Protein misfolding disorders are an emerging complex group of chronic and progressive entities driven by structural transitions in the native state of specific proteinaceous components and the generation of polymeric aggregates that assemble into poorly soluble tissue deposits. In all these disorders, through mechanistic pathways still poorly understood, soluble proteins normally found in biological fluids change their conformation and form insoluble structures that accumulate as intra- and extracellular aggregates or as fibrillar deposits. The group comprises a wide range of diseases encompassing disorders that are either (i) localized to the central nervous system (CNS) and particularly associated with cerebrovascular compromise, neuronal vulnerability, and neurodegeneration; (ii) restricted to other individual organs, where their presence correlate with a specific organ dysfunction(s), e.g. the pancreas in type II diabetes or the heart in familial amyloidotic cardiomyopathy; or (iii) affecting multiple organs, as in the case of systemic amyloidosis. The group of disorders affecting the CNS, which is the focus of this book, is quite heterogeneous and, as illustrated in Table 1.1, includes conditions with dissimilar clinical manifestations — ranging from cognitive decline and dementia to severe motor deficits or to recurrent episodes of cerebral hemorrhage — as well as disease-specific pathology .