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Patterns of white matter (WM) abnormalities and correlation with clinical features in patients with blepharospasm (BSP) and patients with blepharospasm-oromandibular dystonia (BOM) remain unknown. Using voxel-based analysis, diffusion behaviors of WM including fractional anisotropy (FA), mean diffusivity (MD) and eigenvalues were compared between 20 BSP patients vs. 11 healthy controls (HCs) and 11 patients with BOM vs. 11 HCs. Correlation analyses were performed to assess possible association between diffusion behaviors of significantly different areas and clinical measures. Compared with HCs, BSP patients showed significant FA reductions in the left anterior lobe of cerebellum. Significant increases of MD and radial diffusivity (RD) were detected in right lentiform nucleus and thalamus. Significantly decreased FA in the right precuneus of parietal lobe, increased MD in the right lentiform nucleus and insula, and increased axial diffusivity in the right insula were observed in BOM patients. The FA values in the WM of left cerebellum negatively correlated with disease severity in BSP patients measured by JRS ( r = −0.655, p = 0.002). The FA values in the right parietal WM negatively correlated with disease duration in BOM patients ( r = −0.745, p = 0.008). Both BSP and BOM are related to microstructural abnormalities of WM in the basal ganglia. WM changes outside the basal ganglia may present trait features that are specific for individual dystonia phenotype. The correlation between FA abnormalities and symptom severity suggests that DTI parameters might be of clinical value in assessing and following disability in BSP patients. [ABSTRACT FROM AUTHOR]

Objectives: Alpha-synuclein is involved in the pathogenesis of multiple system atrophy (MSA) and can be regulated by lipids. This study aims to validate the correlation between lipid levels and the prevalence of MSA as well as its progression. Methods: A total of 234 patients with probable MSA and 240 age- and gender-matched healthy controls were included in this study. Lipid contents, including total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG), were evaluated. The unified MSA rating scale (UMSARS) was used to assess the severity of MSA. Results: Lipid levels in MSA patients were significantly lower than those in healthy controls. Patients with MSA-C were significantly younger, had higher body mass indices (BMIs), higher UMSARS scores, and lower HDL-C contents compared with MSA-P patients. Subjects with the lowest quartiles and the second quartiles of total cholesterol, LDL-C, and HDL-C had high prevalence of MSA compared with subjects with the highest quartiles. No correlation was found between the mean rate of annualized changes and serum levels of lipids as well as other independent factors, such as age, BMI, gender, subtypes (C-type or Ptype), and disease duration at the initial visit, in 107 followed-up MSA patients. Discussion: Low levels of total cholesterol, LDL-C, HDL-C, and TG increased the prevalence of MSA in a Chinese population. Patients with MSA-C showed significantly lower levels of HDL-C than MSA-P patients. However, lipids did not deteriorate or improve the progression of MSA. [ABSTRACT FROM AUTHOR]

Background: The time of survival in patients with amyotrophic lateral sclerosis (ALS) varies greatly, and the genetic factors that contribute to the survival of ALS are not well studied. There is a lack of a comprehensive study to elucidate the role of genetic factors in the survival of ALS.Methods: The published studies were systematically searched and obtained from PubMed, EMBASE, and the Cochrane Library without any language restrictions from inception to Oct 27, 2021. A network meta-analysis for ALS causative/risk genes and a systematic review and pairwise meta-analysis for other genetic modifiers were conducted. The PROSPERO registration number: CRD42022311646.Results: A total of 29,764 potentially relevant references were identified, and 71 papers were eligible for analysis based on pre-decided criteria, including 35 articles in network meta-analysis for 9 ALS causative/risk genes, 17 articles in pairwise meta-analysis for four genetic modifiers, and 19 articles described in the systematic review. Variants in three genes, including ATXN2 (HR: 3.6), C9orf72 (HR: 1.6), and FUS (HR:1.8), were associated with short survival of ALS, but such association was not identified in SOD1, TARDBP, TBK1, NEK1, UBQLN2, and CCNF. In addition, UNC13A rs12608932 CC genotype and ZNF521B rs2275294 C allele also caused a shorter survival of ALS; however, APOE ε4 allele and KIFAP3 rs1541160 did not be found to have any effect on the survival of ALS.Conclusions: Our study summarized and contrasted evidence for prognostic genetic factors in ALS and would help to understand ALS pathogenesis and guide clinical trials and drug development. [ABSTRACT FROM AUTHOR]

The proline-rich transmembrane protein 2 ( PRRT2) gene has been recently identified as a causative gene of paroxysmal kinesigenic dyskinesia (PKD), with an insertion mutation c.649_650insC (p.P217fsX7) reported as the most common mutation. However, the pathogenic mechanism of the mutation of PRRT2 remains largely unknown. Resting-state functional magnetic resonance imaging is a promising approach to assess cerebral function and reveals underlying functional changes. Resting-state functional magnetic resonance imaging was performed in 4 Chinese PKD patients with p.P217fsX7 mutation, 6 Chinese PKD patients without the mutation, and 10 healthy control subjects. Voxel-based analysis was used to characterize alterations in the amplitude of low-frequency fluctuation (ALFF). When compared with the healthy control subjects, both groups of PKD patients showed alterations in spontaneous brain activities within cortical–basal ganglia circuitry. Besides, the group of patients with p.P217fsX7 mutation also exhibited increased ALFF in the right postcenral gyrus and right rolandic operculum area, while the alteration of ALFF in group of patients without the mutation additionally involved the middle orbitofrontal cortex. Direct comparative analysis between these two patient groups revealed significantly increased ALFF in the right postcentral gyrus in the group with p.P217fsX7 mutation. Increased spontaneous brain activity in the cortical–basal ganglia circuitry, especially in the motor preparation areas, is a common pathophysiology in PKD. Differences in the spatial patterns of increased ALFF between patients with and those without the mutation might reflect the distinct pathological mechanism resulting from PRRT2 mutation. [ABSTRACT FROM AUTHOR]

Oxidative stress is involved in the pathogenesis of multiple system atrophy (MSA). Uric acid has an antioxidative effect. Our aim is to clarify the correlations between serum uric acid and MSA in Chinese population. A total of 234 patients with probable MSA and 240 age- and gender- matched healthy controls were included in the study. The serum uric acid levels of all the patients and controls were evaluated. The Unified MSA Rating Scale (UMSARS) was used to assess the severity and the mean rate of annualized changes of UMSARS to assess the progression of MSA. The mean age of MSA patients was 58.90 ± 9.00 years and the mean disease duration was 2.60 ± 1.75 years. The serum uric acid levels of MSA patients were significantly lower than that of controls in males ( p = 0.0001). The occurrence of MSA was increased in the lowest uric acid quartiles compared with the highest uric acid quartiles ( p = 0.005). In a gender-specific analysis, increased occurrence was found in the lowest quartiles and second quartiles compared with the highest quartiles in males ( p = 0.001 and p = 0.0001 respectively), but not in females. No correlation was found between the mean rate of annualized changes and serum levels of uric acid, as well as other independent factors, such as age, BMI, gender, subtype (C-type or P-type) and disease duration at the initial visit in 107 followed-up patients. MSA patients have lower levels of serum uric acid than controls. High levels of serum uric acid may be associated with a lower prevalence of MSA in the Chinese population, especially in males. However, serum uric acid does not deteriorate or ameliorate the progression of MSA. [ABSTRACT FROM AUTHOR]

Chorea-acanthocytosis is a rare autosomal recessive disorder. To date, treatment is only symptomatic and supportive. Results from the few reports of chorea-acanthocytosis patients treated with deep brain stimulation (DBS) have been inconsistent. We present case reports for two patients with chorea-acanthocytosis who received DBS treatment and compare the outcomes with results from the literature. Both patients showed the typical clinical features of chorea-acanthocytosis with motor symptoms resistant to medical treatment. Chorea was significantly improved following low-frequency DBS treatment in both patients. However, dystonia was only mildly improved. Four chorea-acanthocytosis patients treated with DBS treatment have been reported in the literature. One patient had improvement with low-frequency DBS stimulation, while another two had improvement with higher-frequency DBS. One patient, however, did not improve with either low-frequency or high-frequency DBS. Bilateral DBS to the GPi can improve chorea and dystonia in some patients with intractable chorea-acanthocytosis. However, selection criteria for the most promising candidates must be defined, and the long-term benefits evaluated in clinical studies. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a heterogeneous group of fatal neurodegenerative diseases characterized by a selective loss of motor neurons in the brain and spinal cord. Creation of transgenic mice expressing mutant Cu/Zn superoxide dismutase (SOD1), as ALS models, has made an enormous impact on progress of the ALS studies. Recently, it has been recognized that genetic background and gender affect many physiological and pathological phenotypes. However, no systematic studies focusing on such effects using ALS models other than SOD1G93A mice have been conducted. To clarify the effects of genetic background and gender on gross phenotypes among different ALS models, we here conducted a comparative analysis of growth curves and lifespans using congenic lines of SOD1G93A and SOD1H46R mice on two different genetic backgrounds; C57BL/6N (B6) and FVB/N (FVB). Copy number of the transgene and their expression between SOD1G93A and SOD1H46R lines were comparable. B6 congenic mutant SOD1 transgenic lines irrespective of their mutation and gender differences lived longer than corresponding FVB lines. Notably, the G93A mutation caused severer disease phenotypes than did the H46R mutation, where SOD1G93A mice, particularly on a FVB background, showed more extensive body weight loss and earlier death. Gender effect on survival also solely emerged in FVB congenic SOD1G93A mice. Conversely, consistent with our previous study using B6 lines, lack of Als2, a murine homolog for the recessive juvenile ALS causative gene, in FVB congenic SOD1H46R, but not SOD1G93A, mice resulted in an earlier death, implying a genetic background-independent but mutation-dependent phenotypic modification. These results indicate that SOD1G93A- and SOD1H46R-mediated toxicity and their associated pathogenic pathways are not identical. Further, distinctive injurious effects resulted from different SOD1 mutations, which are associated with genetic background and/or gender, suggests the presence of several genetic modifiers of disease expression in the mouse genome. [ABSTRACT FROM AUTHOR]

This study mainly focused on investigating listening strategy uses at different proficiency levels for different linguistic patterns. Three main questions were examined in regards to Taiwanese listeners of English as a foreign language (EFL): (1) For listeners with different proficiency levels, which pattern may result in a higher level of listening comprehension when the negative, functional, and contrary-to-fact statements are used? (2) Are there any significant differences between item type and proficiency level? (3) What are the differences and frequency in listening strategy use reported by individual listeners? To explore the above issues, a quantitative research method was applied, including a self-perceived survey, a t-test technique, and an analysis of variance. Results of this study demonstrate that listeners with both advanced and beginning proficiency levels yielded higher scores on contrary-to-fact statements, followed by functional expression and then negative expression. Advanced proficiency listeners mostly used the combination of various strategies when listening to contrary-to-fact statements, while beginning-level listeners heavily employed memory strategies when listening to negative expression. Implications for EFL educators to recognize the directions of instructional practices for enhancing listening comprehension are presented. [ABSTRACT FROM AUTHOR]

This study focused on examining the overall effect of using email on the improvement of writing performance in aspects of syntactic complexity, grammatical accuracy and lexical density, as well as investigating the relation between the number of email exchanges and writing performance. Subjects in this study were 40 non-traditional EFL students enrolled in an intermediate reading class at a university in Taiwan. By applying qualitative and quantitative research methods, the major finding demonstrates that students made improvements on syntactic complexity and grammatical accuracy. An increase in lexical density, however, was not observed in this study. Another finding suggests that exchanging email messages with their peers at least four times might have a greater overall improvement on their writing performance. Findings from students' self-reports reveal that the email approach was a positive strategy that helped improve students' foreign language learning and attitudes towards English. Instructional implications for designing an effective email task to enhance foreign language writing development and attitudes are also presented. [ABSTRACT FROM AUTHOR]

Typical clinical manifestations of MNGIE include severe gastrointestinal dysmotility, cachexia, ptosis and external ophthalmoplegia, sensorimotor neuropathy, and leukoencephalopathy. However, whether multiple intracranial hemorrhages are primary in MNGIE or secondary to other unclear causes should be elucidated by the longitudinal brain imaging study in a large MNGIE cohort. [Extracted from the article]

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by a selective loss of upper and lower motor neurons. Recent studies have shown that mutations in SQSTM1 are linked to ALS. SQSTM1 encodes SQSTM1/p62 that regulates not only autophagy via the association with MAP1LC3/LC3 and ubiquitinated proteins but also the KEAP1-NFE2L2/Nrf2 anti-oxidative stress pathway by interacting with KEAP1. Previously, we have demonstrated that loss of SQSTM1 exacerbates disease phenotypes in a SOD1H46R-expressing ALS mouse model. To clarify the effects of SQSTM1 overexpression in this model, we generated SQSTM1 and SOD1H46R double-transgenic (SQSTM1;SOD1H46R) mice. SQSTM1;SOD1H46R mice exhibited earlier disease onset and shorter lifespan than did SOD1H46R mice. Conversely, disease progression after the onset rather slightly but significantly slowed in SQSTM1;SOD1H46R mice. However, there were observable differences neither in the number of Nissl positive neurons nor in the distribution of ubiquitin-positive and/or SQSTM1-positive aggregates between SOD1H46R and SQSTM1;SOD1H46R mice. It was noted that these protein aggregates were mainly observed in neuropil, and partly localized to astrocytes and/or microglia, but not to MAP2-positive neuronal cell bodies and dendrites at the end-stage of disease. Nonetheless, the biochemically-detectable insoluble SQSTM1 and poly-ubiquitinated proteins were significantly and progressively increased in the spinal cord of SQSTM1;SOD1H46R mice compared to SOD1H46R mice. These results suggest that overexpression of SQSTM1 in SOD1H46R mice accelerates disease onset by compromising the protein degradation pathways. [ABSTRACT FROM AUTHOR]

Background: Little is known about the impact of the COVID-19 pandemic on patients with Parkinson's disease (PD) at different stages of the pandemic. This study aims to assess the lives and disease status of PD patients during the zero-COVID policy period and after ending the zero-COVID policy. Methods: This multicenter cross-sectional study included two online surveys among PD patients in China, from May 30 to June 30 in 2022 and from January 1 to February 28 in 2023, respectively. The survey questionnaires contained four sections: (1) status of COVID-19 infection; (2) impact on motor and non-motor symptoms; (3) impact on daily and social lives; and (4) impact on PD disease management. Results: A total of 1764 PD patients participated in the first online survey, with 200 patients having lockdown experience and 3 being COVID-19-positive (0.17%). In addition, 537 patients participated in the second online survey, with 467 patients having COVID-19 infection (86.96%). (1) During zero-COVID, all of the COVID-19-positive patients had mild symptoms of COVID-19 and no death was reported. After zero-COVID, 83.51% of the COVID-19-positive patients had mild symptoms. The overall death rate and inpatient mortality rate of COVID-19-positive PD patients were 3.21% and 30.00%, respectively. (2) During zero-COVID, 49.43% of PD patients reported worsening of PD-related symptoms (lockdown vs. unlockdown, 60.50% vs. 48.02%, P = 0.0009). After zero-COVID, 54.93% of PD patients reported worsening of PD-related symptoms (COVID-19 positive vs. COVID-19 negative, 59.31% vs. 25.71%, P < 0.0001). (3) During zero-COVID, 62.36% of patients felt worried, and 'limited outdoor activities' (55.39%) was the top reason for mental health problems. After zero-COVID, 59.03% of patients felt worried, with 'poor health' (58.10%) being the top reason. The PD patients tended to change their daily activities from offline to online, and their economic and caregiver burdens increased both during and after zero-COVID. (4) Most PD patients would like to choose online rehabilitation during (69.56%) and after zero-COVID (69.27%). The demand for online medication purchasing also increased during (47.00%) and after zero-COVID (26.63%). Conclusions: The COVID-19 pandemic aggravated the motor and non-motor symptoms of PD patients either during or after the zero-COVID policy period. The PD patients also experienced prominent mental health problems, changes in daily activities, and increases in economic and caregiver burdens. The COVID-19 pandemic has changed ways of PD management with increasing demands for online medication purchasing and rehabilitation. [ABSTRACT FROM AUTHOR]

Background and aim: Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder caused by CAG repeats expansion. Cognitive decline contributes to the loss of daily activity in manifest HD. We aimed to examine the cognition status in a Chinese HD cohort and explore factors influencing the diverse cognitive domains. Methods: A total of 205 participants were recruited in the study with the assessment by neuropsychological batteries, including the mini–mental state examination (MMSE), Stroop test, symbol digit modalities test (SDMT), trail making test (TMT), verbal fluency test (VFT), and Hopkins verbal learning test–revised, as well as motor and psychiatric assessment. Pearson correlation and multiple linear regression models were applied to investigate the correlation. Results: Only 41.46% of patients had normal global function first come to our center. There was a significantly difference in MMSE, Stroop test, SDMT, TMT, and VFT across each stage of HD patients (p <.05). Apathy of PBA‐s was correlated to MMSE, animal VFT and Stroop‐interference tests performance. Severity of motor symptoms, functional capacity, age, and age of motor symptom onset were correlated to all neuropsychological scores, whereas education attainment and diagnostic delay were correlated to most neuropsychological scores except TMT. Severity of motor symptoms, functional capacity, and education attainment showed independent predicting effect (p <.05) in diverse cognitive domains. Conclusion: Cognitive impairment was very common in Chinese HD patients at the first visit and worse in the patients in advanced phase. The severity of motor symptoms and functional capacity were correlated to the diverse cognitive domains. [ABSTRACT FROM AUTHOR]

Background: Genetic studies have indicated that variants in several lysosomal genes are risk factors for idiopathic Parkinson's disease (PD). However, the role of lysosomal genes in PD in Asian populations is largely unknown. Objective: This study aimed to analyze rare variants in lysosomal related genes in Chinese population with early-onset and familial PD. Methods: In total, 1,136 participants, including 536 and 600 patients with sporadic early-onset PD (SEOPD) and familial PD, respectively, underwent whole-exome sequencing to assess the genetic etiology. Rare variants in PD were investigated in 67 candidate lysosomal related genes (LRGs), including 15 lysosomal function-related genes and 52 lysosomal storage disorder genes. Results: Compared with the autosomal dominant PD (ADPD) or SEOPD cohorts, a much higher proportion of patients with multiple rare damaging variants of LRGs were found in the autosomal recessive PD (ARPD) cohort. At a gene level, rare damaging variants in GBA and MAN2B1 were enriched in PD, but in SCARB2, MCOLN1, LYST, VPS16, and VPS13C were much less in patients. At an allele level, GBA p. Leu483Pro was found to increase the risk of PD. Genotype-phenotype correlation showed no significance in the clinical features among patients carrying a discrepant number of rare variants in LRGs. Conclusion: Our study suggests rare variants in LRGs might be more important in the pathogenicity of ARPD cases compared with ADPD or SEOPD. We further confirm rare variants in GBA are involve in PD pathogenecity and other genes associated with PD identified in this study should be supported with more evidence. [ABSTRACT FROM AUTHOR]

Background: Camptocormia is common in patients with multiple system atrophy (MSA). The current study was aimed at assessing the frequency of camptocormia and its related factors in MSA patients with different disease durations. Also, the impact of camptocormia on disability was evaluated.Methods: A total of 716 patients were enrolled in the study. They were classified into three groups based on disease duration (≤ 3, 3-5, ≥ 5 years). Specific scales were used to evaluate the motor and non-motor symptoms. Disease severity was assessed using the Unified Multiple System Atrophy Rating Scale (UMSARS). The binary logistic regression model was used to explore the factors related to camptocormia. To analyze the impact of camptocormia on disability in patients with disease duration less than 5 years, propensity score matching (PSM) and stratified Cox regression analysis were used.Results: In the current study, we found that the frequency of camptocormia was 8.9, 19.7 and 19.2% when the disease duration was ≤3, 3-5, ≥ 5 years, respectively. In the disease duration ≤3 years group, we found that MSA-parkinsonian subtype (MSA-P) (OR = 2.043, P = 0.043), higher total UMSARS score (OR = 1.063, P < 0.001), older age of onset (OR = 1.047, P = 0.042), and lower score on the frontal assessment battery (FAB) (OR = 0.899, P = 0.046) were associated with camptocormia. Only greater disease severity was associated with camptocormia in the group of patients with disease duration 3-5 years (OR = 1.494, P = 0.025) and in the group of patients with disease duration ≥5 years (OR = 1.076, P = 0.005). There was no significant impact of camptocormia on disability in patients with a disease duration of < 5 years (HR = 0.687, P = 0.463).Conclusion: The frequency of camptocormia increased with prolonged disease duration. Disease severity was related to camptocormia at different stages of the disease. The MSA-P subtype, older age of onset, and lower FAB score were associated with camptocormia in the early stage of the disease. [ABSTRACT FROM AUTHOR]

Background: Epidemiological and clinical studies have suggested comorbidity between amyotrophic lateral sclerosis (ALS) and autoimmune disorders. However, little is known about their shared genetic architecture.Methods: To examine the relation between ALS and 10 autoimmune diseases, including asthma, celiac disease (CeD), Crohn's disease (CD), inflammatory bowel disease (IBD), multiple sclerosis (MS), psoriasis, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), and ulcerative colitis (UC), and identify shared risk loci, we first estimated the genetic correlation using summary statistics from genome-wide association studies, and then analyzed the genetic enrichment leveraging the conditional false discovery rate statistical method.Results: We identified a significant positive genetic correlation between ALS and CeD, MS, RA, and SLE, as well as a significant negative genetic correlation between ALS and IBD, UC, and CD. Robust genetic enrichment was observed between ALS and CeD and MS, and moderate enrichment was found between ALS and UC and T1D. Thirteen shared genetic loci were identified, among which five were suggestively significant in another ALS GWAS, namely rs3828599 (GPX3), rs3849943 (C9orf72), rs7154847 (G2E3), rs6571361 (SCFD1), and rs9903355 (GGNBP2). By integrating cis-expression quantitative trait loci analyses in Braineac and GTEx, we further identified GGNBP2, ATXN3, and SLC9A8 as novel ALS risk genes. Functional enrichment analysis indicated that the shared risk genes were involved in four pathways including membrane trafficking, vesicle-mediated transport, ER to Golgi anterograde transport, and transport to the Golgi and subsequent modification.Conclusions: Our findings demonstrate a specific genetic correlation between ALS and autoimmune diseases and identify shared risk loci, including three novel ALS risk genes. These results provide a better understanding for the pleiotropy of ALS and have implications for future therapeutic trials. [ABSTRACT FROM AUTHOR]

1·8 billion people of diverse ethnicities and cultures live in the Western Pacific Region. The increasing longevity of populations in this region is a major contributor to the exponential increase in Parkinson's disease prevalence worldwide. Differences exist between Parkinson's disease in the Western Pacific Region and in Europe and North America that might provide important insights into our understanding of the disease and approaches to management. For example, some genetic factors (such as LRRK2 mutations or variants) differ, environmental exposures might play differential roles in modulating the risk of Parkinson's disease, and fewer dyskinesias are reported, with some differences in the profile of non-motor symptoms and comorbidities. Gaps in awareness of the disease and inequitable access to treatments pose challenges. Further improvements in infrastructure, clinical governance, and services, and concerted collaborative efforts in training and research, including greater representation of the Western Pacific Region in clinical trials, will improve care of patients with Parkinson's disease in this region and beyond. [ABSTRACT FROM AUTHOR]

In addition, of the 232 patients who received DRT for more than 5 years, 69 patients (29.7%, 69/232) developed LIDs in the first 5 years of DRT. In a previous study, the incidence of LIDs has been reported to be 21.7% in Chinese LOPD patients [[5]], suggesting that the LIDs are common in EOPD, and EOPD patients are susceptible to the development of LIDs. Main text The levodopa-induced dyskinesias (LIDs) in Parkinson' disease (PD) patients during levodopa treatment can lead to significant disability. [Extracted from the article]

Highlights • Four GWAS-identified loci in Alzheimer's disease don't contribute to PD, ALS, and MSA risk in a Chinese population. • Rs28834970 in the PTK2B gene may modulate the phenotype of cognitive function in PD. • No significant differences were found in MAFs between these variants and the different subgroups in different diseases. Abstract Background A number of genetic variants have previously been identified and associated with the risk of Alzheimer's disease (AD), including rs10838725 in CELF1 , rs28834970 in PTK2B , rs17125944 in FERMT2, and rs10410544 in SIRT2 based on genome-wide association studies. Considering the overlap between the clinical manifestation and pathological characteristics of AD and Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple system atrophy (MSA), we conducted a large sample study to investigate the associations between these variants and these three common neurodegenerative diseases in a Chinese population. Methods A total of 2449 patients, including 1219 PD, 870 sporadic ALS, and 360 MSA, and 821 healthy controls were examined for this study. All cases were genotyped for single-nucleotide polymorphisms using Sequenom iPLEX assay technology. Results No significant differences were found in genotype distribution and minor allele frequencies between the four candidate variants and the three neurodegenerative diseases. However, a significant difference was found in the minor allele frequency of rs28834970 in PTK2B between PD patients with normal and abnormal cognitive function (p = 0.001). Moreover, the minor allele "C" was associated with an increased risk for cognitive impairment in PD (OR = 1.84). Although this observation was not significant (p = 0.064), the mean Addenbrooke's Cognitive Examination-Revised (ACER) score of PD patients with the risk allele of rs28834970 was 2.913 ± 1.569 points lower than that of PD patients without the risk allele. Conclusion This study provides new insight into some of the phenotypes that may share the common pathogenesis of different neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: Resting tremor is one of the cardinal motor features of Parkinson's disease (PD). Several lines of evidence suggest resting tremor may have different underlying pathophysiological processes from those of bradykinesia and rigidity. The current study aims to identify white matter microstructural abnormalities associated with resting tremor in PD. Methods: We recruited 60 patients with PD (30 with tremor-dominant PD and 30 with nontremor-dominant PD) and 26 normal controls. All participants underwent clinical assessment and diffusion tensor MRI. We used tract-based spatial statistics to investigate white matter integrity across the entire white matter tract skeleton. Results: Compared with both healthy controls and the nontremor-dominant PD patients, the tremor-dominant PD patients were characterized by increased mean diffusivity (MD) and axial diffusivity (AD) along multiple white matter tracts, mainly involving the cerebello-thalamo-cortical (CTC) pathway. The mean AD value in clusters with significant difference was correlated with resting tremor score in the tremor-dominant PD patients. There was no significant difference between the nontremor-dominant PD patients and controls. Conclusion: Our results support the notion that resting tremor in PD is a distinct condition in which significant microstructural white matter changes exist and provide evidence for the involvement of the CTC in tremor genesis of PD. [ABSTRACT FROM AUTHOR]

Background The vesicular monoamine transporter type 2 ( VMAT2 ) and transmembrane Protein 106B ( TMEM106B ) were reported to be associated with neurodegenerative diseases. Recent studies found that two polymorphisms (rs363371 and rs363324) in VMAT2 might be a risk factor for Parkinson's disease (PD) in Caucasians, while the two other variants (rs1990622 and rs3173615) in TMEM106B increased the risk for frontotemporal dementia (FTD). Considering the overlap between clinical manifestation and pathologic characteristics in neurodegenerative diseases, we conducted a large-sample study to investigate the associations between these four polymorphisms and the risk for PD, sporadic amyotrophic lateral sclerosis (SALS), and multiple system atrophy (MSA) in a Chinese patient population. Methods A total of 1121 PD, 863 SALS, and 356 MSA patients, as well as 829 healthy controls (HCs), were included in the study. These four polymorphisms were genotyped using Sequenom iPLEX Assay technology. Results Significant differences were found in the genotype distribution of VMAT2 rs363371 between SALS patients and HCs ( p = 0.001). In an additive model, “GG” of rs363371 significantly decreased the risk for SALS ( p < 0.001, OR: 0.49, 95% CI [0.36–0.67]). The frequencies of minor alleles for rs1990622 and rs3173615 in TMEM106B were significantly different between PD patients with initial symptoms of tremor and rigidity/bradykinesia ( p = 0.001), and between patients with initial symptom of rigidity/bradykinesia and HCs ( p < 0.001). The minor alleles “T” of rs1990622 and “C” of rs3173615 increased the risk for PD patients with initial symptom of rigidity/bradykinesia (OR: 1.21[1.10–1.34] and OR: 1.19[1.07–1.31], respectively). No differences were found in the genotype distribution and allele frequency of the four polymorphisms between MSA patients and HCs. Conclusion In this Chinese patient population, “GG” of rs363371 in VMAT2 may reduce the risk for SALS, while minor alleles of rs1990622 and rs3173615 in TMEM106B may be associated with PD patients with initial symptom of rigidity/bradykinesia. [ABSTRACT FROM AUTHOR]

The hexanucleotide repeat expansions in the C9ORF72 gene has been found in some patients with atypical Parkinsonism. A number of hexanucleotide repeats were examined in a Chinese population, including 619 patients with Parkinson's disease (PD), 381 patients with multiple system atrophy (MSA), and 632 healthy controls. We did not identify any pathogenic repeat expansions in either patients or controls, and any associations between repeats number and disease risk. C9ORF72 expansions are not involved the wider spectrum of Parkinsonism. [ABSTRACT FROM AUTHOR]

To shed more light on the contribution of brain structural changes to PD-related depressive symptoms, this study conducted cortical thickness analysis in drug-naive PD patients with and without depression. We recruited 27 PD patients with depression (PD-Dep), 29 PD patients without depression (PD-NDep), and 56 normal controls. T1 weighted magnetic resonance imaging and surface-based morphometric analyses were performed to examine morphometric abnormalities in PD patients and their relationship to depression. We found decreased thickness in the left prefrontal cortex in PD-Dep group compared with PD-NDep group. No significant difference was found between PD patients and controls. In addition, we found there is a trend of inverse correlation between the structural changes and the score of depressive symptom in depressed PD patients. This study demonstrates that cortical thinning in prefrontal area in drug-naive PD patients with depression and highlights the critical role of prefrontal region in the depression associated with PD. [ABSTRACT FROM AUTHOR]

Neuroimaging holds the promise that it may one day aid the clinical assessment. However, the vast majority of studies using resting-state functional magnetic resonance imaging (fMRI) have reported average differences between Parkinson's disease (PD) patients and healthy controls, which do not permit inferences at the level of individuals. This study was to develop a model for the prediction of PD illness severity ratings from individual fMRI brain scan. The resting-state fMRI scans were obtained from 84 patients with PD and the Unified Parkinson's Disease Rating Scale-III (UPDRS-III) scores were obtained before scanning. The RVR method was used to predict clinical scores (UPDRS-III) from fMRI scans. The application of RVR to whole-brain resting-state fMRI data allowed prediction of UPDRS-III scores with statistically significant accuracy (correlation = 0.35, P-value = 0.001; mean sum of squares = 222.17, P-value = 0.002). This prediction was informed strongly by negative weight areas including prefrontal lobe and medial occipital lobe, and positive weight areas including medial parietal lobe. It was suggested that fMRI scans contained sufficient information about neurobiological change in patients with PD to permit accurate prediction about illness severity, on an individual subject basis. Our results provided preliminary evidence, as proof-of-concept, to support that fMRI might be possible to be a clinically useful quantitative assessment aid in PD at individual level. This may enable clinicians to target those uncooperative patients and machines to replace human for a more efficient use of health care resources. [ABSTRACT FROM AUTHOR]

Background The association between the polymorphism rs3794087 in the solute carrier family 1, member 2 ( SLC1A2 ) and the risk of essential tremor (ET) among different studies is controversial. Considering the overlap of the clinical manifestations and pathological characteristics of ET, Parkinson's disease (PD), multiple system atrophy (MSA), as well as amyotrophic lateral sclerosis (ALS), we explored the possible genetic association of rs3794087 with ET, PD, MSA and ALS in a Chinese cohort. Methods A total of 112 ET, 621 PD, 356 MSA, 513 sporadic ALS (SALS) patients and 437 healthy controls (HCs) were genotyped for rs3794087 using the Sequenom iPLEX Assay technology. Results Significant association was found between SLC1A2 rs3794087 and PD in the additive model ( p = 0.006), which was more obvious in early onset PD. The minor allele of rs3794087 decreased the risk for early onset PD ( p = 0.011, OR: 0.73, 95% CI: 0.56–0.94). However, no significant differences in the genotype distributions and allele frequency were observed in the allelic, additive, dominant or recessive genetic models of SLC1A2 rs3794087 between ET patients and HCs, between SALS patients and HCs, and between MSA and HCs. Conclusions Our results suggested SLC1A2 rs3794087 may decrease the risk for PD in a Chinese cohort, but do not support a role in the susceptibility to SALS or MSA. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background and objective Oxidative stress is involved in the pathogenesis of multiple system atrophy (MSA) and cognitive impairment. Uric acid has an anti-oxidative effect. Our objective is to clarify the correlations between serum uric acid and cognitive function as well as frontal lobe function in Chinese MSA patients. Methods All of MSA patients were evaluated using Addenbrooke's Cognitive Examination-Revised (ACE-R), Frontal Assessment Battery (FAB), and Unified MSA Rating Scale (UMSARS). The fasting serum uric acid concentrations of MSA patients were measured. Results A total of 89 probable MSA patients with a mean age of 58.6 ± 10.0 years old and disease duration of 2.6 ± 1.5 years were included. Thirty-three patients (37.1%) had global cognitive deficits according to ACE-R. Based on FAB, 35 patients (39.3%) had frontal lobe dysfunction. After adjusting for educational years, patients with cognitive deficits had lower uric acid level than patients without cognitive deficits. Patients with frontal lobe dysfunction had lower uric acid level after adjusting for UMSARS scores. In a forward multiple linear regression, uric acid level and educational years were the variables predicting the ACE-R score (F = 36.540, R 2 = 0.459, p = 0.0001), uric acid accounting for 14% of the total variables. Uric acid was the only variable contributing to the FAB score (F = 18.551, R 2 = 0.176, p = 0.0001). Conclusion Our study suggested that low level of serum uric acid was associated with cognitive deficits in MSA. Low uric acid level predicting cognitive decline in MSA needs more studies. [ABSTRACT FROM AUTHOR]

Although rs75932628 in triggering receptor expressed on myeloid cells 2 (TREM2) was shown to increase the risk for Alzheimer's disease, there is no agreement on the association between this variant and the risk for Parkinson's disease (PD). Considering the overlapping of clinical manifestation and pathologic characteristics of PD and multiple system atrophy (MSA), we conducted a large-sample study to investigate the associations between this variant and these two neurodegenerative diseases in a Chinese population. A total of 1216 PD, 406 MSA patients, and 869 healthy controls were included. All cases were genotyped for the Single Nucleotide Polymorphisms (SNP) using Sequenom iPLEX Assay technology. The rs75932628-T variant of the TREM2 gene was not identified in PD patients and controls. The genotype frequency of rs75932628-T SNP in MSA patients was 0.25% (1/406). However, no significant correlation was identified between this variant and the risk for MSA. TREM2 rs75932628 is unlikely to play a major role in the pathogenesis of these neurodegenerative diseases. Our findings argue against a generalized immune dysfunction triggered by the variant in the TREM2 gene. [ABSTRACT FROM AUTHOR]

Objective We aim to investigate the disturbance of neural network associated with the different clinical stages of Parkinson's disease (PD). Method We recruited 80 patients at different H&Y stages of PD (28 at H&Y stage I, 28 at H&Y stage II, 24 at H&Y stage III) and 30 normal controls. All participants underwent resting-state fMRI scans on a 3-T MR system. The amplitude of low-frequency fluctuation (ALFF) of blood oxygen level-dependent signals was used to characterize regional cerebral function. Functional integration across the brain regions was evaluated by a seed voxel correlation approach. Results PD patients had decreased regional activities in left occipital and lingual regions; these regions show decreased functional connection pattern with temporal regions, which is deteriorating as H&Y stage ascending. In addition, PD patients, especially those at stage II, exhibit increased regional activity in the posterior regions of default mode network (DMN), increased anticorrelation between posterior cingulate cortex (PCC) and cortical regions outside DMN, and higher temporal coherence within DMN. Those indicate more highly functioned DMN in PD patients at stage II. Conclusions Our study demonstrated the trajectories of resting-state cerebral function disturbance in PD patients at different H&Y stages. Impairment in functional integration of occipital-temporal cortex might be a promising measurement to evaluate and potentially track functional substrates of disease evolution of PD. Hum Brain Mapp 36:3104-3116, 2015. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The purpose of this study is to investigate whether the topological organization of whole-brain functional network is disrupted in patients with Parkinson's disease (PD). We employed resting-state functional MRI (R-fMRI) and graph theory to investigate the topological organization of the functional connectome in 47 early-stage drug-naïve PD patients and 47 healthy control subjects. Correlations between network properties and clinical variables were tested. Both the PD and control groups showed small-world architecture in brain functional networks. However, the PD patients had lower clustering coefficient and local efficiency relative to control subjects, indicating disrupted topologic organization and a shift toward randomization in their functional brain network. At node and connection level, reduced node centralities and connectivity strength were found mainly in temporal-occipital regions and also in sensorimotor regions of PD patients. In PD patients, altered global network properties correlated with cognitive function, while motor impairment was correlated with local connection changes. This study demonstrates a disruption of whole-brain topological organization of the functional brain networks in early-stage drug-naïve PD patients and this disruption might contribute to preclinical changes in cognitive process in these patients. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective loss of motor neurons in the brain and spinal cord. Recent studies have shown that mutations in SQSTM1 are linked to ALS. It has also been demonstrated that a systemic loss of SQSTM1 exacerbates disease phenotypes in an ALS mouse model. However, it is still unclear whether and how SQSTM1 in the central nervous system (CNS) specifically regulates ALS-associated disease phenotypes. To address this issue, we generated CNS-specific Sqstm1 deficient SOD1H46R transgenic mice, and conducted gross phenotype analyses as well as the immunohistochemical and biochemical examinations of spinal cord tissues using these mice. CNS-specific SQSTM1 deficiency accelerated the disease onset and shortened the lifespan of SOD1H46R mice. The CNS-specific SQSTM1 ablation also resulted in increased number of ubiquitin-positive aggregates, while their size rather became much smaller. Remarkably, ubiquitin-positive aggregates, which were usually present in extracellular space and/or neuropil in SOD1H46R mice, were preferentially localized to soma and neurites of spinal neurons in CNS-specific SQSTM1 deficient SOD1H46R mice. Next, to further clarify the function of SQSTM1 in neurons, we investigated the contribution of SQSTM1 to the accumulation of polyubiquitinated proteins in relation to the ubiquitin proteasome system (UPS) and the autophagy-endolysosomal system (APELS) in primary cultured motor neurons (PMNs). Loss of SQSTM1 in PMNs resulted in decreased accumulation of insoluble polyubiquitinated proteins, which was induced by simultaneous treatment with proteasome and lysosome inhibitors, suggesting a pivotal role of SQSTM1 in the formation of insoluble protein aggregates. However, SQSTM1 silencing had a limited impact on the susceptibility to proteasome and/or lysosome inhibitor-induced apoptosis in PMNs. Taken together, neuronal SQSTM1, whose functions are associated with both the UPS and APELS, might primarily regulate the distribution and accumulation of misfolded protein aggregates in the CNS, thereby protecting neurons from degeneration in mice. • CNS-specific loss of SQSTM1 exacerbates the onset of ALS mice. • SQSTM1 regulates the distribution of ubiquitin-positive aggregates in spinal cord. • SQSTM1 facilitates the formation of insoluble polyubiquitinated proteins in cells. • SQSTM1 has a limited impact on apoptosis in proteolytically-stressed neurons. • SQSTM1 is implicated in the formation of disease protective protein aggregates. [ABSTRACT FROM AUTHOR]

Abstract: Background: The determinants of the quality of life (QoL) of patients with Parkinson's disease (PD) in Chinese population remain largely unknown. Methods: A total of 649 PD patients from Southwest China participated in this cross-sectional study. Non-motor Symptoms Scale (NMSS) was used to evaluate the non-motor symptoms (NMS), whereas PD Quality of Life Questionnaire (PDQ-39) was used to assess the QoL of the PD patients. Multiple stepwise regression analysis was conducted to identify the determinants of the QoL. Results: NMS, H–Y stage, female, disease duration, UPDRS III score, single/divorced/widowed, and motor complications accounted for 66.3% of the variables in the multiple regression analysis and were the negative determinants of the QoL. Among these variables, NMS and H–Y stage accounted for 46.7% and 14.5%, respectively. NMS were closely associated with each domain of PDQ-39. Female sex especially predicted poor emotional well-being and bodily discomfort, whereas single/divorced/widowed especially predicted poor stigma and social support of PD patients. Comorbidity, motor complications and rural living predicted poor mobility, activities of daily living and emotional well-being, respectively. Conclusion: Both demographic and disease-specific factors influence the QoL in PD patients. NMS are the strongest independent negative determinant of the overall QoL and closely associated with each domain of PDQ-39. The treatment of NMS may help to improve the QoL of PD patients. [Copyright &y& Elsevier]

Abstract: The goal of this study was to describe Parkinson׳s disease (PD)-related modulation of functional connectivity (FC) associated with the striatum in the resting state in a nonhuman primate model of early-stage PD. Weekly intravenous injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (0.5mg/kg body weight) were performed until parkinsonian motor symptoms developed in four macaques. After 13 weeks of MPTP treatment, all monkeys displayed parkinsonian symptoms. During the course of the experiment, each animal underwent four magnetic resonance imaging scans and four positron emission tomography (PET) scans with the vesicular monoamine transporter 2 (VMAT2)-selective ligand 9-[18F] fluoropropyl-(+)-dihydrotetrabenazine, performed prior to the beginning of MPTP administration as well as after 4, 9, and 13 MPTP injections. The FC profile of the striatum was evaluated using a seed voxel correlation approach and post hoc region of interest analysis on resting-state functional magnetic resonance imaging data. The PET images were subjected to region of interest analysis to examine brain regional reductions in VMAT2 density in the PD model. Significant reductions in the connectivity pattern of the striatal regions were observed: limbic striatum and left hippocampus; caudate nucleus/associative and brain regions, including the right pre-supplementary motor area and bilateral dorsolateral prefrontal cortex; putamen/associative region and left inferior temporal gyrus or right orbital and medial prefrontal cortex; and putamen/motor and cortical structures, including the right superior temporal gyrus and bilateral postcentral gyrus. Subsequent PET studies showed the progressive loss of striatal VMAT2 in the striatum with the presentation of parkinsonism. Significant differences between the specific uptake ratio reductions in each striatal subdivision were not found. By using a long-term, low-dose MPTP-lesioned nonhuman primate model, this study demonstrated PD-related decreased corticostriatal FC in a resting state; moreover, altered sensorimotor integration was also found in early-stage PD. [Copyright &y& Elsevier]

Abstract: Although cardinal motor symptoms in Parkinson's disease (PD) are attributed to dysfunction of corticostriatal loops, early clinical nonmotor features are more likely to be associated with other pathologic mechanisms. We enrolled 52 early-stage drug-naive PD patients and 52 age- and sex-matched healthy controls and used resting-state functional connectivity magnetic resonance imaging to evaluate alteration of the functional brain network in PD, focusing in particular on the functional connectivity of the striatum subregions. Relative to healthy controls, the PD patient group showed reduced functional connectivity in mesolimbic-striatal and corticostriatal loops. Although the deceased functional connectivity within cortical sensorimotor areas was only evident in the most affected putamen subregion, reduced functional connectivity with mesolimbic regions was prevalent throughout the striatum. No increased functional connectivity was found in this cohort. By studying a cohort of early-stage drug-naive PD patients, we ruled out the potential confounding effect of prolonged antiparkinson medication use on the functional integration of neural networks. We demonstrate decreased functional integration across neural networks involving striatum, mesolimbic cortex, and sensorimotor regions in these patients and postulate that the prevalent disconnection in mesolimbic-striatal loops is associated with some early clinical nonmotor features in PD. This study offers additional insight into the early functional integration of neural networks in PD. [Copyright &y& Elsevier]

Abstract: Background: The impact of non-motor symptoms (NMS) on the Health-Related Quality of Life (HRQoL) of patients with Parkinson's disease (PD) in the Chinese population are largely unknown. Objectives: To study the impact of NMS on the HRQoL in Chinese PD patients. Methods: A total of 693 PD patients from Southwest China were included in the study. NMS of patients were evaluated by non-motor symptoms scale (NMSS) and Parkinson's disease questionnaire-39 item version (PDQ-39) was used to evaluate the HRQoL of PD. Results: The mean total score of NMSS was 37.2 ± 33.0 and the most prevalent NMS domain was sleep/fatigue (79.8%). There was a significant strong positive correlation between total NMSS score (r s = 0.71, P < 0.01), sleep/fatigue domain (r s = 0.60, P < 0.01) and PDQ-39 SI. Mood/apathy (r s = 0.55, P < 0.01), attention/memory (r s = 0.42, P < 0.01), gastrointestinal (r s = 0.44, P < 0.01) and Miscellany domains (r s = 0.46, P < 0.01) moderately correlated with PDQ-39 SI. A strong correlation was found between PDQ-39 SI (r s = 0.71, P < 0.01), emotional well-being (r s = 0.62, P < 0.01), cognitions (r s = 0.62, P < 0.01), and the total score of NMSS. Moderate correlation was found between mobility (r s = 0.45, P < 0.01), activities of daily living (r s = 0.43, P < 0.01), stigma (r s = 0.42, P < 0.01), communication (r s = 0.47, P < 0.01), bodily discomfort (r s = 0.46, P < 0.01) and the total score of NMSS. Female, H–Y stage, UPDRS-III and NMSS total score were the potential determinants of worse HRQoL of PD patients. Conclusions: NMS have close association with various aspects of the HRQoL. Severe NMS may be related to dramatic decline of the HRQoL of PD patients. [Copyright &y& Elsevier]

Highlights: [•] This is a study to identify the consistent GMV changes found by published individual studies. [•] This study demonstrates increased GM in bilateral prefrontal cortex and ACC in JME patients. [•] Moreover, decreased GM in bilateral thalamus was also identified in JME patients. [•] This study supported the notion of thalamocortical circuitry involved in the pathogenesis of JME. [Copyright &y& Elsevier]

Abstract: The differences in non-motor symptoms (NMS) along with the duration of Parkinson's disease (PD) in Chinese populations remain largely unknown. A total of 616 PD patients consisting of 189 patients with disease duration of less than 2years, 239 patients with duration between 2 and 5years, 122 patients with duration between 5 and 10years, and 66 patients with duration more than 10years from Southwest China were studied. Each patient was assessed using the non-motor symptoms scale (NMSS). The mean affected number of NMS was 8.8±5.8, and the mean total NMSS score was 36.3±33.2. The mean affected number of NMS and the mean total NMSS score increased with the disease progression. The following symptoms became more common and severe with the disease duration: falls due to fainting, fatigue, difficulty falling asleep, restless legs, perceptual problem/hallucination domain (i.e., “hallucinations,” “delusions,” and “double vision”), gastrointestinal domain (i.e., “dribbling saliva,” “swallowing,” and “constipation”), urinary domain (i.e., “urgency,” “frequency,” and “nocturia”), and miscellaneous domain (i.e., “excessive sweating”). However, some symptoms such as mood/apathy pleasure, sexual dysfunction, and others remained stable. NMS are prevalent in all disease duration of the Chinese PD patients. Although the mean affected number of NMS and NMMS score increased with the disease duration, NMS progression is symptom specific. [Copyright &y& Elsevier]

Abstract: Background: The deletion mutation of glutamate codon (GAG) in the TOR1A gene is a major cause of primary generalized dystonia. Recent genetic studies suggest that the rs1182 polymorphism in the same gene may represent a risk factor for primary dystonia. However, this finding has been inconsistent. Furthermore, no data on such an association in a Chinese population have been published. Methods: A total of 291 patients with primary dystonia from the Department of Neurology, West China Hospital of Sichuan University were included. From the same region, 294 healthy individuals were recruited as a control group. The SNP was identified by polymerase chain reaction–restriction fragment length polymorphism. Results: In the present study, focal dystonia was the most common presented form. No difference was found in the genotype frequency, minor allele frequencies, and “G” allele frequency between all dystonia patients and controls. No difference was found either, between early- and late-onset dystonia patients, patients with and without a positive family history, patients with pain and without pain, and patients with and without sensory trick. Moreover, no significant differences in the genotype and allele frequencies were found among different dystonia subtypes. Conclusion: No association of the rs1182 of TOR1A with Chinese primary dystonia was found. More studies on such an association involving a larger number of participants, especially from Asian populations, are needed to confirm the present findings. [Copyright &y& Elsevier]

Abstract: Background: Clinical presentation and DYT6/THAP1 mutations among Chinese patients with primary dystonia have not been well studied. Methods: Patients with primary pure dystonia from Southwest China who did not have a mutation in DYT1 exon 5 were included in the present study. Mutations of the THAP1 gene were screened by direct sequencing. Results: A total of 231 patients were examined. Cervical dystonia (58.47%) was found to be the most frequent form of focal dystonia. Novel heterozygous missense mutation [c.521A>G (p.E174G)] was found in exon 3 of the THAP1 gene in one patient and one insertion mutation [c.214_215InsA (p.L72fsX86)] in exon 2 in another. Initial symptoms of patients with these mutations were early-onset cervical dystonia. Both patients had no dysarthria. A silent change [c.489C>G (p.L63L)] in exon 3 was identified in three patients with Meige syndrome. Conclusion: The mutation frequency of the THAP1 gene was 0.87% in Chinese patients with primary pure dystonia, similar to the mutation frequency found in other ethnic groups. Patients presenting with early-onset cervical dystonia should be screened for THAP1 gene mutations to fully assess all the possible etiologies of dystonia. Further studies are needed for p.L63L in THAP1 in Meige syndrome. [Copyright &y& Elsevier]

Summary: Objective: Our aim is to use the high field MR scanner (3T) to verify whether diffusion tensor imaging (DTI) could help in locating the epileptogenic zone in patients with MRI-negative refractory partial epilepsy. Method: Fifteen patients with refractory partial epilepsy who had normal conventional MRI, and 40 healthy volunteers were recruited for the study. DTI was performed on a 3T MR scanner, individual maps of mean diffusivity (MD) and fractional anisotropy (FA) were calculated, and Voxel-Based Analysis (VBA) was performed for individual comparison between patients and controls. Result: Voxel-based analysis revealed significant MD increase in variant regions in 13 patients. The electroclinical seizure localization was concurred to seven patients. No patient exhibited regions of significant decreased MD. Regions of significant reduced FA were observed in five patients, with two of these concurring with electroclinical seizure localization. Two patients had regions of significant increase in FA, which were distinct from electroclinical seizure localization. Conclusion: Our study''s results revealed that DTI is a responsive neuroradiologic technique that provides information about the epileptogenic areas in patients with MRI-negative refractory partial epilepsy. This technique may also helpful in pre-surgical evaluation. [Copyright &y& Elsevier]

Abstract: To investigate the frequency and clinical characteristics of camptocormia in Chinese PD patients, we included 705 patients with PD and studied the clinical features and prevalence of camptocormia. Forty-six (6.5%) patients presented with camptocormia at the time of evaluation. The mean disease duration of PD patients with camptocormia was significantly longer than that without camptocormia (P <0.01). After adjusted for age and disease duration, compared with patients without camptocormia, PD patients with camptocormia presented with higher score of UPDRS part III (P <0.01), higher H&Y stage (P <0.01), higher score of Non-Motor Symptoms Scale (P <0.01) and lower score of Mini-Mental Status Examination (P <0.01). Binary logistic regression models indicated that camptocormia is associated with higher H&Y stage and UPDRS part III score. Camptocormia is not rare (6.5%) with the disease progression of PD in Chinese PD population and is associated with more advanced PD. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Multiple-system atrophy (MSA) is a fatal neurodegenerative disorder with unknown etiology. It is widely considered to be a nongenetic disorder, but accumulating evidence suggests that several genes are linked to MSA. Recently, functionally impaired variants in the coenzyme Q2 4-hydroxybenzoate polyprenyltransferase ( COQ2 ) gene have been reported to increase the risk of MSA in familial and sporadic Japanese patients. In this study, we investigated the mutation spectrum of COQ2 and analyzed the association between the common variant Val393Ala in exon 7 of COQ2 and MSA in a Chinese population. This study included 312 sporadic MSA patients from the Department of Neurology, West China Hospital of Sichuan University. All 7 exons of COQ2 in all the patients and exon 7 in 598 healthy controls (HCs) were directly sequenced. Novel candidate mutations and variations were confirmed by direct sequencing in 300 HCs. Two novel nonsynonymous variants, including p.R173H and p.N386I, and a reported missense variant, p.L162F, were found in 4 patients (p.R173H in 2 patients). However, the Val393Ala variant was not detected in the above 4 patients. Thirteen MSA patients (4.17%) and 18 controls (3.01%) had the heterozygous variant (Val393Ala/NM) of COQ2 . No significant differences existed in the genotype frequency and minor allele frequency of Val393Ala between patients and controls or between MSA characterized predominantly by cerebellar ataxia and by pakinsonism groups. The mutation frequency of COQ2 is 1.28% in a Chinese MSA population. The common variant Val393Ala in COQ2 does not appear to be associated with MSA in ethnic Chinese. [ABSTRACT FROM AUTHOR]