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 Parkinson Disease: HELP Articles by Yu Zhang
Based on 23 articles published since 2009

 Between 2009 and 2019, Yu Zhang wrote the following 23 articles about Parkinson Disease.

 1 Review The association between the LRRK2 G2385R variant and the risk of Parkinson's disease: a meta-analysis based on 23 case-control studies. 2014 Department of Neurology, Xinhua Hospital, Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China. ·Neurol Sci · Pubmed #25027012. ABSTRACT: Clinical diagnosis of Parkinson's disease (PD) is essential but misdiagnosis of PD-like diseases is quite common. LRRK2 G2385R variants have been extensively examined for the association to the risk of Parkinson's disease. However, results from different studies are inconsistent. The purpose of this meta-analysis was to assess the association between the LRRK2 G2385R variants and the risk of PD. A systematic literature search was performed for 6 databases up to January of 2014 to identify case-control studies involving LRRK2 G2385R variants and the risk of PD. A total of 12,915 cases and 12,451 controls in 23 case-control studies were included in this meta-analysis. The results indicated that the variant A allele carriers (GA + AA) increased risk of PD when compared with the homozygote GG (GA + AA vs. GG: OR = 2.4, 95 % CI = 1.97 to 2.92, P < 0.00001). In the subgroup analysis by ethnicity, increased risks were identified among Chinese (OR = 2.69, 95 % CI = 2.1-3.45, P < 0.00001) as well as in non-Chinese (OR = 2.17, 95 % CI 1.75-2.69, P < 0.00001). In the subgroup analysis by age of onset, significant associations were found in both later-onset PD (LOPD) and early-onset PD (EOPD) cases. And there was no significant difference of the allele frequency between patients with LOPD and EOPD (OR = 1.18, 95 % CI = 0.77-1.80, P = 0.45). Our results suggest that the LRRK2 G2385R variants contribute to the susceptibility of PD especially in Chinese PD. Meanwhile, it is possible that age is not the risk factor to facilitate G2385R gene mutation. 2 Review Cells therapy for Parkinson's disease--so close and so far away. 2009 Cell Therapy Center, Xuanwu Hospital, Capital Medical University and Key Laboratory of Neurodegeneration, Ministry of Education, Beijing, 100053, China. ·Sci China C Life Sci · Pubmed #19641865. ABSTRACT: One of the strategies of treating Parkinson's disease (PD) is the replacement of lost neurons in the substantia nigra with healthy dapamingergic cells. Potential sources for cells range from autologous grafts of dopamine secreting cells, fetal ventral mesencephalon tissue, to various stem cell types. Over the past quarter century, many experimental replacement therapies have been tried on PD animal models as well as human patients, yet none resulted in satisfactory outcomes that warrant wide applications. Recent progress in stem cell biology has shown that nuclear transfer embryonic stem cells (ntES) or induced pluripotent stem cells (iPS) derived cells can be used to successfully treat rodent PD models, thus solving the problem of immunorejection and paving the way for future autologous transplantations for treating PD. Meanwhile, however, post mortem analysis of patients who received fetal brain cell transplantation revealed that implanted cells are prone to degeneration just like endogenous neurons in the same pathological area, indicating long-term efficacy of cell therapy of PD needs to overcome the degenerating environment in the brain. A better understanding of neurodegeneration in the midbrain appeared to be a necessary step in developing new cell therapies in Parkinson's disease. It is likely that future cell replacement will focus on not only ameliorating symptoms of the disease but also trying to slow the progression of the disease by either neuroprotection or restoring the micro-environment in the midbrain. 3 Article Abnormal Spontaneous Neuronal Discharge and Local Field Potential both in Cortex and Striatum of a Non- human Primate of Parkinson's Disease using Implantable Microelectrode Arrays. 2018 ·Conf Proc IEEE Eng Med Biol Soc · Pubmed #30440282. ABSTRACT: Parkinson's disease (PD) is a neurodegenerative disease with the loss of dopaminergic neurons in substantia nigra. This study described abnormal spontaneous neuronal information both in cortex and striatum of a non-human primate of PD using implantable microelectrode arrays. In cortex of PD monkey, Neurons discharged from single-spike mode to burst-firing mode compared to normal monkey; Mean amplitude was $197 \mu \mathrm{V}$ that was twice of mean amplitude of normal monkey, and mean firing rate was 82Hz; burst-firing activity showed distinctive, stereotypic periods of oscillatory lasted for $20 \pm 5\mathrm{s}$ occurring ever 30-40 seconds, which was consistent with local field potential (LFP) oscillating at 4.79Hz related to PD tremor; neuronal discharge were approximately synchronous from four channels, that were consistent with local field potential fluctuating greatly with a correlation coefficient of 0.99997, and the main frequency of local field potential had a good respond to firing rate of spike with a correlation coefficient of 0.9891. In striatum of PD monkey, two types of neurons were detected with mean amplitude of $102 \mu \mathrm{V}$ and $296 \mu \mathrm{V}$ respectively; the mean firing rate was 62 Hz significantly higher than that in normal monkey; as for one representative type of neurons, with respect to local field potential oscillating at a period in cortex, local field potential continuously oscillated in striatum at low frequency at the range of 4-7Hz which was constituent with neuronal burst firing rate, while single neuron discharged at the range of 10-32Hz, almost at beta frequencies. Abnormal neural information detection by microelectrode arrays with ifferent signals in different position will play an important role in target location in brain of PD patients, especially for treatment. 4 Article Ceruloplasmin in Parkinson's disease and the nonmotor symptoms. 2018 Department of Radiology, The First Hospital of Tsinghua University, Beijing, China. · Department of Neurology, China-Japan Friendship Hospital, Beijing, China. · The School of Medicine, Tsinghua University, Beijing, China. · Department of Neurology, The First Hospital of Tsinghua University, Beijing, China. ·Brain Behav · Pubmed #29733522. ABSTRACT: OBJECTIVES: To investigate the relationship between ceruloplasmin (CP) and Parkinson's disease (PD), and the correlation between CP level and the time difference between nonmotor symptoms and motor symptoms and the diagnosis were also mentioned. MATERIALS AND METHODS: Sixty-six patients diagnosed with PD for the first time were included in the study. They were divided into CP reduction group (31 cases) and CP normal group (35 cases) according to their CP level. The estimated time difference between nonmotor symptoms and motor symptoms and the diagnosis were recorded respectively. The magnetic sensitive nigra phase value was measured by susceptibility weighted imaging (SWI). RESULTS: Ceruloplasmin level was middling correlated with age (r = .561, p < .001). There was strong negative correlation between CP level and UPDRS scores (r = -.727, p < .001). The CP level was significantly correlated with the magnetic sensitive nigra phase value (r = .891, p < .001). CP level showed moderate correlation with the time difference from nonmotor symptoms to motor symptoms (r = .559, p < .001), besides, the time difference between nonmotor symptoms and the diagnosis (r = .525, p < .001) and CP level was also moderately related. CONCLUSIONS: Ceruloplasmin interference in iron metabolism was closely related with PD development. And there were slight corrections between CP level and the time difference from nonmotor symptoms to motor symptoms or the diagnosis. 5 Article Concerns Regarding Opicapone as Adjunct to Levodopa Therapy. 2017 The Neurological Diseases Center, The Affiliated Hospital of Chengdu University, Chengdu, Sichuan, China. ·JAMA Neurol · Pubmed #28531250. ABSTRACT: -- No abstract -- 6 Article Clinical characteristics of impulse control and related disorders in Chinese Parkinson's disease patients. 2017 Department of Neurology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kong jiang Road, Shanghai, 200092, People's Republic of China. · Department of Neurology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kong jiang Road, Shanghai, 200092, People's Republic of China. liuzhengguoneuron@126.com. ·BMC Neurol · Pubmed #28521736. ABSTRACT: BACKGROUND: Impulse control and related disorders (ICRDs) are clinically complications in Parkinson's disease (PD). However, the clinical characteristics of ICRDs in Chinese PD patients were rarely reported. We aimed to explore the prevalence and the clinical profile of ICRDs in Chinese patients with PD. METHODS: 142 Chinese PD patients were consecutively enrolled. The symptoms of ICRDs were assessed with the Questionnaire for Impulsive-Compulsive Disorders. The clinical characteristics of patients with ICRDs and without ICRDs were compared. RESULTS: ICRDs were present in 31% of our patients. The most common ICRDs were compulsive medication use (11.3%) and punding (9.2%); the least frequent were walkabout (1.4%). Variables independently associated with ICRDs were earlier onset of the disease (≤55 years), severe cognitive impairment (MMSE 10-20), the dose of dopamine agonist (>1 mg/d) and dyskinesia. CONCLUSIONS: ICRDs was commonly found in Chinese PD patients. Earlier onset of the disease, the dose of dopamine agonist, severe cognitive impairment and dyskinesia are independent factors associated with ICRDs. Our results will be benefit for clinicians to assess the risk of developing ICRDs before delivering dopaminergic medication. 7 Article Multiple modality biomarker prediction of cognitive impairment in prospectively followed de novo Parkinson disease. 2017 Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, IA, United States of America. · Feinberg School of Medicine, Northwestern University, Chicago, IL, United States of America. · University of California, San Francisco, San Francisco, CA, United States of America. · Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, United States of America. · Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States of America. · Department of Pharmacology & Clinical Pharmacology, Inha University School of Medicine, Incheon, Republic of Korea. · Avid Radiopharmaceuticals, Philadelphia, PA, United States of America. · Institute for Neurodegenerative Disorders (IND) and Molecular NeuroImaging, LLC (MNI), New Haven CT, United States of America. · Department of Old Age Psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, England. · Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway. · Institute for Ageing and Health, Newcastle University, Newcastle, England. · Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States of America. · Department of Neurology, University of Cincinnati Academic Health Center, Cincinnati, OH, United States of America. · Department of Psychiatry, Yale School of Medicine, New Haven, CT, United States of America. · UCSD Movement Disorder Center, Department of Neurosciences, University of California San Diego, San Diego, CA, United States of America. · Departments of Neurology and Psychiatry, University of Rochester School of Medicine and Dentistry, Rochester, NY, United States of America. · Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States of America. · Parkinson's Disease Research, Education and Clinical Center (PADRECC and MIRECC), Philadelphia Veterans Affairs Medical Center, Philadelphia, PA, United States of America. · Mental Illness Research, Education and Clinical Center (MIRECC), Philadelphia Veterans Affairs Medical Center, Philadelphia, PA, United States of America. ·PLoS One · Pubmed #28520803. ABSTRACT: OBJECTIVES: To assess the neurobiological substrate of initial cognitive decline in Parkinson's disease (PD) to inform patient management, clinical trial design, and development of treatments. METHODS: We longitudinally assessed, up to 3 years, 423 newly diagnosed patients with idiopathic PD, untreated at baseline, from 33 international movement disorder centers. Study outcomes were four determinations of cognitive impairment or decline, and biomarker predictors were baseline dopamine transporter (DAT) single photon emission computed tomography (SPECT) scan, structural magnetic resonance imaging (MRI; volume and thickness), diffusion tensor imaging (mean diffusivity and fractional anisotropy), cerebrospinal fluid (CSF; amyloid beta [Aβ], tau and alpha synuclein), and 11 single nucleotide polymorphisms (SNPs) previously associated with PD cognition. Additionally, longitudinal structural MRI and DAT scan data were included. Univariate analyses were run initially, with false discovery rate = 0.2, to select biomarker variables for inclusion in multivariable longitudinal mixed-effect models. RESULTS: By year 3, cognitive impairment was diagnosed in 15-38% participants depending on the criteria applied. Biomarkers, some longitudinal, predicting cognitive impairment in multivariable models were: (1) dopamine deficiency (decreased caudate and putamen DAT availability); (2) diffuse, cortical decreased brain volume or thickness (frontal, temporal, parietal, and occipital lobe regions); (3) co-morbid Alzheimer's disease Aβ amyloid pathology (lower CSF Aβ 1-42); and (4) genes (COMT val/val and BDNF val/val genotypes). CONCLUSIONS: Cognitive impairment in PD increases in frequency 50-200% in the first several years of disease, and is independently predicted by biomarker changes related to nigrostriatal or cortical dopaminergic deficits, global atrophy due to possible widespread effects of neurodegenerative disease, co-morbid Alzheimer's disease plaque pathology, and genetic factors. 8 Article Nuclear Accumulation of Histone Deacetylase 4 (HDAC4) Exerts Neurotoxicity in Models of Parkinson's Disease. 2017 CAS Key Laboratory of Receptor Research, Chinese Academy of Sciences, Shanghai Institute of Materia Medica, 555 Zu Chong Zhi Road, Shanghai, 201203, People's Republic of China. · CAS Key Laboratory of Receptor Research, Chinese Academy of Sciences, Shanghai Institute of Materia Medica, 555 Zu Chong Zhi Road, Shanghai, 201203, People's Republic of China. lyfeng@simm.ac.cn. ·Mol Neurobiol · Pubmed #27785754. ABSTRACT: Histone deacetylase 4 (HDAC4) is a class II HDAC which is highly expressed in the brain. Previous reports have shown that HDAC4 is essential for normal brain physiology and its deregulation leads to several neurodegenerative disorders. However, it remains unclear whether dysregulation of HDAC4 is specifically involved in the development of Parkinson's disease. In this study, we demonstrate that intracellular trafficking of HDAC4 is important in regulating dopaminergic cell death. While HDAC4 normally localizes to the cytoplasm, nuclear accumulation of HDAC4 was observed in dopaminergic neurons overexpressing A53T mutant α-synuclein treated with MPP 9 Article Progression of Regional Microstructural Degeneration in Parkinson's Disease: A Multicenter Diffusion Tensor Imaging Study. 2016 Department of Veteran Affairs Medical Center, San Francisco, California, United States of America. · Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, United States of America. · Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, Iowa, United States of America. ·PLoS One · Pubmed #27798653. ABSTRACT: This study aimed to identify the utility of diffusion tensor imaging (DTI) in measuring the regional distribution of abnormal microstructural progression in patients with Parkinson's disease who were enrolled in the Parkinson's progression marker initiative (PPMI). One hundred and twenty two de-novo PD patients (age = 60.5±9) and 50 healthy controls (age = 60.6±11) had DTI scans at baseline and 12.6±1 months later. Automated image processing included an intra-subject registration of all time points and an inter-subjects registration to a brain atlas. Annualized rates of DTI variations including fractional anisotropy (FA), radial (rD) and axial (aD) diffusivity were estimated in a total of 118 white matter and subcortical regions of interest. A mixed effects model framework was used to determine the degree to which DTI changes differed in PD relative to changes in healthy subjects. Significant DTI changes were also tested for correlations with changes in clinical measures, dopaminergic imaging and CSF biomarkers in PD patients. Compared to normal aging, PD was associated with higher rates of FA reduction, rD and aD increases predominantly in the substantia nigra, midbrain and thalamus. The highest rates of FA reduction involved the substantia nigra (3.6±1.4%/year from baseline, whereas the highest rates of increased diffusivity involved the thalamus (rD: 8.0±2.9%/year, aD: 4.0±1.5%/year). In PD patients, high DTI changes in the substantia nigra correlated with increasing dopaminergic deficits as well as with declining α-synuclein and total tau protein concentrations in cerebrospinal fluid. Increased DTI rates in the thalamus correlated with progressive decline in global cognition in PD. The results suggest that higher rates of regional microstructural degeneration are potential markers of PD progression. 10 Article Parkinson's disease classification using gait analysis via deterministic learning. 2016 School of Mechanical & Electrical Engineering, Longyan University, Longyan 364012, PR China. Electronic address: zw0597@126.com. · School of Mechanical & Electrical Engineering, Longyan University, Longyan 364012, PR China. · Department of Orthopaedic Surgery, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou 510010, PR China. ·Neurosci Lett · Pubmed #27693437. ABSTRACT: Gait analysis plays an important role in maintaining the well-being of human mobility and health care, and is a valuable tool for obtaining quantitative information on motor deficits in Parkinson's disease (PD). In this paper, we propose a method to classify (diagnose) patients with PD and healthy control subjects using gait analysis via deterministic learning theory. The classification approach consists of two phases: a training phase and a classification phase. In the training phase, gait characteristics represented by the gait dynamics are derived from the vertical ground reaction forces under the usual and self-selected paces of the subjects. The gait dynamics underlying gait patterns of healthy controls and PD patients are locally accurately approximated by radial basis function (RBF) neural networks. The obtained knowledge of approximated gait dynamics is stored in constant RBF networks. The gait patterns of healthy controls and PD patients constitute a training set. In the classification phase, a bank of dynamical estimators is constructed for all the training gait patterns. Prior knowledge of gait dynamics represented by the constant RBF networks is embedded in the estimators. By comparing the set of estimators with a test gait pattern of a certain PD patient to be classified (diagnosed), a set of classification errors are generated. The average L 11 Article Chronic mild stress accelerates the progression of Parkinson's disease in A53T α-synuclein transgenic mice. 2016 CAS Key Laboratory of Receptor Research, Chinese Academy of Sciences, Shanghai Institute of Materia Medica, 555 Zu Chong Zhi Road, Shanghai 201203, PR China. · CAS Key Laboratory of Receptor Research, Chinese Academy of Sciences, Shanghai Institute of Materia Medica, 555 Zu Chong Zhi Road, Shanghai 201203, PR China. Electronic address: lyfeng@simm.ac.cn. ·Exp Neurol · Pubmed #27637804. ABSTRACT: Daily stress is associated with increased risk for various diseases, and numerous studies have provided evidence that environmental stress leads to deleterious effects on the central nervous system. However, it remains unclear whether chronic stress exacerbates the progression of Parkinson's disease (PD). To investigate this hypothesis, we determined the effect of chronic mild stress (CMS) on the pathogenesis of PD in a transgenic mice line that overexpresses the human A53T mutant α-synuclein (A53T Tg mice). We show that when exposed to CMS, male, but not female, A53T Tg mice developed profound motor disabilities and exhibited olfactory sensitivity deficits. Pathological analysis also identified robust dopaminergic neuron degeneration and strong reduction of dopamine levels in A53T Tg male mice who underwent CMS treatment. Systematic examination of the abnormal aggregation of α-synuclein revealed a profound increase of inclusion in A53T Tg male mice subject to CMS resembling key pathological changes of PD. An insight into the mechanism underlying stress leading to the acceleration of neurodegeneration in those with genetic susceptibility, was revealed by evidence of microglia activation and elevated pro-inflammatory factor levels in A53T Tg male mice following CMS. Notably, these effects of CMS on the pathogenesis of PD showed a remarkable sexual dimorphism: only male A53T Tg mice exhibited exacerbation of the progression of PD. However, the molecular and cellular bases for this difference remains to be elucidated. Our results indicate a causative role for chronic mild stress using a PD animal model. Based on these findings, we propose that CMS acts as an environmental risk factor that leads to neuroinflammation and progressive neurodegeneration on a background of PD susceptibility. 12 Article Network structure of brain atrophy in de novo Parkinson's disease. 2015 McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Canada. · Service de Neurologie A, CHU Clermont-Ferrand, Clermont-Ferrand, France. ·Elife · Pubmed #26344547. ABSTRACT: We mapped the distribution of atrophy in Parkinson's disease (PD) using magnetic resonance imaging (MRI) and clinical data from 232 PD patients and 117 controls from the Parkinson's Progression Markers Initiative. Deformation-based morphometry and independent component analysis identified PD-specific atrophy in the midbrain, basal ganglia, basal forebrain, medial temporal lobe, and discrete cortical regions. The degree of atrophy reflected clinical measures of disease severity. The spatial pattern of atrophy demonstrated overlap with intrinsic networks present in healthy brain, as derived from functional MRI. Moreover, the degree of atrophy in each brain region reflected its functional and anatomical proximity to a presumed disease epicenter in the substantia nigra, compatible with a trans-neuronal spread of the disease. These results support a network-spread mechanism in PD. Finally, the atrophy pattern in PD was also seen in healthy aging, where it also correlated with the loss of striatal dopaminergic innervation. 13 Article Diffusion imaging of nigral alterations in early Parkinson's disease with dopaminergic deficits. 2015 Department of Veteran Affairs Medical Center, San Francisco, California, USA. · Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, USA. · Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, Iowa, USA. · Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA. · Institute for Neurodegenerative Disorders (IND) and Molecular Neuroimaging, LLC (MNI), New Haven, Connecticut, USA. · Baylor College of Medicine, Houston, Texas, USA. · Department of Neurology, University of California, San Francisco, CA, USA. · Emory University, Atlanta, Georgia, USA. · University of Tuebingen, Tuebingen, Germany. · Innsbruck Medical University, Innsbruck, Austria. · Paracelsus-Elena Klinik, Kassel, Germany. · Johns Hopkins University, Baltimore, Maryland, USA. · Macquarie University, Sydney, Australia. ·Mov Disord · Pubmed #26260437. ABSTRACT: BACKGROUND: This study reports the baseline characteristics of diffusion tensor imaging data in Parkinson's disease (PD) patients and healthy control subjects from the Parkinson's Progression Markers Initiative. The main goals were to replicate previous findings of abnormal diffusion imaging values from the substantia nigra. in a large multicenter cohort and determine whether nigral diffusion alterations are associated with dopamine deficits. METHODS: Two hundred twenty subjects (PD = 153; control = 67) from 10 imaging sites were included. All subjects had a full neurological exam, a ((123) I)ioflupane dopamine transporter (DAT) single-photon emission computer tomography scan, and diffusion tensor imaging. Fractional anisotropy as well as radial and axial diffusivity was computed within multiple regions across the substantia nigra. RESULTS: A repeated-measures analysis of variance found a marginally nonsignificant interaction between regional fractional anisotropy of the substantia nigra and disease status (P = 0.08), conflicting with an earlier study. However, a linear mixed model that included control regions in addition to the nigral regions revealed a significant interaction between regions and disease status (P = 0.002), implying a characteristic distribution of reduced fractional anisotropy across the substantia nigra in PD. Reduced fractional anisotropy in PD was also associated with diminished DAT binding ratios. Both axial and radial diffusivity were also abnormal in PD. CONCLUSIONS: Although routine nigral measurements of fractional anisotropy are clinically not helpful, the findings in this study suggest that more-sophisticated diffusion imaging protocols should be used when exploring the clinical utility of this imaging modality. 14 Article Diffusion tensor imaging of the nigrostriatal fibers in Parkinson's disease. 2015 Center for Imaging of Neurodegenerative Diseases, San Francisco VA Medical Center, San Francisco, CA, USA. · Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA. · Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, IA, USA. · Institute for Neurodegenerative Disorders (IND) and Molecular NeuroImaging, LLC (MNI), New Haven, CT, USA. ·Mov Disord · Pubmed #25920732. ABSTRACT: BACKGROUND: Parkinson's disease (PD) is histopathologically characterized by the loss of dopamine neurons in the substantia nigra pars compacta. The depletion of these neurons is thought to reduce the dopaminergic function of the nigrostriatal pathway, as well as the neural fibers that link the substantia nigra to the striatum (putamen and caudate), causing a dysregulation in striatal activity that ultimately leads to lack of movement control. Based on diffusion tensor imaging, visualizing this pathway and measuring alterations of the fiber integrity remain challenging. The objectives were to 1) develop a diffusion tensor tractography protocol for reliably tracking the nigrostriatal fibers on multicenter data; 2) test whether the integrities measured by diffusion tensor imaging of the nigrostriatal fibers are abnormal in PD; and 3) test whether abnormal integrities of the nigrostriatal fibers in PD patients are associated with the severity of motor disability and putaminal dopamine binding ratios. METHODS: Diffusion tensor tractography was performed on 50 drug-naïve PD patients and 27 healthy control subjects from the international multicenter Parkinson's Progression Marker Initiative. RESULTS: Tractography consistently detected the nigrostriatal fibers, yielding reliable diffusion measures. Fractional anisotropy, along with radial and axial diffusivity of the nigrostriatal tract, showed systematic abnormalities in patients. In addition, variations in fractional anisotropy and radial diffusivity of the nigrostriatal tract were associated with the degree of motor deficits in PD patients. CONCLUSION: Taken together, the findings imply that the diffusion tensor imaging characteristic of the nigrostriatal tract is potentially an index for detecting and staging of early PD. 15 Article Small peptide inhibitor of JNK3 protects dopaminergic neurons from MPTP induced injury via inhibiting the ASK1-JNK3 signaling pathway. 2015 Department of Neurology and Institute of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. · Department of Neurology and Institute of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Key Laboratory of Stem Cell Biology & Laboratory of Neurodegenerative Diseases, Institute of Health Science, Shanghai Institutes of Biological Sciences (SIBS), Chinese Academy of Science (CAS) and Shanghai Jiao Tong University School of Medicine, Shanghai, China. ·PLoS One · Pubmed #25856433. ABSTRACT: INTRODUCTION AND AIMS: The ASK1-JNK3 signaling pathway plays a pivotal role in the pathogenesis of Parkinson's disease (PD). The specific binding of β-arrestin2 to JNK3 is essential for activation of the ASK1-JNK3 cascade, representing a potential therapeutic target for preventing dopaminergic neuronal death in PD. The aim of this study was to identify a novel strategy for the prevention of dopaminergic neuronal death in PD. METHODS: Based on the specific binding of β-arrestin2 to JNK3, a 21-amino-acid fusion peptide, termed JNK3-N-Tat, was synthesized. We evaluated the ability of this peptide to inhibit the binding of β-arrestin2 to its target domain in JNK3 in vitro and in vivo. RESULTS: The JNK3-N-Tat peptide inhibited activation of the ASK1-JNK3 cascade by disrupting the interaction between β-arrestin2 and JNK3. JNK3-N-Tat exerted beneficial effects through pathways downstream of JNK3 and improved mitochondrial function, resulting in attenuated MPP+/MPTP-induced damage. JNK3-N-Tat protected mesencephalic dopaminergic neurons against MPTP-induced toxicity. CONCLUSIONS: JNK3-N-Tat, a JNK3-inhibitory peptide, protects dopaminergic neurons against MPP+/MPTP-induced injury by inhibiting the ASK1-JNK3 signaling pathway. 16 Article Angiogenin variants are not associated with Parkinson's disease in the ethnic Chinese population. 2013 Department of Neurology and Institute of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. ·Parkinsonism Relat Disord · Pubmed #23231972. ABSTRACT: Recently, the angiogenin gene has been reported to be significantly associated with Parkinson's disease and amyotrophic lateral sclerosis in populations of European and American ancestry. But there have been no studies investigating the association between angiogenin and Parkinson's disease in the ethnic Chinese population. We conducted a case-control study to evaluate the association between angiogenin and Parkinson's disease in a Chinese population from mainland China. We sequenced the exons of angiogenin in 532 Parkinson's disease patients and 480 controls. We did not detect an angiogenin coding region mutation in either the patients or the controls. Our data do not support the association of angiogenin variants with PD in Han Chinese of mainland China. 17 Article Association study of SCARB2 rs6812193 polymorphism with Parkinson's disease in Han Chinese. 2012 Department of Neurology and Institute of Neurology, Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China. ·Neurosci Lett · Pubmed #22465138. ABSTRACT: Recently, a nucleotide polymorphism rs6812193 near SCARB2 was found to be significantly associated with Parkinson's disease (PD) in populations of European ancestry. Herein, we conducted a case-control study with attempt to further evaluate the association between SNP rs6812193 and PD in a Chinese population from mainland China. rs6812193 was genotyped by PCR-RFLP technique in 449 PD patients and 452 controls in a Chinese population. In our study, we did not detect statistically significant differences between cases and controls in terms of both allele and genotype distribution of the rs6812193 polymorphism (P=0.97 and P=0.77, respectively), even after stratification by age at onset. Our data do not support the association of SNP rs6812193 with PD in Han Chinese of mainland China. 18 Article Vacuolar protein sorting 35 Asp620Asn mutation is rare in the ethnic Chinese population with Parkinson's disease. 2012 Department of Neurology and Institute of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. ·Parkinsonism Relat Disord · Pubmed #22410496. ABSTRACT: Vacuolar protein sorting 35 (VPS35) Asp620Asn mutation has been identified in late-onset familial Parkinson's disease (PD) patients of Swiss and Austrian descent as well as sporadic PD patients in the United States. In order to determine the contribution of VPS35 mutations in mainland Chinese PD patients and to better understand the association between VPS35 and PD, we sequenced all 17 exons of VPS35 in 32 probands of presumed autosomal-dominant, late-onset familial PD and 35 normal controls. Meanwhile, we analyzed VPS35 Asp620Asn mutation in 512 PD patients. A total of 371 subjects without neurological disorders from the same region in China were set as a control group. We did not find any VPS35 coding region mutation in 32 familial PD patients. VPS35 Asp620Asn mutation was either not found in 480 PD patients. Our results suggested that VPS35 Asp620Asn may be not associated with PD in Chinese population. 19 Article Regional alterations of brain microstructure in Parkinson's disease using diffusion tensor imaging. 2012 Department of Radiology and Medical Imaging, Center of Imaging for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, California, USA. Wang.Zhan@gmail.com ·Mov Disord · Pubmed #21850668. ABSTRACT: This study tested the hypothesis that diffusion tensor imaging can detect alteration in microscopic integrity of white matter and basal ganglia regions known to be involved in Parkinson's disease (PD) pathology. It was also hypothesized that there is an association between diffusion abnormality and PD severity and subtype. Diffusion tensor imaging at 4 Tesla was obtained in 12 PD and 20 control subjects, and measures of fractional anisotropy and mean diffusivity were evaluated using both region-of-interest and voxel-based methods. Movement deficits and subtypes in PD subjects were assessed using the Motor Subscale (Part III) of the Unified Parkinson's Disease Rating Scale. Reduced fractional anisotropy (P < .05, corrected) was found in PD subjects in regions related to the precentral gyrus, substantia nigra, putamen, posterior striatum, frontal lobe, and the supplementary motor areas. Reduced fractional anisotropy in the substantia nigra correlated (P < .05, corrected) with the increased rating scale motor scores. Significant spatial correlations between fractional anisotropy alterations in the putamen and other PD-affected regions were also found in the context of PD subtypes index analysis. Our data suggest that microstructural alterations detected with diffusion tensor might serve as a potential biomarker for PD. 20 Article DJ-1 modulates the expression of Cu/Zn-superoxide dismutase-1 through the Erk1/2-Elk1 pathway in neuroprotection. 2011 Laboratory of Neurodegenerative Diseases, Institute of Health Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Science and Shanghai Jiao Tong University School of Medicine, Shanghai, China. ·Ann Neurol · Pubmed #21796667. ABSTRACT: OBJECTIVE: Loss of function mutations of Park7/DJ-1 gene increase the susceptibility of dopaminergic cells to reactive oxygen species and cause early onset familial Parkinson disease (PD). However, the mechanisms underlying dopaminergic neuron loss related to DJ-1 mutation remain undefined. Therefore, it is important to find the new mechanisms underlying the antioxidative functions of DJ-1. METHODS: DJ-1 knockdown cells and DJ-1 knockout mice were used to elucidate the mechanisms underlying the antioxidative stress of DJ-1. Preliminary study of the saliva from PD patients and controls was used to confirm our findings obtained from the above studies. RESULTS: Our experiments showed that DJ-1 interacted with Erk1/2 and was required for the nuclear translocation of Erk1/2 upon oxidative stimulation. The translocation of Erk1/2 activated Elk1 and sequentially promoted superoxide dismutase1 (SOD1) expression. The nuclear translocation of Erk1/2, the activation of Elk1, and the ensuing upregulation of SOD1 were all suppressed in DJ-1 knockdown cells and DJ-1 null mice treated with oxidative insult. Furthermore, reintroduction of SOD1 into DJ-1 knockdown cells protected them against oxidative stress. Finally, in the preliminary study, we found close correlation between the protein levels of DJ-1 and SOD1 in the saliva samples from different stages of PD patients. INTERPRETATION: Our studies suggest that DJ-1 regulates SOD1 expression through Erk1/2-Elk1 pathway in its protective response to oxidative insult. 21 Article Small peptide inhibitor of JNKs protects against MPTP-induced nigral dopaminergic injury via inhibiting the JNK-signaling pathway. 2010 Institute of Health Science, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) & Shanghai Jiao Tong University School of Medicine, Shanghai, PR China. ·Lab Invest · Pubmed #20010851. ABSTRACT: Increasing evidence suggests that apoptosis may be the mechanism underlying cell death in selective loss of nigral dopaminergic neurons in Parkinson's disease (PD). Previous studies strongly suggested that c-Jun N-terminal kinase (JNK) signaling pathway has a critical role in the animal model with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD. In this study, we report the inhibitory effect of a peptide designated as Tat-JBD on JNKs activation. The sequence of Tat is corresponding to the cell-membrane transduction domain of human immunodeficiency virus-type 1 (HIV-1) and the sequence of an 11-amino acid peptide is corresponding to the residues of JNK-binding domain (JBD) on JNK-interacting protein-1 (JIP-1). Tat-JBD is confirmed to perturb the assembly of JIP-1-JNKs complex, inhibit the activation of JNKs induced by MPTP and consequently diminish the phosphorylation of c-Jun. It also inhibits the phosphorylation of Bcl-2 and the releasing of Bax from Bcl-2/Bax dimmers, sequentially attenuates the translocation of Bax to mitochondria, the release of cytochrome c, the activation of caspase3 and the hydrolyzation of poly-ADP-ribose-polymerase. The death of dopaminergic neurons and the loss of dopaminergic axon in the striatum were significantly suppressed by infusion of the peptide Tat-JBD in MPTP-treated mice. Our findings imply that Tat-JBD offers neuroprotection against MPTP injury via inhibiting the JNK-signaling pathway, and may provide a promising therapeutic approach for PD. 22 Article Acoustic analysis of the tremulous voice: assessing the utility of the correlation dimension and perturbation parameters. 2010 Shanghai Eye, Ear, Nose and Throat Hospital of Fudan University, Shanghai, China. ·J Commun Disord · Pubmed #19909966. ABSTRACT: LEARNING OUTCOMES: The reader will understand the utility of applying select perturbation parameters and the nonlinear measure of correlation dimension for the characterization of the tremulous voice. 23 Article GIGYF2 Asn56Ser mutation is rare in Chinese Parkinson's disease patients. 2009 Department of Neurology and Institute of Neurology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. ·Neurosci Lett · Pubmed #19638301. ABSTRACT: Grb10-Interacting GYF Protein-2 gene (GIGYF2) has been suggested as a candidate gene for PARK11 locus since seven different GIGYF2 missense mutations were identified in familial Parkinson's disease (PD) patients of European descent. To evaluate the frequency and distribution of GIGYF2 Asn56Ser mutation in Chinese PD patients, we analyzed 469 patients with PD from mainland China, including 36 cases with familial PD and 433 cases with sporadic PD. A total of 451 subjects without neurological disorders from the same region in China were set as a control group. The result showed that the GIGYF2 Asn56Ser mutation was not present in all subjects. Our finding suggests that the GIGYF2 Asn56Ser mutation is rare in Chinese PD patients.