Geriatric Depression: PET Studies of Pathophysiology and Treatment Response

描述（由申请人提供）：在过去的十年中，首席研究员和她的同事将神经影像学纳入治疗研究，以了解老年抑郁症的神经生物学。该策略为评估神经化学系统的功能完整性和大脑补偿年龄和疾病相关（神经化学和神经病理）变化的能力提供了独特的机会。这些研究用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治疗反应。与对照组相比，患者的皮质糖代谢增加。在抗抑郁药物干预后，在同一区域观察到代谢降低，并且这种降低与情绪和认知症状的改善相关。确定了功能性神经解剖学，下一步是检查潜在的病理生理学。拟议的研究整合了PET仪器和放射性示踪化学的最新进展，以及死后和神经影像学数据，以研究选择性5 -羟色胺再摄取抑制剂（SSRI，西酞普兰）和β -淀粉样蛋白沉积对5 -羟色胺转运体（SERT）的占用。在高代谢和受西酞普兰治疗影响的区域，SERT占用率越高，心境症状的改善程度越高。认知障碍在SSRI治疗缓解情绪症状后持续存在的观察表明，除血清素功能障碍外，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。β -淀粉样蛋白沉积也见于高代谢区域，与老年抑郁症和正常衰老的情景记忆障碍有关（Butters等人，2008；Sojkova等人，2008）。修订后的申请的具体目的是：1。测量老年抑郁症患者和非抑郁症患者的SERT可用性，以及测量西酞普兰在患者和老年人中的SERT占用率。测量老年抑郁症患者和非抑郁的老年对照者的A沉积。假设将被验证，在葡萄糖代谢PET研究中涉及的相同区域，相对于对照组，在患者中观察到较低的SERT可用性，西酞普兰在患者中的SERT占用和更大的A沉积。拟议研究的最终目标是获得对情感和认知症状的机制理解，以便为制定更有效的预防和干预策略提供信息。老年抑郁症是一个重大的公共卫生问题，因为它与自杀率的急剧上升和患病老年人的更高死亡率有关。据估计，在社区居住的老年人中，临床显著抑郁症状的患病率为8%至16%，而在住院和患病的老年人中，患病率高达50%。尽管有有效的抗抑郁药物可用，但许多患者仍然难以治疗，并表现出持续的认知障碍和认知能力下降，尽管情绪症状有所改善。

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.