AR CAREER DEVELOPMENT COBRE: NOVEL TREATMENT FOR ALZHEIMER'S DISEASE

AR 职业发展 COBRE：阿尔茨海默病的新疗法

• 批准号: 8168238
• 负责人: Ann Riggs
• 金额: $ 21.6万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168238
• 关键词: Affect; Aging; Alzheimer' s Disease; Applications Grants; Arousal; Attention; Attentional deficit; Auditory Evoked Potentials; Blood flow; Brain Stem; Categories; Clinical; Clinical Trials; Cognitive deficits; Computer Retrieval of Information on Scientific Projects Database; Data; Equilibrium; Functional disorder; Funding; Generations; Grant; Human; Innovative Therapy; Institution; Investigation; Judgment; Learning; Magnetic Resonance Imaging; Measures; Mental Depression; Mental disorders; Near-Infrared Spectroscopy; Neuraxis; Neurologic; Neuropsychological Tests; Output; Participant; Patients; Performance; Physiological; Population; Prevalence; Process; Questionnaires; Reaction Time; Recording of previous events; Relative (related person); Research; Research Personnel; Resources; Role; Short-Term Memory; Signal Transduction; Site; Sleep; Sorting - Cell Movement; Source; Specific qualifier value; Stimulus; System; TNFRSF5 gene; Task Performances; Testing; Thalamic structure; Time; Time Perception; Tinnitus; United States National Institutes of Health; Wisconsin; Work; base; behavior measurement; career development; cognitive function; cohort; design; economic impact; equilibration disorder; frontal lobe; frontal lobe function; novel; preclinical study; programs; sensory gating; therapy development; treatment strategy; vigilance

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Alzheimer's disease (AD) has captured the attention of the public because of its predicted prevalence in the next two decades with aging of the Boomer generation, i.e. 18% of them, or 14 million. The economic impact of a half million cases increasing to the estimated million new cases of AD per year is staggering. These figures make discovery of mechanisms and treatments for the development of the AD imperative. We have preliminary data that suggest that AD patients show pre-attentional deficits, determined using the P50 auditory evoked potential, indicative of disturbances in brainstem-thalamus processes. The results showed decreased amplitude in ~40% of subjects, indicative of decreased levels of arousal, and decreased habituation to paired stimulation, indicative of decreased sensory gating in ~60% of subjects. To date, no studies using the Psychomotor Vigilance Task (PVT), a recognized measure of attention using simple reaction time, has been used in AD patients in combination with P50 potential pre-attentional measures. The participants will be selected from our cohort of 200 well-characterized AD patients (clinical work up, history, standard battery of neuropsychological tests and an MRI). In addition to these tests, routine for assessing participants, patients will be assessed for P50 potential and PVT performance. These studies will provide data for the submission of an NIH grant application for the implementation of preclinical studies, with a view toward developing clinical trials to determine quantitatively if AD patients include two separate populations who require specific and different treatment strategies to alleviate deficits in pre-attentional and/or attentional processing. Aim 3. Determine if rTMS treatment promotes lasting improvement in tinnitus patients. All patients will be reassessed at 3 and 6 months post-rTMS on behavioral measures (RT) and questionnaires. In addition, the 5 best and 5 worst responders, based on perceived tinnitus at 6 months, will also have a repeat PET-CT at 6 months and a repeat of all assessments, including PET-CT, at 12 months. Novel Studies on Sites of Action and Mechanisms in Balance Dysfunction Specific Aim 1. Investigate the role of the ascending Reticular Activating System (RAS). We will measure the output of the RAS, i.e. pre-attentional/arousal processes, using the sleep state-dependent P50 midlatency auditory evoked potential, whose amplitude is a measure of level of arousal, and whose habituation to repetitive stimuli is a measure of sensory gating, the process behind distractibility. Specific Aim 2. Investigate thalamo-cortical processing. We will assess attentional processing using the Psychomotor Vigilance Task (PVT), a measure of simple (not choice) reaction time, and evaluate the patient's ability to sustain attention and respond in a timely manner to salient signals. We will test the participant's ability to select a specified stimulus from two or more choice stimuli presented by using the Continuous Performance Task (CPT) which is a standardized clinical measure of attention, reaction time, and distractibility. Specific Aim 3. Investigate cortical function. We will measure relative frontal lobe blood flow using Near Infrared Spectroscopy (NIRS) before and during performance of the P50 and PVT tasks to assess changes in relative blood flow to cortical regions involved in critical judgment, which are impaired in depression and other psychiatric disorders. Additionally, we will administer the Wisconsin Card Sorting Task (WCST) to access human frontal lobe function and to measure the participant's ability to shift attention from one category to another (set-shifting) with no warning using a trial and error paradigm. We will use the Operant Test Battery (OTB) to evaluate the higher cognitive functions of short-term memory, time estimation, and learning. This design will allow us to determine at which level of the neuraxis (brainstem-thalamus, thalamo-cortical, and/or cortical) patients with balance disorders manifest quantitative physiological deficits. By localizing the level of the neuraxis affected, we can develop more informed therapies that may selectively alleviate pre-attentional, attentional, and/or cognitive deficits. The proposed research will provide answers to the following questions: Do patients with balance disorders show differential changes in P50 potential amplitude, i.e. level of arousal? Do these patients show differential changes in P50 potential habituation, i.e. sensory gating? Do they show differences in mean reaction time, number of lapses, or other measures of simple attentional mechanisms? Do they show differences in higher cognitive function as evidenced by performance accuracies and latencies in short-term memory, time perception, and learning tasks? Do they show differences in relative frontal lobe blood flow before (i.e. continuous hypofrontality) and/or during (i.e. task-related) the performance of an attentional task? Quantitative physiological investigation of these potential neurological substrates for balance disorders represents a novel, comprehensive program of research with great promise for developing innovative therapies for this condition.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 阿尔茨海默病（AD）已经引起了公众的注意，因为其预测在未来二十年中随着婴儿潮一代的老龄化而流行，即他们中的18%，或1400万。 每年50万例增加到估计的100万例新AD病例的经济影响是惊人的。 这些数字使得发现AD发展的机制和治疗势在必行。我们有初步的数据表明，AD患者表现出前注意缺陷，确定使用P50听觉诱发电位，脑干丘脑过程的干扰的指示。 结果显示，约40%的受试者振幅降低，表明唤醒水平降低，对成对刺激的习惯性降低，表明约60%的受试者感觉门控降低。 到目前为止，没有研究使用心理警觉任务（PVT），一个公认的措施，注意使用简单的反应时间，已被用于AD患者结合P50潜在的预注意措施。 参与者将从我们的200名特征良好的AD患者（临床检查、病史、标准神经心理学测试和MRI）中选出。 除了这些常规评估受试者的检查外，还将评估患者的P50电位和PVT表现。这些研究将为提交NIH拨款申请提供数据，以实施临床前研究，以期开发临床试验，以定量确定AD患者是否包括两个单独的人群，他们需要特定和不同的治疗策略来缓解前注意力和/或注意力处理的缺陷。 目标3。确定rTMS治疗是否促进耳鸣患者的持久改善。 所有患者将在rTMS后3个月和6个月重新评估行为测量（RT）和问卷调查。 此外，根据6个月时感知的耳鸣，5名最佳和5名最差应答者还将在6个月时重复PET-CT，并在12个月时重复所有评估，包括PET-CT。 平衡功能障碍的作用部位和机制的新研究 具体目标1。 研究上行网状激活系统（RAS）的作用。 我们将使用睡眠状态依赖的P50中潜伏期听觉诱发电位来测量RAS的输出，即前注意/唤醒过程，其幅度是唤醒水平的量度，并且其对重复刺激的习惯是感觉门控的量度，这是注意力分散背后的过程。 具体目标2。 研究丘脑-皮层处理。 我们将使用心理警觉任务（PVT）评估注意力处理，这是一种简单（而不是选择）反应时间的测量方法，并评估患者保持注意力并及时对显著信号做出反应的能力。我们将测试参与者的能力，选择一个指定的刺激，从两个或两个以上的选择刺激，通过使用连续性能任务（CPT），这是一个标准化的临床措施的注意力，反应时间和分心。 具体目标3。 检查皮质功能。 我们将使用近红外光谱（NIRS）在P50和PVT任务执行之前和期间测量相对额叶血流量，以评估参与关键判断的皮质区域的相对血流量变化，这些区域在抑郁症和其他精神疾病中受损。此外，我们将管理威斯康星州卡片分类任务（WCST），以访问人类额叶功能，并测量参与者的能力，转移注意力从一个类别到另一个（集转移）没有警告使用试错范式。我们将使用操作测试组合（OTB）来评估短期记忆，时间估计和学习的高级认知功能。 这种设计将使我们能够确定在哪一个水平的神经轴（脑干丘脑，丘脑皮质，和/或皮质）平衡障碍患者表现出定量生理缺陷。 通过定位受影响的神经轴水平，我们可以开发出更明智的治疗方法，可以选择性地减轻前注意力，注意力和/或认知缺陷。 拟议的研究将回答以下问题：平衡障碍患者是否表现出P50电位振幅（即唤醒水平）的差异性变化？ 这些患者是否表现出P50电位习惯化（即感觉门控）的差异性变化？ 他们在平均反应时间、失误次数或其他简单注意力机制的测量上是否存在差异？ 他们在短期记忆、时间知觉和学习任务中的表现准确性和延迟性是否证明了他们在高级认知功能上的差异？ 他们在执行注意力任务之前（即持续性额叶功能减退）和/或期间（即任务相关）是否表现出相对额叶血流的差异？ 这些潜在的神经基板平衡障碍的定量生理研究代表了一种新的，全面的研究计划，为这种情况下开发创新的疗法有很大的希望。