MORPHOLOGIC/NEUROCHEMICAL CORRELATES OF DEPRESSION IN AD

描述(申请人摘要)：新出现的临床病理研究 阿尔茨海默病的主要抑郁症(AD+D)表明 阿尔茨海默病的这种行为并发症与退行性变有关 脑干胺能核与胆碱能神经元的相对保存 BNM。AD+D的神经病理及相关神经化学相关性研究 对于这种情况似乎是相对具体的，并可以解释一些方面 重度抑郁症的病程和治疗反应性 背景。严重抑郁症的家族史也可能更常见 AD+D患者，提示先前存在的家族成员之间的相互作用 AD+D发病机制中的脆弱性和关键神经退行性事件 据报道，路易体变异体(ADLBV)伴随着更多 脑干胺能核的侵袭性变性和更高的 严重抑郁症的患病率高于单纯的AD。如果得到确认，后者 观察结果将加强生物多样性退化的关系 脑干胺能核对AD+D发育的影响 我们建议继续我们对这些关系的临床病理研究。 并使用尸检确认的AD/ADLBV评估其概括性 具有前瞻性特征的病例和对照 四个由NIA资助的ADDC/ADRC。更有甚者。我们将检验这一假设 阿尔茨海默病患者抑郁的严重程度/慢性化程度与程度相关 脑干胺能核团的变性。要评估 这些发现对于抑郁症的特异性，我们还将探索 精神病和其他行为的形态和神经化学相关性 AD的异常。除了家族史研究外，我们还将 确定AD+D的出现是否受APOE基因的影响 阿尔茨海默病患者中。我们还将继续调查 阿尔茨海默病患者脑干胺能核团神经元丢失的细胞凋亡。我们的 数据表明AD+D患者对神经元的易感性增加 由于漏洞增加导致LC(可能还有DR和SN)丢失 使这些细胞发生凋亡。我们假设这增强了 由于细胞数量减少而导致的对细胞凋亡的易感性 保护机制，反映在神经元比例的减少 表现为Bcl2表达上调。 拟议研究计划的长期目标是更好地界定 AD+D的生物底物，促进更多的发展 有效的治疗方法，并为临床提供更多的洞察力 老年抑郁症的生物学研究。

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.