From the Aix Marseille Université, APHM, INSERM, CIC CPCET Service de Pharmacologie Clinique et Pharmacovigilance, Institut de Neurosciences des Systèmes, Marseille.
MEDES-Institut de Médecine et de Physiologie Spatiale; Clinique Spatiale, Toulouse.
J Clin Psychopharmacol. 2020 May/Jun;40(3):222-230. doi: 10.1097/JCP.0000000000001199.
PURPOSE/BACKGROUND: Alzheimer disease (AD) is a public health issue because of the low number of symptomatic drugs and the difficulty to diagnose it at the prodromal stage. The need to develop new treatments and to validate sensitive tests for early diagnosis could be met by developing a challenge model reproducing cognitive impairments of AD. Therefore, we implemented a 24-hour sleep deprivation (SD) design on healthy volunteers in a randomized, double-blind, placebo-controlled, crossover study on 36 healthy volunteers.
METHODS/PROCEDURE: To validate the SD model, cognitive tests were chosen to assess a transient worsening of cognitive functions after SD and a restoration under modafinil as positive control (one dose of 200 mg). Then, the same evaluations were replicated after 15 days of donepezil (5 mg/d) or memantine (10 mg/d). The working memory (WM) function was assessed by the N-back task and the rapid visual processing (RVP) task.
FINDINGS/RESULTS: The accuracy of the N-back task and the reaction time of the RVP revealed the alteration of the WM with SD and its restoration with modafinil (changes in score after SD compared with baseline before SD), respectively, in the placebo group and in the modafinil group (-0.2% and +1.0% of satisfactory answers, P = 0.022; +21.3 and +1.9 milliseconds of reaction time, P = 0.025). Alzheimer disease drugs also tended to reverse this deterioration: the accuracy of the N-back task was more stable through SD (compared with -3.0% in the placebo group, respectively, in the memantine group and in the donepezil group: -1.4% and -1.6%, P = 0.027 and P = 0.092) and RVP reaction time was less impacted (compared with +41.3 milliseconds in the placebo group, respectively, in the memantine group and in the donepezil group: +16.1 and +29.3 milliseconds, P = 0.034 and P = 0.459).
IMPLICATIONS/CONCLUSIONS: Our SD challenge model actually led to a worsening of WM that was moderated by both modafinil and AD drugs. To use this approach, the cognitive battery, the vulnerability of the subjects to SD, and the expected drug effect should be carefully considered.
目的/背景：阿尔茨海默病（AD）是一个公共卫生问题，因为目前针对该疾病的症状性药物数量较少，并且在疾病前驱阶段难以诊断。为了开发新的治疗方法并验证用于早期诊断的敏感测试，可以通过开发一种复制 AD 认知障碍的挑战模型来满足这一需求。因此，我们在 36 名健康志愿者中进行了一项随机、双盲、安慰剂对照、交叉研究，对健康志愿者实施了 24 小时睡眠剥夺（SD）设计。
方法/程序：为了验证 SD 模型，我们选择了认知测试来评估 SD 后认知功能的短暂恶化，并使用莫达非尼作为阳性对照（一次 200mg 剂量）来恢复。然后，在 15 天后，重复使用多奈哌齐（5mg/d）或美金刚（10mg/d）进行相同的评估。工作记忆（WM）功能通过 N-back 任务和快速视觉处理（RVP）任务进行评估。
结果/发现：在安慰剂组和莫达非尼组中，N-back 任务的准确性和 RVP 的反应时间分别揭示了 WM 的改变（与 SD 前的基线相比，SD 后的评分变化），以及在莫达非尼组中，WM 得到了恢复（在安慰剂组中分别为-0.2%和+1.0%的满意答案，P=0.022；在莫达非尼组和安慰剂组中分别为+21.3 和+1.9 毫秒的反应时间，P=0.025）。AD 药物也倾向于逆转这种恶化：N-back 任务的准确性在 SD 期间更稳定（与安慰剂组的-3.0%相比，在美金刚组和多奈哌齐组分别为-1.4%和-1.6%，P=0.027 和 P=0.092），而 RVP 反应时间的影响较小（与安慰剂组的+41.3 毫秒相比，在美金刚组和多奈哌齐组中分别为+16.1 和+29.3 毫秒，P=0.034 和 P=0.459）。
结论/意义：我们的 SD 挑战模型实际上导致 WM 恶化，而莫达非尼和 AD 药物对此具有调节作用。为了使用这种方法，应仔细考虑认知测试、受试者对 SD 的易感性以及预期的药物作用。
