Molecular Imaging Studies Research Articles

Molecular brain imaging and the neurobiology and genetics of schizophrenia.

It has been hypothesized that schizophrenia is related to dysfunction in temporolimbic-prefrontal neuronal networks, which is acquired early in an individual's development. After puberty, relatively reduced prefrontal control of striatal dopaminergic neurotransmission may lead to unmodulated striatal dopamine (DA) activity, and the positive symptoms of acute psychosis. Brain imaging studies support the notion of prefrontal dysfunction in schizophrenia and correlated upregulation of presynaptic striatal DA activity. Recent molecular brain imaging studies have combined genetic assessments with a multimodal neuroimaging approach to further refine our understanding of the pathophysiologic architecture of the disorder. We review the literature on functional brain imaging in schizophrenia and discuss genotype effects on core psychotic symptoms. A promising research strategy is the identification of genetic and environmental factors that contribute to intermediate phenotypes such as working memory deficits in schizophrenia. Molecular brain imaging can help to unravel the complex interactions between genes and environment and its association with neuronal network dysfunction in schizophrenia.

Glutamate, dopamine, and schizophrenia: from pathophysiology to treatment.

The fundamental pathological process(es) associated with schizophrenia remain(s) uncertain, but multiple lines of evidence suggest that this condition is associated with (1) excessive stimulation of striatal dopamine (DA) D2 receptors, (2) deficient stimulation of prefrontal DA D1 receptors and, (3) alterations in prefrontal connectivity involving glutamate (GLU) transmission at N-methyl-d-aspartate (NMDA) receptors. This chapter first briefly discusses the current knowledge status for these abnormalities, with emphasis on results derived from clinical molecular imaging studies. The evidence for hyperstimulation of striatal D2 receptors rests on strong pharmacological evidence and has recently received support from brain imaging studies. The hypothesis of deficient prefrontal cortex (PFC) D1 receptor stimulation is almost entirely derived from preclinical studies. Preliminary imaging data compatible with this hypothesis have recently emerged. The NMDA hypofunction hypothesis originates mainly from indirect pharmacological data. The interactions between DA and GLU systems relevant to schizophrenia are then reviewed. Animal and imaging data supporting the general model that the putative DA imbalance in schizophrenia (striatal excess and cortical deficiency) might be secondary to NMDA hypofunction in the PFC and its connections are presented. Equally important are the potential consequences of this DA imbalance for NMDA function in the striatum and the cortex, which are subsequently discussed. In conclusion, it is proposed that schizophrenia is associated with strongly interconnected abnormalities of GLU and DA transmission: NMDA hypofunction in the PFC and its connections might generate a pattern of dysregulation of DA systems that, in turn, further weakens NMDA-mediated connectivity and plasticity.

Molecular imaging of cardiac cell transplantation in living animals using optical bioluminescence and positron emission tomography.

The current method of analyzing myocardial cell transplantation relies on postmortem histology. We sought to demonstrate the feasibility of monitoring transplanted cell survival in living animals using molecular imaging techniques. For optical bioluminescence charged-coupled device imaging, rats (n=20) underwent intramyocardial injection of embryonic rat H9c2 cardiomyoblasts (3x10(6) to 5x10(5)) expressing firefly luciferase (Fluc) reporter gene. Cardiac bioluminescence signals were present for more than 2 weeks with 3x10(6) cells: day 1 (627 000+/-15%), day 2 (346 100+/-21%), day 4 (112 800+/-20%), day 8 (78 860+/-24%), day 12 (67 780+/-12%), and day 16 (62 200+/-5% p x s(-1) x cm(2-1) x sr(-1)). For micro-positron emission tomography imaging, rats (n=20) received cardiomyoblasts (3x10(6)) expressing mutant herpes simplex type 1 thymidine kinase (HSV1-sr39tk) reporter gene. Detailed tomography of transplanted cells is shown by 9-(4-[18F]-fluoro-3hydroxymethylbutyl)guanine ([18F]-FHBG) reporter probe and nitrogen-13 ammonia ([13N]-NH3) perfusion images. Within the transplanted region, there was a 4.48+/-0.71-fold increase of in vivo [18F]-FHBG activity and a 4.01+/-0.51-fold increase of ex vivo gamma counting compared with control animals. Finally, the in vivo images of cell survival were confirmed by ex vivo autoradiography, histology, immunohistochemistry, and reporter protein assays. The location(s), magnitude, and survival duration of embryonic cardiomyoblasts were monitored noninvasively. With further development, molecular imaging studies should add critical insights into cardiac cell transplantation biology.

Neuroreceptor imaging in psychiatric disorders.

Molecular imaging, the study of receptors, transporters and enzymes, as well as other cellular processes, has grown in recent years to be one of the most active neuroimaging areas. The application of single photon emission tomography (SPECT) and positron emission tomography (PET) techniques to the study of psychiatric illness has lead to increased understanding of disease processes as well as validated, in vivo, theories of illness etiology. Within the field of psychiatry these techniques have been applied most widely to the study of schizophrenia. Studies within schizophrenia are largely limited to either the dopamine or serotonin system. This is due in large part to the availability of suitable radiotracers as well as the current theories on the etiology of the illness. Two basic study designs are used when studying schizophrenia using molecular imaging and make up the majority of studies reviewed in this manuscript. The first type, termed "clinical studies," compares the findings from PET and SPECT studies in those with schizophrenia to normal controls in an attempt to understand the pathophysiology of the illness. The second study design, termed "occupancy studies," uses these techniques to enhance the understanding of the mechanism of action of the medications used in treating this illness. This review will focus on the findings of molecular imaging studies in schizophrenia, focusing, for the most part, on the serotonin and dopamine systems. Emphasis will be placed on how these findings and techniques are currently being used to inform the development of novel treatments for schizophrenia.

Insights into the use of paramagnetic Gd(III) complexes in MR-molecular imaging investigations.

Can gadolinium III [Gd(III)] complexes be considered good candidates for magnetic resonance (MR)-molecular imaging studies? In this review article, we examine the principal issues that are the basis of successful use of Gd-based protocols in molecular imaging applications. High relaxivity is the primary requisite. Therefore, the design of such paramagnetic probes has to be pursued keeping in mind the relationships between structure, dynamics, and the relevant parameters involved in paramagnetic relaxation processes. Moreover, the limited number of target molecules on cellular membranes makes it necessary to define strategies aimed at delivering many Gd-containing moieties to the sites of interest. Examples are reported for the attainment of very high relaxivities for the design of new routes for pursuing the accumulation of small sized Gd(III) complexes at the targeting sites. An efficient cellular uptake of Gd-containing probes is the key step for attaining the visualization of targeted cells by MR imaging, and selected examples are reported. In this context, the problem of the assessment of the minimum amount of Gd(III) complexes necessary for the MR imaging-visualization of cells has been addressed by reporting the authors' observations on the cell-internalization of Gd(III) complexes. A particularly efficient delivery system is represented by Gd-loaded apoferritin, which allows the MR visualization of hepatocytes when the number of Gd-complexes per cell is 4 +/- 1 x 10(7). Finally, the potential of responsive systems is considered by outlining the exploitation of the amplification effect brought about by the action of a specific enzymatic activity on the relaxivity of a suitably functionalized Gd(III) complex.

Applications of In Vivo Molecular Imaging in Biology and Medicine

After completing this article, readers should be able to: 1. Describe the clinical applications for which molecular imaging may be most effective in the near term and the research applications of molecular imaging that are relevant to clinical imaging. 2. Delineate the significance of data generated by current molecular imaging studies. The methods of in vivo molecular Wimaging have arisen out of the need for in vivo assays in many different fields; it is the progress in each of these fields that has led to a wealth of new tools for in vivo molecular and cellular analyses. In vivo molecular imaging has been used in the study of gene expression and cell migration during mammalian and other vertebrate development, in the evaluation of animal models of human cancer, in drug discovery, and in revealing patterns of infectious disease and host response to infection. In highlighting some of these studies, we illustrate the overall goals of in vivo analysis and some of the challenges for future studies. A spectrum of optically based imaging strategies, and more recently, nuclear magnetic resonance imaging approaches have revealed cellular and molecular changes that occur during development in mouse, fish, chick, and frog embryos.1,2 The goal of in vivo imaging in the study of development is to evaluate the molecular events that occur as an embryo executes cell migration or as a specific cell divides and gives rise to daughter cells that have distinct and mature phenotypes. The challenge lies in performing assays at the cellular and molecular levels within the intact embryo while maintaining as normal a setting as possible. The imaging strategies used to study embryonic development, typically light microscopy, generally can address questions at the cellular level, but the future of developmental biology lies in linking these analyses, which reveal how and …

The role of secondary ion mass spectrometry (SIMS) in biological microanalysis: technique comparisons and prospects

The virtues and limitations of SIMS ion microscopy are compared with other spectroscopic techniques applicable to biological microanalysis, with a special emphasis on techniques for elemental localization in biological tissue (electron, X-ray, laser, nuclear, ion microprobes). Principal advantages of SIMS include high detection sensitivity, high depth resolution, isotope specificity, and possibilities for three-dimensional imaging. Current limitations, especially in comparison to X-ray microanalysis, center on lateral spatial resolution and quantification. Recent SIMS instrumentation advances involving field emission liquid metal ion sources and laser post-ionization will help to minimize these limitations in the future. The molecular surface analysis capabilities of static SIMS, especially with the new developments in commercial time-of-flight spectrometers, are promising for application to biomimetic, biomaterials, and biological tissue or cell surfaces. However, the direct microchemical imaging of biomolecules in tissue samples using SIMS will be hindered by limited concentrations, small analytical volumes, and the inefficiencies of converting surface molecules to structurally significant gas phase ions. Indirect detection using elemental or isotopically tagged molecules, however, shows considerable promise for molecular imaging studies using SIMS ion microscopy.