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、死亡率和医疗合并症的风险。虽然抑郁症继发的认知障碍可能在治疗成功后消退，但一些患者甚至在抑郁症状缓解后仍可能出现持续的认知障碍或认知能力下降。多年来认知能力下降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与认知障碍之间的神经机制，建立认知障碍风险抑郁个体的早期识别生物标志物，并了解有和没有认知障碍的LLD在预防方案和临床干预后的神经可塑性。我们的初步研究表明，在目标检测过程中，背前扣带（dACC）激活的减少与LLD未来的认知能力下降有关。认知障碍的LLD患者也发现dACC-海马连通性降低。鉴于dACC是阿尔茨海默病和抑郁症都涉及的区域之一，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活动（即dACC激活减少和海马-dACC连接减少）将预测LLD的认知能力下降。为了验证这一假设，我们建议对140名无药LLD患者进行为期两年的纵向神经影像学研究。本提案的目的是研究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。所有参与者将在静息状态、基线和第2年的简单目标检测任务期间进行扫描。我们的具体目标是：1)表征急性LLD患者与dACC活性降低相关的认知特征；2)检验基线时dACC活动降低是否预示2年认知能力下降；3)研究LLD患者2年认知变化与2年脑激活和功能连接变化之间的关系。我们假设，dACC活性降低的LLD患者在基线时认知功能较低，在两年的随访期间认知功能下降更大。提出的研究是创新的，因为我们计划描述基于功能激活模式的LLD的临床概况。这种方法将刺激未来“基于大脑的分类”研究，根据大脑的激活来预测个人的临床状态。拟议的研究具有重要意义，因为研究的积极结果将潜在地帮助临床识别LLD患者

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.