Inference by interference: Task-dependent pupil responses as an early detection method for Alzheimer's disease related brainstem functional change

干扰推理：任务依赖性瞳孔反应作为阿尔茨海默病相关脑干功能变化的早期检测方法

• 批准号: 10805667
• 负责人: Joost Riphagen
• 金额: $ 42.64万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2025-09-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10805667
• 关键词: Affect; Age; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Animal Model; Attention; Auditory; Behavioral; Biological Markers; Brain; Brain Stem; Brain region; Carbon Dioxide; Cells; Cerebellum; Clinical; Cognition; Cognitive; Detection; Diagnosis; Early Diagnosis; Equilibrium; Female; Fire - disasters; Future; Goals; Health; Human; Hyperactivity; Image; Impaired cognition; Individual; Intervention; Learning; Life; Limbic System; Magnetic Resonance Imaging; Measures; Mission; Modeling; Morphology; Mydriasis; Neocortex; Neurofibrillary Tangles; Neurons; Participant; Pathologic; Pathology; Pattern; Persons; Phase; Phenotype; Physiological; Play; Population Intervention; Populations at Risk; Positron-Emission Tomography; Prevention trial; Preventive treatment; Process; Proxy; Public Health; Pupil; Rattus; Reaction; Research; Risk; Role; Short-Term Memory; Shortness of Breath; Site; Spinal Cord; Stress; Support System; Symptoms; System; Target Populations; Testing; Time; Treatment Efficacy; United States National Institutes of Health; Work; cognitive process; cognitive task; cognitive testing; cohort; detection method; executive function; improved; in vivo; inclusion criteria; innovation; insight; locus ceruleus structure; middle age; neocortical; neuron loss; neuronal patterning; norepinephrine system; novel; prevent; recruit; resilience; response; sample fixation; sex; tau Proteins; tau aggregation; tau expression

ABSTRACT Trials aimed at changing the hallmark proteinopathies of Alzheimer Disease (AD), Aβ and tau, have been disappointing in halting or reducing cognitive decline. As these trials are often performed in symptomatic individuals, where brain changes are irreversible, shifting interventions to asymptomatic individuals may be more effective. The conundrum is to identify people who are more likely to be at risk of AD and who will benefit from these interventions. While Aβ starts in the neocortex about 15 years before clinical symptoms, tau pathology starts to accumulate from age 20 in the locus coeruleus (LC) before propagating towards the transenthorhinal cortex, the limbic system and subsequently to the cortical regions. However, it is important to note that even though by age 50, tau is omnipresent in the LC, not everyone will develop AD. Given that accumulation of tau in the LC is associated with loss of projections, we posit that functional measures of the LC-Norepinephrine system (LC-NE) may be more sensitive to distinguish individuals at-risk from those who are likely to maintain cognitive health. The LC-NE system plays an important modulatory role in behavioral and cognitive processes including ‘executive’ functions like attention and working memory. The overall goal of the proposed project is to detect the earliest AD related changes through read-outs related to LC function, which will ultimately contribute to improved identification of the target population for interventions and increase the efficacy of these interventions. LC neuronal function is characterized by tonic (that we can elicit by increasing CO2) and phasic firing patterns (that can be elicited by novelty). Changes in pupil dilation receive contributions from the LC-NE system, and by providing specific cognitive task loads, phasic and tonic LC function can be derived. Wehypothesize that the pupil response in a task reacting to new tones after a short breath hold vs no breath hold can be a biomarker of very early AD-related processes. We will test these hypotheses in a group of clinically normal individuals (age range 55-80 years, n=70, 50% female) leveraging to an ongoing deeply phenotyped cohort (SerialMK) that already collects Aβ and tau-PET imaging. The results of this proposed project will contribute to improved detection of individuals at-risk by determining (Aim 1): To investigate the tonic-phasic balance in pupil responses in different task settings (oddball, and oddball after breath hold) and their relation to age and sex. (Aim 2): Relating pupillary responses in these different task settings to AD pathology. The proposed research is innovative as it aims to identify at-risk populations in a non- invasive, functionally relevant manner, using a readout of one of the earliest affected brain systems and thereby opening up the opportunity to benefit prevention trials at a time in life when pathology is not yet extensive.

抽象的 旨在改变阿尔茨海默氏病（AD），Aβ和TAU的标志性蛋白质病的试验已是 在停止或减少认知能力下降时令人失望。由于这些试验通常在症状中进行 大脑变化不可逆的个人，将干预转移到不对称个体可能是 更有效。难题是确定更有可能有广告风险并受益的人 从这些干预措施中。虽然Aβ在临床症状前约15年开始在新皮层开始，但TAU病理 从20岁开始积聚在二元基因座（LC）之前 皮质，边缘系统，后来是皮层区域。但是，重要的是要注意 尽管到50岁时，Tau在LC中无处不在，但并不是每个人都会发展广告。鉴于tau的积累 LC与项目的损失有关，我们的海报是LC-肾上腺素系统的功能度量 （LC-NE）可能更敏感地将处于风险的人与可能保持认知能力的人区分开 健康。 LC-NE系统在行为和认知过程中起重要的调制作用，包括 “执行”功能如注意力和工作记忆。拟议项目的总体目标是 通过与LC功能相关的读出来检测最早的广告相关的更改，这将 最终有助于改善干预措施的目标人群的识别 提高这些干预措施的效率。 LC神经元功能的特征是补品（我们可以 通过增加二氧化碳和阶段性射击模式（可以通过新颖性引起）引起。学生词典的变化 从LC-NE系统获得贡献，并通过提供特定的认知任务负载，Phasic和Tonic LC 函数可以得出。 wehypothess，在任务中对新音调做出反应的学生响应之后 短暂的呼吸保持与无呼吸可能是非常早期广告相关过程的生物标志物。我们 将在一组临床正常个体中检验这些假设（年龄范围55-80岁，n = 70，50％女性） 利用已经收集Aβ和TAU-PET成像的正在进行的深层表型队列（SerialMK）。 该拟议项目的结果将通过确定，有助于改善对处于风险的个人的检测 （目标1）：调查不同任务设置中学生反应中的补品量平衡（ODBALL和ODBALL 呼吸后）及其与年龄和性别的关系。 （AIM 2）：在这些不同的任务中关联瞳孔回应 广告病理学的设置。拟议的研究具有创新性，因为它旨在确定非风险人群 使用最早受影响的大脑系统之一的读数，从而具有侵入性，功能相关的方式 在病理学尚未广泛的情况下，开放了有益于预防试验的机会。