MORPHOLOGIC/NEUROCHEMICAL CORRELATES OF DEPRESSION IN AD

描述（申请人摘要）： 阿尔茨海默病（AD+D）中的重度抑郁症表明， AD的这种行为并发症与 脑干胺能神经核团和胆碱能神经核团的相对保存 bnM。 AD+D的神经病理学和相关神经化学相关性 似乎是相对具体的这种情况，并可能解释方面 抑郁症的病程和治疗反应 上下文 重度抑郁症的家族史也可能更常见于 AD+D患者，表明既存家族性疾病之间的相互作用， 脆弱性和AD+D发病机制中的关键神经退行性事件。 据报道，路易体变异（ADLBV）伴随着更多的 脑干胺能核的侵袭性变性和更高的 抑郁症的患病率高于单独的AD。 如果得到证实， 观察将加强退化的关系， 脑干胺能神经核团与AD+D的发生、发展密切相关。 我们建议继续对这些关系进行临床病理学研究 并使用尸检证实的AD/ADLBV评估其概括性 病例组和对照组的前瞻性特征为： 四个国家免疫局资助的发展合作中心/发展合作中心。 而且。 我们将测试假设， AD中抑郁症的严重程度/慢性程度与 脑干胺能神经核的退化 评估 这些发现对抑郁症的特异性，我们还将探讨 精神病和其他行为的形态学和神经化学相关性 AD的异常。 除了家族史研究， 确定AD+D的出现是否受APOE基因型的影响 AD患者。 我们还将继续调查 AD中脑干胺能核神经元丢失中的细胞凋亡。 我们 数据表明AD+D患者对神经元的易感性增加， 由于脆弱性增加而导致LC（可能还有DR和SN）的损失 导致细胞凋亡。 我们假设这增强了 易受凋亡性细胞死亡的影响是由于细胞内 保护机制反映在神经元的比例减少， 显示Bcl-2的上调。 拟议研究计划的长期目标是更好地界定 生物基质AD+D，促进更多 有效的治疗，并提供更多的洞察临床 老年抑郁症的生物学

DESCRIPTION (applicant's abstract): Emerging clinicopathological studies of major depression in Alzheimer's disease (AD+D) suggest that the development of this behavioral complication of AD is associated with degeneration of the brainstem aminergic nuclei and the relative preservation of the cholinergic bnM. The neuropathologic and related neurochemical correlates of AD+D appear to be relatively specific for this condition, and may explain aspects of the course and treatment responsiveness of major depression in this context. Family histories of major depression may also be more common for AD+D patients, suggesting an interaction between a preexisting familial vulnerability and key neurodegenerative events in the pathogenesis of AD+D. The Lewy body variant (ADLBV) has been reported to be accompanied by more aggressive degeneration of the brainstem aminergic nuclei and a higher prevalence of major depression than AD alone. If confirmed, the latter observations would strengthen the relationship of degeneration of the brainstem aminergic nuclei to the development of AD+D. We propose to continue our clinicopathologic studies of these relationships and to evaluate their generalizability using autopsy-confirmed AD/ADLBV cases and controls who were prospectively characterized by a consortium of four NIA-funded ADCs/ADRCs. Moreover. we will test the hypothesis that the severity/ chronicity of major depression in AD is correlated with the extent of degeneration of the brainstem aminergic nuclei. To assess the specificity of these findings for depression, we will also explore the morphologic and neurochemical correlates of psychosis and other behavioral abnormalities in AD. In addition to family history studies we will determine whether the emergence of AD+D is influenced by the APOE genotype of AD patients. We will also continue our investigation of the role of apoptosis in neuronal loss from the brainstem aminergic nuclei in AD. Our data suggest that AD+D patients have increased susceptibility to neuronal loss in the LC (and possibly the DR and SN) due to increased vulnerability of these cells to apoptosis. We hypothesize that this enhanced vulnerability to apoptotic cell death results from a reduction in cellular protective mechanisms as reflected by a reduced proportion of neurons that manifest the upregulation of Bcl-2. The long-term goals of the proposed research plan are to better define the biological substrates of AD+D, to facilitate the development of more effective treatments, and to provide additional insight into the clinical biology of depression in the elderly.