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.

摘要 旨在改变阿尔茨海默病（AD）标志性蛋白质病Aβ和tau的试验已经完成 在阻止或减少认知能力下降方面令人失望。由于这些试验通常是在有症状的情况下进行的， 个体，其中大脑变化是不可逆的，将干预措施转移到无症状个体可能是 更有效地难题是确定哪些人更有可能患AD，哪些人将受益 这些干预措施。虽然Aβ在临床症状出现前约15年就开始在新皮层中出现，但tau病理学 从20岁开始在蓝斑（LC）中积累，然后向经内嗅扩散 皮质，边缘系统，随后到皮质区域。然而，值得注意的是，即使 虽然到50岁时，tau在LC中无处不在，但不是每个人都会发展AD。考虑到tau蛋白在 LC与投射功能丧失有关，我们对LC-去甲肾上腺素系统功能进行了测量 （LC-NE）可能更敏感地区分处于风险中的个体与那些可能保持认知障碍的个体。 健康LC-NE系统在行为和认知过程中起着重要的调节作用，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功能相关的读数检测最早的AD相关变化， 最终有助于更好地确定干预措施的目标人群， 提高这些干预措施的有效性。LC神经元功能的特点是紧张（我们可以 通过增加CO2引起）和阶段性放电模式（可以通过新奇引起）。瞳孔扩张的变化 接收来自LC-NE系统的贡献，并通过提供特定的认知任务负荷， 函数可以导出。我们假设，在一项任务中，瞳孔对新音调的反应， 短屏气与无屏气可以是非常早期AD相关过程的生物标志物。我们 将在一组临床正常个体（年龄范围55-80岁，n=70，50%女性）中检验这些假设 利用正在进行的深度表型队列（SerialMK），该队列已经收集了Aβ和tau-PET成像。 这一拟议项目的结果将有助于通过确定 (Aim 1）：研究不同任务设置（oddball和oddball）下瞳孔反应的张力-相位平衡 屏气后）以及它们与年龄和性别的关系。(Aim 2）：在这些不同的任务中关联瞳孔反应 设置为AD病理学。拟议的研究是创新的，因为它的目的是确定在非危险人群， 侵入性的，功能相关的方式，使用最早受影响的大脑系统之一的读数，从而 在病理学还不广泛的时候，为预防试验提供了机会。