Identifying physiological and anatomical signatures of disease in signals and images is one of the fundamental challenges in biomedical engineering. The challenge is most apparent given that such signatures must be identified in spite of tremendous inter and intra-subject variability and noise. Crucial for uncovering these signatures has been the development of methods that exploit general statistical properties of natural signals. The signal processing and applied mathematics communities have developed, in recent years, signal representations which take advantage of Gabor-type and wavelet-type functions that localize signal energy in a joint time-frequency and/or space-frequency domain. These techniques can be expressed as multi-resolution transformations, of which perhaps the best known is the wavelet transform. In this paper we review wavelets, and other related multi-resolution transforms, within the context of identifying signatures for disease. These transforms construct a general representation of signals which can be used in detection, diagnosis and treatment monitoring. We present several examples where these transforms are applied to biomedical signal and imaging processing. These include computer-aided diagnosis in mammography, real-time mosaicking of ophthalmic slit-lamp imagery, characterization of heart disease via ultrasound, predicting epileptic seizures and signature analysis of the electroencephalogram, and reconstruction of positron emission tomography data.

Paul Sajda

Andrew Laine

Yehoshua Zeevi

Multi-Resolution and Wavelet Representations for Identifying Signatures of Disease

Barbara Y. Croft

Foreword

Diffuse optical tomography (DOT) is emerging as a viable new biomedical imaging modality. Using near-infrared (NIR) light, this technique probes absorption as well as scattering properties of biological tissues. First commercial instruments are now available that allow users to obtain cross-sectional and volumetric views of various body parts. Currently, the main applications are brain, breast, limb, joint, and fluorescence/bioluminescence imaging. Although the spatial resolution is limited when compared with other imaging modalities, such as magnetic resonance imaging (MRI) or X-ray computerized tomography (CT), DOT provides access to a variety of physiological parameters that otherwise are not accessible, including sub-second imaging of hemodynamics and other fast-changing processes. Furthermore, DOT can be realized in compact, portable instrumentation that allows for bedside monitoring at relatively low cost. In this paper, we present an overview of current state-of-the -art technology, including hardware and image-reconstruction algorithms, and focus on applications in brain and joint imaging. In addition, we present recent results of work on optical tomographic imaging in small animals.

A. H. Hielscher

A. Y. Bluestone

G. S. Abdoulaev

A. D. Klose

J. Lasker

M. Stewart

U. Netz

J. Beuthan

Near-Infrared Diffuse Optical Tomography

Animal models can be used in the study of disease. This chapter discusses imaging animal models to elucidate the process of human disease. The mouse is used as the primary model. Though this choice simplifies many research choices, it necessitates compromises for in vivo imaging. In the future, we can expect improvements in both animal models and imaging techniques.

Animal Models for imaging

In vivo endoscopic optical microscopy provides a tool to assess tissue architecture and morphology with contrast and resolution similar to that provided by standard histopathology &#x2013; without need for physical tissue removal. In this article, we focus on optical imaging technologies that have the potential to dramatically improve the detection, prevention, and therapy of epithelial cancers. Epithelial pre-cancers and cancers are associated with a variety of morphologic, architectural, and molecular changes, which currently can be assessed only through invasive, painful biopsy. Optical imaging is ideally suited to detecting cancer-related alterations because it can detect biochemical and morphologic alterations with sub-cellular resolution throughout the entire epithelial thickness. Optical techniques can be implemented non-invasively, in real time, and at low cost to survey the tissue surface at risk. Our manuscript focuses primarily on modalities that currently are the most developed: reflectance confocal microscopy (RCM) and optical coherence tomography (OCT). However, recent advances in fluorescence-based endoscopic microscopy also are reviewed briefly. We discuss the basic principles of these emerging technologies and their current and potential applications in early cancer detection. We also present research activities focused on development of exogenous contrast agents that can enhance the morphological features important for cancer detection and that have the potential to allow vital molecular imaging of cancer-related biomarkers. In conclusion, we discuss future improvements to the technology needed to develop robust clinical devices.

Konstantin Sokolov

Kung-Bin Sung

Tom Collier

Anne Clark

Dizem Arifler

Alicia Lacy

Michael Descour

Rebecca Richards-Kortum

Endoscopic Microscopy

Ultrasound has been a popular clinical imaging modality for decades. It is well established as a means of displaying the macroscopic anatomy of soft-tissue structures. While conventional ultrasound methodologies (i.e., B-mode and Doppler methods) are well proven and continue to advance technically on a daily basis, e.g. by extending into higher frequencies and taking advantage of harmonic phenomena in tissues, fundamentally new ultrasound technologies also are emerging and offer exciting promise for making significant improvements in the clinical imaging of disease. These emerging methods include spectrum analysis, elasticity imaging, contrast-agent methods, and advanced flow detection and measurement techniques. Each provides independent information and, used alone, each can provide powerful new imaging capabilities; combined with each other, their capabilities may be even greater in many applications; and all in principle can be used in concert with other imaging modalities to offer the possibility of further improvements in disease detection, evaluation, and monitoring.

Ernest J. Feleppa

S. Kaisar Alam

Cheri X. Deng

Emerging Ultrasound Technologies for Early Markers of Disease

The purpose of this report is to present an overview of the use of fluorescence imaging in vivo, with particular emphasis on oncology. It is important to note, however, that many of the methods described herein have been applied to the study of non-malignant tissues as well. Modern medicine and biology research has benefited greatly from an ever-expanding assortment of fluorescent markers and labels. These markers and labels have allowed investigators to observe the behavior and properties of cell and molecular entities of interest in the context of complicated biological systems such as a mammalian cell or a whole mouse. Methods developed to image fluorescence in whole mice have been valuable in studying patterns of tumor growth and metastases. Alternatively, more detailed information and a wide variety of endpoints can be obtained using &#x201C;intravital&#x201D; preparations. This review focuses on use of fluorescence imaging for intravital preparations. For detail on fluorescence imaging of whole animals, refer to reviews on this subject &#x5B;1,2&#x5D;. For oncologic applications, studies have focused primarily on window chamber preparations that allow for real-time visualization of tumor growth, vascularity, vascular responses to stimulation, vascular permeability, vascular orientation, flow instability, and the like. These endpoints have been used to show that there are functional differences between tumor and normal tissues with respect to these functions under baseline conditions and after therapeutic manipulation. Examples of some of these differences are provided in this review as a means to illustrate how they can be used.

Mark W. Dewhirst

S. Shan

Yiting Cao

Benjamin Moeller

Fan Yuan

Chuan-Yuan Li

Intravital Fluorescence Facilitates Measurement of Multiple Physiologic Functions and Gene Expression in Tumors of Live Animals

Positron emission tomography (PET) provides a powerful means to non-invasively image and quantify protein expression and biochemical changes in living subjects at nano- and picomolar levels. As the field of molecular imaging develops, and as advances in the biochemistry, pharmacology, therapeutics, and molecular biology of disease are made, there is a corresponding increase in the number of clinically relevant, novel disease-associated biomarkers that are brought to the attention of those developing imaging probes for PET. In addition, due to the high specificity of the PET radiotracers being developed, there is a demand for PET cameras with higher sensitivity and resolution. This manuscript reviews advances over the past five years in clinical and pre-clinical PET instrumentation and in new PET probes and imaging methods associated with the latest trends in the molecular imaging of cancer. Included in the PET tracer review is a description of new radioligands for steroid receptors, growth factor receptors, receptor tyrosine kinases, sigma receptors, tumor-associated enzymes, gene reporter probes, markers for tumor hypoxia and metabolism, and sites associated with angiogenesis and cellular proliferation. The use of PET imaging in drug development, including the monitoring of cancer chemotherapy, also is discussed.

T. Lee Collier

Roger Lecomte

Timothy J. McCarthy

Steve Meikle

Thomas J. Ruth

Francesco Scopinaro

Alberto Signore

Henry Van Brocklin

Christophe Van de Wiele

Rikki N. Waterhouse

Assessment of Cancer-Associated Biomarkers by Positron Emission Tomography: Advances and Challenges

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Disease Markers publishes papers related to the identification of disease markers, the elucidation of their role and mechanism, as well as their application in the prognosis, diagnosis and treatment of diseases.

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Chief Editor Paola Gazzaniga is an Associate Professor in the Department of Molecular Medicine at Sapienza University of Rome, Italy. Her core research focuses on liquid biopsies in patients with solid tumors.

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