Cognitive ageing and Alzheimer's disease: the cholinergic system redux.
Cognitive ageing and Alzheimer's disease: the cholinergic system redux.
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DOI：
10.1093/brain/awy040
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发表时间：
2018-03
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影响因子：
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通讯作者：
D. Sultzer
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作者：
D. Sultzer
胆碱能神经递质系统长期以来一直被认为在阿尔茨海默病的认知衰退中起重要作用，更广泛地说，在随着年龄增长和神经退行性疾病发生的记忆缺陷中起重要作用。在20世纪70年代，尸检研究显示皮质中的胆碱能酶和基底前脑中的胆碱能细胞损失显著，特别是在那些投射到阿尔茨海默病影响皮质的次区域。这些发现，加上已知的胆碱能对记忆和其他认知技能的贡献，导致了阿尔茨海默病的“胆碱能假说”。随后，其他病理学如淀粉样蛋白-β蛋白病、神经纤维缠结和神经炎症被认为是该疾病的标志。然而，最近的研究表明，胆碱能神经递质系统的改变可能不仅仅是一个历史脚注。在包括胆碱能系统的阿尔茨海默病病理学之间存在已知的相互作用：淀粉样蛋白-β对胆碱能受体可能是有毒的，相反，烟碱胆碱能受体刺激可以抑制淀粉样蛋白-β产生和磷酸化tau积累（Ovsepian et al. 2016年）。在胆碱能系统内，基底前脑细胞损失或局部tau积累在阿尔茨海默病过程中非常早期发生（Mesulam，2013），与皮质淀粉样蛋白沉积相关（Grothe et al.，2014），并且先于和预测内嗅体积损失和记忆障碍（Schmitz等人，2016年）。在健康的老年人中，基底前脑体积与一般认知相关，并且该结构的完整性可能有助于大脑在衰老中的弹性和对阿尔茨海默病中认知下降的抵抗力（Wolf等人，2014年）。关于下游皮质受体，烟碱胆碱能受体的可用性随着健康老龄化而下降，并且在轻度认知障碍（MCI）和早期阿尔茨海默病中更显著地下降，与记忆缺陷相关并且至少部分独立于海马体积，这表明在认知下降中的主要作用（Sultzer et al.，2017年）。在本期《脑》杂志中，Richter及其同事采取了重要的下一步措施，以更好地定义处于阿尔茨海默病风险中的MCI患者的胆碱能系统功能，以及相关的治疗意义（Richter等人，2018年）。Richter等人的工作评估了皮质乙酰胆碱酯酶活性、任务相关神经系统激活和MCI记忆之间的关系，包括胆碱酯酶抑制剂药物急性治疗前后。该研究的假设认识到，目前可用的前胆碱能药物的临床益处在阿尔茨海默病中差异很大，平均而言，并不稳健。此外，虽然有证据表明正常衰老和MCI中胆碱能系统功能障碍，但MCI中的胆碱能原治疗通常未显示有效。Richter等人推测，胆碱能治疗的临床获益可能取决于局部胆碱能功能障碍的存在，这可能在MCI阶段没有充分进展。因此，他们测量了胆碱能治疗对健康老年人和MCI患者神经系统激活的影响。研究人员还测量了皮质胆碱酯酶活性及其对同一模型中任务相关皮质激活的影响。调查人员解决这些问题的方法有几个明显的优势。首先，MCI样本符合临床诊断标准，但除此之外，还具有阿尔茨海默病过程的CSF生物标志物证据以及神经元疾病的证据。
The cholinergic neurotransmitter system has long been known to play an important role in the cognitive decline of Alzheimer’s disease and, more broadly, in the memory deficits that occur with age and across neurodegenerative disorders. In the 1970s, autopsy studies revealed marked loss of cholinergic enzymes in the cortex and cholinergic cell loss in the basal forebrain, particularly in those subregions that project to Alzheimer’s disease-affected cortex. These findings, together with the known cholinergic contribution to memory and other cognitive skills, led to the ‘cholinergic hypothesis’ of Alzheimer’s disease. Subsequently, other pathologies such as amyloid-β proteinopathy, neurofibrillary tangles, and neuroinflammation have been considered the hallmarks of the disease. Recent research, however, indicates that alterations in the cholinergic neurotransmitter system are probably more than a historical footnote. There are known interactions among Alzheimer’s disease pathologies that include the cholinergic system: amyloid-β can be toxic to cholinergic receptors and, conversely, nicotinic cholinergic receptor stimulation can inhibit amyloid-β production and phosphorylated tau accumulation (Ovsepian et al., 2016). Within the cholinergic system, basal forebrain cell loss or local tau accumulation occurs very early in the Alzheimer’s disease process (Mesulam, 2013), is associated with cortical amyloid deposition (Grothe et al., 2014), and precedes and predicts entorhinal volume loss and memory impairment (Schmitz et al., 2016). In healthy older adults, basal forebrain volume is associated with general cognition, and the integrity of this structure may contribute to brain resiliency in ageing and resistance to cognitive decline in Alzheimer’s disease (Wolf et al., 2014). With regard to downstream cortical receptors, nicotinic cholinergic receptor availability declines with healthy ageing and more substantially in mild cognitive impairment (MCI) and early Alzheimer’s disease, in association with memory deficits and at least partly independent of hippocampal volume, suggesting a primary role in cognitive decline (Sultzer et al., 2017). In the current issue of Brain, Richter and co-workers take an important next step to better define cholinergic system function in those with MCI at risk for Alzheimer’s disease, and the related treatment implications (Richter et al., 2018). The work by Richter et al. evaluates relationships among cortical acetylcholinesterase enzyme activity, taskrelated neural system activation, and memory in MCI, both before and after acute treatment with cholinesterase inhibitor medication. The study’s hypotheses recognize that the clinical benefit of currently available pro-cholinergic medications varies considerably in Alzheimer’s disease and, on average, is not robust. Moreover, while there is evidence of cholinergic system dysfunction in normal ageing and MCI, procholinergic treatments in MCI have not generally been shown to be effective. Richter et al. speculate that the clinical benefit of cholinergic treatment may depend on the presence of regional cholinergic dysfunction, which may not be sufficiently advanced at the MCI stage. Thus, they measured the effect of cholinergic treatment on neural system activation in both healthy elderly and those with MCI. The investigators also measured cortical cholinesterase activity and its impact on task-related cortical activation in the same model. The approach taken by the investigators to address these questions has several distinct strengths. First, the MCI sample met clinical diagnostic criteria, but in addition had CSF biomarker evidence of the Alzheimer’s disease process as well as evidence of neuronal …