Fatal familial insomnia is a rare disease caused by a D178N mutation in 
combination with methionine (Met) at codon 129 in the mutated allele of PRNP 
(D178N-129M haplotype). FFI is manifested by sleep disturbances with insomnia, 
autonomic disorders and spontaneous and evoked myoclonus, among other symptoms. 
This study describes new neuropathological and biochemical observations in a 
series of eight patients with FFI. The mediodorsal and anterior nuclei of the 
thalamus have severe neuronal loss and marked astrocytic gliosis in every case, 
whereas the entorhinal cortex is variably affected. Spongiform degeneration only 
occurs in the entorhinal cortex. Synaptic and fine granular proteinase K 
digestion (PrPres) immunoreactivity is found in the entorhinal cortex but not in 
the thalamus. Interleukin 6, interleukin 10 receptor alpha subunit, colony 
stimulating factor 3 receptor and toll-like receptor 7 mRNA expression increases 
in the thalamus in FFI. PrPc levels are significantly decreased in the thalamus, 
entorhinal cortex and cerebellum in FFI. This is accompanied by a particular 
PrPc and PrPres band profile. Altered PrP solubility consistent with 
significantly reduced PrP levels in the cytoplasmic fraction and increased PrP 
levels in the insoluble fraction are identified in FFI cases. Amyloid-like 
deposits are only seen in the entorhinal cortex. The RT-QuIC assay reveals that 
all the FFI samples of the entorhinal cortex are positive, whereas the thalamus 
is positive only in three cases and the cerebellum in two cases. The present 
findings unveil particular neuropathological and neuroinflammatory profiles in 
FFI and novel characteristics of natural prion protein in FFI, altered PrPres 
and Scrapie PrP (abnormal and pathogenic PrP) patterns and region-dependent 
putative capacity of PrP seeding.