Nicotine mechanisms in Alzheimer’s diseaseImaging brain cholinergic activity with positron emission tomography: its role in the evaluation of cholinergic treatments in Alzheimer’s dementia
Introduction
Acetylcholine is widely distributed within the human brain, where its physiologic functions are not well understood. Behavioral studies provide evidence that acetylcholine participates in complex functions such as attention, memory, and cognition, and clinical and postmortem studies suggest its involvement in the cognitive deterioration seen in Alzheimer’s disease (AD) and in the memory loss associated with normal aging (Mihailescu and Drucker-Colin 2000). This has led to the use of drugs that enhance acetylcholine activity in the brain as treatments for AD.
Access to imaging technologies such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) and appropriate radiotracers makes it possible to evaluate noninvasively the acetylcholine system in the human brain. This review focuses on the use of PET to evaluate the acetylcholine system in the human brain and its use to evaluate drugs that enhance acetylcholine activity for the treatment of AD (acetylcholinesterase inhibitors, cholinergic agonists, and acetylcholine releasers). It should be noted that although we focus on cholinergic drugs, these are not the only treatments for AD, and similar strategies can be used to assess the effects of noncholinergic symptomatic or preventive treatments for AD (i.e., antioxidants, amyloid vaccine, estrogen replacement).
Positron emission tomography radiotracers are available that can be used to study various elements involved with cholinergic neurotransmission and function (Figure 1). These include:
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Acetylcholine neuronal integrity. Ligands have been developed to measure the acetylcholine vesicular transporter (transports acetylcholine from the cytoplasm to the vesicle) and acetylcholinesterase (enzyme that metabolizes acetylcholine).
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Acetylcholine receptors. Radioligands have been developed to measure both muscarinic and nicotinic receptors.
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Brain function. Tracers are available that enable measurement of regional brain glucose metabolism and cerebral blood flow (CBF), which can be used to assess activity of the regions modulated by acetylcholine.
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Amyloid plaques and fibrillary tangles. Though plaques are not part of the cholinergic system, they are an integral part of brain pathology in AD and hence are of relevance in the evaluation of drug treatments for AD. Tracers have been developed to measure the concentration of amyloid in the brain.
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Transduction signaling. Cholinergic activity is likely to be regulated by intracellular signaling. Though there are PET radiotracers such as [11C]arachidonic acid (Rapoport 2000) that permit evaluation of intracellular signal transduction processes, these have not been used to assess AD.
These radiotracers can be used with PET to investigate directly in the human brain a drug’s 1) pharmacokinetics and distribution and 2) mechanism(s) of action (pharmacodynamics). Because these studies are done in living patients, they can be used to determine the relationship between the neurochemical and cognitive/behavioral effects of the drug. So far very few PET studies have been done to assess the effects of drug treatment in AD. However, there are assumptions that, with the increase in PET centers and the greater availability of radiotracers, PET will become an important tool in the evaluation of new treatments in AD.
Section snippets
Acethylcholine neuronal markers
Loss of acetylcholine cells is a characteristic feature of AD. Hence, radiotracers that serve as markers of acetylcholine neuronal integrity could be very useful for the evaluation of treatments in AD. In postmortem tissue, cholinergic cell loss is assessed by measuring the activity of choline acetyltransferase (ChAT), the enzyme that catalyzes the synthesis of acetylcholine. In patients with AD, postmortem studies have consistently documented a selective loss of cholinergic neurons in the
Pharmacokinetics and distribution in the brain
Drugs can be labeled with positron emitters without changing their pharmacologic properties. This allows for the investigation of their regional distribution and pharmacokinetics in the human brain. Acetylcholine-enhancing drugs that have been labeled with positron emitters include nicotine, tacrine, and physostigmine.
Studies using [11C]nicotine showed that its highest uptake occurred in the cortex, thalamus, and striatum Halldin et al 1992, Nordberg et al 1989. This pattern was poorly altered
Summary
Positron emission tomography has an important role in the investigation of treatments for AD during early stages of drug development and during the later stages of clinical use. At early stages PET is able to provide information that helps to determine optimal dosing regimes and to understand the drug’s mechanism(s) of action. At later stages PET can be used to monitor the effects of drug treatment. Once the drug has been approved, PET can still play a role by helping to identify individuals
Acknowledgements
This research was supported by the U.S. Department of Energy/OBER (Grant No. DE-ACO2-98CH10886) and the National Institute on Drug Abuse (Grants Nos. DA06278 and DA09490).
Aspects of this work were presented at the symposium “Nicotine Mechanisms in Alzheimer’s Disease,” March 16–18, 2000, Fajardo, Puerto Rico. The conference was sponsored by the Society of Biological Psychiatry through an unrestricted educational grant provided by Janssen Pharmaceutica LP.
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