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

摘要 旨在改变阿尔茨海默病(AD)标志性蛋白病变Aβ和tau的试验已经完成 在阻止或减少认知衰退方面令人失望。因为这些试验通常是在有症状的情况下进行的 个人的大脑变化是不可逆的，将干预措施转移到无症状的个人可能是 更有效。难题是找出哪些人更有可能面临AD的风险，哪些人将受益 从这些干预措施中。虽然β在临床症状出现前大约15年开始于新皮质，但tau病理 从20岁开始在蓝斑(LC)积聚，然后向经胸腺扩散 皮质、边缘系统，然后到达皮质区域。然而，重要的是要注意到，即使 虽然到了50岁，tau在LC中无处不在，但并不是每个人都会患上AD。鉴于牛磺酸在体内的积累 LC与投射丢失有关，我们假设LC-去甲肾上腺素系统的功能指标 (LC-NE)可能更敏感地区分高危个体和可能保持认知能力的个体 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”功能包括注意力和工作记忆。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AD相关变化，这将 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强直(我们可以 通过增加二氧化碳)和阶段性放电模式(这可以由新奇事物引发)。瞳孔散大的变化 接受来自LC-NE系统的贡献，并通过提供特定的认知任务负荷、相性LC和强直性LC 可以推导出函数。我们假设，在一项任务中，学生对新的音调做出反应 短时间屏气与不屏气可能是早期AD相关过程的生物标志物。我们 将在一组临床正常的人(年龄范围55-80岁，n=70，50%女性)中测试这些假设 利用一个持续的深表型队列(系列MK)，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改进对处于危险中的个人的检测，通过确定 (目标1)：研究不同任务情境(奇数、奇数和奇数)下小学生反应的时相平衡 屏气后)以及它们与年龄和性别的关系。(目标2)：将这些不同任务中的瞳孔反应联系起来 设置为AD病理学。这项拟议的研究是创新的，因为它的目标是在非 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 在生活中病理学还不广泛的时候，打开机会让预防试验受益。

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.