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

项目摘要/摘要 路易体痴呆症(LBD)是导致痴呆症的第二大常见原因，与无情有关 与阿尔茨海默病相比，认知能力下降、沉重的照顾者负担以及更高的医疗成本 (Ad)。尽管LBD的发病率和预后较差，但LBD患者仍会被误诊和延误。 诊断，这可能会导致使用发病率增加的药物，并延误适当的临床 关心。因此，LBD的准确和早期诊断是一个严重的未得到满足的需求。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记物，这是 LBD将其与其他痴呆症区分开来。这一目标解决了与NIH阿尔茨海默病相关的 痴呆(ADRD)峰会建议在LBD中开发生物标记物。认知波动(CF)是 被定义为自发的注意力受损和觉醒减少的时期，对应于 衡量持续关注的标准。Cf是LBD患者认知障碍的核心临床特征， 伴随着日常生活能力的更大损害和生活质量的降低。尽管它们很普遍， Cf临床诊断具有挑战性，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在场。一种准确且广泛可用的 CF的生物标志物将大大提高对CF的诊断能力，从而提高LBD的诊断能力。LBD的脑电差异是 有充分的证据证明，但目前没有足够的证据将特定的脑电结果视为指示性的 LBD的生物标志物。一些研究发现，较低的主频和较高的主频 脑电变异性与CF值相关。这些脑电与CF的相关性被认为反映了 大脑皮层同步化，但主频的扰动并未在时间上与短期相关 持续注意力的临床波动。LBD患者脑电与CF相关性的研究 持续注意力在短时间尺度上的差异将为脑电的临床相关性提供证据 作为生物标记物。我们假设，降低的主频和更高的主频变异性 脑电可以准确地识别LBD患者的CF，且脑电的主要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背后的脑电特征 LBD合并CF患者与LBD、AD、帕金森病及健康对照脑电特征的比较 不带配置文件在目标2中，我们将LBD患者CF的脑电特征与持续性注意障碍联系起来。我们 预计这项提议将导致LBD患者的CF的临床相关生理生物标记物，然后 在大规模多中心研究中得到验证。事实上，脑电是非侵入性的，相对便宜， 广泛使用将支持将其作为LBD中CF的生物标记物。准确诊断LBD的能力 并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， 对于在LBD的早期阶段研究和建立新的治疗方法将是非常宝贵的。

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.