Neuroimaging is central to the diagnostic process in amyotrophic lateral sclerosis (ALS). Neuroimaging, particularly magnetic resonance imaging (MRI), is uniquely powerful in identifying tumors and other lesions of the brain, spinal cord, or nerve roots that can masquerade as ALS. High-quality MRI of these structures is widely available and most patients with suspected ALS have MRI scans of the brain and/or spinal cord, although this may not always be necessary. Prior to the advent of neuroimaging, there was limited scope for understanding the nature and importance of the cerebral lesions in ALS. The development of neuroimaging techniques in the past 30 years has permitted the detailed study of brain pathology in vivo, and has revolutionized the study of neurologic diseases more than any other single development. Conventional techniques that can be applied in almost all modern neuroimaging units include T1- and T2–weighted images, proton density-weighted images and fluid attenuated inversion recovery (FLAIR)-weighted images.
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is the most common motor neuron disease. The pathologic hallmark of ALS is the selective death of motor neurons in the brain and spinal cord that innervate skeletal muscles, with symptoms of progressive weakness, muscle wasting and spasticity. Genetic susceptibility is an important determinant of the risk for ALS. The rapid rise and subsequent fall of ALS incidence rates in the Western Pacific suggest that the cause may be an environmental agent that peaked after World War II and has declined, but not completely disappeared. The classic example of a neurodegenerative disorder caused by an environmental excitotoxin is lathyrism, a disease of upper motor neurons caused by excessive consumption of the chickling pea which contains an unusual amino acid that acts as a glutamate-like excitotoxin. The epidemiologic study of ALS and motor neuron diseases has spanned several recent decades and has undergone evolution over this time period.
During development of higher vertebrates, many types of neurons including spinal and bulbar motoneurons are generated in excess. When developing motoneurons become postmitotic, they grow out axons and make contact with their target tissue, the skeletal muscle. Subsequently, about 50% of the motoneurons are lost during a critical process, which is called physiological motoneuron cell death. This phenomenon has been the focus of research for about a century and has led to the identification of neurotrophic factors that regulate survival of motoneurons during this developmental period. Motoneuron cell death is also observed in vitro when these neurons are isolated from the embryonic avian or rodent spinal cord. These cultured motoneurons have been a useful tool for studying basic mechanisms underlying neuronal degeneration. Such studies have revealed insights into signaling pathways that modulate survival during development and that might be disturbed under pathophysiological conditions in neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). However, specific differences in mechanisms that regulate survival of developing and postnatal motoneurons have also been identified. These findings could help to develop new therapeutic strategies that could counteract the pathophysiological processes underlying ALS.
ABSTRACT Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which leads to a progressive degeneration of motoneurons. Since the pharmacological options available provide only a slight increase in life expectancy, cell therapy is emerging as a promising therapeutic alternative for ALS. A growing body of evidence from studies using genetically engineered ALS animal models demonstrate the safety and efficacy of therapies based on different cell types such as mononuclear cells, neural progenitors, and mesenchymal stem cells. Despite the encouraging results in preclinical studies, cell therapy-based clinical trials for ALS have achieved only modest results so far, probably due to the genotypic variations seen among ALS patients, which is difficult to reproduce in animal models. The advent of induced pluripotent stem cells (iPSCs) has enabled the development of patient-specific cell lines, a valuable tool to investigate in vitro molecular mechanisms of the disease and therapies in different genetic backgrounds. The applications of ALS iPSCs and their future therapeutic potential are also briefly discussed in this chapter.
This chapter introduces the reader to neurodegenerative diseases linked to dementia or movement disorders in which a protein or proteins containing mutations have been identified as causative factors of the disease. The specific mechanisms for those vulnerabilities are still unknown, but together they illustrate a variety of molecular pathways, triggered perhaps by aggregation of specific proteins, that lead to neurodegenerative syndromes. Mutation or overexpression of a-synuclein leads to cytoplasmic inclusions of presumably misfolded a-synuclein recognized histologically as Lewy bodies (LB). Tau is present in the brain in six major isoforms derived from alternative splicing of a single tau gene. The mutations in the tau gene that cause missense amino acid substitutions tend to cluster around the microtubule-binding domains of tau. Alzheimer's Disease (AD) is the most common neurodegenerative disease, with over 4 million Americans affected.
