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Original Investigation |

Evolution of Diffusion-Weighted Magnetic Resonance Imaging Signal Abnormality in Sporadic Creutzfeldt-Jakob Disease, With Histopathological Correlation

Laura Eisenmenger, MD1; Marie-Claire Porter, MD2; Christopher J. Carswell, PhD2; Andrew Thompson, PhD2; Simon Mead, PhD2; Peter Rudge, FRCP2; John Collinge, FRS2; Sebastian Brandner, MD, FRCPath2; Hans R. Jäger, MD, FRCR3; Harpreet Hyare, PhD2
[+] Author Affiliations
1Department of Radiology, University of Utah, Salt Lake City
2Medical Research Council Prion Unit, Department of Neurodegenerative Diseases, University College London Institute of Neurology, London, England
3Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, London, England
JAMA Neurol. 2016;73(1):76-84. doi:10.1001/jamaneurol.2015.3159.
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Importance  Prion diseases represent the archetype of brain diseases caused by protein misfolding, with the most common subtype being sporadic Creutzfeldt-Jakob disease (sCJD), a rapidly progressive dementia. Diffusion-weighted imaging (DWI) has emerged as the most sensitive magnetic resonance imaging (MRI) sequence for the diagnosis of sCJD, but few studies have assessed the evolution of MRI signal as the disease progresses.

Objectives  To assess the natural history of the MRI signal abnormalities on DWI in sCJD to improve our understanding of the pathogenesis and to investigate the potential of DWI as a biomarker of disease progression, with histopathological correlation.

Design, Setting, and Participants  Gray matter involvement on DWI was assessed among 37 patients with sCJD in 26 cortical and 5 subcortical subdivisions per hemisphere using a semiquantitative scoring system of 0 to 2 at baseline and follow-up. A total brain score was calculated as the summed scores in the individual regions. In 7 patients, serial mean diffusivity measurements were obtained. Age at baseline MRI, disease duration, atrophy, codon 129 methionine valine polymorphism, Medical Research Council Rating Scale score, and histopathological findings were documented. The study setting was the National Prion Clinic, London, England. All participants had a probable or definite diagnosis of sCJD and had at least 2 MRI studies performed during the course of their illness. The study dates were October 1, 2008 to April 1, 2012. The dates of our analysis were January 19 to April 20, 2012.

Main Outcomes and Measures  Correlation of regional and total brain scores with disease duration.

Results  Among the 37 patients with sCJD in this study there was a significant increase in the number of regions demonstrating signal abnormality during the study period, with 59 of 62 regions showing increased signal intensity (SI) at follow-up, most substantially in the caudate and putamen (P < .001 for both). The increase in the mean (SD) total brain score from 30.2 (17.3) at baseline to 40.5 (20.6) at follow-up (P = .001) correlated with disease duration (r = 0.47, P = .003 at baseline and r = 0.35, P = .03 at follow-up), and the left frontal SI correlated with the degree of spongiosis (r = 0.64, P = .047). Decreased mean diffusivity in the left caudate at follow-up was seen (P < .001). Eight patients demonstrated decreased SI in cortical regions, including the left inferior temporal gyrus and the right lingual gyrus.

Conclusions and Relevance  Magnetic resonance images in sCJD show increased extent and degree of SI on DWI that correlates with disease duration and the degree of spongiosis. Although cortical SI may fluctuate, increased basal ganglia SI is a consistent finding and is due to restricted diffusion. Diffusion-weighted imaging in the basal ganglia may provide a noninvasive biomarker in future therapeutic trials.

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Figure 1.
Anatomical Distribution of Diffusion-Weighted Imaging Signal Intensity at Baseline and Follow-up

Shown are percentages of participants with diffusion-weighted imaging signal intensity of 1 or 2 in each of 31 brain regions at baseline (light blue) and follow-up (dark blue). L indicates left; R, right.aP < .05.

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Figure 2.
Average Signal Intensity in Each Region at Baseline and Follow-up

Shown is the mean signal intensity in each of 31 brain regions at baseline (light blue) and follow-up (dark blue). L indicates left; R, right.aP < .05.

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Figure 3.
Typical Examples of Change in the Extent and Intensity of Signal Abnormality on Diffusion-Weighted Imaging

A-H, Shown are axial diffusion-weighted images in a 66-year-old woman with the codon 129 methionine valine polymorphism. A and B, The left temporo-occipital cortical signal abnormality (A) progresses to bilateral temporo-occipital cortical signal abnormality at follow-up 30 months later (arrowhead) (B). C and D, Signal intensity 0 in the right putamen at baseline (C) progresses to signal intensity 2 (arrowheads) and new right lateral occipital cortical signal abnormality at follow-up (arrow) (D). E and F, Bifrontal and biparietal cortical signal abnormality (E) progresses to increased right superior parietal cortical signal abnormality at follow-up (F). The arrowheads in F indicate increased right superior parietal signal abnormality. Note that the cortical signal abnormality progresses in contiguous cortical areas. G and H, Coronal T1-weighted images show progression of central and parietal atrophy from baseline (G) to follow-up (H). The arrow in H indicates increased central atrophy on follow-up. I and J, Axial diffusion-weighted images in a 60-year-old woman with the codon 129 valine homozygous polymorphism show an increase in caudate and thalamic signal intensity (arrows) from baseline (I) to follow-up 4 months later (J). K-P, Shown are axial diffusion-weighted images in a 53-year-old woman with the codon 129 methionine homozygous polymorphism. K-N, Baseline (K and M) and follow-up (L and N) axial diffusion-weighted images show decrease in cortical signal abnormality in the occipital lobes (arrowheads) at follow-up (L) compared with baseline (K) and decrease in cortical signal abnormality in the parietal lobes (arrowheads) at follow-up (N) compared with baseline (M). O and P, T1-weighted coronal images show progression of central and perisylvian atrophy (arrow) from baseline (O) to follow-up (P).

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Figure 4.
Correlation of Total Brain Score With Disease Duration at Baseline and Follow-up

Scatterplots show positive correlation between baseline total brain score and disease duration and between follow-up total brain score and disease duration.

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Figure 5.
Change in Basal Ganglia Mean Diffusivity Over Time

Symbols represent separate individuals.

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