In vivo mapping of cerebral acetylcholinesterase activity in aging and Alzheimer's disease
In vivo mapping of cerebral acetylcholinesterase activity in aging and Alzheimer's disease
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DOI：
10.1212/wnl.52.4.691
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发表时间：
1999-03-10
期刊：
影响因子：
9.9
通讯作者：
Kilbourn, MR
中科院分区：
文献类型：
--
作者：
Kuhl, DE;Koeppe, RA;Kilbourn, MR
目的：验证活体定位人脑内乙酰胆碱酯酶(AChE)活性的方法，为监测AD的抑制剂治疗做准备。背景：死后阿尔茨海默病患者脑组织AChE活性降低。由于缺乏可靠的体内测量，人们对AD早期的中枢活动知之甚少，因为AD通常是AChE抑制剂药物治疗的靶点。方法：静脉注射N-[C-11]丙酸甲酯([C-11]PMP)作为体内AChE底物。在26名正常对照组和14名AD患者中，用脑部PET确定AChE活性，以示踪动力学估计[C-11]PMP的局部水解率。11例AD患者还同时进行了体内脑部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。结果：脑AChE活性测量1)与大脑皮层示踪剂输送的变化无关；2)与已报道的关于正常的大脑相对分布、正常衰老中没有大的年龄效应以及AD的缺陷的死后数据一致；3)AD大脑皮层与伴随的体内胆碱能终末缺陷的测量相关，但与代谢缺陷无关；4)与毒扁豆碱诱导的大脑AChE抑制水平的预测定量一致。结论：在体正电子发射计算机断层扫描方法可以有效地测量正常人和AD患者的中枢AChE活性。在AD早期应用，它应该通过确认中枢抑制、优化药物剂量、识别可能的应答者以及测试治疗反应的替代标记物来促进抑制剂的治疗。
Objective: To validate an in vivo method for mapping acetylcholinesterase (AChE) activity in human brain, preparatory to monitoring inhibitor therapy in AD. Background: 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. Methods: Intravenous N- [C-11]methylpiperidin-4-yl propionate ([C-11]PMP) served as an in vivo AChE substrate. AChE activity was defined using cerebral PET for tracer kinetic estimates of the local rate of [C-11]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. Results: 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. Conclusions: 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.