Chapter 19 - Etiology, Pathology, and Pathogenesis

Abstract

Publisher Summary This chapter reviews the available evidence on the etiopathogenesis and pathology of multiple system atrophy (MSA). MSA is a neurodegenerative disease of unknown etiology that manifests clinically with autonomic failure, parkinsonism, cerebellar ataxia, and pyramidal signs in various combinations. The finding of polymorphisms in various proinflammatory pathways is a promising step in elucidating the pathogenesis of MSA. There is significant overlap in the clinical features between the fragile X–associated tremor/ataxia syndrome (FXTAS) and atypical parkinsonism—in particular, MSA associated with cerebellar ataxia (MSA-C). Polymorphisms associated with an elevated risk for MSA include interleukin (IL)-1A, IL-1β, IL-8, intercellular adhesion molecule-1, tumor necrosis factor-1031C,38, and α1-antichymotrypsin. Diffuse neuronal cytoplasmic α-synuclein immunoreactivity is often referred to as “preinclusions” and may reflect incipient inclusion or Lewy body-like formation enhanced in sympathetic ganglia in MSA patients. Although MSA is now widely accepted as a single multisystem disease, there is evidence of clinicopathological heterogeneity. Autonomic failure in MSA is caused by dysfunction of (1) central and preganglionic efferent autonomic activity, (2) neuronal networks in the brainstem that control cardiovascular and respiratory function, and (3) the neuroendocrine component of the autonomic regulation via the hypothalamopituitary axis. The correlation of subregional glial cytoplasmic inclusion (GCI) density and neuronal loss suggests that α-synuclein aggregation is tightly linked to selective neurodegeneration in MSA.