Contribution of neuropathology to the understanding of human prion disease

Neuropathology is an important tool for definitive diagnosis of sporadic, genetic, and acquired prion disease. Classical neuropathological hallmark is the highly disease-specific spongiform change accompanied by neuronal loss, astro- and microgliosis. Spongiform change of the neuropil consists of either microcystic or confluent vacuoles and varies greatly within the same brain. In addition, the most important aspect of confirmatory diagnosis is the demonstration of disease-associated prion protein (PrP(d)) by immunohistochemistry or Western blotting. Different PrP(d) immunostaining patterns include patchy/perivacuolar surrounding spongiform change, diffuse/synaptic, perineuronal, or plaque type. The latter includes unicentric kuru-type plaques or multicentric plaques as in the peculiar genetic prion disorder, Gerstmann-Sträussler-Scheinker disease. PrP(d) immunostaining patterns correlate well with phenotypes defined by the polymorphic codon 129 and the type of protease resistant PrP(d) seen on Western blots. PrP(d) immunoreactivity in the cerebellum may be highly informative about disease subtypes. Although the central nervous system is the major site of PrP(d) accumulation, it may also be observed in peripheral nerves as adaxonal deposits; in skeletal muscle as granular immunoreactivity in particular in abundance in a unique instance of concomitant Creutzfeldt-Jakob disease and inclusion body myositis; as well as associated with dendritic cells and macrophages in vessel walls. A subset of inhibitory GABAergic neurons is selectively affected in experimental and human prion disease. The central pathogenetic cascade includes oxidative stress and apoptosis. Deposition of terminal complement components on neurons accompanies tissue damage.