Imaging brain cholinergic activity with positron emission tomography: its role in the evaluation of cholinergic treatments in Alzheimer’s dementia

doi:10.1016/S0006-3223(00)01112-4

Biological Psychiatry

Volume 49, Issue 3, 1 February 2001, Pages 211-220

https://doi.org/10.1016/S0006-3223(00)01112-4 Get rights and content

Abstract

One of the strategies in the treatment of Alzheimer’s disease is the use of drugs that enhance cholinergic brain function, since it is believed that cholinergic dysfunction is one of the factors that contributes to cognitive deterioration. Positron emission tomography is a medical imaging method that can be used to measure the concentration, kinetics, and distribution of cholinergic-enhancing drugs directly in the human brain and assess the effects of the drugs at markers of cholinergic cell viability (vesicular transporters, acetylcholinesterase), at muscarininc and nicotinic receptors, at extracellular acetylcholine, at markers of brain function (glucose metabolism and blood flow), and on amyloid plaque burden in vivo in the brains of patients with Alzheimer’s disease. In addition, these measures can be applied to assess the drugs’ pharmacokinetic and pharmacodynamic properties in the human brain. Since the studies are done in living human subjects, positron emission tomography can evaluate the relationship between the drugs’ biological, behavioral, and cognitive effects; monitor changes in brain function in response to chronic treatment; and determine if pharmacologic interventions are neuroprotective. Moreover, because positron emission tomography has the potential to identify Alzheimer’s disease during early disease, it can be used to establish whether early interventions can prevent or delay further development.

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:

•
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).
•
Acetylcholine receptors. Radioligands have been developed to measure both muscarinic and nicotinic receptors.
•
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.
•
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.
•
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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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

Abstract

Introduction

Section snippets

Acethylcholine neuronal markers

Pharmacokinetics and distribution in the brain

Summary

Acknowledgements

Nucl Med Biol

Brain Res

Nucl Med Biol

Lancet

Int J Rad Appl Instrum

Brain Res

Arch Med Res

Nucl Med Biol

Neurobiol Aging

Neuroimage

Nucl Med Biol

Neurochemical correlates of dementia severity in Alzheimer’s diseaseRelative importance of the cholinergic deficits

J Neurochem

Potential for imaging cerebral amyloid deposits using 123I-labelled serum amyloid P component and SPECT

Nucl Med Commun

Muscarinic cholinergic receptor measurements with [18F]FP-TZTPControl and competition studies

J Cereb Blood Flow Metab

2-[18F]F-A-85380A PET radioligand for alpha4beta2 nicotinic acetylcholine receptors

Neuroreport

A comparison of the binding of nicotine and nornicotine stereoisomers to nicotinic binding sites in rat brain cortex

Naunyn Schmiedebergs Arch Pharmacol

Alzheimer’s diseaseA disorder of cortical cholinergic innervation

Science

Striatal binding of the PET ligand 11C-raclopride is altered by drugs that modify synaptic dopamine levels

Synapse

Age-related decreases in muscarinic cholinergic receptor binding in the human brain measured with positron emission tomography (PET)

J Neurosci Res

Mapping nicotinic acetylcholine receptors with PET

Synapse

Occupancy of brain nicotinic acetylcholine receptors by nicotine doses equivalent to those obtained when smoking a cigarette

Synapse

External imaging of cerebral muscarinic acetylcholine receptors

Science

18F-2-Deoxy-2-fluoro-D-glucose as a tracer in the positron emission tomographic study of senile dementia

Am J Psychiatry

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Rev Neurol (Paris)

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Proc Natl Acad Sci U S A

Intravenous physostigmine treatment of Alzheimer’s disease evaluated by psychometric testing, regional cerebral blood flow (rCBF) measurement, and EEG

Psychopharmacology (Berl)

Synthesis and application of 11C-nicotine to positron emission tomographyR-isomer for cerebral blood flow and s-isomer for study of Alzheimer’s disease

Impairment of neocortical metabolism predicts progression in Alzheimer’s disease

Dement Geriatr Cogn Disord

The scintigraphic appearance of Alzheimer’s diseaseA prospective study using technetium-99 m-HMPAO SPECT

J Nucl Med

Pharmacological evaluation of [11C]A-84543An enantioselective ligand for in vivo studies of neuronal nicotinic acetylcholine receptors

Life Sci

In vivo mapping of cholinergic neurons in the human brain using SPECT and IBVM

J Nucl Med

In vivo mapping of cerebral acetylcholinesterase activity in aging and Alzheimer’s disease

Neurology

Nicotine mechanisms in Alzheimer’s disease
Imaging brain cholinergic activity with positron emission tomography: its role in the evaluation of cholinergic treatments in Alzheimer’s dementia

Potential for imaging cerebral amyloid deposits using ¹²³I-labelled serum amyloid P component and SPECT

Muscarinic cholinergic receptor measurements with [¹⁸F]FP-TZTPControl and competition studies

2-[¹⁸F]F-A-85380A PET radioligand for alpha4beta2 nicotinic acetylcholine receptors

Striatal binding of the PET ligand ¹¹C-raclopride is altered by drugs that modify synaptic dopamine levels

¹⁸F-2-Deoxy-2-fluoro-D-glucose as a tracer in the positron emission tomographic study of senile dementia

Synthesis and application of ¹¹C-nicotine to positron emission tomographyR-isomer for cerebral blood flow and s-isomer for study of Alzheimer’s disease

Pharmacological evaluation of [¹¹C]A-84543An enantioselective ligand for in vivo studies of neuronal nicotinic acetylcholine receptors