Overview Of Imaging In Biological Research

From their inception, the various noninvasive imaging modalities have been used widely in basic biological research. The broad utility of imaging in biological research reflects the breadth of fundamental physical processes that underlie all imaging technologies. The same types of probes and methods of detection that are used in biochemistry and in molecular and cellular biology [e.g., optical, nuclear (gamma emission), nuclear magnetic resonance (NMR) spectroscopy, x-ray] also form the basis of imaging technologies. When the electron microscope was introduced in the 1930s, the morphology of submi-croscopic cellular structures that had only been inferred by indirect methods such as x-ray diffraction or structural chemistry could be visualized directly for the first time in electron micrographs [2]. By analogy, the development of medical imaging technologies (e.g., SPECT [3] - PET [4,5] - CT [6] - and MRI [7,8]) has provided the ability to visualize in vivo biological processes previously accessible only by indirect or invasive means. As the science of biological imaging has grown, the development of new imaging applications has been driven by the unique ability of noninvasive imaging to reveal information about anatomical structure and physiological function as well as various disease states in living subjects.

It will be helpful to review briefly the use of imaging in biological research in order to understand the context and source of imaging biomarkers. We describe some common clinical imaging technologies and then highlight some of the image-based methods for measuring biological function that have been proposed in the literature, providing a background for detailed examples. Several examples of biological imaging applications in drug discovery are also provided in a recent monograph [9].

Clinical Imaging Technologies

Although we limit our discussion here to nuclear PET and SPECT, CT, and MRI modalities, the following applies equally well to other imaging technologies, including ultrasound, which is widely used clinically, and various forms of optical imaging which are becoming more prevalent [ 10]. An accessible general introduction to imaging technologies is available [11], as is a comprehensive treatment of the theoretical basis of imaging [12].

CT, the most commonly used clinical imaging modality, provides three-dimensional images of anatomical structure. The main source of contrast in CT images arises from the differential attenuation of x-rays by tissues in the body. In CT images, mineralized tissues appear brighter due to higher attenuation of the x-rays, and soft tissues have intermediate intensity due to lower attenuation. Because of limited contrast differences between soft tissues, an injectable iodine -based contrast agent is often necessary to better highlight anatomical lesions. Despite this limitation, CT provides the highest spatial resolution (less than 0.5 mm), and acquisition of CT data is straightforward and rapid.

MRI may be characterized as a large family of methods to detect molecular- and cellular-dependent image contrasts through the manipulation of nuclear spin magnetic resonance during data acquisition. The proton nuclei of hydrogen in water and lipids are the most commonly imaged, although in principle the NMR basis of detection permits imaging or spatially localized spectroscopy of other nuclei, such as -3C, 19F, 23Na, and 31P. The sensitivity of MRI is relatively poor, generally requiring tens of micromolar to millimolar volumes of nuclei for detection. However, excellent soft tissue contrast with high spatial resolution (ca. 1 mm) may be obtained. Acquisition of MRI data is controlled by a pulse sequence, which is a computer program that orchestrates the transmission of radio-frequency pulses and magnetic field gradients, as well as the reception of radio-frequency signals from the subject [13]. Vendor-supplied pulse sequences provide a broad range of available acquisition methods; however, additional pulse sequences and improved methods are constantly being introduced in MRI research.

While MRI applications tend to be focused on the seemingly limitless variations in MR acquisition methods, data acquisition in nuclear imaging (PET

and SPECT) is relatively straightforward, being based on either detection of single gamma photons (SPECT) or coincident collinear pairs of gamma photons (PET). Image contrast in nuclear imaging relies on the use of targeted biomolecular probes or tracers labeled with radionuclides to detect in vivo molecular processes and biological function. Thus, the scope of radionuclide imaging is limited primarily by the ability to efficiently radiolabel biologically relevant molecules, and applications are centered primarily on the skill and creativity of the radiochemist. In general, the sensitivity of nuclear imaging methods is the highest of all clinical modalities, with the picomolar sensitivity of PET being about two to three orders of magnitude higher than that of SPECT [14] . The low intrinsic resolution of PET (ca. 5 mm) and SPECT (ca. 15 mm) has been mitigated somewhat through the development of multimo-dality image acquisition combining PET/CT or SPECT/CT [ 15] . and more recently PET/MRI [16], which provide high-resolution anatomical images registered with functional nuclear images.

In all imaging modalities, the resulting images must be reconstructed from the data acquired using computational methods of varying complexity [17,18], and additionally, in some cases, a series of images may be used to calculate parametric images representing image-based measures corresponding to particular biological functions.

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