Abstract
Sporadic Creutzfeldt–Jakob disease (sCJD) is a transmissible brain proteinopathy. Five main clinicopathological subtypes (sCJD-MM(V)1, -MM(V)2C, -MV2K, -VV1, and -VV2) are currently distinguished. Histopathological evidence suggests that the localisation of prion aggregates and spongiform lesions varies among subtypes. Establishing whether there is an initial site with detectable imaging abnormalities (epicentre) and an order of lesion propagation would be informative for disease early diagnosis, patient staging, management and recruitment in clinical trials. Diffusion magnetic resonance imaging (MRI) is the most-used and most-sensitive test to detect spongiform degeneration. This study was designed to identify, in vivo and for the first time, subtype-dependent epicentre and lesion propagation in the brain using diffusion-weighted images (DWI), in the largest known cross-sectional dataset of autopsy-proven subjects with sCJD. We estimate lesion propagation by cross-sectional DWI using event-based modelling, a well-established data-driven technique. DWI abnormalities of 594 autopsy-diagnosed subjects (448 patients with sCJD) were scored in 12 brain regions by 1 neuroradiologist blind to the diagnosis. We used the event-based model to reconstruct sequential orderings of lesion propagation in each of five pure subtypes. Follow-up data from 151 patients validated the estimated sequences. Results showed that epicentre and ordering of lesion propagation are subtype specific. The two most common subtypes (-MM1 and -VV2) showed opposite ordering of DWI abnormality appearance: from the neocortex to subcortical regions, and vice versa, respectively. The precuneus was the most likely epicentre also in -MM2 and -VV1 although at variance with -MM1, abnormal signal was also detected early in cingulate and insular cortices. The caudal-rostral sequence of lesion propagation that characterises -VV2 was replicated in -MV2K. Combined, these data-driven models provide unprecedented dynamic insights into subtype-specific epicentre at onset and propagation of the pathologic process, which may also enhance early diagnosis and enable disease staging in sCJD.
Highlights
From the collection of 619 Sporadic Creutzfeldt–Jakob disease (sCJD) patients with diffusion-weighted images (DWI) and autopsy-confirmed diagnosis, 448 subjects with pure subtype and positive magnetic resonance imaging (MRI) were selected and subdivided in 7 groups according to their molecular subtype or, in the case of sCJD-MV2K and -MV2C, according to their histopathological phenotype (Fig. 1)
Current notions of prion propagation in sporadic CJD have been informed by neurological signs observed at diagnosis or on basic comparisons of lesion topography at autopsy in small samples of cases having variable disease duration
Our study shows for the first time by direct in vivo observation that the histopathological process in sCJD is subtype-specific both in terms of epicentre and propagation profile
Summary
They may occur sporadically, be inherited, or acquired from dietary or iatrogenic exposure to prions. Despite their rarity, Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention, Atlanta, Georgia, USA. Sporadic Creutzfeldt–Jakob disease (sCJD), the most common type of prion disease, accounts for 85–90% of all human cases [34]. Familial or genetically determined CJD (gCJD), the second most common type, accounts for an additional ~ 10% of the total, while the remainder includes very rare sporadic and familial types of fatal insomnia (sFI and FFI), variably protease-sensitive prionopathy (VPSPr) and Gerstmann–Sträussler–Scheinker (GSS) as well as the
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