL7 rs7715147. Because of the genetic heterogeneity, we aimed to explore the possible genetic association between above 4 single nucleotide polymorphisms (SNPs) and MSA in Chinese Han population from Mainland China, Taiwan, and Singapore. A total of 1847 subjects comprising 906 MSA patients and 941 unrelated healthy controls were genotyped by directly sequencing for these SNPs. No significant differences in the genotype distributions, minor allele frequency of EDN1 rs16872704, MAPT rs9303521, FBXO47 rs78523330, and ELOVL7 rs7715147 between MSA patients and healthy controls, and between subtypes of MSA patients (MSA-C and MSA-P), were found. In conclusion, we demonstrated that genome-wide association study-linked SNPs in Caucasians do not confer a significant risk for MSA in the Chinese population.

Clinical Staging of Amyotrophic Lateral Sclerosis in Chinese Patients

Objective: It is important to explore the utility of clinical staging systems in the management of amyotrophic lateral sclerosis (ALS). Our aim was to assess the validity of Kings College in a Chinese ALS cohort, by evaluating the duration and informativeness of each stage and examining the association between stage and prognosis. Methods: From May 2008 to December 2016, patients with a likely diagnosis of ALS were registered. We prospectively assessed the progression of the patients through the stages and calculated the duration of each stage. Results: The median duration in Stage 1 was 12.00 months, Stage 2 7.50 months, Stage 3 6.50 months, and Stage 4 4.10 months. Subset analysis revealed that the spinal-onset and early-onset patients had a longer median time in Stage 1 compared to bulbar-onset and late-onset patients, respectively. Riluzole treatment extended the durations of Stages 1 and 2, and the effect was maintained in patients with long-term use of riluzole (>6 months). Patients who initiated long-term riluzole therapy early, in Stage 1 or 2, had a longer Stage 2. Patients who received percutaneous gastrostomy endoscopy (PEG) or non-invasive positive-pressure ventilation (NIPPV) showed longer durations of Stage 4. The differences in survival time measured from each stage to death or censor date were significant. Conclusions: We validated the Kings College staging system in a Chinese population, and showed this system to be useful in clinical practice. Patients with bulbar-onset or an age of onset>45 years tended to have rapidly progressing ALS. Riluzole may be more effective when initiated in an early disease stage and continued long-term. PEG and NIPPV treatments can extend disease duration of Stage 4.

Functional variant rs3135500 in NOD2 increases the risk of multiple system atrophy in a Chinese population

Background: Given the overlap of clinical manifestations and pathological characteristics between Parkinsons disease (PD) and multiple system atrophy (MSA), we investigated the associations between five functional polymorphisms of nucleotide-binding oligomerization domain protein 2 (NOD2) which were associated with PD, and MSA in a Chinese population. Methods: A cohort of 431 MSA patients and 441 unrelated healthy controls (HCs) were included in the study. Five polymorphisms in NOD2, including P268S, R702W, G908R, 1007fs, and rs3135500, were genotyped. The mRNA expression of NOD2 in peripheral mononuclear cells (PBMCs) in 32 MSA patients were analyzed using RT-PCR, and the concentration of NOD2 and α-synuclein from plasma of 57 MSA patients were also measured by ELISA analysis. Results: No heterozygous or homozygous for R702W, G908R, and 1007fs were found in all the subjects. For rs3135500, differences in genotype distributions, dominant and additive genetic models, were found between MSA and HCs, and between MSA Parkinsonism (MSA-P) patients and HCs. Interestingly, patients carrying the “A” allele of rs3135500 had higher mRNA NOD2 level from PBMCs and NOD2 protein from plasma than patients without this allele (p = 0.028 and p = 0.036, respectively). In addition, we also found the concentration of NOD2 in plasma was positively correlated with the levels of NOD2 mRNA in PBMC and α-synuclein in plasma (R = 0.761 and 0.832, respectively). Conclusion: Our findings suggest that the rs3135500 variant in the NOD2 gene might increase the risk for MSA and might provide new evidence that inflammation mediated by NOD2 involved in the pathogenesis of MSA. Further association studies involving a larger number of participants, as well as functional studies, are needed to confirm our current findings.

Clinical and prognostic features of ALS/MND in different phenotypes–data from a hospital-based registry

OBJECTIVES To explore the natural history, clinical features, and survival relevance of patients presenting with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) with different phenotypes. METHODS All patients were prospectively enrolled in a hospital-based register from 2006 to 2015. Cases were classified according to established phenotypes: classic, bulbar, flail arm, flail leg, upper motor neuron dominate, respiratory, pure lower motor neuron and pure upper motor neuron. Survival was analyzed using Kaplan-Meier curves and Cox regression analysis. RESULTS A total of 1157 patients with complete clinical information were registered in the current cohort study. The classic phenotype was the most frequent phenotype. The mean age of onset, diagnostic delay, smoking status, exposure to pesticides and mean survival time were significantly different among different phenotypes. The median survival time was 3.1 years for all patients. At the end of the analysis, the 3-year survival rate was 62.1%, the 5-year survival rate was 39.6%, and the 10-year survival rate was 22.0%. The Cox analysis revealed that the disease phenotype was an independent predictor of survival (hazard ratio = 0.825, P < 0.001), after adjusting for other factors. CONCLUSIONS This study showed the natural history data of ALS/MND and supported the theory that varied disease phenotypes had different clinical, demographic and prognostic characteristics, which provided the basis for analysis of future management and treatment for ALS/MND. Furthermore, the phenotypic expression of ALS/MND with distinctive characteristics is important for providing complementary information for identifying the underlying mechanisms of the diseases.

Depression and anxiety in multiple system atrophy

It has been noticed that the patients with multiple system atrophy (MSA) can accompany with depression and anxiety. This study aimed to establish the incidence and determinants of depression and anxiety symptoms in Chinese MSA patients.