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

摘要 一种进行性神经退行性疾病，占老年人痴呆症病例的大部分， 阿尔茨海默病(AD)已经是美国第六大死亡原因，而且在美国将翻一番。 在接下来的十年内流行。神经精神症状(NPS)，如激越、冷漠、精神病 是已知的AD的核心特征，通常出现在疾病的前驱阶段，以及 晚期(痴呆症)。尽管经过几十年的研究，但潜在的致病机制 导致AD相关NPS的原因很少，尽管已经提出了几个假设， 反映了核动力源在个体间的异质性。此应用程序采用精准医学方法 并重点研究了脑单胺环路中断是NPS的原因之一的假说 出现在一些NPS患者身上。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。 他们的单胺类大脑系统的活动/效率的差异。 这一应用是基于我们实验室最近成功地产生人类诱导的 AD患者和健康人的多能干细胞(HiPSCs)，并正在分化 转化成具有淀粉样变性特性的人脑细胞。我们最重要的假设是特定的人 共40例患者外周血中培养出IPSCs，包括(1)伴NPS的AD患者和(2) 无NPS并分化为NPS相关脑细胞的AD患者，如5-羟色胺能神经元-建议 在这里，将在个人层面上建立有用的体外机制模型。进一步的内部比较研究 这些细胞的生理功能(神经递质的产生、转录组)的个体差异 神经元可以解释一些NPS病例/类型，并预测药物治疗的有效性，例如 5-羟色胺再摄取抑制剂。 我们预计，这项研究将为新一代NPS体外人体模型奠定基础， 以及简单、容易重现的预测药物筛选模型，在该模型中 现有的和新的量身定制的治疗化合物可以进行测试。

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.