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

点击翻译按钮获取中文摘要

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.