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前驱期多系统萎缩的研究进展

中华老年医学杂志 2024年第9期43卷 1191-1195页

作者：潘竞康佳王新海日罕陈彪内蒙古医科大学第二附属医院神经内科呼和浩特010010 首都医科大学宣武医院神经生物室/神经内科/老年医学北京100053

多系统萎缩(MSA)是一种进展迅速的神经系统退行性疾病,和帕金森病(PD)、路易体痴呆(DLB)同属于α-突触核蛋白病。由于同类疾病早期临床症状的重叠以及目前诊断标准对疾病早期缺乏敏感性,开展疾病早期修饰治疗药物的临床试验困难重重,疾... 详细信息

多系统萎缩(MSA)是一种进展迅速的神经系统退行性疾病,和帕金森病(PD)、路易体痴呆(DLB)同属于α-突触核蛋白病。由于同类疾病早期临床症状的重叠以及目前诊断标准对疾病早期缺乏敏感性,开展疾病早期修饰治疗药物的临床试验困难重重,疾病修饰治疗药物的研发以及诊断工具的开发和验证进展缓慢。因此,国际运动障碍协会(MDS)开发了新的MSA诊断标准,首次提出可能的前驱期MSA的定义和诊断标准。本综述介绍了可能的前驱期MSA诊断标准以及与其他前驱期α-突触核蛋白病鉴别诊断,以提高疾病在早期阶段诊断的准确性,有利于疾病早期研究的开展。

关键词：多系统萎缩 α突触核蛋白诊断,鉴别

Brain activity in Parkinson's disease patients with mild cognitive impairment

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Science Bulletin 2016年第24期61卷 1876-1883页

作者： Linlin Gao Xuemin Wu Jiarong Zhang piu chan Tao Wu Department of Neurobiology Key Laboratory on Neurodegenerative Disorders of Ministry of Education Beijing Institute of Geriatrics Xuanwu Hospital Capital Medical University Beijing Key Laboratory on Parkinson’s Disease Parkinson Disease Center of Beijing Institute for Brain Disorders Community Health Station China University of Mining and Technology

Mild cognitive impairment （MCI） is common in patients with Parkinson＇s disease （PD）, yet the underlying neural mechanisms of this disease state remain unclear. We investigated alterations in the spontaneous brain activity of PD patients with MCI （PD-MCI） relative to cognitively normal PD patients （PD-CN） and healthy control （HC） subjects. In this work, 13 PD-MCI patients, 16 PD-CN patients, and 16 HC subjects completed resting state functional MRI. Spontaneous brain activity was measured by calculating amplitude of low frequency fluctuation （ALFF） values across the whole brain. Between-group differences and correlations between ALFF values and cognitive test scores were analyzed. ALFF values decreased in the right superior temporal gyrus and increased in the left middle temporal gyrus and left superior frontal gyms of PD-MCI patients compared with PD-CN patients. In the PD-MCI group, ALFF values in the left middle temporal gyrus were negatively correlated with Montreal Cognitive Assessment and vocabulary test scores, and the ALFF values in the left superior frontal gyms were negatively correlated with vocabulary test scores. Our study demonstrates that PD-MCI is associated with abnormal spontaneous brain activity in the temporal and frontal lobes. These findings inform the underlying neural mechanism of cognitive impairment in PD.

关键词： Parkinson's disease - Mild cognitive impairment ~ Resting state functional MRI - Low frequency fluctuation

Significance of the potential role of pharmacological MRI （phMRI） in diagnosis of Parkinson＇s disease

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Frontiers in Biology 2012年第4期7卷 307-312页

作者： Feng YUE piu chan Zhiming ZHANG Department of Neurobiology and Neurology Beijing Institute of Geriatrics Xuanwu Hospital of Capital University of Medical Sciences Beijing 100053 China Department of Anatomy and Neurobiology University of Kentucky College of Medicine Lexington KY 40536 USA

The initial diagnosis of Parkinson＇s disease （PD） is currently based on a clinical assessment. Many patients who receive an initial diagnosis of PD have parkinsonian features related to other diseases such as essential tremor, vascular parkinsonism and atypical parkinsonian disorder. It has been challenging to differentiate PD from those disorders, especially in the early disease stages, due to an overlap of clinical signs and symptoms. Therefore, there is a great need for development of noninvasive, highly sensitive, and widely available imaging methods that can potentially be used to assistant physicians to make more accurate diagnosis of the disease; and to longitudinally monitor treatment of PD. Recent advance of pharmacological MRI （phMRI） technology allows non-invasively mapping functional stages for nigrostriatal dopamine （DA） system. This article aims to review research findings primarily from our group in nonhuman primates modeling the neurodegenerative disease on the value of phMRI techniques in the diagnosis of PD.

关键词： pharmacological MRI (phMRI) Parkinson's disease phMRI techniques

MPTP Induces Systemic Parkinsonism in Middle-Aged Cynomolgus Monkeys:Clinical Evolution and Outcomes

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Neuroscience Bulletin 2017年第1期33卷 17-27页

作者： Feng Yue Sien Zeng Rongping Tang Guoxian Tao piu chan Department of Neurobiology Beijing Institute of GeriatricsXuanwu Hospital of Capital Medical UniversityBeijing 100053China Key Laboratory on Parkinson's Disease Beijing 100053China Department of Pathology Guilin Medical CollegeGuilin 541001China Wincon Thera Cells Biotechnologies Co. Ltd.Nanning 530003China

In this study, we developed a systemic PD model in middle-aged cynomolgus monkeys using individualized low-dose MPTP, to explore effective indicators for the early prediction of clinical outcomes. MPTP was not stopped until the animals showed typical PD motor symptoms on days 10 to 13 after MPTP administration when the Kurlan score reached 10; this abrogated the dif- ferences in individual susceptibility to MPTP. The clinical symptoms persisted, peaking on days 3 to 12 after MPTP withdrawal （rapid progress stage）, and then the Kurlan score plateaued. A Kurlan score at the end of the rapid progress stage 〉15 reflected stable or slowly-progressive PD, while a score 〈15 indicated spontaneous recovery. The entire clinical evolution and outcome of the systemic PD model was characterized in this study, thus providing options for therapeutic and translational research.

关键词： Parkinson's disease Cynomolgus monkeys MPTP Motor behavior Spontaneous recovery Clinicalevolution

Anti-parkinsonian effects of octacosanol in 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-treated mice

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Neural Regeneration Research 2012年第14期7卷 1080-1087页

作者： Tao Wang Yanyong Liu Nan Yang Chao Ji piu chan Pingping Zuo Department of Neurobiology Beijing Institute of Geriatrics Xuanwu Hospital of Capital Medical University Beijing 100053 China Department of Pharmacology Institute of Basic Medical Sciences Peking Union Medical College ＆ Chinese Academy of Medical Sciences Beijing 100005 China

Our previous research showed that octacosanol exerted its protective effects in 6-hydroxydopamine-induced Parkinsonian rats. The goal of this study was to investigate whether octacosanol would attenuate neurotoxicity in 1-methyl-4-phenyl-l,2,3,6 tetrahydropyridine （MPTP）-treated C57BL/6N mice and its potential mechanism. Behavioral tests, tyrosine hydroxylase immunohistochemistry and western blot were used to investigate the effects of octacosanol in a mouse model of Parkinson＇s disease. Oral administration of octacosanol （100 mg/kg） significantly improved behavioral impairments Jn mice treated by MPTP and markedly ameliorated morphological appearances of tyrosine hydroxylase-positive neuronal cells in the substantia nigra. Furthermore, octacosanol blocked MPTP-induced phosphorylation of p38MAPK and JNK, but not ERK1/2. These findings implicated that the protective effects afforded by octacosanol might be mediated by blocking the phosphorylation of p38MAPK and JNK on the signa transduction in vivo. Considering its excellent tolerability, octacosanol might be considered as a candidate agent for clinical application in treating Parkinson＇s disease.

关键词： Parkinson's disease neuroprotecion mitogen-activated protein kinase c-Jun N-terminal kinase p38MAPK substantia nigra neural regeneration

Seropositivity rates of water channel protein 4 antibodies compared between a cell-based immunofluorescence assay and an enzyme-linked immunosorbent assay in neuromyelitis optica patients

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Neural Regeneration Research 2011年第32期6卷 2490-2494页

作者： Xiaoli Wu Zhangyuan Liao Jing Ye Huiqing Dong ChaodongWang piu chan Department of Neurology and Key Laboratory Ministry of Education on Neurodegenerative Diseases Xuanwu Hospital of Capital MedicalUniversity Beijing 100053 China Department of Neurology Xuanwu Hospital of Capital Medical University Beijing 100053 China

A total of 66 samples （from 27 cases with neuromyelitis optica, 26 cases with multiple sclerosis, aa 13 cases with optic neuritis） were tested for aquaporin-4 antibody by a cell-based immunofluorescence assay and an enzyme-linked immunosorbent assay. The sensitivities and specificities of the two assays were similar. We further analyzed an additional 68 patients and 93 healthy controls using the enzyme-linked immunosorbent assay. A Kappa test showed good consistency between the two methods in terms of detection of anti-aquaporin-4 antibody in the se of neuromyelitis optica patients. No significant correlations were identified with onset age or disea duration, suggesting that aquaporin-4 antibody is a good marker for neuromyelitis optica. The enzyme-linked immunosorbent assay can be used for quantifying aquaporin-4 antibody concentrations and may be useful to dynamically monitor changes in the levels of aquaporin-4 antibody during disease duration.

关键词： neuromyelitis optica cell-based immunofluorescence assay anti-aquaporin 4 antibody enzyme-linked immunosorbent assay long and extended spinal cord lesions neural regeneration

Progressive loss of striatal dopamine terminals in MPTP-induced acute parkinsonism in cynomolgus monkeys using vesicular monoamine transporter type 2 PET imaging([^(18)F]AV-133)

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Neuroscience Bulletin 2014年第3期30卷 409-416页

作者： Yajing Liu Feng Yue Rongping Tang Guoxian Tao Xiaomei Pan Lin Zhu Hank F.Kung piu chan Department of Neurobiology Xuanwu Hospital of Capital Medical University Key Laboratory of Neurodegenerative Diseases Ministry of Education Xuanwu Hospital of Capital Medical University Beijing Key Laboratory on Parkinson's Disease Wincon Theracells Biotechnologies Inc. Key Laboratory of Radiopharmaceuticals Beijing Normal University Department of Radiology University of Pennsylvania

The 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine （MPTP）-induced parkinsonism model, particularly in non-human primates, remains the gold-standard for studying the pathogenesis and assessing novel therapies for Parkinson＇s disease. However, whether the loss of dopaminergic neurons in this model is progressive remains controversial, mostly due to the lack of objective in vivo assessment of changes in the integrity of these neurons. In the present study, parkinsonism was induced in cynomolgus monkeys by intravenous administration of MPTP （0.2 mg/kg） for 15 days; stable parkinsonism developed over 90 days, when the symptoms were stable. Noninvasive positron emission tomographic neuroimaging of vesicular monoamine transporter 2 with 9-[18F] fluoropropyl-（＋）-dihydrotetrabenazine （[18F]AV-133） was used before, and 15 and 90 days after the beginning of acute MPTP treatment. The imaging showed evident progressive loss of striatal uptake of [18SF]AV-133. The dopaminergic denervation severity had a significant linear correlation with the clinical rating scores and the bradykinesia subscores. These findings demonstrated that [18F]AV-133 PET imaging is a useful tool to noninvasively evaluate the evolution of monoaminergic terminal loss in a monkey model of MPTP-induced parkinsonism.

关键词： Parkinson's disease non-human primate [18F]AV-133 VMAT2 positron emission tomography

Biomarker discovery for Parkinson’s disease

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Biomarker discovery for Parkinson’s disease

Early morning off in patients with Parkinson's disease:a Chinese nationwide study and a 7-question screening scale

中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： piu chan Department of Neurology Neurobiology and GeriatricsBeijing Institute of GeriatricsXuanwu Hospital of Capital Medical University

＜正＞Parkinson’s disease（PD） is a chronic debilitating disease characterized by the selective and progressive loss of nigrostriatal dopamine *** mechanisms underlying the pathophysiology of this disease are not fully *** dysfunction,oxidative damage,excitotoxicity,excessive iron accumulation and inflammation are likely to play a role in cell *** it is believed that toxic environmental factors,along with a possible genetic susceptibility,may lead to disease *** of the most imperative and challenging issues in PD field is to establish a standard for early *** one hand,by the time patients with PD become symptomatic and seek medical treatment,60%-80%of the neurons in the substantia nigra pars compacta have been irreversibly lost,meaning the present clinical diagnostic means are not sensitive *** the other,although parkinson’s disease affects patients later in life,abundant evidence suggests the existence of a "preclinical" stage that could start years before a subject can be diagnosed clinically,when an individual appears normal but is developing extensive pathological changes in he ***,early detection of PD is realizable,and in turn will improve disease management and enable potential neuroprotective therapies to be introduced at a stage when they would provide the greatest *** addition,biomarkers would also be useful in monitoring the effectiveness of treatments for *** undertake the initiative for discovery of biomarkers for PD,efforts have been made to establish national consortium and community longitudinal cohorts using standardized protocols for collection of clinical information and tissue *** addition,non-human primate model for PD has also been established to mimic the pathological processes of PD for novel biomarker *** talk will be focused on the establishment of the above-mentioned cohorts and models and preliminary results.

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Translational Neurodegeneration 2020年第3期9卷 370-382页

作者： Chao Han Wei Mao Jing An Lifei Jiao piu chan on behalf of the China Early Morning Off(EMO)Study Group National Clinical Research Center for Geriatric Disorders Xuanwu Hospital of Capital Medical UniversityBeijingChina Department of Neurobiology Neurology and GeriatricsXuanwu Hospital of Capital Medical University45 Changchun RoadBeijing 100053China Beijing Institute of Geriatrics Xuanwu Hospital of Capital Medical University45 Changchun RoadBeijing 100053China Clinical Center for Parkinson's Disease Xuanwu Hospital of Capital Medical University45 Changchun RoadBejjing 100053China Key Laboratories for Neurodegenerative Diseases of the Ministry of Education Xuanwu Hospital of Capital Medical University45 Changchun RoadBeijing 100053China Bejjing Key Laboratory for Parkinson's Disease Xuanwu Hospital of Capital Medical University45 Changchun RoadBeijing 100053China Parkinson Disease Center of Beiing Institute for Brain Disorders Xuanwu Hospital of Capital Medical University45 Changchun RoadBeijing 100053China Advanced Innovative Center for Human Brain Protection Xuanwu Hospital of Capital Medical University45 Changchun RoadBejing 100053China Medical department Lundbeck(Bejjing)Pharmaceutical Co.ItdBeijingChina 不详

Background:Early morning off(EMO)is a common feature of Parkinson's disease(PD).This study aimed to characterize its clinical features and develop a convenient and pragmatic self-assessment instrument in a Chinese nationwide ***:This study was conducted on 942 PD patients admitted to 55 clinic centers for movement disorders between June 2018 and May 2019 in *** logistic regression analyses were performed to determine potential risk factors and the most predictive symptoms of EMO,as well as whether EMO was an independent risk factor of functional dependency in daily *** on this,a 7-question scale was derived for EMO *** accuracy of this scale was assessed from the area under the receiver operative characteristic curve(AUROC)and its 95%confidence intervals(CIs).We further calculated sensitivity,specificity,positive predictive value(PPV),and negative predictive value(NPV)for the optimal cutoff ***:EMO occurred in 49.2%of PD patients across all disease *** identified 7 symptoms most predictive of EMO,including bradykinesia or rigidity,excessive sweating or salivation,ificulty in turning on or getting out of bed,muscle cramp,fatigue or sleepiness,frozen state or freezing gait,and *** resulting 7-item scale was confirmed to be of good discrimination with a relatively large AUROC of 0.83,a relatively high sensitivity of 75.7%,specificity of 77.5%,PPV of 76.5%,and NPV of 76.7%.Nonideal nighttime sleep,long PD duration,advanced H&Y stages,posture instability gait difficulty-dominant or mixed subtypes,and high levodopa dose were independently associated with increased risk of *** patients were at 87%higher(OR=1.87,95%C:1.07-3.32)risk of experiencing functional dependency in daily living compared with their ***:We demonstrated that EMO is a common feature for PD patients across all disease stages and put forward an EMO-specific screening card of sufficient accuracy and ***

关键词： Parkinson's disease Early morning off Motor symptoms Non-motor symptoms Screening scale