Prion propagation estimated from brain diffusion MRI is subtype dependent in sporadic Creutzfeldt–Jakob disease

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.

Subtype Diagnosis of Sporadic Creutzfeldt–Jakob Disease with Diffusion Magnetic Resonance Imaging

“…In the longitudinal component of this study, we have shown that signal abnormality on DWI extends to new brain regions in the first 3 months after symptom onset. In a prior cross‐sectional MRI study, we demonstrated that the disease process is first detected in one distinct anatomical region or epicenter, and propagates along different trajectories that are subtype specific in subsequent stages 33 . The present study brings to the fore the impact that the appearance of new DWI hyperintensities associated with distinct stages of the disease may have on MRI diagnostic accuracy.…”

“…The early diagnosis of sCJD subtypes is clinically relevant not only because the subtypes significantly differ as to survival time and lesion propagation in the brain, 33 but also because evidence indicates that subtypes may respond differently to drug treatment 36,37 . This notion implies that, once treatments become available, they may have to be tailored to the sCJD subtype.…”

“…Brain MRIs of patients with suspected prion disease were referred to the National Prion Disease Pathology Surveillance Center (NPDPSC) in Cleveland, Ohio as part of an MRI consultation service program. We considered a cohort of patients with multiple MRI examinations that was collected from January 2003 to April 2020 and has been the object of two recently published studies 27,33 . To select subjects for this study, the following two inclusion criteria were applied: (1) autopsy diagnosis of sCJD with a pure subtype (MM1, MM2, MV1, MV2C, MV2K, VV1, and VV2) and (2) MRI study with at least one positive brain region examined on DWI.…”

Neurons with Cat’s Eyes: A Synthetic Strain of α-Synuclein Fibrils Seeding Neuronal Intranuclear Inclusions

“…Different α-Syn fibril strains [15,[23][24][25][26][27][28] could affect the characteristics of every single step [15,29,30]. Thus, just as different prion strains cause different human disease phenotypes [31], distinct α-Syn fibril strains could be at the origin of PD, DLB and MSA [32].…”

A precise bare simulation approach to the minimization of some distances. Foundations

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