Geriatric Depression: PET Studies of Pathophysiology and Treatment Response

描述(由申请人提供)：在过去的十年里，首席研究员和她的同事将神经成像纳入治疗研究，以了解老年性抑郁症的神经生物学。这一战略提供了一个独特的机会来评估神经化学系统的功能完整性和大脑对年龄和疾病相关(神经化学和神经病理)变化的补偿能力。这些研究通过正电子发射断层扫描(PET)确定了老年抑郁症的功能神经解剖学和抗抑郁药物的治疗反应。与对照组相比，患者的皮质葡萄糖代谢增加。在抗抑郁药物干预后，相同区域的代谢水平下降，并且这种下降与情绪和认知症状的改善有关。确定了功能神经解剖学后，下一步是检查潜在的病理生理学。拟议的研究结合了PET仪器和放射示踪化学的最新进展，以及尸检和神经成像数据，以研究选择性5-羟色胺再摄取抑制剂(SSRI，西酞普兰)对5-羟色胺转运体(SERT)的占用和β-淀粉样蛋白的沉积。SERT占有率越高，情绪症状的改善越大，这与高代谢和受西酞普兰治疗影响的区域有关。SSRI治疗情绪症状缓解后认知障碍持续存在的观察表明，除5-羟色胺功能障碍外，其他机制可能是认知障碍的基础。β-淀粉样蛋白沉积可以解释代谢改变和持续性认知障碍。在老年性抑郁症和正常衰老中，还观察到与间歇性记忆损害有关的高代谢区域中的β-淀粉样蛋白沉积(Butters等人，2008年，Sojkova等人，2008年)。修订后的应用程序的具体目的是：1.测量老年抑郁症患者和非抑郁症老年对照组的SERT可用性，并通过西酞普兰测量患者的SERT占有率；2.测量老年抑郁症患者和非抑郁症老年对照组的A沉积。这些假设将被检验，即在葡萄糖代谢PET研究中涉及的相同区域将观察到较低的SERT可用性、患者中西酞普兰对SERT的占有率以及患者相对于对照组将观察到更大的A沉积。建议研究的最终目标是从机制上理解情感和认知症状，为制定更有效的预防和干预策略提供信息。老年性抑郁症是一个重大的公共卫生问题，因为它与完全自杀率的急剧增加和患有内科疾病的老年人更高的死亡率有关。在社区居住的老年人中，临床上显著的抑郁症状的流行率估计在8%到16%之间，在住院和患有内科疾病的老年人中高达50%。即使有有效的抗抑郁药物可用，许多患者仍然难以治疗，并表现出持续的认知障碍和认知下降，尽管情绪症状有所改善。 公共卫生相关性：60岁以上的抑郁症患者将在抗抑郁药物治疗之前和期间进行扫描，以了解为什么晚年的抑郁症更难治疗。我们将测量一种名为5-羟色胺的大脑化学物质，以及一种与阿尔茨海默病痴呆的神经细胞丢失有关的蛋白质。我们将验证这样的假设，即治疗无效的患者大脑中的5-羟色胺较少，而β-淀粉样蛋白较多。

DESCRIPTION (provided by applicant): Over the past decade, the principal investigator and her colleagues have incorporated neuroimaging into treatment studies to understand the neurobiology of geriatric depression. This strategy provides a unique opportunity to assess the functional integrity of neurochemical systems and the capacity of the brain to compensate for age and disease related (neurochemical and neuropathological) changes. These studies identified the functional neuroanatomy of geriatric depression and antidepressant treatment response with positron emission tomography (PET). Increased cortical glucose metabolism was observed in patients relative to controls. Decreased metabolism was observed in the same regions after antidepressant interventions and the decreases were correlated with improvement of mood and cognitive symptoms. Having identified the functional neuroanatomy, the next step is to examine the underlying pathophysiology. The proposed studies integrate recent advances in PET instrumentation and radiotracer chemistry, with postmortem and neuroimaging data, to investigate serotonin transporter (SERT) occupancy by a selective serotonin reuptake inhibitor (SSRI, citalopram) and beta-amyloid deposition. Greater SERT occupancy is correlated with greater improvement of mood symptoms, in regions that are hypermetabolic and are affected by citalopram treatment. The observation that cognitive impairment persists after mood symptom remission by SSRI treatment indicates that mechanisms other than serotonin dysfunction may underlie cognitive impairment. Beta-amyloid deposition may explain the metabolic alterations and persistent cognitive impairment. Beta-amyloid deposition is also observed in the regions that are hypermetabolic and is associated with episodic memory impairment in geriatric depression and normal aging (Butters et al., 2008, Sojkova et al., 2008). The specific aims of the revised application are: 1. to measure SERT availability in patients with geriatric depression and non-depressed, elderly controls and to measure SERT occupancy by citalopram in the patients and 2. to measure A deposition in patients with geriatric depression and non-depressed, elderly controls. The hypotheses will be tested that lower SERT availability, SERT occupancy by citalopram in the patients and greater A deposition will be observed in patients relative to controls will be observed in the same regions implicated in the glucose metabolism PET studies. The ultimate goal of the proposed studies is to obtain a mechanistic understanding of affective and cognitive symptoms to inform the development of more effective prevention and intervention strategies. Geriatric depression is a significant public health problem as it is associated with a dramatic increase in the rate of completed suicide and with greater mortality in the medically ill elderly. The prevalence of clinically significant depressive symptoms in community-residing elderly has been estimated from 8% to 16% and up to 50% in institutionalized and medically ill elderly. Even though there are effective antidepressant agents available, many patients are still refractory to treatment and demonstrate persistent cognitive impairment and cognitive decline, despite mood symptom improvement. PUBLIC HEALTH RELEVANCE: Depressed patients over age 60 will be scanned before and during antidepressant treatment to understand why depression later in life is more difficult to treat. We will measure a brain chemical called serotonin and a protein related to the loss of nerve cells in Alzheimer's dementia. We will test the hypotheses that patients who do not respond as well to treatment have less serotonin in their brains and greater beta-amyloid protein.