Wesnes Cognition Ltd., Little Paddock, Streatley Hill, Streatley on Thames RG8 9RD, UK ; Department of Psychology, Northumbria University, Newcastle, UK ; Centre for Human Psychopharmacology, Swinburne University, Melbourne, VIC, Australia.
Bracket, Wayne, PA, USA.
Alzheimers Res Ther. 2014 Apr 15;6(2):20. doi: 10.1186/alzrt250. eCollection 2014.
Emerging evidence suggests that decreased adult hippocampal neurogenesis represents an early critical event in the course of Alzheimer's disease (AD). In mice, adult neurogenesis is reduced by knock-in alleles for human apolipoprotein E (ApoE) ∈4. Decreased dentate gyrus (DG) neural progenitor cells proliferation has been observed in the triple-transgenic mouse model of AD (3xTg-AD); this reduction being directly associated with the presence of amyloid-β (Aβ) plaques and an increase in the number of Aβ-containing neurons in the hippocampus. Cognitive tasks involving difficult pattern separations have been shown to reflect DG activity and thus potentially neurogenesis in both animals and man. This study involved the administration of a pattern separation paradigm to Alzheimer's patients to investigate relationships between task performance and both ApoE status and cerebrospinal fluid (CSF) Aβ42 levels.
The CDR System pattern separation task involves the presentation of pictures that must later be discriminated from closely similar pictures. This paper presents pattern separation data from 66 mild to moderate AD patients, of which 50 were genotyped and 65 in whom CSF Aβ42 was measured.
ApoE ∈4 homozygotes were not compromised on the easy pattern separations compared with the other patients, but they were statistically significantly poorer at the difficult separations. In all patients CSF Aβ42 correlated significantly with the ability to make the difficult discriminations, but not easier discriminations. Pattern separation speed correlated negatively with CSF Aβ42, and thus the association was not due to increased impulsivity.
These are, to our knowledge, the first human pattern separation data to suggest a possible genetic link to poor hippocampal neurogenesis in AD, as well as a relationship to Aβ42. Therapies which target neurogenesis may thus be useful in preventing the early stages of AD, notably in ApoE ∈4 homocygotes.
新出现的证据表明，成人海马神经发生减少代表了阿尔茨海默病（AD）病程中的一个早期关键事件。在小鼠中，载脂蛋白 E（ApoE）∈4 的基因敲入等位基因可减少成年神经发生。在 AD 的三转基因小鼠模型（3xTg-AD）中观察到齿状回（DG）神经祖细胞增殖减少；这种减少与淀粉样β（Aβ）斑块的存在直接相关，并且海马中含有 Aβ 的神经元数量增加。涉及困难模式分离的认知任务已被证明反映了 DG 活动，从而潜在地反映了动物和人类的神经发生。本研究通过对 AD 患者进行模式分离范式的给药，来研究任务表现与 ApoE 状态和脑脊液（CSF）Aβ42 水平之间的关系。
CDR 系统模式分离任务涉及呈现必须稍后从相似的图片中区分的图片。本文介绍了来自 66 名轻度至中度 AD 患者的模式分离数据，其中 50 名患者进行了基因分型，65 名患者测量了 CSF Aβ42。
与其他患者相比，ApoE ∈4 纯合子在简单模式分离方面没有受到影响，但在困难的分离方面统计学上明显较差。在所有患者中，CSF Aβ42 与进行困难区分的能力显著相关，但与更容易区分的能力无关。模式分离速度与 CSF Aβ42 呈负相关，因此这种关联不是由于冲动性增加所致。
据我们所知，这些是人类模式分离数据首次表明 AD 中可能存在与海马神经发生不良的遗传联系，以及与 Aβ42 的关系。因此，针对神经发生的治疗方法可能对预防 AD 的早期阶段有用，尤其是在 ApoE ∈4 纯合子中。
