第一部分 神经黑色素磁共振成像在帕金森病早期诊断中的应用研究 第一小部分 初诊帕金森病黑质和蓝斑的神经黑色素磁共振成像特征 研究背景和目的：帕金森病(Parkinson’s disease，PD)是中老年常见的神经退行性疾病之一，以含有神经黑色素的多巴胺能神经元坏死为重要的病理学特征。 T1-加权神经黑色素磁共振成像(neuromelanin-sensitive magnetic resonance imaging，NM-MRI)可在体检测脑内神经黑色素。本研究旨在通过NM-MRI成像技术研究初诊PD患者黑质和蓝斑的神经黑色素变化。 材料与方法：本研究共纳入51名初诊未服药PD患者(Hoehn&Yahr分级12)和28名健康志愿者。所有研究对象均接受临床资料采集、运动和认知评估，并予以NM-MRI检查。将NM-MRI图像上黑质致密带(substantia nigra pars compacta，SNc)分为内侧部、中间部和外侧部三个亚区，分别对SNc三个亚区进行宽度和对比噪声比(contrast-to-noise ratio，CNR)测量：对蓝斑(locus coeruleus，LC)进行CNR测量。比较PD组和健康对照组之间NM-MRI测量值的差异，并分析PD组NM-MRI测量值与临床指标的相关性。 结果：初诊PD组SNc外侧部、中间部和内侧部的宽度及CNR均较健康对照组显著减低。PD患者临床重侧的UPDRS运动评分与对侧SNc平均宽度存在弱相关性(r =-0.289，p=0.040)。PD组左侧LC的CNR值显著低于对照组(p=0.011)。 结论：通过NM-MRI技术发现，初诊PD患者黑质致密带和蓝斑神经黑色素显著减少。NM-MRI可用于检测初诊PD脑干神经黑色素的变化，该技术有望成为PD早期诊断的神经影像标记物。 关键词：帕金森病，神经黑色素，磁共振成像 中图分类号：R445 第二小部分 NM-MRI对特发性震颤和初诊震颤型帕金森病的鉴别诊断效能评估 研究背景和目的：特发性震颤(essential tremor，ET)和帕金森病(Parkinson’s disease，PD)，尤其是震颤型帕金森病(tremor-dominant PD，PD〓)部分症状重叠，临床易误诊。本研究旨在评估神经黑色素磁共振成像(neuromelanin-sensitive MRI，NM-MRI)对ET和初诊PD〓的鉴别诊断价值。 材料与方法：本研究共纳入18名未经治疗的ET患者、21名初诊PD〓患者及21名健康志愿者。所有入组的研究对象均接受临床检查、运动和认知评估以及包括NM-MRI序列的磁共振检查。将NM-MRI图像上黑质致密带(substantia nigra pars compacta，SNc)分为内侧部、中间部和外侧部三个亚区，分别对SNc三个亚区进行宽度、对比噪声比(contrast-to-noise ratio，CNR)测量。此外，对SNc每个亚区进行3级视觉评分，将所有SNc亚区评分相加得到视觉评分总和，用于视觉分析。 NM-MRI图像特征对ET和PD〓的鉴别诊断效能评估由受试者工作特征曲线(receiver operating characteristic，ROC)和净重分类改善指标(net reclassification improvement，NRI)进行评价。 结果：PD〓组sNc外侧部及中间部的宽度及CNR值均显著低于ET组和正常对照组， ET和正常对照组的SNc测量值无统计学差异。利用视觉分析的方法，PD〓的SNc视觉评分总和显著低于ET组和正常对照组。鉴别ET和PD〓，SNc的外侧部宽度具有最佳鉴别诊断效能(ROC曲线下面积=0.923)，视觉分析亦具有较高的诊断价值(ROC曲线下面积=0.865)。NRI结果显示视觉分析与SNc外侧部宽度具有相同的诊断效能。 结论：ET和PD〓的黑质致密带神经黑色素改变方式不同。NM-MRI图像上，SNc的定量测量及视觉评价对鉴别ET和PD〓均具有较高的诊断效能。NM-MRI结合视觉评价有助于临床进行震颤疾病的鉴别诊断。 关键词：帕金森病，特发性震颤，神经黑色素，磁共振成像，诊断试验 中图分类号：R445 第二部分 神经黑色素影像特征和帕金森病临床特征的在体研究 第一小部分 基于NM-MRI探讨初诊帕金森病不同临床表型的神经黑色素变化 研究背景和目的：帕金森病(Parkinson’s disease，PD)临床症状多样，可能存在不同的临床亚型。神经黑色素磁共振成像(neuromelanin-sensitive magnetic resonance imaging，NM-MRI)可在体检测PD神经黑色素变化。本研究旨在通过NM-MRI成像探讨(1)PD运动亚型的脑干神经黑色素是否存在差异；(2)伴或不伴抑郁症状的PD患者脑干神经黑色素的变化特征。 材料与方法：本研究共纳入51名初诊未服药PD患者和28名健康志愿者。所有研究对象接受临床体检、运动、认知和抑郁量表评估，以及NM-MRI磁共振检查。根据PD患者的UPDRS运动评分结果进行运动分型，根据患者抑郁量表结果将患者分为PD伴抑郁症状和PD不伴抑郁症状两组。NM-MRI图像上黑质致密带(substantia nigra pars compacta，SNc)分为内侧部、中间部和外侧部三个亚区，分别对SNc三个亚区进行宽度、对比噪声比(contrast-to-noise ratio，CNR)测量；对蓝斑(locus coeruleus，LC)进行CNR测量。分析NM-MRI测量值在PD不同运动亚型间的差异以及与抑郁症状的关系。 结果：初诊PD各运动亚型黑质致密带和蓝斑的NM-MRI测量值无显著统计学差异。PD伴抑郁症状组的左侧蓝斑CNR值显著低于健康对照组和PD不伴抑郁症状组，PD伴／不伴抑郁症状患者的SNc测量值无差异。 结论：初诊PD运动亚型之间的黑质和蓝斑的神经黑色素改变无显著差异。PD伴抑郁症状患者的蓝斑神经黑色素减少较PD不伴抑郁症状患者更为显著。本研究结果可能为帕金森病的非运动症状提供了新的病理生理学证据。 关键词：帕金森病，神经黑色素，磁共振成像，临床表型，抑郁 中图分类号：R445 第二小部分 利用NM-MRI技术在体评价黑质神经黑色素与帕金森病严重程度的关系 研究背景和目的：帕金森病(Parkinson’s disease，PD)中，黑质多巴胺能神经元的坏死与PD病程、疾病严重程度等临床特征相关。本研究旨在利用NM-MRI技术，探讨黑质神经黑色素与帕金森病严重程度相关性，以期为PD疾病监测的长期目标寻找有效、可行的生物学标记物。 材料与方法：本研究共纳入66例帕金森病患者和31例健康志愿者。所有研究对象均接受病史采集、体格检查、运动评估以及NM-MRI检查。PD患者根据症状严重程度分为PD轻症组(Hoehn&Yahr 1-2.5级)和PD重症组(Hoehn&Yahr 3级及以上)。首先，比较对照组、PD轻症组和PD重症组NM-MRI图像的主观评分和脑桥的信号-噪声比(signal-to-noise ratio，SNR)。然后，剔除NM-MRI图像质量不佳的病例后，对筛选后NM-MRI图像进行测量和后续分析。测量黑质致密带(substantia nigra pars compacta，SNc)内侧部、中间部及外侧部高信号区域的宽度和对比-噪声比(contrast-to-noise ratio，CNR)，分析NM-MRI测量值在对照组、PD轻症组和PD重症组间的差异，以及NM-MRI测量值与病程和疾病严重程度之间的相关性。 结果：对照组、PD轻症组和PD重症组三组间NM-MRI图像主观评估结果和SNR均无统计学差异。剔除3例NM-MRI图像质量不佳的病例后进一步分析， PD组(n=63)SNc内侧部、中间部和外侧部宽度和CNR值均较对照组(n=31)显著减低。PD重症组(n=13)SNc中间部宽度和CNR值较PD轻症组(n=50)显著减低，SNc内侧部和外侧部测量值两组间无统计学差异。部分SNc测量值与PD病程、Hoehn&Yahr分级和UPDRS-III评分具有相关性。 结论：NM-MRI图像质量不受PD疾病严重程度影响。NM-MRI可有效评估黑质神经黑色素与PD严重程度的关系。NM-MRI具有监测PD疾病进展的潜力。 关键词：帕金森病，神经黑色素，磁共振成像，疾病严重程度 中图分类号：R445

Part I Neuromelanin-sensitive MRI in early diagnosis of Parkinson’s disease: a clinical study Subpart I Neuromelanin-sensitive MRI features of the substantia nigra and locus coeruleus in de novo Parkinson’s disease Objectives: Neuromelanin of the brainstem, which is considered a marker of neurodegeneration in Parkinson’s disease (PD), can be detected by T1-weighted neuromelanin-sensitive magnetic resonance imaging (NM-MRI). We aimed to investigate the NM-MRI features of de novo PD. Materials and Methods: Fifty-one patients with de novo PD (Hoehn and Yahr stage 1-2) and 28 healthy controls were recruited. All subjects underwent clinical and MRI examinations including NM-MRI sequence. The width and contrast-to-noise ratio (CNR) of the substantia nigra pars compacta (SNc) and the CNR of the locus coeruleus (LC) were measured on NM-MRI images. Results: Both the width and CNR values of the high-intensity signals in the SNc were significantly decreased in the lateral, central and medial SNc subregions in de novo PD patients compared to control subjects. A significant weak correlation was observed between the average width of the contralateral SNc and the lateralized UPDRS motor score from the clinically most-affected side in PD patients. The CNR value of left LC in PD patient was significantly lower than controls. Conclusions: Neuromelanin of SNc and LC was decresed in de novo PD patients. NMMRI may be a biomarker for the diagnosis of early PD. Key Words: Parkinson’s disease, neuromelanin, MRI 中图分类号:R445 Subpart II Neuromelanin-sensitive MRI of substantia nigra: an imaging biomarker to differentiate essential tremor from tremor-dominant Parkinson’s disease Objectives: Essential tremor (ET) and Parkinson’s disease (PD) have overlapping manifestations that can be possibly misdiagnosed in clinical work, particularly tremor-dominant subtype. We aimed to evaluate whether neuromelanin-sensitive magnetic resonance imaging (NM-MRI) features in the substantia nigra pars compacta(SNc) were of diagnostic value to differentiate untreated ET from de novo tremor-dominant PD (PD〓). Materials and Methods: Eighteen untreated ET patients, 21 de novo PD〓 patients and 21 healthy control subjects were recruited. All the subjects underwent clinical examination, motor and cognitive evaluations, as well as NM-MRI. High signal intensity of lateral, central and medial SNc subregions on NM-MRI were evaluated using the width, signal intensity (contrast-to-noise ratio, CNR) and visual rating analysis. Diagnostic test performance of SNc values was investigated by using receiver operating characteristic (ROC) analyses and net reclassification improvement (NRI). Results: The width and CNR values in lateral and central SNc subregions in PD〓 were significantly decreased compared with those in ET and control group. Using visual rating analysis, the total score of all SNc subregions were significantly reduced in PD〓 when compared with ET and control group. Width of lateral SNc subregion allowed the best differentiation between ET and PD〓 subjects (area under ROC curve, 0.923), and visual rating analysis also showed good diagnostic value (area under ROC curve, 0.865). NRI result showed that visual rating analysis and width of lateral SNc subregion had the same diagnostic power. Conclusion: The neuromelanin changes of SNc in ET and PD〓 follow the different patterns. Both the measurements and visual rating analysis of SNc on NM-MRI provide high diagnostic accuracy for differentiating ET from PD〓 subtype. NM-MRI combining visual rating analysis is a potential tool in diagnostic work-up of tremor disorders. Key words: Parkinson’s disease; essential tremor; neuromelanin; magnetic resonance imaging; diagnostic test 中图分类号:R455 Part II The application of neuromelanin-sensitive MRI in evaluating the clinical features in Parkinson’s disease: an in vivo study Subpart I The NM-MRI features in de novo Parkinson’s disesase phenotypes Objectives: The clinical manifestations of Parkinson’s disease (PD) varies from person to person. The loss of neuromelanin in PD can be detected by T1-weighted neuromelanin-sensitive magnetic resonance imaging (NM-MRI). We aimed to investigate whether the NM-MRI features are associated with motor and non-motor symptoms in de novo PD patients. Materials and Methods: Fifty-one patients with de novo PD and 28 healthy controls were recruited. All subjects underwent clinical examination, motor, cognitive and depression evaluations, as well as NM-MRI. De novo PD patients were classified into motor subtypes according to their UPDRS motor scores, meanwhile the patients were classified into PD with depressive symptom (PDd) and PD without depressive symptom (PDnd) based on the results of their depression evaluation. The width and contrast-tonoise ratio (CNR) of the substantia nigra pars compacta (SNc) and the CNR of the locus coeruleus (LC) were measured on NM-MRI images. Then the NM-MRI difference in PD clinical phenotypes was analyzed. Results: The measurements in the SNc and LC on NM-MRI were not significantly different among the PD motor subgroups. The CNR values of the left LC were significantly lower in the PD group than in the control group. Specifically, the subtype of PDd exhibited a significantly lower CNR in the left LC than the control and PDnd group. There was no significant difference in measurements of SNc between PDd and PDnd. Conclusions: SNc neuromelanin changes occur across both motor and non-motor (with and without depressive symptoms) subtypes, while LC changes are more notable in PD patients with depressive symptoms. Our results may provide new evidence to understand the pathophysiology of non-motor symptoms in PD. Key words: Parkinson’s disease, neuromelanin, phenotypes, depression 中图分类号:R445 Subpart II Neuromelanin-sensitive MRI features of the substantia nigra: relationship to disease severity in Parkinson's disease Objectives: Pathological evidence showed that the loss of dopaminergic neurons was associated with some clinical features in Parkinson’s disease (PD). Here, we aimed to investigate wheather neuromelanin-sensitive magnetic resonance imaging (NM-MRI) features in substantia nigra pars compacta(SNc) has correlations with disease duration and severity in PD, with the long-term goal of enabling clinical application of NM-MRI to track the progression in PD. Materials and Methods: Sixty-six patients with PD and 31 healthy controls were recruited. PD patients were classified into low disease severity subgroup (PD-low) and high disease severity subgroup (PD-high) according to their Hoehn & Yahr stage (H-Y stage). Firstly, subjective evaluating and signal-to-noise ratio (SNR) measuring were used to compare the quality of NM-MRI images among controls, PD-low patients and PD-high patients. Next, after exclusion the subjects with unqualified NM-MRI, the width and contrast-to-noise ratio (CNR) of SNc were measured on the qualified NM-MRI images. Then the measured NM-MRI parameters were compared among the control, PD-low and PD-high groups, and correlation between NM-MRI parameters and disease duration, H-Y stage and UPDRS-III score was analyzed. Results: No significant difference in the subjective evaluation and SNR of NM-MRI images was found among the control, PD-low and PD-high groups. Three subjects were excluded from the further analysis because of their bad NM-MRI quality. Both width and CNRs of the high signal intensity in SNc were significantly decreased in the lateral, central and medial SNc subregions in PD group, when compared with controls. The width and CNRs in the central subregion were significant lower in PD-high group than those in PD-low group. Some SNc measured parameters were correlated with disease duration、 Hoehn & Yahr stage and UPDRS-III score. Conclusion: The quality of NM-MRI was not affected by the PD severity. NM-MRI could detect the decrease of SNc neurolemanin in PD patients. Some NM-MRI features were related to the disease duration and severity. NM-MRI may be a potential tool to track the disease progression in PD. Key words: Parkinson’s disease, neuromelanin, magnetic resonance imaging, disease severity 中图分类号:R445