Selective vulnerability to atrophy in sporadic Creutzfeldt‐Jakob disease

Abstract

Objective: Identification of brain regions susceptible to quantifiable atrophy in sporadic Creutzfeldt-Jakob disease (sCJD) should allow for improved understanding of disease pathophysiology and development of structural biomarkers that might be useful in future treatment trials. Although brain atrophy is not usually present by visual assessment of MRIs in sCJD, we assessed whether using voxel-based morphometry (VBM) can detect group-wise brain atrophy in sCJD. Methods: 3T brain MRI data were analyzed with VBM in 22 sCJD participants and 26 age-matched controls. Analyses included relationships of regional brain volumes with major clinical variables and dichotomization of the cohort according to expected disease duration based on prion molecular classification (i.e., short-duration/Fast-progressors (MM1, MV1, and VV2) vs. long-duration/ Slow-progressors (MV2, VV1, and MM2)). Structural equation modeling (SEM) was used to assess network-level interactions of atrophy between specific brain regions. Results: sCJD showed selective atrophy in cortical and subcortical regions overlapping with all but one region of the default mode network (DMN) and the insulae, thalami, and right occipital lobe. SEM showed that the effective connectivity model fit in sCJD but not controls. The presence of visual hallucinations correlated with right fusiform, bilateral thalami, and medial orbitofrontal atrophy. Interestingly, brain atrophy was present in both Fast-and Slow-progressors. Worse cognition was associated with bilateral mesial frontal, insular, temporal pole, thalamus, and cerebellum atrophy. Interpretation: Brain atrophy in sCJD preferentially affects specific cortical and subcortical regions, with an effective connectivity model showing strength and directionality between regions. Brain atrophy is present in Fast-and Slow-progressors, correlates with clinical findings, and is a potential biomarker in sCJD.

Default Mode Network quantitative diffusion and resting‐state functional magnetic resonance imaging correlates in sporadic Creutzfeldt‐Jakob disease

“…For the first time, we identified abnormally increased functional connectivity at rest in sCJD, both in the dorsal and ventral components of the DMN. Our multimodal analysis corroborates our atrophy‐based hypothesis that DMN areas are particularly vulnerable in sCJD (Younes et al, 2021 ).…”

“…Visual and quantitative assessments of diffusivity abnormalities in sCJD, although heterogeneous, generally show prominent involvement of the anterior cingulate, parieto-angular, retrosplenial, and middle temporal cortices Vitali et al, 2011) areas that are part of the Default Mode Network (DMN) (Alves et al, 2019;Buckner et al, 2008;Leech & Sharp, 2014). In a recent voxel-based morphometry study, we found selective atrophy in almost all regions part of DMN, further suggesting that DMN network could be a preferential site of involvement in prion disease (Younes et al, 2021).…”

PRNP expression predicts imaging findings in sporadic Creutzfeldt‐Jakob disease

“…It has recently been suggested that such propagation in neurodegenerative proteinopathies may involve trans‐neuronal spread of misfolded protein between interconnected brain regions and may therefore be spatially constrained by structural connectivity across the brain 36,44 . Whether because of increased susceptibility to PrP C misfolding, increased PrP Sc propagation, or increased vulnerability to PrP Sc related neuronal damage, our findings suggest that brain regions that show correlated levels of PRNP expression also define networks that have selective vulnerability to CJD pathology 45 …”

“…36,44 Whether because of increased susceptibility to PrP C misfolding, increased PrP Sc propagation, or increased vulnerability to PrP Sc related neuronal damage, our findings suggest that brain regions that show correlated levels of PRNP expression also define networks that have selective vulnerability to CJD pathology. 45 Our overall findings point to the importance of regional expression of PRNP in forming the genetic landscape on which the pathobiology of sCJD unfolds and raises the possibility that multiple genetic or environmental factors may be important in determining the regional characteristics of different sCJD subtypes. Currently, the specifics of these other factors are unknown.…”

Case report: Two clusters of Creutzfeldt–Jakob disease cases within 1 year in West Michigan

“…The sensitivity of RT-QuIC for detecting MM1 and VV2 is high (96.3%) but can be negative for MM2 and VV1 subtypes ( 33 , 42 ). Younes et al reported that MM1, MV1, and VV2 are related to short duration/fast progression, while MV2, VV1, and MM2 are associated with long duration/slow progression ( 43 ). Our case series revealed that patients 3 and 4 were sCJD-MM1 but with an 8-month difference in survival length; patients 1 and 5 were diagnosed with sCJD-VV2 with similar survival durations, 8 vs. 6 months.…”