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  • PET in neurology Introduction PET provides functional information about the brain, ranging from hemodynamic information about blood flow and blood volume to metabolic data about glucose and oxygen utilization, as well as metabolic processes such as protein synthesis. It also permits the evaluation of pre- and post-synaptic neurotransmitter systems. Moreover, if one simultaneously evaluates anatomy, physiology, and biochemistry of the brain in patients exhibiting pathological behavioral symptoms, one should be able to obtain information that may answer fundamental questions about its pathogenesis. Clinically, PET has been used successfully in the grading of brain tumor, differentiation between recurrent tumor and radiation necrosis, evaluation of dementia, evaluation of intractable epilepsy, evaluation of Parkinsons disease, schizophrenia, depression, functional activation and many others. Radiopharmaceuticals 1. Tracers for CBF Measurements The oxygen-15 inhalation technique, a PET method first described in Europe by Frackowiak et al, enables the evaluation in the same session and with absolute values, blood flow (rCBF), oxygen consumption (rCMRO2), oxygen extraction ratio (OER), and blood volume (rCBV). This method has been mainly applied to the evaluation of patients with cerebrovascular disease to understand the pathological mechanisms underlying stroke. However, its application in clinical practice is limited because of its complex and somehow cumbersome technique. Furthermore, because of the high energy emitted by 15 O, image resolution is approximately 10 mm, significantly lower than that obtained with 18 F. 2. Tracers of Metabolic Substrates The tracer most commonly used for PET studies of metabolic substrates has been 18F- fluorodeoxyglucose (18F-FDG). The high-quality images obtained, the possibility of quan- tifying glucose consumption in standardized units, and the relative simplicity of radiotracer
  • production are probably the main reasons for its frequent use in the evaluation of different neurological and psychiatric disorders. The use of compartmental models enables measure- ments of transport and metabolic rates in the brain for FDG. Unfortunately, these transport and metabolic rates are different for glucose. However, if one knows the relationship between FDG and glucose for transport and phosphorylation, the measurement of those rates for glucose are within reach. Based on the principles of competitive substrate kinetics, a correction constant (lumped constant) can be applied to FDG measurements for the conversion into corresponding values for glucose. It is also possible to measure protein synthesis in the brain with PET and amino acids 13 11 13 11 labeled with either N or C, e.g., N-Methionine and C-L-Leucine. The main application of these tracers has been in the assessment of tumor metabolism. 3. Tracers for the Study of Neurotransmission One of the most challenging chapters in functional brain imaging is the in vivo evalua- tion of neurotransmission. This includes two main sites of interest: (1) evaluation of the functional integrity of presynaptic neurons of different systems with radioligands for several sites, such as 18F-DOPA, an intraneuronal marker of the dopa-decarboxylase; and (2) study of postsynaptic neuronal response by using radioligands to study the 11 18 availability/distribution of postsynaptic receptors such as C-methylspiperone and F- ethylspiperone as PET examples of ergocalciferol (D2) dopamine receptor ligands. Today, there are several tracers available for the examination of various neurochemical transmitter systems, including serotoninergic (ketanserin and nitroquipazine NQP), opiate (carfentanil), and cholinergic (scopolamine and vesamicol) systems, as well as benzodiazepine receptors. Clinical applications 1.Detection of Brain Tumors The incidence rate for primary brain tumors in the United States is 8 per 100,000 per year. This translates into about 17,000 new cases annually. Gliomas are responsible for 9,000 of these cases and have an incidence rate of 4.4 per 100,000 per year. Astrocytoma is by far the most common form of glioma. This neoplasm exists in pathologically distinct forms that vary in terms of their growth rate. Hence patient survival is highly variable and depends on the type of brain tumor and the relative proportion of various pathological cell
  • types within it. The presence of a suspected glioma can be confirmed with x-ray com- puterized tomography, magnetic resonance imaging, or positron emission tomography. X-ray computerized tomographic scanning with contrast media defines areas of the brain where the structural integrity of the blood-brain barrier has been disrupted. This can be seen when a contrast medium escapes from the blood vessels into the surrounding tissue. This pathological change is a characteristic feature of blood vessels within the tumor or of areas of the brain where normal tissue is displaced by tumor. The resolution attainable with CT may not always clearly delineate the margins of a neoplasm if the blood-brain barrier at the outer reaches remains sufficiently intact and prevents the escape of adequate amounts of contrast agent. Magnetic resonance imaging with or without a contrast agent (gadolinium-DPTA) provides better resolution and definition than CT. Like CT, the use of contrast only demonstrates deterioration of the blood-brain barrier; it does not demonstrate the actual tumor or regions of necrosis. Tumors themselves, however, produce variable diagnostic MR images, depending on the type of tumor and the extent of associated brain edema or hemorrhage. PET imaging with 18-fluorodeoxyglucose (18-FDG) is also a reliable method for localizing tumors. Images of the tumor are produced with this positron emitter because neoplastic glioma cells exhibit increased glucose metabolism relative to normal tissue. Resolution of the histologic margins of the tumor, however, does not appear to be substantially better than that obtained with MRI gadolinium-DPTA. Preliminary experiments have shown that positron-emitting radiopharmaceuticals such as PK 11195- labeled 11-carbon are selectively taken up by tumor cells and may allow for more complete delineation of neoplasms in the near future. None of the currently available imaging procedures can identify tumor cells outside the solid tumor mass. The introduction of '8F-2-deoxyglucose (FDG) to measure the degree of cerebral glucose use gave a new impetus to the metabolic imaging of brain tumors. Based on Otto Warburg's suggestion that tumors have higher rates of aerobic glycolysis (lactate production) with increasing degree of malignancy, several groups around the world have been using FDG and PET to grade primary tumors in vivo and to distinguish between tumor recurrence and postirradiation necrosis. Gliomas exhibit increased glucose utilization relative to
  • surrounding tissue. Studies of glucose metabolism with 18-FDG have shown that PET can provide a non-invasive method of grading gliomas. Deterioration of patients clinical condition because of either recurrence of a brain tumor or postirradiation necrosis in the radiotherapy field is not rare. CT scan, MRI, and cerebral angiography are unable to provide clear differentiation between these conditions. Intracerebral lesions, either tumor recurrence or radiation necrosis, may show enhancement with contrast-enhancing agents. The most likely tool to assist in the distinction between metabolic active tumor (primary or recurrence) and postirradiation necrotic tissue is the radionuclide method because of its physiological behavior. There are radionuclide tracers able to study BBB properties, regional cerebral blood flow (perfusion), regional metabolic rate of glucose use, and amino acid use by tumors. Assessments of glucose metabolism with 18-FDG currently provide the best available noninvasive method for differentiating radiation necrosis from recurrent tumor. When changes in postoperative neurological status signal the spread of tumor beyond its initial site, PET may be a useful addition to conventional methods in establishing a prognosis or determining if additional surgery is indicated. Other tracers labeled with positron emitters (e.g., 18F, '1C, or 13N) have been suggested for the evaluation of brain tumors. They include sugar derivatives, amino acids, putrescence, and receptor ligands. Among them, the amino acid 11C-methionine seems to be the most promising. In 36 patients with cerebral tumors of different grades, "C-methionine uptake in the tumors correlated with histopathological grades from multiple biopsies. In 23 cases, delineation of the tumor was more accurate with PET and 11C-methionine than with CT scan. 2. Evaluation of Dementia Alzheimers disease (AD) is the leading cause of dementia in the United States. More than 2,000,000 people are incapacitated by this disease. The age-specific prevalence rates increase from about 5 percent to 7 percent at age 60 to somewhere between 20 percent to 40 percent at age 80. At present, no specific curative or palliative treatment exists for this condition. Only about 5 percent to 10 percent of cases of dementia that result from causes other
  • than AD are due to reversible conditions such as B-12 deficiency or hypothyroidism. CT or MR imaging can identify most if not all of the space