Kuhl D E, Koeppe R A, Minoshima S, Snyder S E, Ficaro E P, Foster N L, Frey K A, Kilbourn M R
Division of Nuclear Medicine, University of Michigan, Ann Arbor, USA.
Neurology. 1999 Mar 10;52(4):691-9. doi: 10.1212/wnl.52.4.691.
To validate an in vivo method for mapping acetylcholinesterase (AChE) activity in human brain, preparatory to monitoring inhibitor therapy in AD.
AChE activity is decreased in postmortem AD brain. Lacking a reliable in vivo measure, little is known about central activity in early AD, when the disease is commonly targeted by AChE inhibitor drug therapy.
Intravenous N-[11C]methylpiperidin-4-yl propionate ([11C]PMP) served as an in vivo AChE substrate. AChE activity was defined using cerebral PET for tracer kinetic estimates of the local rate of [11C]PMP hydrolysis in 26 normal controls and 14 patients with AD. Eleven AD patients also had concomitant in vivo cerebral measures of vesicular acetylcholine transporter (cholinergic terminal) density and glucose metabolism.
Cerebral AChE activity measures 1) were independent of changes in tracer delivery to cerebral cortex; 2) agreed with reported postmortem data concerning normal relative cerebral distributions, absence of large age-effect in normal aging, and deficits in AD; 3) correlated in AD cerebral cortex with concomitant in vivo measures of cholinergic terminal deficits, but not with metabolic deficits; and 4) agreed quantitatively with predicted level of cerebral AChE inhibition induced by physostimine.
This in vivo PET method provided valid measures of central AChE activity in normal subjects and AD patients. Applied in early AD, it should facilitate inhibitor treatment by confirming central inhibition, optimizing drug dosage, identifying likely responders, and testing surrogate markers of therapeutic response.
验证一种用于绘制人脑中乙酰胆碱酯酶（AChE）活性图谱的体内方法，为监测阿尔茨海默病（AD）的抑制剂治疗做准备。
AD患者死后大脑中的AChE活性降低。由于缺乏可靠的体内测量方法，对于早期AD（此时该疾病通常是AChE抑制剂药物治疗的靶点）的中枢活性了解甚少。
静脉注射N-[11C]甲基哌啶-4-基丙酸酯（[11C]PMP）作为体内AChE底物。使用脑PET对26名正常对照者和14名AD患者进行示踪动力学估计，以确定[11C]PMP局部水解速率，从而定义AChE活性。11名AD患者还同时进行了体内脑内囊泡乙酰胆碱转运体（胆碱能终末）密度和葡萄糖代谢的测量。
脑AChE活性测量值1）与示踪剂向大脑皮质输送的变化无关；2）与已报道的关于正常脑相对分布、正常衰老中无明显年龄效应以及AD患者缺陷的死后数据一致；3）在AD大脑皮质中与胆碱能终末缺陷的体内测量值相关，但与代谢缺陷无关；4）在数量上与毒扁豆碱诱导的脑AChE抑制预测水平一致。
这种体内PET方法为正常受试者和AD患者的中枢AChE活性提供了有效的测量。应用于早期AD时，它应有助于通过确认中枢抑制、优化药物剂量、识别可能的反应者以及测试治疗反应的替代标志物来促进抑制剂治疗。
