Precision pharmacology for Alzheimer's disease.
Precision pharmacology for Alzheimer's disease.
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DOI：
10.1016/j.phrs.2018.02.014
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发表时间：
2018-04
影响因子：
9.3
通讯作者：
Alzheimer Precision Medicine Initiative (APMI)
中科院分区：
文献类型：
--
作者：
Hampel H;Vergallo A;Aguilar LF;Benda N;Broich K;Cuello AC;Cummings J;Dubois B;Federoff HJ;Fiandaca M;Genthon R;Haberkamp M;Karran E;Mapstone M;Perry G;Schneider LS;Welikovitch LA;Woodcock J;Baldacci F;Lista S;Alzheimer Precision Medicine Initiative (APMI)
多基因阿尔茨海默病（AD）复杂的多因素性质对药物开发提出了重大挑战。AD病理生理学以非线性动态方式跨越多个系统水平-从分子到器官系统-并通过适应、补偿和失代偿到系统衰竭而进展。适应和补偿维持稳态：基因组、表观基因组和环境之间动态非线性相互作用的动态平衡。个体对压力源的脆弱性存在于个体触发因素、驱动因素和阈值的基础上，这些因素决定了适应性和补偿性反应的启动和失败。因此，AD病理生理学在空间和时间上的独特模式必须在个体生物构成的基础上进行研究。这需要实施系统生物学和神经生理学，以促进精准医学（PM）和精准药理学（PP）。从基因表达到细胞周期到组织修复和系统范围的网络激活，在多个复杂性水平上的几个过程的调节根据受影响的系统（空间尺度）具有不同的时间延迟（时间尺度）。最初的失败可能起源于并发生在每一个潜在影响有机体内整个动态相关系统的层面。解开空间和时间动态的非线性病理生理机制，在连续的层次自组织系统水平和系统稳态系统故障是理解AD的关键。测量并可能控制AD期间发生的空间和时间尺度的适应性和代偿性反应将是实现在最佳合适的时间点大幅改变疾病进程和进展的能力的关键步骤，从而抵消破坏关键的病理生理学输入。这种方法将为有效的基于疾病修饰途径的靶向治疗提供概念基础。PP基于对复杂疾病（如脑蛋白病，包括AD）的探索性和综合性策略，旨在识别同时异常的分子通路并预测其对系统水平的时间影响。对复杂疾病的基于途径的分子特征的描述有助于在治疗干预可能逆转、停止或延迟疾病的最早代偿阶段对个体的不同亚群进行准确和机械分层。此外，个体化药物选择可以通过降低副作用和不良反应的风险和幅度来优化治疗安全性。从方法学的角度来看，全面的“组学”为基础的生物标志物将引导探索时空系统的形态功能转变沿着连续的AD病理生理学，从适应到不可逆的失败。阿尔茨海默病精准医学计划（APMI）和APMI队列计划（APMI-CP）已经开始促进向AD有效药物发现和开发的范式转变。
The complex multifactorial nature of polygenic Alzheimer’s disease (AD) presents significant challenges for drug development. AD pathophysiology is progressing in a non-linear dynamic fashion across multiple systems levels – from molecules to organ systems – and through adaptation, to compensation, and decompensation to systems failure. Adaptation and compensation maintain homeostasis: a dynamic equilibrium resulting from the dynamic non-linear interaction between genome, epigenome, and environment. An individual vulnerability to stressors exists on the basis of individual triggers, drivers, and thresholds accounting for the initiation and failure of adaptive and compensatory responses. Consequently, the distinct pattern of AD pathophysiology in space and time must be investigated on the basis of the individual biological makeup. This requires the implementation of systems biology and neurophysiology to facilitate Precision Medicine (PM) and Precision Pharmacology (PP). The regulation of several processes at multiple levels of complexity from gene expression to cellular cycle to tissue repair and system-wide network activation has different time delays (temporal scale) according to the affected systems (spatial scale). The initial failure might originate and occur at every level potentially affecting the whole dynamic interrelated systems within an organism. Unraveling the spatial and temporal dynamics of non-linear pathophysiological mechanisms across the continuum of hierarchical self-organized systems levels and from systems homeostasis to systems failure is key to understand AD. Measuring and, possibly, controlling space- and time-scaled adaptive and compensatory responses occurring during AD will represent a crucial step to achieve the capacity to substantially modify the disease course and progression at the best suitable timepoints, thus counteracting disrupting critical pathophysiological inputs. This approach will provide the conceptual basis for effective disease-modifying pathway-based targeted therapies. PP is based on an exploratory and integrative strategy to complex diseases such as brain proteinopathies including AD, aimed at identifying simultaneous aberrant molecular pathways and predicting their temporal impact on the systems levels. The depiction of pathway-based molecular signatures of complex diseases contributes to the accurate and mechanistic stratification of distinct subcohorts of individuals at the earliest compensatory stage when treatment intervention may reverse, stop, or delay the disease. In addition, individualized drug selection may optimize treatment safety by decreasing risk and amplitude of side effects and adverse reactions. From a methodological point of view, comprehensive “omics”-based biomarkers will guide the exploration of spatio-temporal systems-wide morpho-functional shifts along the continuum of AD pathophysiology, from adaptation to irreversible failure. The Alzheimer Precision Medicine Initiative (APMI) and the APMI cohort program (APMI-CP) have commenced to facilitate a paradigm shift towards effective drug discovery and development in AD.
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影响因子：
7.8
作者：
Atherton J;Kurbatskaya K;Bondulich M;Croft CL;Garwood CJ;Chhabra R;Wray S;Jeromin A;Hanger DP;Noble W
通讯作者：
Noble W
影响因子：
82.9
作者：
Bateman, Randall J.;Munsell, Ling Y.;Holtzman, David M.
通讯作者：
Holtzman, David M.
影响因子：
3.7
作者：
Anastasiou CA;Yannakoulia M;Kosmidis MH;Dardiotis E;Hadjigeorgiou GM;Sakka P;Arampatzi X;Bougea A;Labropoulos I;Scarmeas N
通讯作者：
Scarmeas N
DOI：
10.3233/jad-150788
发表时间：
2016
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Bennett J;Burns J;Welch P;Bothwell R
通讯作者：
Bothwell R
影响因子：
6.2
作者：
Bernier, Louis-Philippe;Ase, Ariel R.;Seguela, Philippe
通讯作者：
Seguela, Philippe