In vivo mapping of cerebral acetylcholinesterase activity in aging and Alzheimer’s disease
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Abstract
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-[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.
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.
- Received July 22, 1998.
- Accepted in final form November 21, 1998.
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