CLINICAL, GENETIC AND NEUROPATHIC HETEROGENEITY IN ALZHEIMER'S DISEASE

阿尔茨海默病的临床、遗传和神经病理异质性

• 批准号: 3809130
• 负责人: JOHN BREITNER
• 金额: --
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3809130
• 关键词: Alzheimer's disease; adrenergic receptor; brain disorder diagnosis; brain stem; case history; clinical depression; dementia; dorsal raphe nucleus; human population genetics; human subject; interview; locus coeruleus; nervous system disorder; neural degeneration; neurofibrillary tangles

The heterogeneity of Alzheimer's disease (AD) is a source of difficulty in the analysis of its causes and treatment. Heterogeneity is suggested in genetic causes of AD by the contrast between familial and "sporadic" cases and, within familial disease, by the tendency of age at onset to "run true" within families. Heterogeneity in the neuropathology of AD is also apparent, since earlier-onset cases show cell loss in brain stem nuclei including the locus coeruleus and the dorsal raphe nuclei. The clinical heterogeneity of AD is also well known: cases vary not only in age at onset and rate of progression but also in their tendency to show prominent symptoms of depression. We shall investigate the interrelationships among these aspects of heterogeneity in AD as well a their relationship to an additional variable, the heritable tendency toward depression as revealed by patients' past psychiatric histories and family histories of major affective illness. Index cases will comprise a sequential series of 150 subjects with Alzheimer's disease diagnosed clinically with autopsy confirmation, whose brains have been forwarded to the brain bank/neuropathology core of the Bryan ADRC. Neuropathologic investigations, medical records, and detailed information from interviews with multiple family members will be used to test the following central hypothesis: the tendency toward depression in AD is inherited. The trait in question is revealed by a history of depression before the onset of dementia, and by a family history of affective disorder. This same trait results in early onset of symptoms and involvement of the locus coeruleus, serotonergic midbrain nuclei, or both during the pathologic process of AD. This involvement in turn results in symptoms of depression along with dementia. Therefore, clinical, neuropathologic and family/genetic investigations of AD cases will show association among family history of affective disorders, age at onset, depressive symptoms (both prior to and concurrent with symptoms of dementia), and neuropathology in the locus coeruleus and/or the dorsal raphe nuclei.

阿尔茨海默病（AD）的异质性是治疗困难的​​一个根源 分析其原因及治疗方法。 异质性被建议在 通过家族性病例和“散发性”病例的对比来了解 AD 的遗传原因 并且，在家族性疾病中，发病年龄有“真实”的趋势 家庭内部。 AD 神经病理学的异质性也 很明显，因为早期发病的病例显示脑干核细胞丢失 包括蓝斑和中缝背核。 临床上 AD 的异质性也是众所周知的：病例不仅发病年龄不同 和进展速度，而且还表现出突出的倾向 抑郁症的症状。 我们将研究这些方面之间的相互关系 AD 的异质性以及它们与附加变量的关系， 患者过去的经历揭示了抑郁症的遗传倾向 重大情感疾病的精神病史和家族史。 索引案例将由 150 个受试者组成的连续系列组成 临床诊断的阿尔茨海默病需要尸检证实，其 大脑已被转发至脑库/神经病理学核心 布莱恩·ADRC。神经病理学检查、医疗记录和详细信息 与多名家庭成员面谈的信息将用于 检验以下中心假设：抑郁倾向 AD是遗传的。 所讨论的特征是由历史揭示的 痴呆症发病前的抑郁症以及家族史 情感障碍。同样的特征会导致症状早期出现， 蓝斑、血清素能中脑核团或两者均受累 AD的病理过程中。 这种参与反过来又导致 抑郁症和痴呆症的症状。 因此，临床上， AD 病例的神经病理学和家族/遗传调查将显示 情感障碍家族史、发病年龄、 抑郁症状（在以下症状之前和同时发生） 痴呆），以及蓝斑和/或背侧的神经病理学 中缝核。