Characterizing Cognitive Decline in Late Life Depression: The ADNI-D Project

项目摘要 晚年抑郁(LLD)是加速的最强烈和最一致被识别的危险因素之一 认知衰退和痴呆症，但导致这些关系的机制尚未得到证实 充分阐明。令人信服的证据表明，进行性皮质边缘萎缩可能是一种 LLD认知功能减退加速的主要机制。然而，一个重要的障碍是 区分早期和未确诊的阿尔茨海默病(AD)与LLD的影响。在我们的 家长奖我们与阿尔茨海默病神经成像倡议(ADNI)合作，开始解决 这项挑战。我们为患有LLD的个体创建了ADNI的附属分支，以收集基因， 认知和神经成像数据，包括正电子发射断层扫描测量淀粉样蛋白(Aβ) 而磁共振成像(MRI)测量的神经退行性变是AD的特征。我们的结果 研究表明：1)与非抑郁症(ND)老年人相比，LLD患者的认知功能下降速度明显加快 在考虑了Aβ、AD遗传风险(载脂蛋白ε4等位基因；ApoE)后30个月以上的成年人，以及 脑血管疾病的测量(白质病变；WML)，2)关键区域的神经变性 与终生抑郁症有关，包括外侧眶前皮质(OFC)、颞上皮质 脑叶(STL)、颞极(TP)、海马区(HC)、杏仁核(AMG)和伏隔区(AA) LLD的特征独立于Aβ、APOE和WML，3)LLD与 与ND相关的异常脑血流但不增加Aβ或WML，以及4)基线边缘皮质 容量是与基线认知和后续认知相关的最强神经生物学因素 认知能力下降和更严重的抑郁症病程。然而，父母的研究只有一项神经成像 评估。因此，我们不能评估LLD的萎缩进展，这对确定 LLD认知功能减退的神经退行性机制此外，我们没有获得tau PET数据 鉴于最近的证据表明LLD与皮质-边缘tau沉积的增加有关，这一点至关重要。 即使在没有Aβ升高的情况下，与Aβ相比，tau与萎缩和认知能力下降的联系也更强 然后。这项研究将：1)确定LLD与进行性皮质-边缘萎缩的相关性，独立于 Aβ，2)确定LLD与皮质-边缘tau沉积增加的关系以及tau的关系 与LLD的神经变性有关，以及3)确定皮质-边缘萎缩与tau沉积的关系 在LLD中有7年的认知和9年的抑郁结果。这些目标将通过开展 来自父母研究的100名参与者的额外评估。我们将进行第二次神经成像 在首次扫描后5年进行评估(MRI、PET)，在5-5岁时完成临床评估(精神、认知) 每六个月评估一次抑郁症状。年300名ND老年人的数据 ADNI-III研究在人口学、AD风险和病理学方面匹配，将用于组间比较。

Project Summary Late life depression (LLD) is one of the strongest and most consistently identified risk factors for accelerated cognitive decline and dementia but the mechanisms contributing to these relationships have not yet been adequately clarified. Compelling evidence suggests that progressive cortico-limbic atrophy may act as a primary mechanism of accelerated cognitive decline in LLD. However, a significant barrier has been differentiating the effects of incipient and undiagnosed Alzheimer’s disease (AD) from those of LLD. In our parent award we partnered with the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to begin to address this challenge. We created an adjunct arm of ADNI for individuals with LLD in order to collect genetic, cognitive, and neuroimaging data, including Positron Emission Tomography (PET) measures of amyloid (Aβ) and Magnetic Resonance Imaging (MRI) measures of neurodegeneration that characterize AD. Our results have shown that: 1) Accelerated cognitive decline is evident in LLD compared to Non-Depressed (ND) older adults over 30 months after accounting for Aβ, AD genetic risk (Apolipoprotein ε4 alleles; APOE), and measures of cerebrovascular disease (white matter lesions; WML), 2) Neurodegeneration in key regions implicated in depression across the lifespan, including the lateral orbitofrontal cortex (OFC), superior temporal lobe (STL), temporal pole (TP) hippocampus (HC), amygdala (AMG) and accumbens area (AA) were characteristic of LLD independent of Aβ, APOE, and WML, 3) LLD was associated with focal regions of abnormal cerebral blood flow (CBF) but not increased Aβ or WML relative to ND, and 4) Baseline cortico-limbic volumes were the strongest neurobiological factors associated with baseline cognition and subsequent cognitive decline and worse course of depression. However the parent study had only one neuroimaging evaluation. As such, we could not evaluate progression of atrophy in LLD which is essential to determine neurodegenerative mechanisms of cognitive decline in LLD. Additionally, we did not obtain tau PET data which is critical given recent evidence that suggests LLD is associated with increased cortico-limbic tau deposition even in absence of elevated Aβ and that tau is more strongly linked to atrophy and cognitive decline than Aβ in ND. This study will: 1) Determine the association of LLD with progressive cortico-limbic atrophy independent of Aβ, 2) Determine the association of LLD with increased cortico-limbic tau deposition and the relationship of tau with neurodegeneration in LLD, and 3) Determine the association of cortico-limbic atrophy and tau deposition with 7-year cognitive and 9-year depression outcomes in LLD. These goals will be achieved by conducting additional evaluations of 100 participants from the parent study. We will conduct a second neuroimaging evaluation (MRI, PET) 5 years after their initial scans, complete clinical evaluations (psychiatric, cognitive) at 5- years and 7-years, and evaluate depression symptoms every six months. Data from 300 ND older adults from the ADNI-III study matched for demographic and AD risk and pathology will be used for group comparisons.