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Grants > Cholinergic Radiotracers for Alzheimer's Disease Updated On: Jan. 19, 2025
Alzheimer's Disease Research Grant

Cholinergic Radiotracers for Alzheimer's Disease

Principal Investigator

S. Mbua Ngale Efange, PhD

University of Minnesota

Minneapolis, MN, USA

About the Research Project

Program

Alzheimer's Disease Research

Award Type

Standard

Award Amount

$111,751

Active Dates

April 01, 1990 - March 31, 1992

Grant ID

A1990029

Summary

Alzheimer’s disease is a progressive neurodegenerative disorder which affects approximately 4% of adults over the age of 65. Given the increasing life expectancy resulting from the techniques of modern medicine and new drugs, a higher percentage of adults is expected to live beyond the age of sixty-five. Consequently, the fraction of adults at risk of developing Alzheimer’s disease is projected to increase significantly by the year 2000 and beyond. Such an increase would result in a major public health problem. In order to address this problem, improvements in the diagnosis and clinical management of Alzheimer’s disease need to be developed.

 

At present, the clinical management of Alzheimer’s disease is limited by problems encountered with diagnosis. Given the present technology, a definitive diagnosis of Alzheimer’s disease can only be made by removing and testing a piece of brain tissue (brain biopsy). Since this procedure would be impractical for routine purposes, an indirect approach is currently employed. In this approach, a combination of chemical, x-ray, magnetic resonance and memory tests are used not to detect Alzheimer’s-specific abnormalities, but to exclude the presence of other disorders. In the absence of other diseases, a diagnosis of “probable Alzheimer’s disease” is made. However, at autopsy, it is found that in up to 40% of these cases, the diagnosis is incorrect – clearly suggesting a need for improvement. Generally, the degree of confidence with which such a diagnosis is made increases with the severity of the disease. Given the progressive nature of Alzheimer’s disease, it is clear that clinical management would be more effective if a definitive diagnosis is made early on in the disease process. Measures taken to arrest the progress of the disease would be more effective when the symptoms are less severe. Since the present technology cannot reliably diagnose this disorder prior to the appearance of overt clinical symptoms, the effectiveness of clinical intervention is clearly limited. In view of the foregoing, sensitive, reliable and noninvasive diagnostic methods are needed for the early diagnosis of Alzheimer’s disease.

 

Several studies have consistently shown that specific nerve pathways degenerate in Alzheimer’s disease. A significant and consistent loss of neurons which produce the neurotransmitter acetylcholine (cholinergic neurons) have been found in the brains of Alzheimer’s patients. This cholinergic deficit appears early on in the progress of the disease. In addition, the loss of these neurons correlates with the severity of the disease. Consequently, noninvasive monitoring of this group of neurons may provide a  sensitive and reliable method for the early diagnosis of  Alzheimer’s disease. Such a procedure may also be useful in  monitoring the effectiveness of clinical intervention in arresting the process of degeneration. However, there are at present no radiopharmaceuticals which can reliably monitor these biochemical abnormalities which are relevant to Alzheimer’s disease.

 

The goal of this project is to develop new radiopharmaceuticals which selectively accumulate within cholinergic neurons. Based on their selectivity for this group of neurons, these radiolabelled molecules may be used to map cholinergic neuronal pathways within the living brain. In view of the correlation between the cholinergic neurons within the cortex and the severity of Alzheimer’s disease, these radiopharmaceuticals may find clinical utility in the early diagnosis and subsequent clinical management of this disorder.

 

Our immediate objectives are: 1) to synthesize radiolabelled analogs of the lead compounds BW8134 and vesamicol, 2) and to evaluate their performance in biological assays and in animals. Both lead compounds have been shown to bind tightly and selectively to targets which are located exclusively within cholinergic neurons. Following their administration to live animals, these compounds should enter the brain by virtue of their lipid solubility. Although the delivery of these agents is dependent on the transport by the blood, their subsequent retention will be determined by the presence of specific binding sites which are located within cholinergic neurons. Therefore, subsequent to their arrival within the brain, these compounds should be retained only within regions of high cholinergic innervation. Images obtained by tomographic gamma camera may then be studied to determine if cholinergic innervation is normal or abnormal. These compounds will also be tested in animals with chemically-induced cholinergic deficit to determine if a cholinergic lesion may be detected noninvasively. Our ultimate goal is to emerge with a clinically useful diagnostic imaging agent for Alzheimer’s disease. The proposed experiments should lay the groundwork for further testing in animals and subsequent clinical application.