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

项目摘要 保持认知能力和大脑健康是老年人的一个突出问题。阿尔茨海默病和 阿尔茨海默病相关痴呆（AD/ADRD）和中风对晚发性癫痫的影响不成比例 (LOE)定义为年龄≥65岁时诊断的LOE。患有LOE的人随后发生的可能性是其他人的2至3倍。 与未发生LOE的患者相比，发生AD/ADRD和卒中的患者。然而，LOE的当前临床实践 主要侧重于缉获控制，没有任何实践指南具体说明如何减少风险， 随后AD/ADRD和中风。保持最佳的大脑健康将需要整合准确的 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是癫痫前血管危险因素过度负荷的早期临床表现-标志物 （VRF）和亚临床或隐性血管性脑损伤（VBI）。在某些患者中，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是认知能力下降、AD/ADRD和中风的重要因素，（B）VRF是 与LOE相关，以及（c）VRF对认知下降和中风的影响在存在 癫痫的症状因此，AD/ADRD和卒中/心血管疾病的现有风险预测算法 (CVD)可能低估了LOE患者的风险，未能确定那些从LOE中受益的人。 积极降低血管风险。我们提出了一个前所未有的努力，利用和汇集个人 参与者数据来自六个NIH资助的美国前瞻性队列研究，因为没有一个队列研究将 足以验证我们的主要假设。我们在这个应用程序中的目标是严格调查 LOE和癫痫前VRF与认知功能下降的关系，并表征潜在的生物学特性 机制，开发AD/ADRD和卒中/CVD的风险预测算法， LOE的设置，并将LOE集成到用于测试VRF效果的微观仿真建模范例中 干预临床试验。我们将追求三个具体目标：（1）量化LOE与 认知能力下降，确定癫痫前VRF和MRI定义的隐性VBI在这种关联中的作用， 探索性别和种族/民族的差异。(2)评估LOE作为隐性VBI的新风险标志物， 当纳入既定风险预测时，AD/ADRD和卒中/CVD的预测风险发生变化 算法(3)使用微观模拟，量化基于风险/获益的定制治疗的增量价值， 与传统的靶向治疗相比， 方法，治疗目标是将VRF指标降低至特定水平，AD/ADRD发生率和 LOE后卒中/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.