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，这增加了痴呆症、死亡率和医学共病的风险。虽然抑郁症继发的认知障碍在成功治疗后可能会得到缓解，但一些患者即使在抑郁症状缓解后仍可能出现持续性认知障碍或认知能力下降。认知能力多年下降的人患阿尔茨海默病或血管性痴呆症的风险增加。确定哪些人有发展认知衰退的风险，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，建立生物标志物以早期识别存在认知障碍风险的抑郁症个体，并了解LLD在预防计划和临床干预后有无认知障碍的神经可塑性。我们的初步研究表明，在目标检测过程中，背侧前扣带核(DACC)激活减少与LLD未来的认知能力下降有关。伴有认知障碍的LLD患者也发现dACC-海马区连接性降低。鉴于dACC是AD和抑郁症共同参与的区域之一，由于该区域的缺陷可能导致抑郁症患者情感和认知网络功能连接的广泛异常，我们假设dACC活动异常(即dACC激活减少和海马-dACC连接减少)将预测LLD的认知功能下降。为了验证这一假设，我们提出了一项为期两年的纵向神经成像研究，研究对象为140名未服用药物的LLD患者。这项建议的目的是研究LLD与认知衰退相关的神经机制，并检验我们提出的成像标志物是否可以预测哪些人处于认知衰退的高危状态。我们的具体目标是：1)确定急性LLD患者dACC活动减少的认知特征；2)检查基线dACC活动减少是否预示两年认知功能下降；3)研究LLD患者两年认知功能变化与脑激活和功能连接的两年变化之间的关系。我们假设，dACC活性降低的LLD患者在基线时认知功能较低，在两年的随访期内认知功能下降更大。这项拟议的研究具有创新性，因为我们计划基于功能激活模式来描述LLD的临床特征。这种方法将刺激未来的“基于大脑的分类”研究，以基于大脑的激活来预测个人的临床状态。这项拟议的研究意义重大，因为这项研究的积极结果可能有助于临床识别患有 认知能力下降的风险。DACC功能障碍模式也可作为监测临床干预的神经标记物。

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.