Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
Transl Stroke Res. 2012 Jul;3(Suppl 1):102-12. doi: 10.1007/s12975-012-0161-1. Epub 2012 Apr 12.
Cerebral amyloid angiopathy (CAA) related intracerebral hemorrhage (ICH) is a devastating form of stroke with no known therapies. Clinical, neuropathological, and genetic studies have suggested both overlap and divergence between the pathogenesis of CAA and the biologically related condition of Alzheimer's disease (AD). Among the genetic loci associated with AD are APOE and TOMM40, a gene in close proximity to APOE. We investigate here whether variants within TOMM40 are associated with CAA-related ICH and CAA neuropathology. Using cohorts from the Massachusetts General Hospital (MGH) and the Alzheimer's Disease Neuroimaging Initiative (ADNI), we designed a comparative analysis of high-density SNP genotype data for CAA-related ICH and AD. APOE ε4 was associated with CAA-related ICH and AD, while APOE ε2 was protective in AD but a risk factor for CAA. A total of 14 SNPs within TOMM40 were associated with AD (p < 0.05 after multiple testing correction), but not CAA-related ICH (all p > 0.20); as a result, all AD-associated SNPs within TOMM40 showed heterogeneity of effect in CAA-related ICH (BD p < 0.001). Analysis of CAA neuropathology in the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP), however, found that neuritic plaque, diffuse plaque burden, and vascular amyloid burden associated with all TOMM40 SNPs (p < 0.02). These results suggest that alterations in TOMM40 can promote vascular as well as plaque amyloid deposition, but not the full pathogenic pathway leading to CAA-related ICH.
脑淀粉样血管病（CAA）相关脑出血（ICH）是一种破坏性的中风形式，目前尚无已知的治疗方法。临床、神经病理学和遗传学研究表明，CAA 的发病机制与生物学上相关的阿尔茨海默病（AD）之间存在重叠和分歧。与 AD 相关的遗传位点包括 APOE 和 TOMM40，这是一个与 APOE 紧密相邻的基因。我们在这里研究 TOMM40 内的变体是否与 CAA 相关的 ICH 和 CAA 神经病理学有关。利用来自马萨诸塞州综合医院（MGH）和阿尔茨海默病神经影像学倡议（ADNI）的队列，我们设计了对 CAA 相关 ICH 和 AD 的高密度 SNP 基因型数据进行比较分析。APOE ε4 与 CAA 相关的 ICH 和 AD 相关，而 APOE ε2 在 AD 中是保护性的，但在 CAA 中是风险因素。TOMM40 内的总共 14 个 SNP 与 AD 相关（在多次测试校正后，p<0.05），但与 CAA 相关的 ICH 无关（所有 p>0.20）；因此，TOMM40 内的所有与 AD 相关的 SNP 在 CAA 相关的 ICH 中显示出效应的异质性（BD p<0.001）。然而，在宗教秩序研究（ROS）和拉什记忆与衰老项目（MAP）中对 CAA 神经病理学的分析发现，所有 TOMM40 SNP 与神经原纤维缠结、弥散斑块负担和血管淀粉样蛋白负担相关（p<0.02）。这些结果表明，TOMM40 的改变可以促进血管和斑块淀粉样蛋白的沉积，但不能促进导致 CAA 相关 ICH 的完整致病途径。
