Since the discovery of x-ray by Wilhelm Röntgen at the turn of the twentieth century, there have been monumental strides in the ability to image biological processes in health and in disease. Imaging has not only improved our understanding of the complex and dynamic underpinnings of disease but it has also entered the center of patient care for many conditions. Molecular imaging is a relatively recent term that has been coined in the world of imaging science. The Society of Nuclear Medicine and Molecular Imaging (SNMMI) formed a task force in 2007 to develop standard definitions and terms to serve as the foundation of all communications, advocacy, and education activities in molecular imaging. The task force recommended and the SNMMI board approved the following definition for molecular imaging (1):

The task force further elaborated that

There are a few comprehensive books now available for detailed descriptions of methods and applications in molecular imaging. The aim of this book is to provide a brief introduction to the world of molecular imaging. It is not intended to provide an exhaustive list of all available or potential imaging techniques or methods, but major modalities and applications are included. The book will be useful for students, physicians in training, and others who desire to grasp the basic concepts of molecular imaging in an efficient manner in a relatively short time.

The book is organized by introduction of instrumentation, physics and methods of various imaging modalities, followed by several key biological processes that may be interrogated with molecular imaging. In each chapter, the brief discussion is followed by a bibliography, which may be referred to for additional information and a more in-depth understanding of the topic.

Introduction

Amyloid is protein composed of linear nonbranching fibrils arranged in sheets. Amyloidosis is a disease characterized by misfolding proteins, aggregation, and extracellular depositions of amyloid in tissue and organs. There are at least 20 described types of amyloid protein in humans which vary by precursor protein and resultant organs of deposition. Amyloid deposition may be localized (e.g. brain in Alzheimer's disease (AD)) or systemic (e.g. primary light chain amyloidosis), and there is a wide range of clinical manifestations, from none to severe organ dysfunction.

In regard to selective imaging of amyloid protein, most work thus far has been on developing agents targeting beta (β)-amyloid (Aβ) plaques in the brain, which will be the focus of this chapter. Clinical applications for amyloid imaging of the heart and systemic amyloid deposition are also emerging.

Beta Amyloid Plaques and Pathologic Basis for Alzheimer's Disease

Aβ protein is a 36–43 amino acid peptide cleaved from the transmembrane Aβ protein precursor by β and gamma (γ) sectretase (Figure 15.1). The normal function of Aβ protein is not well understood. Some described potential roles are activation of kinase enzymes, protection against oxidative stress, regulation of cholesterol transport, and serving as a transcription factor or antimicrobial. Plaques containing Aβ protein are described as diffuse or dense, with current imaging probes having affinity for the latter.

Radiopharmaceuticals for Aβ Amyloid PET Imaging

Carbon-11 Pittsburgh Complex B

Carbon-11 Pittsburgh (11C-PiB) was the first radiopharmaceutical developed for targeting Aβ plaques. 11C-PiB is derived from thioflavin T, a fluorescent dye that binds amyloid and is used to histologically identify plaques in brain tissue specimens. PET imaging is performed 40–50 minutes after tracer injection for 20–30 minutes. Normal distribution of 11C-PiB is in cerebral white matter (Figure 15.2, top row). In disease states, there is usually much less dense plaque deposition in cerebellar gray matter compared to cortical gray matter, so the cerebellum is most commonly used as a reference region. Visually, uptake of 11C-PiB in cortical gray matter at least equal to or greater than white matter is considered abnormal (Figure 15.2, bottom row). Standardized uptake value (SUV) ratios comparing cortical to cerebellar gray matter uptake may also be determined, with the upper limit of normal reported as 1.3–1.6. Correlations between 11C-PiB uptake in cortical gray matter and postmortem assessments of Aβ plaques have been demonstrated.

The Apoptosis Cellular Pathway

Apoptosis is the process of programmed cell death and is critical for growth and development and the maintenance of cellular homeostasis. Cells committed to death through the apoptotic pathway are dissembled according to a coordinated sequence of events. The classic morphologic changes during apoptosis are loss of communication and detachment from neighboring cells, condensation of chromatin at the nuclear membrane, fragmentation of the nuclear membrane, cell shrinkage, and formation of apoptotic bodies which are subsequently phagocytosed. Apoptosis is energy dependent and a distinct feature is that the cell's plasma membrane remains intact. There is no accompanying inflammatory response and no evidence of the cell's previous existence. In contrast, cellular necrosis is a disorderly process which results in surrounding inflammation and oftentimes residual tissue scarring.

Apoptosis is mediated through a number of cellular proteins and signaling pathways (Figure 11.1). The major family of proteins responsible for apoptosis is cysteine proteases called caspases. Caspases are inactivated in the cell cytoplasm (as procaspases) until receiving a death signal. Once activated, initiator caspases activate effector caspases which in turn activate the rest of the machinery needed for programmed cell death. Activation of the initiator caspases occurs via the intrinsic or mitochondrial pathway or via the extrinsic pathway.

The intrinsic (mitochondrial) pathway is induced by cellular stress or the loss of survival signals. Upon receiving such signals, mitochondria release cytochrome c through pores in the mitochondrial membrane causing apoptosome formation through oligomerization of molecules, Apaf-1 in vertebrates. Apoptosome formation results in activation of initiator caspases. The Bcl-2 family of proteins regulates the mitochondrial pathway through both anti-apoptotic (e.g., Bcl-2) and pro-apoptotic (e.g., Bak, Bax) properties.

The extrinsic pathway is activated by the binding of death ligands (e.g., tumor necrosis factor alpha) to the extracellular component of death receptors in the cell membrane. This results in the recruitment of adaptor molecules which activate initiator caspases. Subsquent formation of death receptor signaling complexes activates effector caspases leading to apoptosis. An immune response or tumorigenesis can initiate the extrinsic pathway.