Neuroreceptor Imaging Studies Research Articles

Robustness of post-reconstruction and direct kinetic parameter estimates under rigid head motion in dynamic brain PET imaging

ObjectiveDynamic PET imaging is extensively used in brain imaging to estimate parametric maps. Inter-frame motion can substantially disrupt the voxel-wise time-activity curves (TACs), leading to erroneous maps during kinetic modelling. Therefore, it is important to characterize the robustness of kinetic parameters under various motion and kinetic model related factors. MethodsFully 4D brain simulations ([15O]H2O and [18F]FDG dynamic datasets) were performed using a variety of clinically observed motion patterns. Increasing levels of head motion were investigated as well as varying temporal frames of motion initiation. Kinetic parameter estimation was performed using both post-reconstruction kinetic analysis and direct 4D image reconstruction to assess bias from inter-frame emission blurring and emission/attenuation mismatch. ResultsKinetic parameter bias heavily depends on the time point of motion initiation. Motion initiated towards the end of the scan results in the most biased parameters. For the [18F]FDG data, k4 is the more sensitive parameter to positional changes, while K1 and blood volume were proven to be relatively robust to motion. Direct 4D image reconstruction appeared more sensitive to changes in TACs due to motion, with parameter bias spatially propagating and depending on the level of motion. ConclusionKinetic parameter bias highly depends upon the time frame at which motion occurred, with late frame motion-induced TAC discontinuities resulting in the least accurate parameters. This is of importance during prolonged data acquisition as is often the case in neuro-receptor imaging studies. In the absence of a motion correction, use of TOF information within 4D image reconstruction could limit the error propagation.

Development of (18)F-labeled radiotracers for neuroreceptor imaging with positron emission tomography.

Positron emission tomography (PET) is an in vivo molecular imaging tool which is widely used in nuclear medicine for early diagnosis and treatment follow-up of many brain diseases. PET uses biomolecules as probes which are labeled with radionuclides of short half-lives, synthesized prior to the imaging studies. These probes are called radiotracers. Fluorine-18 is a radionuclide routinely used in the radiolabeling of neuroreceptor ligands for PET because of its favorable half-life of 109.8 min. The delivery of such radiotracers into the brain provides images of transport, metabolic, and neurotransmission processes on the molecular level. After a short introduction into the principles of PET, this review mainly focuses on the strategy of radiotracer development bridging from basic science to biomedical application. Successful radiotracer design as described here provides molecular probes which not only are useful for imaging of human brain diseases, but also allow molecular neuroreceptor imaging studies in various small-animal models of disease, including genetically-engineered animals. Furthermore, they provide a powerful tool for in vivo pharmacology during the process of pre-clinical drug development to identify new drug targets, to investigate pathophysiology, to discover potential drug candidates, and to evaluate the pharmacokinetics and pharmacodynamics of drugs in vivo.

How have developments in molecular imaging techniques furthered schizophrenia research?

Molecular imaging techniques have led to significant advances in understanding the pathophysiology of schizophrenia and contributed to knowledge regarding potential mechanisms of action of the drugs used to treat this illness. The aim of this article is to provide a review of the major findings related to the application of molecular imaging techniques that have furthered schizophrenia research. This article focuses specifically on neuroreceptor imaging studies with PET and SPECT. After providing a brief overview of neuroreceptor imaging methodology, we consider relevant findings from studies of receptor availability, and dopamine synthesis and release. Results are discussed in the context of current hypotheses regarding neurochemical alterations in the illness. We then selectively review pharmacological occupancy studies and the role of neuroreceptor imaging in drug development for schizophrenia.

Cortical Dopamine D2/D3 Receptors Are a Common Site of Action for Antipsychotic Drugs--An Original Patient Data Meta-analysis of the SPECT and PET In Vivo Receptor Imaging Literature

Subject numbers in neuroreceptor imaging studies of antipsychotic treatment in schizophrenia are generally insufficient to directly test the relationship of regional D(2)/D(3) and 5HT(2A) receptor binding to clinical efficacy. We selected positron emission tomography (PET) and single photon emission computed tomography (SPECT) studies of antipsychotic dose vs occupancy at both temporal cortex and striatal D(2)/D(3) receptors. We selected corresponding SPECT and PET studies of 5HT(2A) receptor occupancy. We also selected randomized double-blind clinical trials of antipsychotics, where patients were treated with randomly assigned fixed doses. For each antipsychotic drug, we compared the optimum effective antipsychotic dose with the dose inducing maximal occupancy of D(2)/D(3) receptors in striatum and in temporal cortex as well as at 5HT(2A) receptors. Both first- and second-generation antipsychotic (FGA, SGA) drugs produced high temporal cortex D(2)/D(3) occupancy. Only FGA produced high striatal D(2)/D(3) receptor occupancy. The clinically effective dose showed correlation with doses inducing maximal dopamine D(2)/D(3) receptor occupancy both in striatum and in temporal cortex, the strongest correlation being with temporal cortex binding. Extrapyramidal side effects (EPSE) were primarily related to striatal D(2)/D(3) receptor occupancy. There was no correlation between 5HT(2A) occupancy and clinically effective dose. We conclude that cortical dopamine D(2)/D(3) receptor occupancy is involved in antipsychotic efficacy, with striatal D(2)/D(3) occupancy having a likely therapeutic role while also inducing EPSE. We found no evidence for 5HT(2A) blockade involvement in antipsychotic action, although we cannot exclude this possibility.

Hypothesis: social defeat is a risk factor for schizophrenia?

The increased schizophrenia risks for residents of cities with high levels of competition and for members of disadvantaged groups (for example migrants from low- and middle-income countries, people with low IQ, hearing impairments or a history of abuse) suggest that social factors are important for aetiology. Dopaminergic dysfunctioning is a key mechanism in pathogenesis. This editorial is a selective literature review to delineate a mechanism whereby social factors can disturb dopamine function in the brain. Experiments with rodents have shown that social defeat leads to dopaminergic hyperactivity and to behavioural sensitisation, whereby the animal displays an enhanced behavioural and dopamine response to dopamine agonists. Neuroreceptor imaging studies have demonstrated the same phenomena in patients with schizophrenia who had never received antipsychotics. In humans, the chronic experience of social defeat may lead to sensitisation (and/or increased baseline activity) of the mesolimbic dopamine system and thereby increase the risk for schizophrenia.

Neuroreceptor Imaging Studies in Schizophrenia

The ability of SPECT and PET to image specific biomolecules in the living brain provides a unique tool for clinical researchers. It is therefore not surprising that the use of neuroreceptor-imaging techniques has become more widespread over the past decade. This article reviews the application of these techniques to the study of schizophrenia. The design of neuroreceptor-imaging studies performed in the field of schizophrenia research can be broadly divided into two categories: (1) studies of pathophysiology and (2) studies of pharmacology. The former examines neuroreceptor and neurotransmitter parameters in individuals with schizophrenia compared to control subjects in order to provide a better understanding of the disease process. Studies of pharmacology seek to elucidate the mechanism of action for the treatments utilized in schizophrenia. This review will consider both studies of pathophysiology and pharmacology, with a discussion of the application of these techniques to drug development.

Estudios de neurofarmacología y receptores en la edad avanzada

Functional brain imaging has provided unique and exciting opportunities to strengthen our knowledge of the biological substrate of the aging brain and neuropsychiatric disorders. Positron emission tomography (PET) is a particularly powerful tool for quantifying the neurobiological correlates of cognition, mood and behavior. Initial PET studies of aging, psychiatric disorders and neurodegenerative disease focused primarily on generalized physiological parameters such as cerebral blood flow and metabolism, and early neuroreceptor imaging studies relied on relatively non selective markers. New, selective receptor radioligands now offer a previously inaccessible means to investigate the dynamic relationships among neurochemistry, aging and psychopathology in vivo. This approach has substantial advantages over peripheral (platelet and cerebrospinal fluid) markers, neuroendocrine challenge studies, animal models, and postmortem receptor binding assays. Advances in tracer kinetic modeling, magnetic resonance imaging (MRI) to PET registration, radiochemistry techniques, instrumentation and image processing have helped pave the way for increased emphasis on functional imaging studies of neuropsychiatric disorders of the elderly. The capability to correct PET image data for the confounding effect of cerebral atrophy permits relationships among age related brain changes and neurobiological disease mechanisms to be more accurately examined in the course of normal aging and in elderly patient populations.

Models and methods for derivation of in vivo neuroreceptor parameters with PET and SPECT reversible radiotracers

The science of quantitative analysis of PET and SPECT neuroreceptor imaging studies has grown considerably over the past decade. A number of methods have been proposed in which receptor parameter estimation results from fitting data to a model of the underlying kinetics of ligand uptake in the brain. These approaches have come to be collectively known as model-based methods and several have received widespread use. Here, we briefly review the most frequently used methods and examine their strengths and weaknesses. Kinetic modeling is the most direct implementation of the compartment models, but with some tracers accurate input function measurement and good compartment configuration identification can be difficult to obtain. Other methods were designed to overcome some particular vulnerability to error of classical kinetic modeling, but introduced new vulnerabilities in the process. Reference region methods obviate the need for arterial plasma measurement, but are not as robust to violations of the underlying modeling assumptions as methods using the arterial input function. Graphical methods give estimates of V T without the requirement of compartment model specification, but provide a biased estimator in the presence of statistical noise. True equilibrium methods are quite robust, but their use is limited to experiments with tracers that are suitable for constant infusion. In conclusion, there is no universally “best” method that is applicable to all neuroreceptor imaging studies, and carefully evaluation of model-based methods is required for each radiotracer.

RPM STATISTICS — A statistical tool for receptor parametric mapping

Neuroreceptor Imaging studies using Positron Emission Tomography (PET) allow for the in-vivo assessment of neurotransmission [5]. 4-dimensional spatio-temporal datasets are acquired for a radioligand of interest from each subject during the PET scanning procedure. Subsequent analyses of these data using an appropriate mathematical model produces parametric images of receptor related parameters. Statistical Inferences about these parameters across individuals can then be made, after transformation into stereotaxic space.

Neuropharmacology and receptor studies in the elderly.

Functional brain imaging has provided unique and exciting opportunities to strengthen our knowledge of the biologic substrate of the aging brain and neuropsychiatric disorders. Positron emission tomography (PET) is a particularly powerful tool for quantifying the neurobiologic correlates of cognition, mood, and behavior. Initial PET studies of aging, psychiatric disorders, and neurodegenerative disease focused primarily on generalized physiologic parameters such as cerebral blood flow and metabolism, and early neuroreceptor imaging studies relied on relatively nonselective markers. New, selective receptor radioligands now offer a previously inaccessible means to investigate the dynamic relationships among neurochemistry, aging, and psychopathology in vivo. This approach has substantial advantages over peripheral (platelet and cerebrospinal fluid) markers, neuroendocrine challenge studies, animal models, and postmortem receptor binding assays. Advances in tracer kinetic modeling, magnetic resonance imaging facilitated PET image analysis, radiochemistry techniques, instrumentation, and image processing have helped pave the way for increased emphasis on functional imaging studies of neuropsychiatric disorders. The capability to correct PET image data for the confounding effect of cerebral atrophy permits relationships among age-related brain changes and neurobiologic disease mechanisms to be more accurately examined in the elderly.

NEUROIMAGING IN LATE-LIFE SCHIZOPHRENIA

Late-life onset schizophrenia (LOS) could represent a delay of the usual early-onset disorder to old age, or a different disorder with a separate etiopathology. Examples of the latter could include normal age-associated brain changes (e.g., age-related atrophy affecting a critical structure or pathway, or dopamine receptor alterations), or primary age-associated pathology, such as microvascular disease or early manifestations of a primary dementing illness). Brain imaging studies have the potential utility to decide among the above hypotheses by clarifying the types of brain changes associated LOS and shed light on their possible etiology. The author reviews a series of structural, bloodflow, and neuroreceptor imaging studies in several differently defined populations of LOS patients. It seems apparent that studies that restrict LOS to cases resembling early-onset cases, as far as clinical symptoms, are much less likely to include patients with high likelihood of “organic” or coarse brain disease. Such narrowly defined patients resemble early-onset cases of schizophrenia with regard to brain imaging findings. In contrast, research studies that accept more broadly defined patients tend to increase diagnostic heterogeneity and to include a higher proportion of “organic phenocopies” who have more evidence of cerebral vascular and other brain pathology. To address questions regarding the etiologic subgrouping of LOS more adequately, much larger-scale study populations, longitudinal design, and pathologic examination are needed.

Image reconstruction for dynamic PET based on low-order approximation and restoration of the sinogram.

Many image-reconstruction methods have been proposed to improve the spatial resolution of positron emission tomography (PET) images and, thus, to produce better quantification. However, these techniques, which are designed for static images, may be inadequate for good reconstruction from dynamic data. We present a simple, but effective, reconstruction approach intended specifically for dynamic studies. First, the level of noise in dynamic PET data is reduced by smoothing along the time axis using a low-order approximation. Next, the denoised sinograms are restored spatially by the method of projections onto convex sets. Finally, images are reconstructed from the restored sinograms by ordinary filtered backprojection. We present experimental results that demonstrate substantial improvements in region-of-interest quantification in actual and simulated dopamine D-2 neuroreceptor-imaging studies of a monkey brain.

Amphetamine‐stimulated dopamine release competes in vivo for [123I]IBZM binding to the D2 receptor in nonhuman primates

We used the reversibly binding D2 dopamine receptor radioligand [123I]IBZM (iodobenzamide) to test whether the endogenous neurotransmitter dopamine competes in vivo for radiotracer binding measured with single photon emission computed tomography (SPECT). In a series of nonhuman primate experiments (n = 27), the effects of temperature, amphetamine, haloperidol, and reserpine on brain uptake of [123I]IBZM were measured. Specific brain uptake of [123I]IBZM reached a peak by 100 min postinjection of radioligand and demonstrated a gradual, apparent "steady-state" washout over the next 2 hr. Brain uptake was temperature dependent, with rates of washout of specifically bound radioligand greater under normothermic conditions (26%/hr: core body temperature 35-37 degrees C) than under conditions of controlled hypothermia (11%/hr; 32-34 degrees C). Given the greater retention of radioactivity, low-temperature conditions were used in all other experiments. Administration of haloperidol (0.02 mg/kg IV) during the period of apparent steady state resulted in a dramatic increase in washout (60%/hr; p less than 0.0001), consistent with its potent D2 receptor antagonist properties. d-Amphetamine (1.0 mg/kg IV), which has negligible affinity for the D2 receptor but mediates the release of endogenous stores of dopamine, also enhanced washout (34%/hr; p less than 0.0005). Reserpine pretreatment at doses (1.0 mg/kg) sufficient to cause greater than 90% depletion of striatal dopamine levels blocked this amphetamine-enhanced washout (10%/hr; p less than 0.05). Reserpine did not block the increased washout induced by the direct-acting D2 receptor antagonist haloperidol. These results are consistent with the hypothesis that endogenous dopamine may effectively compete for radioligand binding in vivo in neuroreceptor imaging studies using PET and SPECT.