Haberman Rebecca P, Branch Audrey, Gallagher Michela
Department of Psychological and Brain Sciences, The Johns Hopkins University, 3400 North Charles Street, 116 Dunning Hall, Baltimore, MD, 21218, USA.
Neurotherapeutics. 2017 Jul;14(3):662-676. doi: 10.1007/s13311-017-0541-z.
Sporadic late-onset Alzheimer's disease (LOAD), the most common form of dementia in the elderly, causes progressive and severe loss of cognitive abilities. With greater numbers of people living to advanced ages, LOAD will increasingly burden both the healthcare system and society. There are currently no available disease-modifying therapies, and the failure of several recent pathology-based strategies has highlighted the urgent need for effective therapeutic targets. With aging as the greatest risk factor for LOAD, targeting mechanisms by which aging contributes to disease could prove an effective strategy to delay progression to clinical dementia by intervention in elderly individuals in an early prodromal stage of disease. Excess neural activity in the hippocampus, a recently described phenomenon associated with age-dependent memory loss, was first identified in animal models of aging and subsequently translated to clinical conditions of aging and early-stage LOAD. Critically, elevated activity was similarly localized to specific circuits within the hippocampal formation in aged animals and humans. Here we review evidence for hippocampal hyperactivity as a significant contributor to age-dependent cognitive decline and the progressive accumulation of pathology in LOAD. We also describe studies demonstrating the efficacy of reducing hyperactivity with an initial test therapy, levetiracetam (Keppra), an atypical antiepileptic. By targeting excess neural activity, levetiracetam may improve cognition and attenuate the accumulation of pathology contributing to progression to the dementia phase of LOAD.
散发性晚发型阿尔茨海默病（LOAD）是老年人中最常见的痴呆形式，会导致认知能力的进行性严重丧失。随着越来越多的人活到高龄，LOAD将给医疗系统和社会带来越来越大的负担。目前尚无可用的疾病修饰疗法，最近几种基于病理学的策略的失败凸显了对有效治疗靶点的迫切需求。由于衰老作为LOAD的最大风险因素，针对衰老导致疾病的机制进行干预，可能是一种通过对疾病早期前驱阶段的老年人进行干预来延缓临床痴呆进展的有效策略。海马体中神经活动过度，这是一种最近描述的与年龄相关的记忆丧失现象，最初在衰老动物模型中被发现，随后被转化到衰老和早期LOAD的临床情况中。至关重要的是，在老年动物和人类中，活动增强同样定位于海马结构内的特定回路。在这里，我们综述了海马体活动亢进作为年龄相关认知衰退和LOAD中病理进展性积累的重要因素的证据。我们还描述了一些研究，这些研究证明了用一种初始试验疗法左乙拉西坦（开浦兰）（一种非典型抗癫痫药物）减少活动亢进的疗效。通过针对过度的神经活动，左乙拉西坦可能改善认知并减轻导致LOAD进展到痴呆阶段的病理积累。
