Neuroimaging of the Vulnerable Brain in Delirium: Alzheimer's and Aging Imaging Markers

摘要 谵妄是一种急性的注意力不集中和混乱状态，通常由住院和手术引起， 患有神经退行性疾病如阿尔茨海默病引起的痴呆的患者的病症 (AD)尤其脆弱。越来越多的证据表明，那些没有痴呆症的人， 经历谵妄的患者发生长期认知功能下降（LTCD）和未来痴呆的风险增加; 与临床前AD一致的基础AD病理学解释了这种谵妄的高风险， 不良后果尚不清楚。在该项目的前一个周期中，扩散张量的一些发现 与炎症相关的成像和液体生物标志物被鉴定为易患谵妄。 然而，尚不清楚这些生物标志物是否与临床前AD病理学相关， 脆弱的衰老或其他已知的病理。利用现代磁共振成像（MRI）技术， 我们已经确定了皮质萎缩和海马过度激活的“AD-特征”作为以下生物标志物： 前驱或临床前AD。此外，与年龄相关的大脑变化的测量 在没有神经退行性疾病或脑血管疾病的情况下，认知能力下降可以被检测为 皮质萎缩和额顶叶功能连接减少的“脆弱衰老特征”。因此，我们认为， 这项建议的首要目标是检查临床前AD的神经影像学生物标志物或 脆弱的衰老预示着谵妄、谵妄严重性和复杂性谵妄（即，谵妄 LTCD），并将这些神经影像学生物标志物与在LTCD中测量的病理学分子生物标志物联系起来。 脑脊液（CSF）和血浆。具体目标是：1）确定有证据的人 临床前AD（即具有异常CSF AD生物标志物tau和β-淀粉样蛋白水平的患者），无论AD- 相关脑萎缩或网络功能障碍与谵妄、谵妄严重程度或LTCD相关; 2） 确定无临床前AD证据的人群（即CSF AD生物标志物正常的患者）是否 脆弱的衰老相关性脑萎缩或网络功能障碍与谵妄、谵妄严重程度或 LTCD;以及3）研究纵向皮质萎缩（术前和术后一年测量）是否与LTCD相关， 由于临床前AD或脆弱老化导致的手术）与术后LTCD或并发症相关 精神错乱为了检验这些假设，我们将利用P01 AG 031720的资源， 原始SAGES I队列（共N=560，n=126，纵向MRI），通过新的CSF和MRI数据增强 收集了128例SAGES I概率抽样患者（64例谵妄，64例无谵妄）， 一个新的SAGES II队列（N=400），其中180例患者将在手术前采集CSF和MRI。 有效地该项目的长期目标是提高对脑的病理生理学认识 易患谵妄，以便为预防战略提供信息，并最终以病理生理学为基础， 治疗。

ABSTRACT Delirium, an acute state of inattention and confusion often precipitated by hospitalization and surgery, is a condition for which patients with neurodegenerative diseases such as dementia due to Alzheimer's disease (AD) are especially vulnerable. Evidence is mounting that people who do not have dementia at the time they experience delirium are at increased risk for long-term cognitive decline (LTCD) and future dementia; whether underlying AD pathology consistent with preclinical AD accounts for this heightened risk of delirium and adverse outcomes is not known. In the prior cycle of this Project, a number of findings from diffusion tensor imaging and fluid biomarkers associated with inflammation were identified as predisposing to delirium. However, it is not clear whether those biomarkers might have been associated with preclinical AD pathology, vulnerable aging, or other known pathologies. Using modern magnetic resonance imaging (MRI) techniques, we have identified an “AD-Signature” of cortical atrophy and hippocampal hyperactivation as biomarkers of prodromal or preclinical AD. In addition, measures of changes in the brain that are associated with age-related cognitive decline in the absence of neurodegenerative or cerebrovascular disease can be detected as a “Vulnerable Aging-Signature” of cortical atrophy and reduced frontoparietal functional connectivity. Therefore, the overarching goal of this proposal is to examine whether neuroimaging biomarkers of preclinical AD or vulnerable aging are predictive of delirium, delirium severity, and complicated delirium (i.e., delirium with LTCD), and to link these neuroimaging biomarkers to molecular biomarkers of pathology measured in the cerebrospinal fluid (CSF) and plasma. The Specific Aims are: 1) to determine in people with evidence of preclinical AD (i.e. patients with abnormal CSF AD biomarker levels of tau and beta-amyloid) whether AD- related brain atrophy or network dysfunction are associated with delirium, delirium severity, or LTCD; 2) to determine in people without evidence of preclinical AD (i.e. patients with normal CSF AD biomarkers) whether vulnerable aging-related brain atrophy or network dysfunction are associated with delirium, delirium severity, or LTCD; and 3) to investigate whether longitudinal cortical atrophy (measured pre-operatively and one year after surgery) due to preclinical AD or vulnerable aging is associated with postoperative LTCD or complicated delirium. To test these hypotheses, we will leverage the resources of P01AG031720 which generated the original SAGES I cohort (N=560 total, n=126 with longitudinal MRI), augmented by new CSF and MRI data collected in 128 SAGES I probability sampled patients (64 with delirium, 64 without) about four years after their surgery, and a new SAGES II cohort (N=400), of which 180 patients will have both CSF and MRI collected pre- operatively. The long-term objective of this Project is to improve the pathophysiological understanding of brain vulnerability to delirium in order to inform prevention strategies and, ultimately, pathophysiological-based treatments.