The Phenotypic Spectrum of Sporadic Creutzfeldt‐Jakob Disease Cortical Subtype

Objective: The objective of this study was to characterize the phenotypic spectrum of the rare sporadic Creutzfeldt-Jakob disease cortical subtype (sCJDMM/MV2C) in a large multicentric autopsy cohort. Methods: We evaluated clinical histories, biofluid markers, brain diffusion-weighted (DW)-magnetic resonance imaging (MRI), and electroencephalogram (EEG) findings in 56 patients. The histomolecular assessment included misfolded prion protein (PrP) typing by immunoblotting, histopathology, and PrP immunohistochemistry in several brain areas. Results: Misfolded PrP typing showed a dominant 19 kDa unglycosylated PrP fragment (type 2) in all brains, focally associated with a 21 kDa (type 1) fragment in 53% of participants (MM/MV2C + 1). Immunohistochemistry revealed coarse/perivacuolar PrP deposits in the neocortices and a patchy/coarse pattern in the cerebellar molecular layer. The mean disease duration was 16.0 months. At onset and early stages, most patients manifested only progressive cognitive decline, consistent with the predominant distribution and relative severity of spongiform change in the cerebral cortex. Brain DW-MRI showed cortical hyperintensities in 94% of cases. Cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC) assay was positive in 70% of cases. Compared with pure MM/MV2C, the mixed MM/MV2C + 1 phenotype showed a shorter disease duration (14 vs 19 months), and a higher frequency of striatal DW-MRI hyperintensity (56% vs 19%), EEG periodic sharp-waves complexes (41% vs 6%), and CSF RT-QuIC positivity (86% vs 53%). Interpretation: The clinicopathologic phenotype of sCJDMM/MV2C diverges from that of typical sCJDMM/MV1. Moreover, the histomolecular heterogeneity within MM/MV2C influences clinical features and results of diagnostic investigations, challenging its identification in vivo. Nonetheless, results suggest that DW-MRI and CSF RT-QuIC allow an accurate clinical diagnosis of Creutzfeldt-Jakob disease in most patients. ANN NEUROL 2025.