Introduction

This chapter examines some neuropathological features of ALS. Formerly, neuropathological studies of this disease described the pattern of neuron loss. However, more recent studies have revealed that ALS tissue possesses a wide array of cytoplasmic abnormalities. These abnormalities have become much better understood with immunohistochemical and electron microscopic analysis. For instance, the observation that neurofilaments accumulate within motoneurons and other cells has raised the possibility that this neurofilamentous change could be a cause or consequence of impaired axonal transport. The observation of ubiquitin immunoreactivity has also generated considerable excitement as it is possible that the inclusions may represent a protein that is involved in the pathogenesis of ALS, or a marker of a distinct pathophysiologic process ultimately resulting in the specific pattern of involvement seen in the disease. The role of neuropathological studies in ALS is undergoing a transformation. These studies are no longer purely descriptive but have become a means of validating the importance of various animal models of ALS. This is particularly the case for transgenic mice, in which manipulation of the genome of the animal results in a different phenotype. To evaluate how closely a transgenic mouse model approaches human ALS requires a thorough neuropathological evaluation to describe the distribution and type of cell loss. Conversely, neuropathological studies of mutant animals have provided insights into possible neuropathological features of human ALS which were formerly unrecognized. It is for this reason that descriptions of pathological features of a number of mutant and transgenic animals are included in this chapter.