Contrast enhanced X-ray computed tomography imaging of amyloid plaques in Alzheimer disease rat model on lab based micro CT system
Michaela KavkováTomáš ZikmundAnnu KalaJakub ŠalplachtaStephanie L. Proskauer PenaJozef KaiserKarel Ježek
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Abstract:
Abstract Amyloid plaques are small (~ 50 μm), highly-dense aggregates of amyloid beta (Aβ) protein in brain tissue, supposed to play a key role in pathogenesis of Alzheimer’s disease (AD). Plaques´ in vivo detection, spatial distribution and quantitative characterization could be an essential marker in diagnostics and evaluation of AD progress. However, current imaging methods in clinics possess substantial limits in sensitivity towards Aβ plaques to play a considerable role in AD screening. Contrast enhanced X-ray micro computed tomography (micro CT) is an emerging highly sensitive imaging technique capable of high resolution visualization of rodent brain. In this study we show the absorption based contrast enhanced X-ray micro CT imaging is viable method for detection and 3D analysis of Aβ plaques in transgenic rodent models of Alzheimer’s disease. Using iodine contrasted brain tissue isolated from the Tg-F344-AD rat model we show the micro CT imaging is capable of precise imaging of Aβ plaques, making possible to further analyze various aspects of their 3D spatial distribution and other properties.Keywords:
Amyloid (mycology)
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In vivo molecular imaging is a powerful tool to analyze the human body. Precision medicine is receiving high attention these days, and molecular imaging plays an important role as companion diagnostics in precision medicine. Nuclear imaging with PET or SPECT and optical imaging technologies are used for in vivo molecular imaging. Nuclear imaging is superior for quantitative imaging, and whole-body analysis is possible even for humans. Optical imaging is superior due to its ease of use, and highly targeted specific imaging is possible with activatable agents. However, with optical imaging using fluorescence, it is difficult to obtain a signal from deep tissue and quantitation is difficult due to the attenuation and scattering of the fluorescent signal. Recently, to overcome these issues, optoacoustic imaging has been used in in vivo imaging. In this article, we review in vivo molecular imaging with nuclear and optical imaging and discuss their utility for precision medicine.
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Human Islet Amyloid Polypeptide Accumulates at Similar Sites in Islets of Transgenic Mice and Humans
The cellular mechanisms responsible for conversion of islet amyloid polypeptide (IAPP) into insoluble amyloid deposits in non-insulin-dependent diabetes mellitus (NIDDM) are not clear. Overexpression of IAPP and the amino acid sequence of human IAPP (hIAPP) have both been implicated. To examine factors involved in amyloid formation, transgenic mice expressing the hIAPP or rat IAPP (rIAPP) gene were generated. These mice had elevated plasma IAPP concentrations, and they were normoglycemic and normoinsulinemic. No amyloid deposits were detected by light microscopy. To examine the ultrastructure of islets, pancreatic tissue was studied from hIAPP and rIAPP transgenic mice and from age-matched control mice by immunoelectron microscopy. IAPP was immunolocalized in β-cell secretory granules of all mice, and the COOH- and NH2-terminal flanking peptides of hIAPP were localized in β-cell granules of hIAPP mice. Accumulations of nonfibrillar perivascular IAPP-immunoreactive material were found between capillaries and β-cells in hIAPP transgenic mice but not in rIAPP transgenic or control mice. Similar nonfibrillar masses were identified in islets of an NIDDM patient. Secondary lysosomes in β-cells and macrophages of hIAPP transgenic mice showed dense labeling for IAPP. We suggest that hIAPP is degraded more slowly than rIAPP or mouse IAPP by β-cell lysosomes. Accumulations of IAPP in islet perivascular spaces may represent the early stages of islet amyloid formation.
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Molecular imaging is a powerful tool to visualize and characterize biological processes at the cellular and molecular level in vivo . In most molecular imaging approaches, probes are used to bind to disease‐specific biomarkers highlighting disease target sites. In recent years, a new subset of molecular imaging probes, known as bioresponsive molecular probes, has been developed. These probes generally benefit from signal enhancement at the site of interaction with its target. There are mainly two classes of bioresponsive imaging probes. The first class consists of probes that show direct activation of the imaging label (from “off” to “on” state) and have been applied in optical imaging and magnetic resonance imaging (MRI). The other class consists of probes that show specific retention of the imaging label at the site of target interaction and these probes have found application in all different imaging modalities, including photoacoustic imaging and nuclear imaging. In this review, we present a comprehensive overview of bioresponsive imaging probes in order to discuss the various molecular imaging strategies. The focus of the present article is the rationale behind the design of bioresponsive molecular imaging probes and their potential in vivo application for the detection of endogenous molecular targets in pathologies such as cancer and cardiovascular disease. Copyright © 2015 John Wiley & Sons, Ltd.
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To model islet amyloidogenesis in NIDDM and explore the glucoregulatory role of islet amyloid polypeptide (IAPP), we have created transgenic micye containing a rat insulin‐I promoter‐human IAPP fusion gene. Expression of human IAPP was localized to the islets of Langerhans, anterior pituitary and brain in transgenic animals; blood IAPP levels were elevated 5‐fold while fasting glucose levels remained normal. Amyloid deposits have not been detected in transgenic islets suggesting that other co‐existing abnormalitites in NIDDM may be required for the formation of islet amyloid. These animals provide a unique model for exploring this hypothesis and other proposed functions of IAPP.
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After completing this article, readers should be able to:
1. Describe the emerging field of in vivo molecular imaging.
2. List the various imaging modalities that have been used to detect molecules and track cells in vivo and discuss the basic molecular strategies and principles.
3. Describe several of the selective events, such as binding, enzymatic activation, or molecular switches, that make in vivo imaging of cells and molecules possible.
4. Delineate the strengths and weakness of current imaging strategies.
5. List combined imaging modalities and their use in molecular imaging.
Following cells and molecules in vivo has been a fundamental difficulty in biomedical research. The technologies in the field of in vivo molecular imaging are aimed at obtaining spatiotemporal information about in vivo processes as they occur; that is, monitoring cellular and molecular changes in response to a variety of stimuli in intact animals and eventually in humans. Understanding basic biologic and biochemical mechanisms is required to develop the tools that will enable access to this information.
Traditional imaging modalities largely depend on physical parameters, such as absorption in ultrasonography, x-ray attenuation, or optical scattering, which reveal primarily structural information. For molecular imaging, unique signatures are generated using molecular biology methods that distinctly label host cells, microbial pathogens, tumor cells, or transplanted tissues. These can be detected in vivo by conventional and novel imaging modalities and can be used to examine molecular mechanisms of pathogenesis, facilitate earlier disease detection, and permit evaluation of therapeutic outcomes. The molecular targets for imaging may include DNA, RNA, protein, or protein function. Imaging of inherent levels of DNA, RNA, and protein is difficult, but protein function can be exploited readily for imaging and can be used in reporter gene approaches to create surrogate markers for processes such as messenger RNA (mRNA) and protein synthesis.1,2, …
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Advancements in medical imaging have brought about unprecedented changes in the in vivo assessment of cancer. Positron emission tomography, single photon emission computed tomography, optical imaging, and magnetic resonance imaging are the primary tools being developed for oncologic imaging. These techniques may still be in their infancy, as recently developed chemical molecular probes for each modality have improved in vivo characterization of physiologic and molecular characteristics. Herein, we discuss advances in these imaging techniques, and focus on the major design strategies with which molecular probes are being developed.
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Emission computed tomography
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Molecular Imaging
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