Effects of vascular risk factors on risk for dementia and stroke after late-onset epilepsy (EpilepsyCOG)

项目摘要 保护认知能力和大脑健康是老年人最关心的问题。阿尔茨海默病和 阿尔茨海默病相关痴呆(AD/ADRD)和中风对迟发性癫痫的影响不成比例 (LOE)，定义为在≥65岁时诊断的LOE。患有LOE的人有2到3倍的可能性随后 与那些没有LOE的人相比，经历AD/ADRD和中风的人。然而，目前LOE的临床实践 主要侧重于癫痫控制，没有任何实践指南具体说明如何降低 随后的AD/ADRD和卒中。保持尽可能好的大脑健康将需要准确地整合 将风险评估和有效的预防策略纳入癫痫管理。我们的主要假设是 LOE是癫痫前期血管危险因素负担过重的早期临床表现--标志 (VRF)和亚临床或隐匿性血管性脑损伤(VBI)。在一些患者中，LOE可能是第一个 血管疾病的表现。我们的假设得到了我们之前的工作以及其他人的支持， 这表明(A)VRF是认知功能减退、AD/ADRD和中风的重要贡献者，(B)VRF是 与LOE相关，以及(C)VRF对认知功能减退和中风的影响在存在时更强 癫痫的症状。因此，现有的AD/ADRD和中风/心血管疾病风险预测算法 心血管疾病(CVD)可能低估了LOE患者的风险，未能确定谁将受益于 积极降低血管风险。我们提出了一项史无前例的努力来利用和汇集个人 来自美国国立卫生研究院资助的六项前瞻性队列研究的参与者数据，因为没有一项队列研究将 大到足以检验我们的主要假设。我们在这项申请中的目标是严格调查 LOE和癫痫前VRF与认知功能减退及潜在生物学特征的关系 机制，开发AD/ADRD和中风/CVD的风险预测算法，准确估计 LOE的设置，并将LOE集成到微观仿真建模范式中，以测试VRF的效果 临床试验中的干预。我们将追求三个具体目标：(1)量化LOE与 认知功能下降，确定癫痫前期VRF和MRI定义的隐性VBI在这种关联中的作用，以及 探索性别和种族/民族的差异。(2)评估LOE作为一种新的隐性VBI危险标志物， 将AD/ADRD和卒中/心血管疾病的风险预测变化纳入既定的风险预测 算法。(3)使用微观模拟，量化基于风险/收益的量身定制治疗的增量价值 哪些治疗决策是由个体预测的事件风险来指导的，而不是传统的靶向治疗 治疗目标是将VRF措施减少到特定水平的方法，关于AD/ADRD和 LOE后发生卒中/CVD。该提案的成功完成将推动LOE的临床护理模式 考虑准确的血管风险评估/治疗。

Project Summary Preserving cognitive ability and brain health is a salient concern of older adults. Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD) and stroke disproportionately affect late-onset epilepsy (LOE), defined as LOE diagnosed at ages ≥65. Persons with LOE are 2 to 3 times more likely to subsequently experience AD/ADRD and stroke compared to those without LOE. However, current clinical practice in LOE focuses primarily on seizure control, without any practice guidelines specifying how to mitigate risks for subsequent AD/ADRD and stroke. Preserving the best possible brain health will require integrating accurate risk assessment and effective prevention strategies into epilepsy management. Our main hypothesis is that LOE is an early clinical manifestation—a marker—of an excess burden of pre-epilepsy vascular risk factors (VRFs) and subclinical or covert vascular brain injury (VBI). In some patients, LOE may be the first manifestation of vascular disease. Our hypothesis is supported by our prior work, as well as those of others, that show that (a) VRFs are significant contributors to cognitive decline, AD/ADRD, and stroke, (b) VRFs are associated with LOE, and (c) the effects of VRFs on cognitive decline and stroke are stronger in the presence of epilepsy. Consequently, existing risk prediction algorithms for AD/ADRD and stroke/cardiovascular disease (CVD) may underestimate risk in individuals with LOE, failing to identify those who would benefit from aggressive vascular risk reduction. We propose an unprecedented effort to leverage and pool individual participant data from six NIH-funded US-based prospective cohort studies, because no single cohort study will be large enough to test our main hypothesis. Our objectives in this application are to rigorously investigate relationships of LOE and pre-epilepsy VRFs with cognitive decline and characterize potential biological mechanisms, develop risk prediction algorithms for AD/ADRD and stroke/CVD that accurately estimate risk in the setting of LOE, and integrate LOE into a microsimulation modeling paradigm for testing the effects of VRF interventions in clinical trials. We will pursue three Specific Aims: (1) Quantify the association of LOE with cognitive decline, identify the roles of pre-epilepsy VRFs and MRI-defined covert VBI in this association, and explore differences by sex and race/ethnicity. (2) Assess whether LOE, as a novel risk marker of covert VBI, changes predicted risks for AD/ADRD and stroke/CVD when incorporated into established risk prediction algorithms. (3) Using microsimulation, quantify the incremental value of risk/benefit-based tailored treatment, in which treatment decisions are guided by individual predicted event risk, over a traditional treat-to-target approach, in which the treatment goal is to reduce VRF measures to specific levels, on rates of AD/ADRD and stroke/CVD after LOE. Successful completion of this proposal will propel clinical care models for LOE to consider accurate vascular risk assessment/treatment.