Change of central cholinergic receptors following lesions of nucleus basalis magnocellularis in rats: search for an imaging index suitable for the early detection of Alzheimer's disease

Abstract

Cholinergic system in the central nervous system is involved in the memory function. Thus, because the dysfunction of cholinergic system that project to the cerebral cortex from nucleus basalis of Meynert (nbM) would be implicated in the memory function deficits in Alzheimer's disease (AD), evaluating cholinergic function may be useful for the early detection of AD. In this study, because the nucleus basalis magnocellularis (NBM) in rats is equivalent to nbM in human, we investigated the change in cholinergic receptors in the frontal cortex of rats with unilateral lesion to the NBM to find an appropriate index for the early detection of AD using techniques of nuclear medicine. The right NBM was injected with ibotenic acid. [¹⁸F]FDG-PET images were obtained 3 days later. Some rats were sacrificed at 1 week, whereas others were subjected to a second [¹⁸F]FDG-PET at 4 weeks then sacrificed for membrane preparation. The prepared membranes were subjected to radioreceptor assays to measure the density of nicotinic and muscarinic acetylcholine receptors. Glucose metabolism had decreased on the damaged side compared to the control side at 3 days, but at 4 weeks, there was no difference between the sides. Nicotinic acetylcholine receptors had significantly decreased in density compared to the control side at both 1 and 4 weeks. However, muscarinic receptors were not affected. These results suggested that neuronal dysfunction in AD could be diagnosed at an early stage by imaging nicotinic acetylcholine receptors.

Introduction

Acetylcholine esterase inhibitors have been shown to be effective for treating cognitive dysfunction in mild cases of Alzheimer's disease (AD). Thus, the early diagnosis of AD would be useful for selecting subjects for whom this inhibitor will be effective or for evaluating the drug's effects.

Advances in imaging modalities have led to useful techniques for diagnosis and evaluation of dementias. Computed tomography or MRI can provide structural information on, for example, atrophy of the brain. In contrast, techniques of nuclear medicine such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) can provide images based on neuronal function. Because pathological neuronal dysfunction precedes the appearance of structural damage and physical impairment in AD [1], [2], nuclear medicine may be effective for the early detection of AD.

One characteristic feature of AD is a reduction in the metabolism of glucose in the cerebral cortex [2]. This abnormality can be detected with [¹⁸F]FDG-PET, and many clinical trials for the diagnosis of AD have been carried out. On the other hand, loss of cholinergic neurons that project from the nucleus basalis of Meynert (nbM) to the cerebral cortex can be observed in AD [3]. Cholinergic system in central nervous system is involved in the memory function; the cholinergic dysfunction would be implicated in the memory function deficits in AD, and changes in the cholinergic system would be more characteristic in AD than impairments of glucose metabolism. Therefore, an evaluation of cholinergic function should be useful for the early detection of AD. In fact, some radioligands for PET or SPECT to image the cholinergic system have recently been developed, and some of them are in clinical use [4], [5], [6], [7], [8], [9], [10].

The nucleus basalis magnocellularis (NBM) in rats is equivalent to the nbM in humans, and the cholinergic neurons project to the frontal cortex. Thus, to find an appropriate index for the early diagnosis of AD based on cholinergic dysfunction, we used rats with unilateral lesion to the NBM and investigated the changes in density of muscarinic and nicotinic acetylcholine receptors and uptake of [¹⁸F]FDG in the frontal cortex.