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脑血管淀粉样变早期诊断模型的开发及验证
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注册号：

Registration number：

 ChiCTR2000039365 

最近更新日期：

Date of Last Refreshed on：

 2021-01-27 13:36:56 

注册时间：

Date of Registration：

 2020-10-24 00:00:00 

注册号状态：

预注册

Registration Status：

Prospective registration

注册题目：

脑血管淀粉样变早期诊断模型的开发及验证

Public title：

The Development and Validation of Early Diagnostic Models for Cerebral Amyloid Angiopathy

注册题目简写：

English Acronym：

研究课题的正式科学名称：

脑血管淀粉样变早期诊断模型的开发及验证

Scientific title：

The Development and Validation of Early Diagnostic Models for Cerebral Amyloid Angiopathy

研究课题代号(代码)：

Study subject ID：

在二级注册机构或其它机构的注册号：

The registration number of the Partner Registry or other register：

申请注册联系人：

黄珊珊 

研究负责人：

朱遂强 

Applicant：

Shanshan Huang 

Study leader：

Suiqiang Zhu 

申请注册联系人电话：

Applicant telephone：

 +86 18707165033

研究负责人电话：

Study leader's
telephone：

+86 13035101141

申请注册联系人传真 ：

Applicant Fax：

研究负责人传真：

Study leader's fax：

申请注册联系人电子邮件：

Applicant E-mail：

 65850560@qq.com

研究负责人电子邮件：

Study leader's E-mail：

 zhusuiqiang@163.com

申请单位网址(自愿提供)：

Applicant website(voluntary supply)：

研究负责人网址(自愿提供)：

Study leader's website(voluntary supply)：

申请注册联系人通讯地址：

湖北省武汉市解放大道1095号

研究负责人通讯地址：

湖北省武汉市解放大道1095号

Applicant address：

1095 Jiefang Avenue, Hankou, Wuhan, China

Study leader's address：

1095 Jiefang Avenue, Hankou, Wuhan, China

申请注册联系人邮政编码：

Applicant postcode：

 430030

研究负责人邮政编码：

Study leader's postcode：

 430030

申请人所在单位：

华中科技大学附属同济医院

Applicant's institution：

Tongji Hospital Affiliated to Huazhong University of Science and Technology

研究负责人所在单位：

华中科技大学附属同济医院

Affiliation of the Leader：

Tongji Hospital Affiliated to Huazhong University of Science and Technology

是否获伦理委员会批准：

是

Approved by ethic committee：

Yes

伦理委员会批件文号：

Approved No. of ethic committee：

 [2020]伦审字（S145）号

伦理委员会批件附件：

Approved file of Ethical Committee：

 查看附件View

批准本研究的伦理委员会名称：

华中科技大学同济医学院医学伦理委员会

Name of the ethic committee：

Medical Ethics Committee of Tongji Hospital Affiliated to Huazhong University of Science and Technology

伦理委员会批准日期：

Date of approved by ethic committee：

 2020-06-10 00:00:00

伦理委员会联系人：

陈汇

Contact Name of the ethic committee：

Hui Chen

伦理委员会联系地址：

湖北省武汉市航空路13号

Contact Address of the ethic committee：

13 Hangkong Road, Wuhan, Hubei, China

伦理委员会联系人电话：

Contact phone of the ethic committee：

伦理委员会联系人邮箱：

Contact email of the ethic committee：

研究实施负责（组长）单位：

华中科技大学同济医学院附属同济医院

Primary sponsor：

Tongji Hospital Affiliated to Huazhong University of science and technology

研究实施负责（组长）单位地址：

湖北省武汉市解放大道1095号

Primary sponsor's address：

1095 Jiefang Avenue, Hankou, Wuhan, China

试验主办单位(项目批准或申办者)：

Secondary sponsor：

国家：

中国

省(直辖市)：

湖北

市(区县)：

武汉

Country：

China

Province：

Hubei

City：

Wuhan

单位(医院)：

华中科技大学附属同济医院

具体地址：

解放大道1095号

Institution
hospital：

Tongji Hospital Affiliated to Huazhong University of science and technology

Address：

1095 Jiefang Avenue

经费或物资来源：

湖北省技术创新专项（重大项目）（编号 2019ACA132）

Source(s) of funding：

Hubei Technological Innovation Special Fund (CN) [Grant NO.2019ACA132]

研究疾病：

脑出血 / 脑血管淀粉样变  

Target disease：

Intracerebral hemorrhage / Cerebral amyloid angiopathy

研究疾病代码：

I61+ / E85.414+

Target disease code：

I61+ / E85.414+

研究类型：

观察性研究

Study type：

Observational study

研究所处阶段：

 回顾性研究 

Study phase：

Retrospective study

研究设计：

析因分组（即根据危险因素或暴露因素分组） 

Study design：

Factorial 

研究目的：

1. 建立华中科技大学同济医学院附属同济医院脑出血人群大样本数据库； 2. 建立并验证客观量化多维度CAA高危筛查预警模型及转归预测模型。  

Objectives of Study：

1. Establish a large-scale database of intracerebral hemorrhage population in Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology; 2. Establish and verify an multi-dimensional model for early screening and outcome prediction in high-risk CAA patients.

药物成份或治疗方案详述：

1. 开发和建立多维度评估指标的CAA高危人群筛查技术和转归预测模型 本部分研究是本项目的研究重点与核心内容。采用单中心回顾性队列研究方法。建立脑出血人群大样本数据库，并根据改良的Boston诊断标准，筛选很可能CAA患者，以同年龄高血压脑出血及健康人群作为对照，所有检测指标进行组间对比，进行本阶段所有研究。 1）评估CAA患者临床表型、精神心理认知及个人史。 收集研究对象临床基线信息,包括人口学资料、既往病史、用药情况、个人史, 家族史、经济状况。评估研究对象临床表型，包括脑出血患者出血部位、血肿体积及发病时美国国立卫生研究院中风量表（National Institutes of Health Stroke Scale,NIHSS）评分。2020年6月入院患者分别于14 天、3 月、6 月、12 月进行量表评估，采用汉密尔顿焦虑抑郁量表、神经认知功能量表MMSE/MoCA量表、改良的Rankin 评分对患者行为精神及认知进行全面评估。 综合回顾研究的观察结果，与对照组进行比对分析，筛选与CAA相关的临床表型、精神心理认知、个人史等。 2）确立CAA患者CT及MRI影像学特征性变化。 全面回顾或检测研究对象CT/MRI影像学改变。CAA患者不同核磁共振影像学对应不同临床意义，因其病理生理存在微梗塞及微出血特点，其在影像上主要分为出血性征象及缺血性征象，两种并存的混合性征象及其他临床意义尚未明确的征象。 1． 出血性征象 微出血（Cerebral microbleeds，CMBs），皮质蛛网膜下腔出血（cortical Subarachnoid Hemorrhage，cSAH），皮质含铁血黄素沉积（cortical Superficial Siderosis, cSS） 2． 缺血性征象 皮质微梗塞（Cortical Microinfarcts，CMIs），腔隙性梗塞 3． 混合性征象 白质高密度影（White Matter Hyperintensity，WMH） 4． 其他征象 半卵圆中心-血管周围间隙（Centrum semiovale-perivascular spaces，CSO-PVS） 回顾性观察研究记录发病时间影像学改变，2020年6月后纳入的研究对象分别于14 天、3 月、6 月、12 月进行随访，对比6月及12月影像学征象比对并记录，记录研究对象核磁共振小血管总负荷评分（Total small vessel disease burden，Total SVD burden）。即将核磁共振不同表现形式如脑叶微出血、皮质表面铁沉积、脑白质高信号及半卵圆中心-血管周围间隙四种不同的影像存在及严重程度进行评分，后进行加和，总分0-6。采用多变量回归分析，明确核磁共振小血管总负荷评分与CAA相关血管改变及CAA症状性脑出血、认知功能下降及缺血性卒中发生之间的相互关系。 3）确立CAA患者特定脑区PiB-PET显像指标。 淀粉样蛋白-PET是通过淀粉样蛋白Aβ特异性结合的正电子发射物质（碳11-匹兹堡复合物及AV-45）发放信号，经PET-CT采集后形成分子影像的无创手段，是反映淀粉样沉积一种途径。本项目将记录血管淀粉样变淀粉样沉积部位及严重程度。确立CAA患者特定脑区PiB-PET显像指标参数。 4）筛选CAA患者脑脊液特异性预警生化指标及遗传易感指标。 有研究表明CAA患者脑脊液可出现改变，表现为蛋白升高及细胞数轻度升高，脑脊液Aβ40和Aβ42浓度降低，Aβ抗体可呈阳性。同时70%以上的CAA相关血管炎患者表达为ApoE e4/e4基因型。本项目对研究对象进行血及脑脊液生化检测：检测血及脑脊液Aβ40和Aβ42，Aβ抗体、t-Tau,p-Tau等多种蛋白代谢产物改变。同时进行ApoE e2/e3/e4基因测序检测，明确ApoE e2/e4基因型与CAA临床表型、影像学特征之间的关系，从而找到CAA中国人群的遗传特征。 5）探索CAA患者特异性眼底改变及基于皮肤活检技术的外周血管特征。 CAA是各级小血管的中外膜淀粉样沉积为主要病理特征的脑小血管病变，而视网膜血管存在相同的胚胎演化、代谢及血管管径都与颅内血管相同。本项目拟探索CAA疾病诊断模型的新型、可操作、高度敏感的指标，长期随访观察眼底病变发生发展情况，以此动态观测疾病变化，拟探索CAA疾病转归预测相关的眼底参数。 皮肤是人体不可分割的一部分，皮肤病变是系统性疾病的表现或其组成部分。随着免疫组织化学及电子显微镜技术的发展，皮肤活检在神经系统相关疾病研究中的应用越来越多。本项目拟对2018年后纳入的研究对象取材皮肤组织，培养保存成纤维细胞，检测利用免疫组织化学反映，观察光学显微镜下皮肤小血管形态学改变，本项目将全方位探索CAA患者外周血管特征。 综合评估指标，开发建立多维度CAA高危人群早期筛查和转归预测模型。 2 前瞻性验证CAA多维度预警筛查技术和转归预测模型的有效性。 1）验证CAA早期多维度筛查模型： 单中心收集急性脑出血患者（样本量100，符合纳入及排除标准），根据模型预测患者CAA的患病风险，根据患病风险高低分为高危组、中低危组。对两组患者随访一年，比较1年内两组患者的CAA发病率是否符合预期，验证早期多维度筛查模型灵敏性和特异性。 2）验证CAA人群转归预测模型： 对同济医院神经内科CAA患者（样本量100）进行筛选，根据项目第一阶段开发的针对CAA人群转归预测模型，预测CAA患者转归，分为短期风险（<3月）、长期风险(>3月)。对两组患者随访6月，比较各组CAA患者的转归是否符合预期，验证CAA人群转归预测模型灵敏性和特异性。 

Description for medicine or protocol of treatment in detail：

1. Development and establishment of multi-dimensional evaluation index of CAA high-risk population screening technology and prognosis prediction model This part is the research focus and core content of this project. A single center retrospective cohort study was used. To establish a large sample database of cerebral hemorrhage population, and according to the improved Boston Diagnostic criteria, screen the patients who are likely to have CAA, and take the same age hypertensive cerebral hemorrhage and healthy people as controls. All the detection indexes were compared between groups, and all the studies in this stage were carried out. (1) The clinical phenotype, psychological cognition and personal history of CAA patients were evaluated. Clinical baseline information was collected, including demographic data, past medical history, medication, personal history, family history and economic status. The clinical phenotypes were evaluated, including bleeding site, hematoma volume and NIHSS score. In June 2020, the hospitalized patients were assessed by the Hamilton Anxiety and depression scale, MMSE / MOCA scale and modified Rankin score on 14 days, March, June and December respectively. The clinical phenotypes, psychological cognition and personal history related to CAA were screened. (2) Objective to establish the characteristic changes of CT and MRI in patients with CAA. The CT / MRI imaging changes of the subjects were comprehensively reviewed or detected. Different MRI images of CAA patients correspond to different clinical significance. Because of the characteristics of micro infarction and micro bleeding in pathophysiology, it can be mainly divided into hemorrhagic signs and ischemic signs, two coexisting mixed signs and other signs with unclear clinical significance. Hemorrhagic signs Cerebral microbleeds (CMBS), cortical subarachnoid hemorrhage (csah) and cortical superfacial siderosis (CSS) were observed Ischemic signs Cortical microinfarcts (CMIS), lacunar infarction Mixed signs White matter hyperintensity (WMH) Other signs Centrum semiovale perivascular spaces (cso-pvs) The imaging changes of onset time were observed and recorded retrospectively. After June 2020, the subjects were followed up for 14 days, 3 months, 6 months and 12 months respectively. The imaging signs of June and December were compared and recorded. The total small vessel disease burden (SVD) score of the subjects was recorded. The presence and severity of different MRI manifestations, such as lobar microbleeds, cortical iron deposition, white matter hyperintensity, and the central semiovale perivascular space, were scored, and then the total score was 0-6. Multivariate regression analysis was used to determine the relationship between total small vessel burden score and CAA related vascular changes, CAA symptomatic cerebral hemorrhage, cognitive decline and ischemic stroke. (3) Objective to establish PiB-PET imaging indexes of specific brain regions in patients with CAA. Amyloid pet is a noninvasive method to reflect amyloid deposition, which emits signals through the positron emission materials (C11 Pittsburgh complex and av-45) specifically combined with amyloid a β, and forms molecular images after PET-CT acquisition. This project will record the location and severity of amyloid deposition in vascular amyloidosis. Objective to establish the parameters of PiB-PET imaging in specific brain regions of CAA patients. (4) Objective to screen the specific early-warning biochemical indexes and genetic susceptibility indexes of cerebrospinal fluid in patients with CAA. Some studies have shown that the cerebrospinal fluid of patients with CAA can be changed, which is characterized by increased protein and slightly increased cell number, decreased concentration of a β 40 and a β 42 in cerebrospinal fluid, and positive a β antibody. At the same time, more than 70% of patients with CAA associated vasculitis expressed APOE e4 / E4 genotype. In this project, biochemical detection of blood and cerebrospinal fluid was carried out: detection of a β 40 and a β 42, a β antibody, t-tau, p-tau and other protein metabolites in blood and cerebrospinal fluid. At the same time, apoE 2 / E3 / E4 gene sequencing was carried out to determine the relationship between ApoE 2 / E4 genotype and clinical phenotype and imaging characteristics of CAA, so as to find the genetic characteristics of CAA Chinese population. (5) Objective to explore the specific changes of fundus and the characteristics of peripheral blood vessels based on skin biopsy in patients with CAA. CAA is a small cerebral vascular disease characterized by amyloid deposition in the adventitia and adventitia. Retinal vessels have the same embryonic evolution, metabolism and diameter as intracranial vessels. This project intends to explore the new, operable and highly sensitive indicators of CAA disease diagnosis model, long-term follow-up observation of the occurrence and development of fundus lesions, so as to dynamically observe the changes of diseases, and explore the fundus parameters related to the prognosis of CAA disease. Skin is an integral part of the human body, and skin lesions are the manifestations or components of systemic diseases. With the development of immunohistochemistry and electron microscopy, skin biopsy has been widely used in the study of nervous system related diseases. In this project, skin tissue was collected from the subjects after 2018, fibroblasts were cultured and preserved, immunohistochemistry was used to detect the morphological changes of skin small vessels under the light microscope. This project will explore the characteristics of peripheral blood vessels in patients with CAA in an all-round way. Comprehensive evaluation index, development and establishment of multi-dimensional CAA high-risk population early screening and prognosis prediction model. 2. Prospectively verify the effectiveness of CAA multi-dimensional early warning screening technology and outcome prediction model. (1) To verify the early multidimensional screening model of CAA Patients with acute intracerebral hemorrhage (sample size 100, in line with the inclusion and exclusion criteria) were collected from a single center. According to the model, the risk of patients with CAA was predicted, and they were divided into high-risk group, medium and low-risk group according to the risk. The two groups were followed up for one year. The incidence rate of CAA in the two groups was compared with the expectation in 1 years. (2) To verify the prediction model of CAA population outcome According to the outcome prediction model for CAA population developed in the first stage of the project, the outcome of CAA patients was predicted, which was divided into short-term risk (< 3 months) and long-term risk (> 3 months). The patients in the two groups were followed up for 6 months to compare the outcome of CAA patients in each group, and verify the sensitivity and specificity of CAA population outcome prediction model. 

纳入标准：

Inclusion criteria

排除标准：

① 发病时凝血功能障碍或发病前正在使用抗凝药者（INR>1.5）；
② 血小板计数<100×10^9/L；
③ 合并其他系统功能严重衰竭或各种疾病最终阶段者；
④ 继发性脑出血如颅内动脉瘤、动-静脉畸形或肿瘤卒中等；
⑤ 依从性不好或可能出国等原因导致1年内随访困难者；
⑥ 多维度筛查指标信息严重不完整，如无影像学资料、入院立即死亡。

Exclusion criteria：

1. Patients with coagulation dysfunction at the time of onset or using anticoagulants before onset (INR > 1.5);
2. Patients with platelet count < 100 x 10 ^ 9 / L;
3. Patients with severe failure of other systems or final stage of various diseases;
4. Patients with secondary cerebral hemorrhage such as intracranial aneurysm, arteriovenous malformation or tumor stroke;
5. Patients with poor compliance or going abroad may lead to difficult follow-up within one year;
6. Patients with serious incomplete information of multidimensional screening indicators, if there is no imaging data, will die immediately after admission.

研究实施时间：

Study execute time：

从 From 2020-01-01 00:00:00至 To 2022-02-28 00:00:00  

征募观察对象时间：

Recruiting time：

从 From 2020-11-01 00:00:00 至 To 2021-02-28 00:00:00

干预措施：

Interventions：

组别：

脑血管淀粉样变组、深部出血组及正常对照组

样本量：

 100

Group：

Probable CAA Group, Deep Intracerebral Hemorrhage Group and Healthy Group

Sample size：

干预措施：

无

干预措施代码：

Intervention：

Nil

Intervention code：

研究实施地点：

Countries of recruitment and research settings：

国家：

 中国

省(直辖市)：

 湖北 

市(区县)：

 武汉 

Country：

China

Province：

Hubei

City：

Wuhan

单位(医院)：

 华中科技大学附属同济医院 

单位级别：

 三级甲等 

Institution
hospital：

Tongji Hospital Affiliated to Huazhong University of Science and Technology

Level of the institution：

Tertiary A

测量指标：

Outcomes：

指标中文名：

临床表型

指标类型：

主要指标

Outcome：

Clinical phenotype

Type：

Primary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

指标中文名：

精神心理认知评分

指标类型：

主要指标

Outcome：

Psychological Cognitive Score

Type：

Primary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

指标中文名：

CT及MRI影像学特征

指标类型：

次要指标

Outcome：

CT and MRI imaging features

Type：

Secondary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

指标中文名：

特定脑区PiB-PET显像

指标类型：

次要指标

Outcome：

PiB-PET imaging of brain

Type：

Secondary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

指标中文名：

脑脊液特异性预警生化指标

指标类型：

次要指标

Outcome：

CSF specific biomarkers

Type：

Secondary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

指标中文名：

遗传易感指标

指标类型：

次要指标

Outcome：

Genetic factors

Type：

Secondary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

指标中文名：

特异性眼底改变

指标类型：

次要指标

Outcome：

Specific changes in the fundus

Type：

Secondary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

指标中文名：

基于皮肤活检技术的外周血管特征

指标类型：

次要指标

Outcome：

Characteristics of peripheral vessels based on skin biopsy technique

Type：

Secondary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

指标中文名：

脑出血复发

指标类型：

次要指标

Outcome：

Recurrent intracerebral hemorrhage

Type：

Secondary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

指标中文名：

认知功能减退

指标类型：

次要指标

Outcome：

Cognitive impairment

Type：

Secondary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

指标中文名：

脑缺血事件发生

指标类型：

次要指标

Outcome：

Ischemic events

Type：

Secondary indicator

测量时间点：

测量方法：

Measure time point of outcome：

Measure method：

采集人体标本：

Collecting sample(s)
from participants：

标本中文名：

血液

组织：

Sample Name：

Blood

Tissue：

人体标本去向

 使用后销毁  

说明

Fate of sample：

Destruction after use  

Note：

征募研究对象情况：

Recruiting status：

尚未开始

Not yet recruiting

年龄范围：

Participant age：
最小 Min age 18 岁 years
最大 Max age 80 岁 years

性别：

男女均可

Gender：

Both

随机方法（请说明由何人用什么方法产生随机序列）：

不适用

Randomization Procedure (please state who generates the random number sequence and by what method)：

N/A

是否公开试验完成后的统计结果:

Calculated Results after the Study Completed public access:

公开/Public

盲法：

N/A

Blinding：

N/A

试验完成后的统计结果（上传文件）：

Calculated Results after
the Study Completed(upload file)：

是否共享原始数据：

IPD sharing

是Yes

共享原始数据的方式（说明：请填入公开原始数据日期和方式，如采用网络平台，需填该网络平台名称和网址）：

北京大学临床数据研究平台（www.h6world.net.crdp.pku.edu.cn）

The way of sharing IPD”(include metadata and protocol, If use web-based public database, please provide the url)：

Clinical Research Data Platform of Peking University (www.h6world.net.crdp.pku.edu.cn)

数据采集和管理（说明：数据采集和管理由两部分组成，一为病例记录表(Case Record Form, CRF)，二为电子采集和管理系统(Electronic Data Capture, EDC)，如ResMan即为一种基于互联网的EDC：

病例记录表

Data collection and Management (A standard data collection and management system include a CRF and an electronic data capture：

Case Record Form

数据与安全监察委员会：

Data and Safety Monitoring Committee：

暂未确定/Not yet

注册人：

Name of Registration：

  2020-10-24 13:16:23
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