A personalized medicine approach to the study of monoamine brain systems that underlie the emergence of neuropsychiatric symptoms in person with Alzheimer's disease

总结 一种渐进性神经退行性疾病，占老年痴呆症病例的大多数， 阿尔茨海默病（AD）已经是美国第六大死亡原因， 在未来十年内的普及率。神经精神症状（NPD），如激越、冷漠、精神病 是AD的核心特征，已知其通常存在于疾病的前驱期，以及 老年痴呆症（Dementia）尽管经过几十年的研究， 虽然已经提出了几种假说， 反映了个体间的异质性。该应用程序采用精确医学方法 并着重于大脑单胺回路的中断是脑缺血的原因之一的假设。 出现，在一些人的心脏病。对于某些患者来说，这种差异可能反映了人与人之间的差异。 它们的单胺脑系统的活性/效率的差异。 该应用进一步基于我们实验室最近成功地产生人类诱导的 来自AD患者以及健康个体的多能干细胞（hiPSC）并分化 将其转化为具有淀粉样蛋白生成特性的人脑细胞。我们的首要假设是， 从总共40个个体的外周血产生iPSC，包括（1）患有AD的AD患者和（2）患有AD的AD患者。 AD患者没有脑胶质瘤，并分化成脑胶质瘤相关的脑细胞，如脑胶质瘤能神经元-提出 在这里，将是有用的体外模型的机制，在个人层面。进一步的比较研究， 这些细胞的生理功能（神经递质产生，转录组）的个体差异 神经元可以解释某些情况/类型的神经元疾病，并预测药物治疗的效用，如 血清素再摄取抑制剂。 我们设想，这项研究将为新一代体外人类乳腺癌模型奠定基础， 以及用于简单的、易于再现的预测药物筛选模型，其中， 可以测试现有的和新的定制的治疗化合物。

Summary A progressive neurodegenerative condition that accounts for the majority of dementia cases in the elderly, Alzheimer's disease (AD) is already the sixth-leading cause of death in the US and is set to double in prevalence within the next decade. Neuropsychiatric symptoms (NPS), such as agitation, apathy, psychosis are core features of AD that are known to present commonly in prodromal phases of the disease, as well as in the advanced phase (Dementia). Despite decades of research, the underlying pathogenic mechanisms that lead to AD-associated NPS are poorly understood, although several hypotheses have been proposed, reflecting the heterogeneity of NPS across individuals. This application takes a precision medicine approach and focuses on the hypothesis that disruption of brain monoamine circuits is one of the causes of NPS emergence, in some individuals with NPS. This variability might for some patients reflect person-to-person differences in the activity/efficiency of their monoamine brain systems. This application is further based upon recent successes in our laboratory generating human induced pluripotent stem cells (hiPSCs) from patients with AD, as well as from healthy individuals, and differentiating them into human brain cells with amyloidogenic properties. Our overarching hypothesis is that person-specific iPSCs generated from the peripheral blood of 40 individuals total including (1) AD patients with NPS and (2) AD patients without NPS and differentiated into NPS relevant brain cells like serotonergic neurons—proposed here, will be useful in vitro models of mechanisms at the personal level. Further comparative studies of inter- individual variability in the physiologic functioning (neurotransmitter production, transcriptome) of these neurons could explain some cases/types of NPS, and predict utility of pharmacological therapies, such as serotonin reuptake inhibitors. We envision that this research will lay the groundwork for a new generation of in vitro human models of NPS, as well as for simple, easily reproducible predictive drug screening models in which the effectiveness of existing and new tailored therapeutic compounds can be tested.