Department of Psychiatry, School of Medicine, University of California, San Diego, La Jolla, CA, USA.
VISN-22 Mental Illness, Research, Education and Clinical Center (MIRECC), VA San Diego Healthcare System, San Diego, CA, USA.
J Alzheimers Dis. 2023;91(1):355-362. doi: 10.3233/JAD-220769.
The uncompetitive NMDA antagonist, memantine (MEM), enhances prepulse inhibition of startle (PPI) across species. MEM is used to treat Alzheimer's disease (AD); conceivably, its acute impact on PPI might be used to predict a patient's sensitivity to MEM's therapeutic effects.
To begin to test this possibility, we studied MEM effects on PPI and related measures in AD patients.
18 carefully screened individuals with AD (mean age = 72.8 y; M:F=9 : 9) completed double-blind order-balanced testing with MEM (placebo versus 20 mg), assessing acoustic startle magnitude, habituation, PPI, and latency.
Fifteen out of 18 participants exhibited reliable startle responses. MEM did not significantly impact startle magnitude or habituation. Compared to placebo responses, PPI was significantly increased after MEM (p < 0.04; d = 0.40); this comparison reached a large effect size for the 60 ms interval (d = 0.62), where maximal MEM effects on PPI were previously detected. Prepulses reduced peak startle latency ("latency facilitation") and this effect was amplified after MEM (p = 0.03; d = 0.41; for 60 ms intervals, d = 0.69). No effects of MEM were detected on cognition, nor were MEM effects on startle associated with cognitive or clinical measures.
MEM enhances prepulse effects on startle magnitude and latency in AD; these changes in PPI and latency facilitation with MEM suggest that these measures can be used to detect an AD patient's neural sensitivity to acute MEM challenge. Studies in progress will determine whether such a "biomarker" measured at the outset on treatment can predict sensitivity to MEM's therapeutic effects.
非竞争性 NMDA 拮抗剂美金刚（MEM）增强了各种物种的起始惊吓（PPI）的预脉冲抑制。MEM 用于治疗阿尔茨海默病（AD）；可以想象，其对 PPI 的急性影响可用于预测患者对 MEM 治疗效果的敏感性。
为了开始检验这种可能性，我们研究了 MEM 对 AD 患者 PPI 和相关指标的影响。
18 名经过精心筛选的 AD 患者（平均年龄 72.8 岁；男女比例 9:9）完成了 MEM（安慰剂与 20mg）的双盲顺序平衡测试，评估了声学起始惊吓幅度、习惯化、PPI 和潜伏期。
18 名参与者中有 15 名表现出可靠的起始惊吓反应。MEM 对起始惊吓幅度或习惯化没有显著影响。与安慰剂反应相比，MEM 后 PPI 显著增加（p<0.04；d=0.40）；在 60ms 间隔下，这种比较达到了较大的效应量（d=0.62），之前在该间隔下检测到了 MEM 对 PPI 的最大影响。前置脉冲降低了峰值起始惊吓潜伏期（“潜伏期促进”），而 MEM 后这种效应增强（p=0.03；d=0.41；对于 60ms 间隔，d=0.69）。MEM 对认知没有影响，MEM 对惊吓的影响也与认知或临床指标无关。
MEM 增强了 AD 患者的 PPI 和潜伏期促进惊吓的预脉冲效应；MEM 对 PPI 和潜伏期促进的这些变化表明，这些指标可用于检测 AD 患者对急性 MEM 挑战的神经敏感性。正在进行的研究将确定在治疗开始时测量的这种“生物标志物”是否可以预测 MEM 治疗效果的敏感性。
