Development and characterization of EEG signature of cognitive fluctuations in Lewy body dementia

项目总结/摘要 路易体痴呆症（LBD）是痴呆症的第二大常见原因， 与阿尔茨海默病相比，认知能力下降，严重的照顾者负担和更高的医疗费用 （AD）。尽管其患病率和预后差，但LBD患者仍遭受误诊和延误 诊断，这可能会导致使用的药物增加发病率和延迟适当的临床 在乎因此，LBD的准确和早期诊断是一个严重未满足的需求。更早更准确地支持 诊断，我们寻求开发认知波动的生理生物标志物，这是认知波动的一个特征。 与其他痴呆症的区别。这一目标解决了NIH阿尔茨海默病相关 痴呆症（ADRD）峰会建议开发LBD生物标志物。认知波动（CF） 定义为注意力受损和觉醒减少的自发期，对应于 持续关注的措施。CF是LBD认知障碍的核心临床特征， 与日常生活活动的更大损害和生活质量更差相关。尽管它们普遍存在， CF在临床诊断上具有挑战性，因为常用的正式评估需要管理 由经验丰富的临床医生和可靠的线人提供。一个准确和广泛可用的 CF的生物标志物将极大地提高诊断CF并因此诊断LBD的能力。LBD的EEG差异是 证据充分，但目前没有足够的证据将特定的EEG结果视为指示性 LBD的生物标志物。一些研究发现，无论是低主频还是高主频， EEG变异性与CF相关。CF的这些EEG相关性被认为反映了 皮层同步，但在主导频率的扰动还没有被暂时联系到短期 持续注意力的临床波动。证明LBD中CF的EEG相关性对应于 短时间内持续注意力的差异将为EEG的临床相关性提供证据 作为生物标志物。我们假设，降低的主频和较高的主频变异性， EEG能准确识别LBD患者的CF，且EEG上的优势频率具有时间相关性 在持续注意力测试中的表现。在目标1中，我们将阐明CF的EEG特征 通过比较LBD伴CF与LBD、AD、帕金森病和健康对照者的EEG特征， 没有CF。在目标2中，我们将把LBD中CF的EEG特征与持续注意力障碍相关联。我们 预期该提议将导致LBD中CF的临床相关生理生物标志物， 在大规模多中心研究中得到验证。EEG是非侵入性的，相对便宜， 广泛可用将支持其作为LBD中CF的生物标志物的采用。准确诊断LBD的能力 并且在早期阶段将减轻患者和护理人员的诊断不确定性，促进适当的护理， 并且对于在LBD的早期阶段研究和建立新的疗法将是非常宝贵的。

PROJECT SUMMARY / ABSTRACT Lewy body dementia (LBD) is the second most common cause of dementia and is associated with unrelenting cognitive decline, profound caregiver burden, and higher healthcare costs compared to Alzheimer disease (AD). Despite its prevalence and worse prognosis, patients with LBD suffer from misdiagnosis and delayed diagnosis, which may result in use of medications with increased morbidity and delays in appropriate clinical care. Thus, accurate and early diagnosis of LBD is a serious unmet need. To support earlier and accurate diagnosis, we seek to develop a physiological biomarker of cognitive fluctuations, a characteristic feature of LBD that differentiates it from other dementias. This goal addresses the NIH Alzheimer’s Disease-Related Dementias (ADRD) Summit recommendation to develop biomarkers in LBD. Cognitive fluctuations (CF) are defined as spontaneous periods of impaired attention and reduced arousal that correspond to variability in measures of sustained attention. CF are a core clinical feature of cognitive impairment in LBD and are associated with greater impairment in activities of daily living and worse quality of life. Despite their prevalence, CF are challenging to diagnose clinically, because commonly used formal assessments require administration by an experienced clinician and the presence of a reliable informant. An accurate and widely available biomarker of CF would greatly advance the ability to diagnose CF and thus LBD. EEG differences in LBD are well-documented, but there is currently insufficient evidence to consider specific EEG findings as an indicative biomarker of LBD. A few studies found that both lower dominant frequency and higher dominant frequency variability on EEG correlated with CF. These EEG correlates of CF are thought to reflect dysregulation of cortical synchronization, but perturbations in dominant frequency have not been temporally linked to short-term clinical fluctuations in sustained attention. Demonstrating that EEG correlates of CF in LBD correspond to differences in sustained attention over short timescales will provide evidence of the clinical relevance of EEG as a biomarker. We hypothesize that reduced dominant frequency and higher dominant frequency variability on EEG can accurately identify CF in LBD patients and that dominant frequency on EEG is temporally associated with performance on a test of sustained attention. In Aim 1 we will elucidate the EEG signature underlying CF in LBD by comparing the EEG features of LBD with CF to LBD, AD, Parkinson disease and healthy controls without CF. In Aim 2 we will correlate EEG features of CF in LBD with impairment in sustained attention. We anticipate that this proposal will result in a clinically relevant physiological biomarker of CF in LBD that can then be validated in a large-scale multi-center study. The fact that EEG is non-invasive, relatively inexpensive, and widely available will support its adoption as a biomarker for CF in LBD. The ability to diagnose LBD accurately and at an early stage will alleviate diagnostic uncertainty for patients and caregivers, facilitate appropriate care, and will be invaluable towards investigating and establishing novel therapies in the earliest stages of LBD.