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Published on: March 12, 2018
Prion propagation estimated from brain diffusion MRI is subtype dependent in sporadic Creutzfeldt-Jakob disease
Riccardo Pascuzzo1, Neil P Oxtoby2, Alexandra L Young2,3
1Neuroradiology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria, 11, 20133, Milan, Italy.
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.
Insights
Sporadic Creutzfeldt-Jakob disease (sCJD) progression varies by subtype. Diffusion MRI revealed subtype-specific brain lesion epicenters and propagation patterns, aiding early diagnosis and staging.
Area of Science:
- Neuroscience
- Radiology
- Pathology
Background:
- Sporadic Creutzfeldt-Jakob disease (sCJD) is a fatal neurodegenerative disease characterized by prion protein aggregation.
- Five main clinicopathological subtypes of sCJD exist, with varying prion aggregate and lesion distributions.
- Understanding lesion propagation is crucial for early diagnosis, patient staging, and clinical trial recruitment.
Purpose of the Study:
- To identify, in vivo, subtype-dependent lesion epicenters and propagation patterns in the brain using diffusion-weighted imaging (DWI).
- To analyze the largest cross-sectional dataset of autopsy-proven sCJD subjects using diffusion MRI.
- To establish dynamic insights into the pathological process for improved clinical management.
Main Methods:
- Utilized diffusion-weighted images (DWI) from 448 patients with autopsy-diagnosed sCJD and 594 total subjects.
- Employed event-based modeling, a data-driven technique, to estimate lesion propagation sequences across 12 brain regions.
- Validated estimated sequences using follow-up data from 151 patients.
Main Results:
- Epicenter and lesion propagation order are specific to sCJD subtypes.
- The common -MM1 and -VV2 subtypes exhibited opposite DWI abnormality patterns: neocortex to subcortical, and vice versa.
- The precuneus was a common early epicenter, with variations in other cortical regions depending on the subtype.
Conclusions:
- Data-driven models reveal unprecedented dynamic, subtype-specific insights into sCJD onset and lesion propagation.
- These findings enhance understanding of sCJD's spatiotemporal progression.
- The study provides a foundation for improved early diagnosis and disease staging in sCJD patients.
