TY - JOUR
T1 - Prion propagation estimated from brain diffusion MRI is subtype dependent in sporadic Creutzfeldt–Jakob disease
AU - Pascuzzo, Riccardo
AU - Oxtoby, Neil P.
AU - Young, Alexandra L.
AU - Blevins, Janis
AU - Castelli, Gianmarco
AU - Garbarino, Sara
AU - Cohen, Mark L.
AU - Schonberger, Lawrence B.
AU - Gambetti, Pierluigi
AU - Appleby, Brian S.
AU - Alexander, Daniel C.
AU - Bizzi, Alberto
N1 - Funding Information:
RP, NPO, DCA, and AB have received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 666992. This was supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. NPO is a UKRI Future Leaders Fellow (MRC MR/S03546X/1). PG is supported by NIH P01 AI106705, NIH R01NS083687, NIH P01A107774, and Charles S. Britton Fund. The NPDPSC (JB, MLC, and BSA) is funded by CDC NU2GCK000434.
Publisher Copyright:
© 2020, The Author(s).
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/8/1
Y1 - 2020/8/1
N2 - 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.
AB - 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.
KW - Creutzfeldt–Jakob disease
KW - Disease progression
KW - Epicentre
KW - Magnetic resonance imaging
KW - Prion disease
KW - Prion propagation
KW - Spongiform degeneration
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U2 - 10.1007/s00401-020-02168-0
DO - 10.1007/s00401-020-02168-0
M3 - Article
C2 - 32535770
AN - SCOPUS:85086325468
VL - 140
SP - 169
EP - 181
JO - Acta Neuropathologica
JF - Acta Neuropathologica
SN - 0001-6322
IS - 2
ER -