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Against all odds, nuclear medicine has thrived

Johns Hopkins School of Public Health, 615 N. Wolfe Street, Baltimore, Maryland 21205, USA

The word Oahu, the name of the island where Honolulu is located, means "the gathering place". At the Society of Nuclear Medicine meeting in 2001, physicians and scientists from 41 countries presented 1400 papers or posters; 57% from outside the United States. In 1994, 37% came from outside the U.S. Of interest is the fact that the number of positron emission tomography (PET) presentations was greater than the number of single photon computed tomography (SPECT) presentations. The continuing role of SPECT is documented by the 415 presentations that involved the use of a technetium-99m tracer.

When we look at the problems encountered by nuclear energy, which followed on the heels of World War II just as did nuclear medicine, the thriving of nuclear medicine is remarkable.

Nuclear medicine is the trunk of a tree, representing regional biochemistry, regional physiology and what is increasingly being called molecular nuclear medicine. The branches of the tree include cardiology, neurosciences, oncology and increasingly, radiology.

These questions remain: "Will nuclear medicine lead to a new definition of disease?", "Will nuclear medicine become commonplace in new drug design and development?", "Will the use of the Internet become widespread in nuclear medicine?", "Will PET replace SPECT?", "Will all medical imaging be fused in the next 10 years?", "Will nuclear medicine become widespread in preventative medicine?", "Will in vivo identification of an infecting organism in a particular site within the body become widespread?", "Will the Health Care Financing Administration, which is the governmental insurance programme for Medicare and Medicaid, reimburse and extend beyond the Big Six types of cancer now covered by insurance?", "Which radiopharmaceuticals will be used most widely over the next decade?". In other words, "What will supplement FDG in oncology?".

Will nuclear medicine lead to a new definition of disease?

In 1968, I proposed that you could define a disease by means of the equation

where a specific disease is equal to the sum of the manifestations m of disease, times the weighting factor w for each manifestation. The weighting factors are predominantly determined by their specificity. An important question that rarely can be answered is: "Which of the innumerable manifestations that characterize a disease should be regarded as its cause?". To illustrate the multiplicity of the causes of a specific disease, Pettenkoffer, one of the fathers of Public Health, illustrated the fact that vibrio cholera is not inevitably the only cause of cholera by drinking a glass of cholera organisms, then showing that nothing happened to him subsequently. Two other examples are: when we first imaged dopamine receptors in patients with schizophrenia, we had to resist the temptation to believe that we had found the "cause" of schizophrenia; similarly, we had to resist the belief that the increased accumulation of iodine was the cause of hyperthyroidism.

On the other hand, the manifestation of decreased accumulation of a radiotracer, such as iodine-123 beta-CIT, which binds to the pre-synaptic dopamine transporter, together with normal binding in the basal ganglia of tracers that bind to D2 post-synaptic dopamine receptors, can be used to differentiate different types of movement disorders, including idiopathic Parkinson's disease. In patients with movement disorders, identification of a specific manifestation, that is, a disorder of the dopamine transporter, is important in the choice of treatment.

Will PET replace SPECT?

I do not think by any means that PET is going to replace SPECT. To be sure, the huge advantage of PET is that it is based primarily on the use of the radionuclides fluorine-18, carbon-11, oxygen-15 and nitrogen-13. Each of these radionuclides emits positrons which yield 511 keV photons. Although one can distinguish two different positron-emitting tracers by their different half-lives of 20 min for carbon-11 and 2 h for fluorine-18, it is easier to use the entire electromagnetic spectrum — single photons of different energy as well as the 511 keV photons of the positron-emitters. Furthermore, because a positron is a particle, one is limited in the dosage one can administer safely. With a single photon-emitter, such as technetium-99m, which does not emit particles, much higher doses can be given.

An example is a study from King's College, "Quantitative dopamine transporter SPECT imaging using iodine-123 beta-CIT in the evaluation of patients with atypical tremor". There is a characteristic decrease in availability of dopamine transporter binding sites on the pre-synaptic neurons of the basal ganglia found in patients with classical Parkinson's disease. This deficiency is not found in patients with essential tremor. The ratio of tracer activity in the basal ganglia compared with the occipital region is normal in the latter group, but low in patients with Parkinson's disease. Patients with essential tremor who do not meet the basal ganglia/occipital cortex criteria permitting the diagnosis of Parkinson's disease but who have lower than normal ratios were found to progress to Parkinson's disease when followed for a period of time. Persons with essential tremor with higher ratios did not progress to Parkinson's disease.

Senile dementia of the Alzheimer type (SDAT) is another disease in which predictions can be made about progression to the classical manifestations of the disease by the finding of characteristic abnormalities in regional cerebral glucose utilization in the brain.

Furthermore, there are differences in regional glucose utilization in early onset of Alzheimer's disease, compared with late onset Alzheimer's disease, suggesting that perhaps the two groups of patients should be considered different diseases. This is another example where new manifestations at the molecular level can lead to new definitions of the disease.

Molecular manifestations of disease may become apparent only with perturbation of the physiological state of the patient. This is analogous to the glucose tolerance test for diabetes or the exercise test for coronary artery disease. When patients with minimal memory disorders were compared with patients with Alzheimer's disease, there were differences in the patterns of regional cerebral glucose utilization when the subjects were in the resting state and during audiovisual stimulation.

Regional glucose utilization in patients with Alzheimer's disease is a strong predictor of the cognitive decline in Alzheimer's disease, and can help therapeutic drug design and assessment. About 80% of all clinical drug trials that reach Phase Three do not result in approved drugs. This is one of the main reasons why the cost of developing drugs is in the hundreds of millions of dollars. The patient populations are not homogeneous in the clinical trials. An objective means of classifying the patients on the basis of molecular manifestations can decrease the variability of responses, and increase the sensitivity in detecting meaningful changes resulting from the drug not apparent if the patient populations are heterogeneous, or may not even have the molecular manifestation the drug is designed to effect. Because of statistical variability, one may not be able to show the effectiveness of the drug, while examining a more specific classification of the patients could be shown to be effective.

The nosology of disease

Six hundred years ago most medical diagnoses were based on symptoms alone. Even today in the United States, about one third of the patients who go to doctors' offices never have enough objective manifestations of disease to be able to be classified as having a disease based on objective evidence. Examples include depression, anxiety, chronic fatigue syndrome and temporo-mandibular disorders. The invention of the stethoscope by Laennec and other physical signs of disease extended diagnosis to more physiological criteria as the basis of disease classification. The diagnostic process progressed significantly with autopsy studies, leading to an orientation towards pathology in organs, and subsequently in tissues and cells. Today medical diagnosis is based on molecular manifestations, and is progressing to processes within molecules.

Planning and monitoring treatment

A report from Memorial Sloan Kettering Cancer Center in New York exemplifies how molecular studies help in treatment planning for external irradiation therapy. Regions of lung involved by cancer would be missed if one looked only at the anatomical CT images. The extent of the lesion can often be far greater when the selected irradiation regions are selected on the basis of the combination of CT and FDG-PET. At the same institution, in collaboration with researchers at the MD Anderson Hospital, gating the PET imaging to the respiratory cycle provides better targeting in radiation treatment planning. Thus, techniques that were developed primarily for cardiology are also being used in radiation therapy.

The degree of accumulation of FDG can be used as a biological prognostic marker for predicting subsequent recurrence of surgically resected non-small cell lung cancer. It was reported that the initial degree of uptake of FDG is a good indicator of recurrence. It is increasingly clear that FDG accumulation is related to the grade of malignancy. Diseases such as carcinoma of the prostate, which are not very rapidly growing and are not very invasive, are characterized by a low accumulation of FDG, but as the lesions become more aggressive (more malignant) they accumulate FDG to a greater extent.

A report from the University of Washington indicated that FDG accumulation performed shortly after radiotherapy for brain tumours was not a good predictor of the survival of the patients.

A new definition of disease

In nuclear medicine we measure either whole body or regional decreased or excessive metabolic responses. The sensitivity for detection of disease is increased with perturbation of the molecular homeostatic processes that respond to internal or environmental stress. No other technology is better in yielding this type of information from outside the body. The fact that the whole body can be examined routinely and quickly is a huge advantage. For example, innumerable patients present with lung nodules, that, unfortunately, are associated with extensive involvement of mediastinal lymph nodes or distant metastases in other parts of the body. This information is often the determining factor in planning treatment.

The international classification of disease used today consists of a six digit classification: the first three digits define the location of the disease, e.g. gastrointestinal tract, stomach, pylorus; the next three digits define the cause of the disease, e.g. a toxin, a chemical, mercury. I am proposing a new classification in which one still uses the first three digits to localize the disease but then characterizes the disease by its molecular manifestations, e.g. carbohydrate metabolism, glucose, fluorine-18 FDG.

One study showed that as a patient's pulmonary hypertension became more severe there was a progressive decrease in the FDG accumulation in the left ventricle, which at first seems strange until one realizes that the progression of the disease spares the strain on the left ventricle. As the pulmonary hypertension increased, and the workload on the left ventricle decreased, the left ventricle accumulated less FDG than in the early stage of compensated disease, where accumulation of the FDG increased in both the left and the right ventricles.

Will nuclear medicine become more involved in new drug design and development?

The ability to determine early in the course of drug development that a molecule will or will not be effective in favourably altering a metabolic process provides a whole new approach. Even negative results in collaborative research with the drug industry are valuable in that they can save enormous amounts of money in drug design and development, avoiding very expensive clinical trials that do not result in an approved New Drug Application. For example, it was found that administration of donepezil resulted in a cerebral blood flow increase, but with longer term therapy there was no difference in cerebral blood flow from that observed in the controls, indicating that this drug was not likely to have a long term effectiveness.

Another example of the value of using molecular manifestations to characterize disease is the use of iodine-123 beta-CIT single photon emission CT in patients with social anxiety disorder, or obsessive-compulsive disorder, based on subjective manifestations of disease. These patients were observed to have abnormal serotonin transporter binding sites in the frontal cortex. Patients with social phobia, when compared with control subjects, had half the density of serotonin transporters in the frontal cortex. Patients with obsessive-compulsive disorder were also found to have lesser but statistically significant differences from the control subjects. The importance of these objective, molecular manifestations is that they can have consequences related to prognosis, treatment and monitoring of the treatment.

Another report involved the disease tinnitus. In comparisons between patients with tinnitus and control subjects, there were significant abnormalities in brain benzodiazapine receptor density in cortical regions.

Imaging of molecular manifestations of disease will likely result in a whole new approach to cancer diagnosis. In the future we will not be talking about breast cancer or lung cancer but with the associated molecular manifestation. In lymphoma, for example, today we look at the particular types of non-Hodgkin's lymphoma expressing the CD20 antigens. Those which express the CD22 antigens can be treated with a stable of radioactive ligands that bind to these receptors.

A group in Texas are developing technetium-99m labelled EC-Annexin V to detect apoptosis as well as a technetium label tracer that can be used to study endostatin, which is involved in the vascularization of cancer lesions.

An example of a molecular manifestation in brain diseases is the finding that there are abnormalities in D1 dopamine receptors in schizophrenic patients. They observed that the D1 receptor system was related to cognition in these schizophrenic patients. The investigators proposed that D1 receptors could be a target for drug development to improve cognition in patients with schizophrenia.

Small animal imaging

The great interest today in small animal imaging instruments can be seen by the 28 papers involved with small animal imaging. This reflects the increasing recognition by basic scientists, including those in the pharmaceutical industry, of the value of the study of regional function and metabolism.

Conclusion

This brief review of what I presented in my Highlights talk at the 2001 meeting of the Society of Nuclear Medicine permits me to give preliminary answers to important questions:

1. PET will not replace SPECT, but both will grow in parallel.
   
2. Fused imaging will become commonplace. Most if not all images will reflect fusion of structure and function.
   
3. New PET and SPECT tracers will supplement the use of FDG.
   

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