Weinstein James D
Marshall University School of Medicine, Medical Center, Huntington, WV, USA.
Neural Regen Res. 2018 Feb;13(2):190-193. doi: 10.4103/1673-5374.226381.
Despite decades of research, at present there is no curative therapy for Alzheimer's disease. Changes in the way new drugs are tested appear to be necessary. Three changes are presented here and will be discussed. The first change is that Alzheimer's disease must be considered a disease of four major pathological processes, not one. The four processes are: 1) vascular hypoperfusion of the brain with associated mitochondrial dysfunction, 2) destructive protein inclusions, 3) uncontrolled oxidative stress, and 4) proinflammatory immune processes secondary to microglial and astrocytic dysfunction in the brain. The second change recommended is to alter the standard cognitive measurement tools used to quantify mental decline in test patients. Specifically the Dementia Severity Rating Scale (DSRS) should supersede Mini-Mental State Examination (MMSE) and other popular tests, and a measurement scale developed in research should be used to produce a linear and non-irregular baseline. Finally, accepting the concept that four etiologies cause Alzheimer's disease leads to the last necessary change, that new therapies must be employed directed against all four causes, likely as a combination. There are drugs ready to be employed in such a combinations which are available and used clinically for other purposes so can be used "off label" and one such combination is suggested.
尽管经过了数十年的研究，但目前仍没有针对阿尔茨海默病的治愈性疗法。新药测试方式的改变似乎是必要的。本文提出并将讨论三项改变。第一项改变是，必须将阿尔茨海默病视为一种由四种主要病理过程而非单一过程导致的疾病。这四个过程分别是：1）大脑血管灌注不足及相关的线粒体功能障碍；2）具有破坏性的蛋白质内含物；3）失控的氧化应激；4）大脑中因小胶质细胞和星形胶质细胞功能障碍继发的促炎免疫过程。推荐的第二项改变是改变用于量化受试患者智力衰退的标准认知测量工具。具体而言，痴呆严重程度评定量表（DSRS）应取代简易精神状态检查表（MMSE）及其他常用测试，并且应使用研究中开发的一种测量量表来生成线性且无异常的基线。最后，接受四种病因导致阿尔茨海默病这一概念会带来最后一项必要改变，即必须采用针对所有四种病因的新疗法，可能是联合使用。有一些药物可用于这种联合用药，它们目前已上市且临床上用于其他目的，因此可以“超说明书”使用，本文还建议了一种这样的联合用药方案。
