Elsevier

The Lancet

Volume 349, Issue 9068, 21 June 1997, Pages 1805-1809
The Lancet

Early Report
Measurement of acetylcholinesterase by positron emission tomography in the brains of healthy controls and patients with Alzheimer's disease

https://doi.org/10.1016/S0140-6736(96)09124-6Get rights and content

Summary

Background

Acetylcholinesterase activity, a marker for degeneration of the central cholinergic system, has consistently been reported, in necropsy brain studies, to be reduced in the cerebral cortex of patients with Alzheimer's disease. We have shown regional acetylcholinesterase activity in vivo in rodent and primate brains with radioactive acetylcholine analogues. In the present study, we used one of the analogues to map acetylcholinesterase activity in the brains of living people.

Methods

Positron emission tomography (PET) and a radiolabelled acetylcholine analogue with high hydrolytic specificity to acetylcholinesterase [11C]N-methyl-4-piperidyl acetate (MP4A), was used in eight elderly healthy controls and five patients with Alzheimer's disease who had mild dementia. All participants were given an intravenous injection of [11C]MP4A and then sequential patterns of radioactivity in various brain regions were obtained by PET. Time courses of [11C]MP4A concentration in arterial blood were also measured to obtain an input function. A three-compartment model was used to estimate regional acetylcholinesterase activity in the brain.

Findings

The estimated acetylcholinesterase distribution in the brain of the control participants agreed with the acetylcholinesterase distribution at necropsy. All patients with Alzheimer's disease had multiple cortical regions with a reduced estimated acetylcholinesterase activity in comparison with control participants. The reduction was more pronounced in the parietotemporal cortex, with an average reduction rate of 31% in temporal and 38% in parietal cortex, and less pronounced in other cortical lesions (19% in frontal, 24% in occipital, and 20% in sensorimotor cortex). Each patient was found to have at least two cortical regions with significantly reduced acetyl-cholinesterase activity.

Interpretation

The method we describe for non-invasive in-vivo detection of regional acetylcholinesterase changes in the living human brain that is feasible for biochemical assessment of Alzheimer's disease.

Introduction

Alzheimer's disease is a brain disorder characterised by a progressive dementia that starts in middle-to-late life. The presence of pathological changes such as neuritic plaques and neurofibrillary tangles is required for the definitive diagnosis of the disease. These changes can, however, be detected only by microscopic examination of brain tissue, usually at necropsy. Extensive studies into neurochemical changes in the brain in Alzheimer's disease have been reported1, 2, 3 and correlation of these changes with dementia severity has been sought.4, 5, 6, 7 However, most of these studies have been based on clinical assessment and observation of biological changes of brains at necropsy.

One of the principal difficulties is in the direct comparison between cognitive and functional performance of living patients who have Alzheimer's disease and healthy individuals and biological changes found at necropsy. Studies of cerebral biopsy samples may also be limited by lack of sampling from multiple brain regions.8 Therefore, detection of neurochemical and neuropathological changes by in-vivo techniques such as positron emission tomography (PET)9, 10 and single photon emission computed tomography (SPECT)11 must be developed. Such methods will allow clinical diagnosis and prognosis for dementia severity, understanding of the disease mechanisms, and development of therapeutic drugs.

The degeneration of the cortical cholinergic system is one of the most consistent neurochemical changes in Alzheimer's disease.1, 2, 3, 4, 7, 12 It has been shown that choline acetyltransferase and acetylcholinesterase activities in the cerebral cortex, the reduction of which accompany degeneration of cholinergic neurons in the basal forebrain, were significantly negatively correlated with the number of senile plaques4 and severity of dementia before death.7 Therefore, if choline acetyltransferase and/or acetylcholinesterase in the living human brain could be measured, it would give new insights into Alzheimer's disease.

In the present study, we measured regional acetyl-cholinesterase activity in the living brains of normal elderly people and patients with Alzheimer's disease by PET.

Section snippets

Methods

The principle of the method we used is that a radiolabelled lipophilic substrate analogue, [11C]N-methyl-4-piperidyl acetate (MP4A), for the target enzyme acetylcholinesterase is given as an intravenous injection. The [11C]MP4A then reaches the brain via the blood-brain barrier in a regional cerebral blood-flow dependent manner. A proportion of the [11C]MP4A that reaches the brain tissue diffuses back across the blood-brain barrier, while the rest of the [11C]MP4A is hydrolysed by

Healthy participants

The representative curves of radioactivity in the brain regions—ie, cerebellum for regions with high acetylcholinesterase activity, thalamus for moderate, and temporal cortex for low—and of the metabolite-corrected [11C]MP4A in the arterial plasma from a participant without Alzheimer's disease are shown in figure 3.24, 25 The radioactivity in the cerebellum, following an initial increase, further increases to reach a plateau, whereas that in the cerebral cortex gradually decreases to a certain

Discussion

The ratios for the k3 values for the cerebral cortex/thalamus/cerebellum/striatum found in healthy participants were 1/3/8/10, respectively, corresponding well with the acetylcholinesterase activity ratios in the brain at necropsy (1/3/8/38),24, 25 except for the striatum. The reason that the k3 value in the striatum did not correspond with the necropsy data is explained by the nature of the tracer.13 Most of the tracer entering the region with a very high acetylcholinesterase activity is

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