Explaining cognitive heterogeneity in temporal lobe epilepsy (TLE): Identifying unique imaging features, health-related risk factors and protective factors in TLE subtypes

项目摘要/摘要 颞叶癫痫(TLE)是最常见的局灶性癫痫，其特点是 衰弱和进行性认知障碍。因此，TLE患者经常报告生活质量较差 以及日常功能受损。然而，在认知的性质和严重性上存在显著的差异 在TLE患者中观察到的损害，一些患者表现出全身性损害和 其他人则表现出相对正常的认知特征。尽管众所周知认知能力的可变性 在患者中观察到的损害，很少有研究专注于识别不同的认知 TLE综合征的表型。此外，人们对其他与健康有关的风险或 可能导致这种变异性的个别因素。与健康相关的风险因素，如血管因素和 代谢生物标志物和可改变的危险因素，如高血压、肥胖、缺乏体力活动和吸烟 与认知老化加速甚至痴呆症有关。相比之下，个人因素，如高 患病前的智商，更多的教育年限，更高的职业素养，以及双语能力都被证明是 提供保护因素，防止神经病理对认知的影响。鉴于TLE现在被理解为 代表一系列障碍，识别具有相似认知特征的患者组可能提供 对单个TLE患者存在的潜在神经病理的独特见解，这可能是 重要的预后价值。这项拟议的研究将是第一次整合先进的神经成像数据， 认知数据，以及与健康相关的风险因素和保护因素，努力揭开儿童精神疾病的异质性 TLE患者的认知功能障碍。在这项研究中，我们将识别和定义TLE的认知表型，其基础是 语言、记忆、执行功能和运动速度等神经心理指标的损害。 然后，我们将研究与每种表型相关的大脑网络差异和临床特征。 大脑网络的差异将使用结构和扩散数据进行评估，使用区域和 基于连接组的新方法。此外，我们将确定与健康相关的重要风险因素(即BMI、 脉压指标、空腹血糖、既往或当前血管病史、吸烟史、饮食和 运动)和保护性因素(即，病前智商、教育、职业成就、双语能力) 调节脑网络异常与认知功能障碍的关系。的最终目标是 这项提案是为了解决美国国立神经疾病和中风研究所(NINDS)的主要 Benchmark的重点是预防和逆转癫痫的共病。鉴于认知障碍 是TLE和癫痫中最常见和最有问题的共病，这一建议的结果是 可能有助于确定进行性认知功能障碍和/或术后认知功能障碍的最大风险 拒绝。此外，该提案还可以通过帮助确定可修改的风险/保护来直接满足这一要求 可用于制定旨在降低进一步认知衰退风险的干预措施的因素。

Project Summary/Abstract Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy, and it is often characterized by debilitating and progressive cognitive impairment. As a result, patients with TLE often report poor quality of life and impaired daily functioning. However, there is significant variability in the nature and severity of cognitive impairments observed across patients with TLE, with some patients demonstrating generalized impairment and others demonstrating relatively normal cognitive profiles. Despite the well-known variability in cognitive impairment that is observed across patients, few studies have focused on identifying distinct cognitive phenotypes within the syndrome of TLE. In addition, very little is known about other health-related risk or individual factors that may contribute to this variability. Health-related risk factors such as vascular factors and metabolic biomarkers, and modifiable risk factors such as hypertension, obesity, physical inactivity, and smoking have been linked to accelerated cognitive aging and even dementia. In contrast, individual factors such as high pre-morbid IQ, more years of education, higher occupational attainment, and bilingualism have been shown to offer a protective factor against the effects of neuropathology on cognition. Given that TLE is now understood to represent a spectrum of disorders, identifying groups of patients with similar cognitive profiles may provide unique insight into the underlying neuropathology that exists in individual patients with TLE, which could have important prognostic value. The proposed study will be the first to integrate advanced neuroimaging data, cognitive data, and health-related risk factors and protective factors in an effort to unravel the heterogeneity of cognitive impairment in TLE. In this study, we will identify and define cognitive phenotypes in TLE based on impairment across neuropsychological measures of language, memory, executive function, and motor speed. We will then investigate brain network differences and clinical features associated with each phenotype. Differences in brain networks will be evaluated using structural and diffusion data utilizing both a regional and a novel connectome-based approach. In addition, we will identify important health-related risk factors (i.e., BMI, pulse pressure proxy, fasting glucose, history of past or current vascular disease, history of smoking, diet, and exercise) and protective factors (i.e., pre-morbid IQ, education, occupation attainment, bilingualism) that moderate the relationship between brain network abnormalities and cognitive dysfunction. The ultimate goal of this proposal is to address the National Institutes of Neurological Diseases and Strokes (NINDS) major benchmark focused on the prevention and reversal of comorbidities in epilepsy. Given that cognitive impairment is the most common and problematic comorbidity in TLE and epilepsy in general, the results from this proposal may help identify those at greatest risk for progressive cognitive dysfunction and/or post-operative cognitive decline. Furthermore, this proposal can directly address this request by helping identify modifiable risk/protective factors that may be used to develop interventions targeted at reducing the risk of further cognitive decline.