Search

Receptors have a prominent role in brain function, as they are the effector sites of neurotransmission at the postsynaptic membrane, have a regulatory role on presynaptic sites for transmitter reuptake and feedback, and are modulating various functions on the cell membrane. Distribution, density, and activity of receptors in the brain can be visualized by radioligands labeled for SPECT and PET, and the receptor binding can be quantified by appropriate tracer kinetic models, which can be modified and simplified for particular application. Selective radioligands are available for the various transmitter systems, by which the distribution of these receptors in the normal brain and changes in receptor binding during various physiologic activities or resulting from pathologic conditions can be visualized. The quantitative imaging for several receptors has gained clinical importance-for example, dopamine (D2)) receptors for differential diagnosis of movement disorders and for assessment of receptor occupancy by neuroleptics drugs; serotonin (5-hydroxytryptamine, 5-HT) receptors and the 5-HT transporter in affective disorders and for assessment of activity of antidepressants; nicotinic receptors and acetylcholinesterase as markers of cognitive and memory impairment; central benzodiazepine-binding sites at the gamma-aminobutyric acid A (GABAA) receptor complex as markers of neuronal integrity in neurodegenerative disorders, epilepsy, and stroke and as the site of action of benzodiazepines; peripheral benzodiazepine receptors as indicators of inflammatory changes; opioid receptors detecting increased cortical excitability in focal epilepsy but also affected in perception of and emotional response to pain; and several receptor systems affected in drug abuse and craving. Further studies of the various transmitter/receptor systems and their balance and infraction will improve our understanding of complex brain functions and will provide more insight into the pathophysiology of neurologic and psychiatric disease interaction.

Dementia is a chronic brain syndrome with enormous impact on health care provision. Emission tomography (single photon emission computed tomography (SPECT) and positron emission tomography (PET)) provides a unique tool to investigate functional and neurochemical changes, both in those with established dementia and in those at risk of subsequent cognitive decline. Alzheimer's disease is characterized by bilateral temporoparietal hypoperfusion on SPECT and hypometabolism on PET, which may precede the onset of dementia as similar changes can be demonstrated in those with mild cognitive impairment and in those genetically at risk of developing Alzheimer's disease. In dementia with Lewy bodies medial parietal and occipital perfusion deficits are seen together with pre-synaptic and post-synaptic dopaminergic changes, most particularly a reduction in the striatal pre-synaptic dopamine transporter which can be visualized using appropriate ligands (e.g., (123)I-FP-CIT). Vascular dementia is associated with multiple, asymmetric, perfusion deficits in multi-infarct dementia. In contrast, subcortical vascular dementia is associated with reduced perfusion but preserved oxygen extraction fraction on PET. Fronto-temporal dementia is characterized by both hypometabolism and hypoperfusion in fronto-temporal lobes, though hypometabolism appears more extensive, affecting large areas of the cerebral hemispheres. Longitudinal studies of treatment response in Alzheimer's disease with cholinergic drugs have found changes in regional blood flow and nicotinic and muscarinic receptor function in those patients who respond to treatment. Currently, emission tomography is widely used for assisting with clinical differential diagnosis. Future developments will entail the development and application of more specific neurochemical ligands and those which bear a closer relationship to the underlying disease processes, including markers of tau, amyloid and synuclein pathology.

The clinical identification and differential diagnosis of dementias is especially challenging in the early stages, but the need for early, accurate diagnosis has become more important, now that several medications for the treatment of mild to moderate Alzheimer's disease (AD) are available. Many neurodegenerative diseases produce significant brain-function alterations detectable with PET or SPECT even when structural images with CT or MRI reveal no specific abnormalities. (18)F-FDG PET images of AD demonstrate focally decreased cerebral metabolism involving especially the posterior cingulate and neocortical association cortices, while largely sparing the basal ganglia, thalamus, cerebellum, and cortex mediating primary sensory and motor functions. Assessment of the precise diagnostic accuracy of PET had until recently been hindered by the paucity of data on diagnoses made using PET and confirmed by definitive histopathologic examination. In the past few years, however, studies comparing neuropathologic examination with PET have established reliable and consistent accuracy for diagnostic evaluations using PET-accuracies substantially exceeding those of comparable studies of the diagnostic value of SPECT or of both modalities assessed side by side, or of clinical evaluations done without nuclear imaging. Similar data are emerging concerning the prognostic value of (18)F-FDG PET. Improvements in the ability of PET to identify very early changes associated with AD and other neurodegenerative dementias are currently outpacing improvements in therapeutic options, but with advances in potential preventive and disease-modifying treatments appearing imminent, early detection and diagnosis will play an increasing role in the management of dementing illness.

Beta-adrenoceptors are predominantly located in the cerebral cortex, nucleus accumbens and striatum. At lower densities, they are also present in amygdala, hippocampus and cerebellum. Beta-2 sites regulate glial proliferation during ontogenic development, after trauma and in neurodegenerative diseases. The densities of beta-1 adrenoceptors are changed by stress, in several mood disorders (depression, excessive hostility, schizophrenia) and during treatment of patients with antidepressants. A technique for beta-adrenoceptor imaging in the human brain is not yet available. Although 24 (ant)agonists have been labeled with either (11)C or (18)F and some of these are successful myocardial imaging agents, only two (S-1'-(18)F-fluorocarazolol and S-1'-(18)F-fluoroethylcarazolol) could actually visualize beta-adrenoceptors within the central nervous system. Unfortunately, these radiopharmaceuticals showed a positive Ames test. They may be mutagenic and cannot be employed for human studies. Screening of more than 150 beta-blockers described in the literature yields only two compounds (exaprolol and L643,717) which can still be radiolabeled and evaluated for beta-adenoceptor imaging. However, other imaging techniques could be examined. Cerebral beta-adrenoceptors might be labeled after temporary opening of the blood-brain barrier (BBB) and simultaneous administration of a hydrophilic ligand such as S-(11)C-CGP12388. Another approach to target beta-adrenoceptor ligands to the CNS is esterification of a myocardial imaging agent (such as (11)C-CGP12177), resulting in a lipophilic prodrug which can cross the BBB and is split by tissue esterases. BBB opening is not feasible in healthy subjects, but the prodrug approach may be successful and deserves to be explored.

This article presents an overview of those animal studies which so far have been performed with dedicated small animal positron emission tomographs in the field of the neurosciences. In vivo investigations focus on energy metabolism, perfusion and receptor/transporter binding in rat models of reinforcement, learning and memory, traumatic brain injury, epilepsy, depression, cardiovascular diseases--such as ischemia and focal stroke--and neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's disease. In the majority of studies, important novel aspects arise from the fact that the investigators made use of an option inherent to in vivo studies, namely to conduct longitudinal investigations on the same animals. Relevant findings pertain to the relationship of brain metabolism/perfusion and the cholinergic system, the regulation state of dopamine receptors upon cocaine administration and withdrawal, the regulation state of dopamine receptors and transporters in animal models of Parkinson's and Huntington's disease, and potential treatments of progressive dopaminergic depletion with adenoviral vectors, embryonic grafts, stem cells and nerve growth factors.

Positron emission tomography (PET) has an established role in the noninvasive localization of epileptic foci during presurgical evaluation. [18F]fluorodeoxyglucose (FDG) PET is able to lateralize and regionalize potentially epileptogenic regions in patients who have normal MR imaging and is also useful in the evaluation of various childhood epilepsy syndromes, including cryptogenic infantile spasms and early Rasmussen's syndrome. Novel PET tracers that were developed to image neurotransmission related to gamma-aminobutyric acid (GABA) [with [11C]flumazenil] and serotonin-mediated [with alpha-[11C]methyl-L-tryptophan (AMT)] function provide increased specificity for epileptogenic cortex and are particularly useful when FDG PET shows large abnormalities of glucose metabolism. Detailed comparisons of PET abnormalities with intracranial electroencephalographic findings also improve our understanding of the pathophysiology of human epilepsy.

Recent advances in the technology of non-invasive neuroimaging techniques, include X-ray CT, magnetic resonance imaging, positron CT, etc. The trend of neuroimaging is from the diagnosis of the brain structural change to the functional localization of the brain function with accurate topographical data. Brain activation studies disclosed the responsible regions in the brain for various kinds of paradigms, including motor, sensory, cognitive functions. Another aspect of brain imaging shows the pathophysiological changes of the neurological disorders, such as Alzheimer's disease by abnormal CBF or metabolism changes. It is very important to note that the neurotransmitter receptor imaging is now available for various kinds of transmitters. We recently developed a new tracer for nicotinic type acetylcholine receptor, which might be involved in the pathophysiology of Alzheimer's disease and its treatment. In the near future, we will be able to visualize the proteins in the brain such as amyloid protein, which will make us to diagnose Alzheimer's patients accurately, and with respect to neuroscience research, not only neuronal functional localizations but also relationship between them will become important to disclose the functional aspects of the brain.

For the past years, substantial amount of experimental data has been published on the use of positron emission tomography in different psychiatric disorders. The different PET methods, which evaluate the whole-brain or regional metabolism, tissue perfusion or receptor density may help to identify the disorder specific changes in brain function and also better understand the underlying pathophysiology. In the clinical practice, PET plays an important role in the diagnosis and differential diagnosis of dementias and, presumably, in the near future the PET technique will be also extensively used in the clinical examination of other psychiatric disorders.

Techniques such as positron-emission tomography, single-photon-emission computed tomography, functional magnetic-resonance imaging and magnetoencephalography permit the observation of biological processes in the brain in a noninvasive manner. They have yielded new insights into the biological interrelations of sensory, motor and cognitive functions, as well as into brain diseases. Combined use of these techniques may provide more information than just the sum of its constituents, and this may narrow the gap between the biological data provided by these techniques and the mental models described by clinicians, mathematicians, psychologists and philosophers.

With the development of noninvasive tomographic imaging techniques, it is now possible to measure local chemical and physiologic functions in various body organs. Studies of local cerebral glucose metabolism in infants and children using positron emission tomography (PET) have provided important information on human brain functional development and plasticity. The clinical application of functional neuroimaging techniques in the management of pediatric neurologic disorders has yielded encouraging results. In children with intractable epilepsy being considered for surgical intervention, PET is highly sensitive in localizing focal areas of cortical dysplasia, heterotopias, and other migrational defects corresponding to surface electrographic localization of epileptogenic regions. Expanding PET technology provides a new approach that holds great promise in the diagnosis and management of brain disorders in children.

The absolute sensitivity of a state-of-the-art, commercial neuroPET tomograph with interplane septa is about 0.5%. This poor utilization of the available photons could be improved by increasing the intrinsic efficiency of the detection process and, more significantly, by increasing the solid angle coverage of the tomography. While multi-ring scanners currently have an axial length of about 10 cm, the useful solid angle is limited by the presence of interplane septa. These septa reduce the acceptance rate not only of scattered photons but also of true unscattered coincidences, although in studies performed at high photon counting rates the loss of potential signal may be less important than a reduction in scatter. Removal of the septa increases the absolute sensitivity of the scanner to about 3%, a figure which also includes an unavoidable increase in scattered photons. However, in studies performed at low photon counting rates, any increase in scattered and random (uncorrelated) coincidences resulting from septa removal may be an acceptable price to pay for the accompanying increase in signal, provided that there is a real improvement in the signal-to-noise ratio. Recently, scanners with automatically retractable septa have become commercially available, thus enabling the configuration (i.e. septa extended or retracted) to be selected according to the study to be performed.

The aim of this paper is to identify future directions for developing instrumentation to measure the tissue kinetics of tracers labelled with positron emitting isotopes. A principal theme developed is the need to realise increased sensitivity for detection. In order to present the case for these improvements, examples are shown of current procedures which would improve with increased sensitivity.

In the foregoing an overview of positron emission tomography has been presented. Its theoretical, technical, and methodological implications, as well as its clinical applications have been outlined. The emphasis has been on the quantitative aspects of the method and its usefulness is investigating normal and pathological functions of brain tissue. Although the potential of this new research technique is obvious, many theoretical and practical difficulties still need to be solved. Nevertheless it provides an opportunity to bridge the gap between basic experimental research and clinical medicine.