RATIONALE The Boston criteria are used worldwide for the in vivo diagnosis of cerebral amyloid angiopathy and are the basis for clinical decision-making and research in the field. Given substantial advances in cerebral amyloid angiopathy's clinical aspects and MRI biomarkers, we designed a multicenter study within the International cerebral amyloid angiopathy Association aimed at further validating the diagnostic accuracy of the Boston and potentially improving and updating them. AIM We aim to derive and validate an updated "version 2.0" of the Boston criteria across the spectrum of cerebral amyloid angiopathy-related presentations and MRI biomarkers. SAMPLE SIZE ESTIMATES Participating centers with suitable available data (see Methods) were identified from existing collaborations and an open invitation to the International Cerebral Amyloid Angiopathy Association emailing list. Our study sample will include: (1) a derivation cohort - Massachusetts General Hospital (MGH), Boston cases from inception to 2012 (∼150 patients); (2) temporal external validation cohort - MGH, Boston cases from 2012 to 2018 (∼100 patients); and (3) geographical external validation cohort - non-Boston cases (∼85 patients). METHODS AND DESIGN Multicenter collaborative study. We will collect and analyze data from patients' age ≥ 50 with any potential sporadic cerebral amyloid angiopathy-related clinical presentations (spontaneous intracerebral hemorrhage, transient focal neurological episodes and cognitive impairment), available brain MRI ("index test"), and histopathologic assessment for cerebral amyloid angiopathy ("reference standard" for diagnosis). Trained raters will assess MRI for all prespecified hemorrhagic and non-hemorrhagic small vessel disease markers of interest, according to validated criteria and a prespecified protocol, masked to clinical and histopathologic features. Brain tissue samples will be rated for cerebral amyloid angiopathy, defined as Vonsattel grade ≥2 for whole brain autopsies and ≥1 for cortical biopsies or hematoma evacuation. Based on our estimated available sample size, we will undertake pre-specified cohort splitting as above. We will: (a) pre-specify variables and statistical cut-offs; (b) examine univariable and multivariable associations; and (c) then assess classification measures (sensitivity, specificity etc.) for each MRI biomarker individually, in relation to the cerebral amyloid angiopathy diagnosis reference standard on neuropathology in a derivation cohort. The MRI biomarkers strongly associated with cerebral amyloid angiopathy diagnosis will be selected for inclusion in provisional (probable and possible cerebral amyloid angiopathy) Boston criteria v2.0 and validated using appropriate metrics and models. STUDY OUTCOMES Boston criteria v2.0 for clinical cerebral amyloid angiopathy diagnosis. DISCUSSION This work aims to potentially update and improve the diagnostic test accuracy of the Boston criteria for cerebral amyloid angiopathy and to provide wider validation of the criteria in a large sample. We envision that this work will meet the needs of clinicians and investigators and help accelerate progress towards better treatment of cerebral amyloid angiopathy.

中文翻译：

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推进散发性脑淀粉样血管病的诊断标准：波士顿标准 v2.0 的多中心 MRI 病理学验证研究方案。

基本原理 波士顿标准在全球范围内用于脑淀粉样血管病的体内诊断，是该领域临床决策和研究的基础。鉴于脑淀粉样血管病的临床方面和 MRI 生物标志物取得了实质性进展，我们在国际脑淀粉样血管病协会内设计了一项多中心研究，旨在进一步验证波士顿的诊断准确性并可能改进和更新它们。目的 我们的目标是在脑淀粉样血管病相关表现和 MRI 生物标志物的范围内推导出和验证波士顿标准的更新“2.0 版”。样本量估计从现有合作中确定了具有合适可用数据（见方法）的参与中心，并公开邀请国际脑淀粉样血管病协会电子邮件列表。我们的研究样本将包括：（1）一个派生队列 - 马萨诸塞州总医院（MGH），波士顿病例从开始到 2012 年（~150 名患者）；(2) 时间外部验证队列——MGH，波士顿病例，2012 年至 2018 年（~100 名患者）；(3) 地理外部验证队列 - 非波士顿病例（~85 名患者）。方法和设计 多中心合作研究。我们将收集和分析年龄 ≥ 50 岁且有任何潜在散发性脑淀粉样血管病相关临床表现（自发性脑出血、暂时性局灶性神经系统发作和认知障碍）、可用的脑部 MRI（“指数测试”）和脑淀粉样血管病的组织病理学评估（诊断的“参考标准”）。训练有素的评估者将根据经过验证的标准和预先指定的方案，对所有预先指定的出血性和非出血性小血管疾病感兴趣的标记物进行 MRI 评估，掩盖临床和组织病理学特征。脑组织样本将被评定为脑淀粉样血管病，定义为 Vonsattel 等级≥2 用于全脑尸检，≥1 用于皮质活检或血肿清除。根据我们估计的可用样本量，我们将如上所述进行预先指定的群组拆分。我们将： (a) 预先指定变量和统计截止值；(b) 检查单变量和多变量关联；(c) 然后根据推导队列中神经病理学的脑淀粉样血管病诊断参考标准，分别评估每个 MRI 生物标志物的分类测量值（敏感性、特异性等）。将选择与脑淀粉样血管病诊断密切相关的 MRI 生物标志物纳入临时（可能和可能的脑淀粉样血管病）波士顿标准 v2.0，并使用适当的指标和模型进行验证。研究结果 用于临床脑淀粉样血管病诊断的波士顿标准 v2.0。讨论 这项工作旨在潜在地更新和提高波士顿脑淀粉样血管病标准的诊断测试准确性，并在大样本中对标准进行更广泛的验证。