REGIONAL DISTRIBUTION OF PROTEASE-RESISTANT PRION PROTEIN IN FATAL FAMILIAL INSOMNIA

Protease-resistant prion protein, total prion protein, and glial fibri llary acidic protein were measured in various brain regions from 9 sub jects with fatal familial insomnia. Six were homozygotes methionine/me thionine at codon 129 (mean duration, 10.7 +/- 4 months) and 3 were he terozygotes methionine/valine (mean duration, 23 +/- 11 months). In al l subjects, protease-resistant prion protein was detected in gray matt er but not in white matter and peripheral organs. Its distribution was more widespread than that of the histopathological lesions, which wer e observed only in the presence of a critical amount of the abnormal p rotein. In the mediodorsal thalamic nucleus, however, a severe neurona l loss and astrogliosis were associated with relatively moderate amoun ts of protease-resistant prion protein, suggesting a higher vulnerabil ity. There was no overall correlation between amount of protease-resis tant prion protein and either glial fibrillary acidic protein or total prion protein. While protease-resistant prion protein was virtually l imited to subcortical areas and showed a selective pattern of distribu tion in the subjects with disease of the shortest duration, it was mor e widespread in the subjects with a longer clinical course, indicating that with time the disease process spreads within the brain. The kine tics of the accumulation of protease-resistant prion protein varied am ong different brain regions: While in the neocortex and to a lesser ex tent in the limbic lobe and in the caudate nucleus, the amount increas ed with disease duration, in the mediodorsal, thalamic nucleus and in the brainstem it was present in comparable amounts in all subjects reg ardless of the disease duration. These findings indicate that in fatal familial insomnia, the pathological phenotype is the result of the va riability, in different brain regions, of the (1) timing and rate of a ccumulation of protease-resistant prion protein, and (2) vulnerability to the presence of protease-resistant prion protein.