Department of Pathology, Stanford University, Stanford, California (T.J.M., S.A.B.) and Pacific Health Research and Education Institute, Honolulu, Hawaii (L.R.W.)
Department of Pathology, Stanford University, Stanford, California (T.J.M., S.A.B.) and Pacific Health Research and Education Institute, Honolulu, Hawaii (L.R.W.).
Pharmacol Rev. 2021 Jan;73(1):152-162. doi: 10.1124/pharmrev.120.000031.
Cognitive impairment and its severe form dementia are increasingly prevalent in older adults and loom as a public health disaster unless effective interventions are developed. Cognitive impairment is a convergent trait caused by damage from an idiosyncratic mix of four prevalent diseases (Alzheimer disease; vascular brain injury; Lewy body diseases, such as Parkinson disease and dementia with Lewy bodies; and limbic-predominant age-related transactive response DNA-binding protein 43 encephalopathy) that is counterbalanced by individually varying resilience, which is comprised of reserve and compensation. Brain regional damage from each of these four prevalent diseases is generated by the net effect of injury and (mal)adaptive response and is accompanied by characteristic lesions. Existing therapeutics enhance resilience, whereas most agents under development target mechanisms of damage with only suppression of vascular brain injury yet to show therapeutic promise. We hope to anticipate future tailored interventions that target mechanisms of damage and thereby avert the oncoming surge of cognitive impairment and dementia in older adults. SIGNIFICANCE STATEMENT: Brain regional damage is generated by the net effect of injury and (mal)adaptive response. The extent to which signs and symptoms of such damage occur is influenced by an underlying resilience comprising reserve and compensation. Finding tailored interventions that target specific mechanisms of damage likely yields the most effective therapies.
认知障碍及其严重形式痴呆在老年人中越来越普遍，如果不开发出有效的干预措施，将会成为一场公共卫生灾难。认知障碍是一种趋同特征，由四种常见疾病（阿尔茨海默病；血管性脑损伤；路易体疾病，如帕金森病和路易体痴呆；和边缘为主的与年龄相关的转录反应 DNA 结合蛋白 43 脑病）的独特混合造成的损伤引起，这种损伤被个体差异的适应能力所平衡，适应能力包括储备和代偿。这四种常见疾病中的每一种对大脑区域的损害都是由损伤和（适应性）反应的净效应产生的，同时伴有特征性病变。现有的治疗方法增强了适应能力，而大多数正在开发的药物都针对损伤机制，只有血管性脑损伤的抑制作用显示出治疗前景。我们希望预测未来针对损伤机制的定制干预措施，从而避免老年人认知障碍和痴呆的即将到来的激增。
大脑区域的损伤是由损伤和（适应性）反应的净效应产生的。这种损伤的迹象和症状的发生程度受到储备和代偿组成的内在适应能力的影响。寻找针对特定损伤机制的定制干预措施可能会产生最有效的治疗方法。
