Regional distribution of protease‐resistant prion protein in fatal familial insomnia

Abstract

Protease-resistant prion protein, total prion protein, and glial fibrillary acidic protein were measured in various brain regions from 9 subjects with fatal familial insomnia. Six were homozygotes methionine/methionine at codon 129 (mean duration, 10.7 +/- 4 months) and 3 were heterozygotes methionine/valine (mean duration, 23 +/- 11 months). In all subjects, protease-resistant prion protein was detected in gray matter but not in white matter and peripheral organs. Its distribution was more widespread than that of the histopathological lesions, which were observed only in the presence of a critical amount of the abnormal protein. In the mediodorsal thalamic nucleus, however, a severe neuronal loss and astrogliosis were associated with relatively moderate amounts of protease-resistant prion protein, suggesting a higher vulnerability. There was no overall correlation between amount of protease-resistant prion protein and either glial fibrillary acidic protein or total prion protein. While protease-resistant prion protein was virtually limited to subcortical areas and showed a selective pattern of distribution in the subjects with disease of the shortest duration, it was more widespread in the subjects with a longer clinical course, indicating that with time the disease process spreads within the brain. The kinetics of the accumulation of protease-resistant prion protein varied among different brain regions: While in the neocortex and to a lesser extent in the limbic lobe and in the caudate nucleus, the amount increased with disease duration, in the mediodorsal thalamic nucleus and in the brainstem it was present in comparable amounts in all subjects regardless of the disease duration.(ABSTRACT TRUNCATED AT 250 WORDS)

A refined method for molecular typing reveals that co-occurrence of PrPSc types in Creutzfeldt–Jakob disease is not the rule

“…In their study, Polymenidou et al 34 suggested that the use of a too high PK concentration could lead to false-negative results and that the PK concentration for the most reliable PrP Sc detection should be the minimum concentration that will completely digest PrP C . We agree that the highest sensitivity is needed when the primary goal is a positive or negative diagnosis based on PrP Sc detection; however, at present, this is rarely a significant issue in CJD diagnosis given the relatively high PrP Sc concentration in CJD brains, the only exceptions being rare cases of genetic TSEs such as FFI or familial CJD associated with extra-repeat insertions 44 (unpublished data). However, when a fine typing analysis is needed, the optimum PK concentration corresponds to the one generating the minimum amount of partially digested fragments together with the maximum possible amount of PrP27-30 resistant core.…”

“…17,19,29,44 Yull et al 35 found that the type 1-like band detected by 12B2 in vCJD maintained the very characteristic glycoform ratio of PrP Sc type 2B and concluded that the band they considered a PrP Sc resistant core could not be a common type 1. We consider this result, which was also reproduced by us, as further evidence that the type 1-like band recognized by 12B2 in vCJD cases represents partially cleaved fragments of PrP Sc type 2B rather than real, bona fide PrP Sc type 1.…”

Sporadic Fatal Insomnia in an Adolescent

“…8 The analyses showed: (1) methionine homozygosity at codon 129 and lack of mutation in the prion protein gene; (2) severe neuronal loss and astrogliosis in the thalamic nuclei; (3) the presence of PK-resistant PrP Sc type 2; (4) glycoform ratios different from those of fatal familial insomnia and consistent with those associated with sFI 8,15 ; and (5) lower amounts of PKresistant PrP Sc in subcortical regions than the cerebral cortex. 16 No evaluation of insomnia or dysautonomia was performed, and their presence or absence is unknown. Insomnia is often difficult to detect without polysomnography, which was not performed in this case.…”

An in vivo 11C‐PK PET study of microglia activation in Fatal Familial Insomnia

“…Postmortem tissue evaluation consistently reveals neuronal death due to apoptosis and gliosis, largely confined to the ventral anterior and dorso‐medial thalamic nuclei and inferior olivary nuclei, not correlating with the amount of PrP Sc deposition 10, 13, 15, 16, 17. Previous studies have reported only mild PrP Sc accumulation in FFI, particularly in patients with the shortest disease duration 16, 18.…”

“…Previous studies have reported only mild PrP Sc accumulation in FFI, particularly in patients with the shortest disease duration 16, 18. Significant microglia activation has been described in association with neuronal apoptosis in FFI, both in terms of topography and magnitude,17 but negative evidence also exists 19, 20…”