Dorsal Cingulate Activity and Cognitive Decline in Late-Life Depression

描述（由申请人提供）：认知障碍经常发生在晚年抑郁症（LLD）中，这会增加痴呆症、死亡率和医学合并症的风险。虽然继发于抑郁症的认知障碍可能在成功治疗后消退，但某些患者即使在抑郁症状缓解后也可能发生持续性认知障碍或认知下降。认知能力下降多年的人患阿尔茨海默病或血管性痴呆的风险增加。识别有认知能力下降风险的个体对于早期干预策略至关重要。因此，该项目的长期目标是更好地了解抑郁症和认知障碍之间的神经机制，建立早期识别有认知障碍风险的抑郁个体的生物标志物，并了解预防计划和临床干预后有认知障碍和无认知障碍的LLD的神经可塑性。我们的初步研究表明，减少背侧前扣带（dACC）激活在目标检测与未来的认知能力下降LLD。在具有认知障碍的LLD患者中也发现dACC-海马连接性降低。鉴于dACC是参与AD和抑郁症的区域之一，并且由于该区域的缺陷可导致抑郁症中情感和认知网络的功能连接的广泛异常，我们假设异常的dACC活性（即，降低的dACC激活和降低的海马-dACC连接）将预测LLD中的认知下降。为了验证这一假设，我们提出了一个为期两年的纵向神经影像学研究140例药物自由LLD患者。这项建议的目的是调查LLD与认知能力下降相关的神经机制，并检查我们提出的成像标记物是否可以预测哪些个体处于认知能力下降的高风险中。所有受试者将在基线和第2年的静息状态和简单目标检测任务期间接受扫描。我们的具体目标是：1）描述急性LLD患者中与dACC活性降低相关的认知特征; 2）检查基线时dACC活性降低是否预测2年认知下降; 3）检查LLD患者中认知的2年变化与脑激活和功能连接的2年变化之间的关联。我们假设dACC活性降低的LLD患者在基线时认知功能较低，在两年随访期间认知功能下降更大。拟议的研究是创新的，因为我们计划根据功能激活模式来表征LLD的临床特征。该方法将刺激未来的“基于大脑的分类”研究，以预测基于大脑激活的个人临床状态。拟议的研究是重要的，因为研究的积极结果将可能有助于临床识别LLD个体， 认知能力下降的风险。dACC功能障碍模式也可以作为监测临床干预的神经标志物。 公共卫生相关性：这项拟议中的研究与公共卫生有关，因为这项调查将有助于识别患有老年抑郁症的人，他们有认知能力下降的高风险。一旦确定了这种“基于大脑的分类”，就可以在疾病过程的早期制定改善认知功能的替代治疗方法，从而改善预后和整体生活质量。

DESCRIPTION (provided by applicant): Cognitive impairment frequently occurs in late-life depression (LLD), which increases the risk of dementia, mortality, and medical comorbidity. While cognitive impairment secondary to depression may resolve after successful treatment, persistent cognitive impairment or cognitive decline may occur in some patients even after remission from depressive symptoms. Individuals with cognitive decline over years have an increased risk of developing either Alzheimer's disease or vascular dementia. Identifying individuals who are at risk for developing cognitive decline is vital for early intervention strategies. Therefore, the long-term goals of the proposed project are to better understand the neural mechanisms linking depression and cognitive impairment, to establish biomarkers for early identification of depressed individuals at risk for cognitive impairment, and to understand the neural plasticity of LLD with and without cognitive impairment following prevention programs and clinical interventions. Our preliminary study indicates that reduced dorsal anterior cingulate (dACC) activation during target detection is associated with future cognitive decline in LLD. Reduced dACC- hippocampus connectivity is also found in LLD patients with cognitive impairment. Given that the dACC is one of the regions that is involved in both AD and depression, and because deficits in this region can result in broad abnormalities in functional connectivity across affective and cognitive networks in depression, we hypothesize that aberrant dACC activity (i.e., reduced dACC activation and reduced hippocampus-dACC connectivity) will predict cognitive decline in LLD. To test this hypothesis, we propose a two-year longitudinal neuroimaging study in 140 medication-free LLD patients. The objectives of this proposal are to investigate the neural mechanisms in LLD associated with cognitive decline and to examine whether our proposed imaging marker can predict which individuals are at a high risk of cognitive decline. All participants will be scanned during a resting state and during a simple target detection task at baseline, and at year 2. Our specific aims are: 1) to characterize the cognitive profile associated with reduced dACC activity in patients with acute LLD; 2) to examine whether reduced dACC activity at baseline predicts two-year cognitive decline; and 3) to examine the association between two-year changes in cognition with two-year changes in brain activation and functional connectivity in LLD patients. We hypothesize that LLD patients with reduced dACC activity will have lower cognitive function at baseline and greater cognitive decline over the two-year follow-up period. The proposed research is innovative because we plan to characterize a clinical profile in LLD based on functional activation pattern. The approach will stimulate future "brain-based classification" studies to predict individuals' clinica status based upon brain activation. The proposed research is significant because positive outcomes of the study will potentially assist clinical identification of LLD individuals who are at risk of cognitive decline. The dACC dysfunction pattern may also serve as a neural marker to monitor clinical intervention. PUBLIC HEALTH RELEVANCE: This proposed research is relevant to public health because the investigation will help identify individuals with late-life depression who are at a high risk o cognitive decline. Once this "brain-based classification" is identified, alternative treatments to improve cognitive functioning can be instituted early on in the course of illness, thus improving prognosis and overall quality of life.