King's College London, Wolfson Centre for Age-Related Diseases, London, UK.
Curr Mol Pharmacol. 2009 Jan;2(1):77-82. doi: 10.2174/1874467210902010077.
Behavioural symptoms are a significant problem in Alzheimer's disease (AD). Symptoms including agitation/aggression and psychosis reduce patient quality of life, significantly increase caregiver burden, and often trigger nursing home placement. Underlying changes in the serotonergic, noradrenergic and cholinergic systems have been linked to some behavioural problems, however, the use of antipsychotics in this population has been associated with significant safety concerns. A role for the glutamate system in schizophrenia, as well as in anxiety and depression, has been suggested, and evidence is emerging for a role for dysfunctional glutamate neurotransmission (via N-methyl-D-aspartate (NMDA) receptors) in certain behavioural changes in dementia. For example, the NMDA receptor antagonist, memantine has been shown to improve cognition, function (activities of daily living, ADLs) and, more recently, agitation/aggression, and delusions in AD patients. To date, little information is available regarding the neurochemical basis of agitation/aggression. However, the frontal and cingulate cortices--specifically, the formation of neurofibrillary tangles in glutamatergic pyramidal neurones of these areas--are proposed as regional substrates of these behaviours. Given that memantine displays a favourable tolerability profile, it is relevant to investigate the underlying mechanism linking memantine with the behavioural elements of AD. One hypothesis proposes that memantine corrects dysfunctional glutamatergic neurotransmission in the frontal and cingulate cortices, thereby normalising pathways responsible for causing agitation. An alternative hypothesis is based on the observation that increased tangle formation is associated with agitation, and on recent studies where memantine has been shown to reduce tau phosphorylation via glycogen synthase kinase (GSK)-3 or activation of protein phosphatase (PP)-2A, which might subsequently lead to reduced agitation.
行为症状是阿尔茨海默病（AD）的一个重大问题。包括激越/攻击和精神病在内的症状会降低患者的生活质量，显著增加护理人员的负担，并经常导致入住疗养院。血清素能、去甲肾上腺素能和胆碱能系统的潜在变化与一些行为问题有关，然而，在这一人群中使用抗精神病药物与显著的安全问题有关。谷氨酸能系统在精神分裂症以及焦虑和抑郁中的作用已经被提出，并且有证据表明，在某些痴呆症的行为改变中，谷氨酸能神经传递功能障碍（通过 N-甲基-D-天冬氨酸（NMDA）受体）发挥作用。例如，NMDA 受体拮抗剂美金刚已被证明可以改善认知功能、功能（日常生活活动，ADLs），以及最近的激越/攻击和妄想。迄今为止，关于激越/攻击的神经化学基础的信息很少。然而，额叶和扣带回皮层——特别是这些区域中谷氨酸能锥体神经元中的神经原纤维缠结的形成——被提议作为这些行为的区域基质。鉴于美金刚具有良好的耐受性特征，因此研究将美金刚与 AD 的行为元素联系起来的潜在机制是相关的。一个假设是，美金刚纠正额叶和扣带回皮层中功能失调的谷氨酸能神经传递，从而使负责引起激越的通路正常化。另一个假设基于以下观察结果：缠结形成增加与激越有关，以及最近的研究表明，美金刚通过糖原合酶激酶（GSK）-3 或蛋白磷酸酶（PP）-2A 的激活减少 tau 磷酸化，这可能随后导致激越减少。
