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. Author manuscript; available in PMC: 2018 Mar 5.
Published in final edited form as: JAMA Neurol. 2016 Jan;73(1):76–84. doi: 10.1001/jamaneurol.2015.3159

Diffusion-weighted MRI signal abnormality in sporadic CJD increases in extent and intensity with disease duration

Laura Eisenmenger 1, Marie-Claire Porter 2, Christopher Carswell 2, Andrew Thompson 2, Simon Mead 2, Peter Rudge 2, John Collinge 2, Rolf Jäger 3, Harpreet Hyare 2
PMCID: PMC5837002  EMSID: EMS76120  PMID: 26569479

Abstract

Importance

Prion diseases represent the archetype of brain diseases caused by protein misfolding, the commonest subtype being sporadic Creutzfeldt-Jakob disease (sCJD), a rapidly progressive dementia. Diffusion weighted iimaging (DWI) has emerged as the most sensitive MRI sequence for the diagnosis of sCJD but few studies have assessed the evolution of these signal abnormalities as the disease progresses.

Objective

The purpose of this study is to assess the natural history of the MRI signal abnormalities on DWI in sCJD in order to improve our understanding of the pathophysiology and to investigate the potential of DWI as a biomarker of disease progression with histopathological correlation.

Design

Grey matter involvement on DWI was assessed in 37 sCJD patients in 26 cortical and 5 subcortical subdivisions per hemisphere using a semi-quantitative scoring system: 0 – 2 at baseline (BL) and follow-up (FU). A total brain score was calculated as a sum of the score in each individual region. In 7 patients serial mean diffusivity (MD) measurements were obtained. Atrophy, age, disease duration, codon 129 and MRC Rating Scale were documented.

Setting

National Referral Centre.

Participants

All participants had a probable or definite diagnosis of sCJD and had at least two MRI studies during the course of the illness.

Exposure for Observational Studies

Not applicable.

Main Outcome Measure

Correlation of regional and total brain score with disease duration.

Results

Significant increase in number of regions demonstrating signal abnormality was seen: 28.0±12.6 at FU versus 21.8±10.76 at BL, p=0.001. 59 of the 62 regions showed increase in signal intensity (SI) on FU, most significantly in the caudate and putamen, p<0.001. Increase in average total brain score from 30.2±7.3 BL to 40.5±20.6 FU, p=0.001 correlated with disease duration and left frontal SI correlated with degree of spongiosis. Decreased MD in the left caudate and putamen on FU was seen, p<0.001. 8 patients showed decreased SI in cortical regions: left inferior temporal and right lingual gyrus.

Conclusion and Relevance

MRIs in sCJD show increased extent and degree of SI on DWI that correlates with disease duration and degree of spongiosis. Although cortical SI may fluctuate, increased basal ganglia SI is a consistent finding and is due to restricted diffusion. DWI in the basal ganglia may provide a non-invasive biomarker in future therapeutic trials.

Introduction

DWI has emerged as the most sensitive MR sequence of the diagnosis of sCJD (1–3) with many studies showing its superiority for detecting signal change in the cortex (4–6). Visual inspection of the trace-weighted diffusion image demonstrates typically increased signal intensity in the cortex with up to 95% of cases showing hyperintensity affecting the insula, cingulate and superior frontal cortex, independently of deep grey matter involvement (3). The extent of involvement and the distribution of signal changes varies amongst patients, thought to be influenced by PRNP genotype and PrPSc strain type (7, 8). However, few studies have assessed the evolution of these signal abnormalities as the disease progresses.

In the largest series of 8 CJD patients with serial DWI, there was progression or constant lesion distribution with increased signal intensity in some lesions and decreased signal intensity in others. In 5 of the 8 patients, a defined temporal sequence of events has been reported where high signal starts in the anteroinferior putamen and spreads to its posterior part, leading to complete involvement of the putamen (9). There is one report of initial expansion of the signal changes but resolution of the cortical signal change with general progression to cerebral atrophy at later stages of the disease (10) and there are two further reports of disappearance of diffusion signal changes at terminal stages of the disease (11, 12).

The purpose of this study is to establish the natural history of the DWI MRI signal abnormalities in patients with sCJD in order to better understand the pathophysiology of the disease and to develop a non-invasive measure of disease progression for future therapeutic trials. Our hypothesis is that the extent and degree of signal intensity increases with disease progression.

Methods

Subjects

In 2004 the Chief Medical Officer wrote to UK neurologists requesting that all patients with suspected CJD are referred to both the National CJD Surveillance Unit in Edinburgh and the National Prion Clinic (NPC) based at the National Hospital for Neurology and Neurosurgery (NHNN), London. MR images of all visited patients are sent to NPC in digital format. The MR images studied in this work were from patients who were referred to the NPC by their local physician with full consent and the patients were enrolled into either the clinical trial PRION-1 or the on-going National Prion Monitoring Cohort study. Both studies were approved by the Eastern Medical Research Ethics Committee and are compliant with the Helsinki Declaration.

We identified 37 consecutive subjects, where at least two serial MRI studies were performed with inclusion of DWI sequence at each study (14 female, mean age 65.3 years, range 39-85 years). In 4 subjects where multiple serial MRI studies were obtained (number of studies: 3,3,3,4 respectively), the initial baseline (BL) and last available follow-up (FU) MRI scans only were included for analysis. The average time between MRI studies was 3.6 months (range 0.5 – 29 months). 30 of the patients had their MRI studies performed at the referring hospital and 7 of the patients had their MRI study performed at our institution. All the external DWI studies were performed at either 1.5T or 3T with a b value of 1000. Slight differences in slice thickness were seen, varying from 3-5mm. The average disease duration at initial MRI was 5.7 months. All patients had a clinical diagnosis of sCJD based on the WHO classification, confirmed by post-mortem which was performed in 21 of the cases (56.7%). Details of the autopsy findings can be seen in eTable 1). The remaining cases were diagnosed as probable sCJD according to accepted diagnostic criteria (13). In all subjects, age, disease duration, PRNP mutation analysis and codon 129 status and clinical evaluation according to the MRC Rating Scale (14) were documented.

MRI acquisition

7 patients were imaged at our institution, of which 3 were imaged a 3T (Siemens Tim Trio) and 4 patients at 1.5T (GE Signa LX) MRI systems. For these patients, both the baseline and follow up MRI studies were performed on the same MRI scanner. The 3T Diffusion Tensor Imaging (DTI) sequence consisted of, 75 slices of thickness 2.0mm with b value = 1000s/mm2 in 64 non-colinear directions were collected (TR/TE 9500/93ms, FoV (19.2cm2), matrix 96x96, 1 average) with 8 images with b value = 0s/mm2. The diffusion trace-weighted image and the corresponding Mean Diffusivity (MD) map were generated by the scanner. At 1.5T, DWI was performed using a single-shot echo-planar technique (TE 101ms, TR 10000ms, one average, matrix 96 x 128, FOV 26 x 26cm, slice thickness 5mm) with diffusion-weighting factors (‘b values’) of 0 and 1000 sec/mm2 applied sequentially along three orthogonal axes.

MRI visual assessment

Signal Intensity

Two neuroradiologists (reader 1, 9 years experience; reader 2, 25 years experience in prion imaging) independently reviewed all MRI sequences. The readers were aware of the clinical diagnosis of sCJD in all patients: either post-mortem confirmed or classified as probable cases according to accepted diagnostic criteria (13). All images were viewed digitally on an Agfa PACS work station with facilities for appropriate windowing and signal intensity measurements. Any MRI studies performed externally were uploaded onto our in-house PACS workstation and were windowed to appear as similar as possible. The grey matter (GM) involvement on the diffusion-weighted trace image was reported according to 26 cortical and 5 subcortical subdivisions per hemisphere (15). Where a discrepancy was identified, the images were re-reviewed in a consensus reading. A kappa statistic was calculated to assess the level of agreement between the 2 independent observers.

We used a semi-quantitative scoring system which was devised on 5 test cases by drawing a region of interest (ROI) in normal appearing white matter (WM) and comparing the average signal intensity in several cortical GM regions visually thought to be normal, mildy hyperintense and clearly hyperintense. The following semi-quantitative scoring system was found to be robust: 0 not involved, the signal intensity (SI) is within 2 standard deviations of the white matter (WM) SI; 1 mildly hyperintense, the SI ≥ 2 standard deviations above WM SI but < 2 x WM SI; 2 clearly hyperintense, the SI > 2 x WM SI (eFigure 1). In order to distinguish DWI cortical ribboning artifact from true cortical signal abnormality, the Mean Diffusivity (MD) map was examined in conjunction with the DWI image to identify corresponding areas of hypointensity. A total brain score was calculated as a sum of the score in each individual region (31 regions per hemisphere), the maximum total brain score being 124. The aim was to assess both the extent and intensity of signal abnormality in a particular MRI scan. A cortical score was also calculated as the sum of all the 52 cortical regions and a subcortical score was calculated as a sum of the 10 subcortical regions.

Volume loss

Temporal lobe, parietal lobe and generalised cortical atrophy were individually assessed on each study according to established criteria (16, 17): 0 normal; 1 mild atrophy; 2 moderate atrophy; 3 severe atrophy.

Quantitative assessment

Pixel-by-pixel MD maps were generated from the directionally-averaged b=0 and b=1000 sec/mm2 images using the Stejskal Tanner equation (18) for MD calculation: MD =-{In(S1/S2)/(b1-b2)}, where S1 and S2 are the signal intensities of diffusion-weighted images with b-factors of 0 (b1) and 1000 sec/mm2 (b2), respectively. The mean MD in 3 regions of interest (ROI) were drawn on the left cerebral hemisphere of the axial b0 image in the head of the left caudate nucleus, left putamen and frontal white matter (volume 587-597 mm3). The ROI-average from each of the corresponding MD maps was recorded.

Statistical analysis

To assess change in signal intensity from baseline to follow up in a particular anatomical area, the Wilcoxon Signed Rank test was performed. As 65 comparisons were performed, the p-values were adjusted to ≤ 0.001 for statistical significance. To assess correlation of total brain score with disease duration, age at baseline MRI, MRC rating scale and atrophy, a Spearman Rank correlation was performed. Finally, to assess change in MD between baseline and follow-up the Wilcoxon Signed Rank test was performed.

Quantitative Histopathological analysis

Of the patients who underwent autopsy, left frontal lobe sections were acquired from 8 subjects for quantitative analysis of the degree of spongiosis, calculated as the number of vacuoles per cm2. Prior to analysis all slides were reviewed by an experienced neuropathologist (ZJ). For quality control purposes, slides that were found to be of poor quality such as those that were inadequately stained or damaged, were replaced with newly acquired ones.

The slides were scanned into Leica slidepath and then loaded into the Definiens workspace. A region of interest (ROI) was manually selected free from artifact and drawn with the guidance of ZJ. An analysis builder was used to: (i) define the magnification strength of 10x, (ii) apply a background to tissue separation in order for the analysis to be confined purely to the brain tissue, (iii) select the layer of tissue being analysed (iv) apply homogeneity/brightness thresholds, (v) select the stain being analysed e.g. H&E, (vi) apply a stain threshold; objects below and above a specific contrast intensity can then be de-selected from the analysis. Additional inclusions/exclusions were applied for the purposes of determining the degree of vacuolation present, these included: (i) exclusion of “vacuoles” in close proximity to both nuclei and blood vessels, (ii) The exclusion of vacuoles under 3 microns in diameter, (iii) vacuoles with a width over x3 the length. The degree of spongiosis was correlated with disease duration at death and signal intensity in left frontal cortex on MRI using the Spearman Rank correlation coefficient.

Results

Consensus Review

On initial analysis there was a disagreement in 3 patients, where there was a discrepancy in score in cortical regions, kappa score 0.835. These images were re-reviewed by consensus and agreement reached.

Baseline analysis

Anatomical regions

The most common cortical region to show signal abnormality on the baseline studies (SI 1 or 2) was the posterior cingulate gyrus with slight asymmetry: 75.9% involvement on the left and 72.4% on the right. The next most commonly involved region was the anterior cingulate gyrus: left, 68.7%; right 65.5% followed by the left superior frontal gyrus which showed signal abnormality in 65.5% of patients. The area least likely to be involved was the hippocampus and amygdala. The average number of anatomical regions involved at baseline was 21.8 ± 10.76 out of 64 regions with slight asymmetry which was not significant: 11.19 ± 5.79 regions in the left hemisphere and 10.59 ± 6.33 regions in the right hemisphere. Please see Figure 1.

Figure 1. Anatomical distribution of DWI signal intensity at baseline and follow up.

Figure 1

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Percentage of subjects with DWI signal intensity of either 1 or 2 in each of the 31 brain regions at baseline (grey) and follow-up (black).

Signal intensity

The greatest SI on the baseline studies were seen in the anterior cingulate gyrus (right 1.0 ± 0.85; left 1.0 ± 0.78) and posterior cingulate gyrus (right 0.95 ± 0.85; left 0.95 ± 0.78) followed by the caudate nucleus (right 0.84 ± 0.76; left 0.89 ± 0.77) and left superior frontal gyrus (0.84 ± 0.73) (Figure 2, eTable2). The least signal intensity was seen in the precentral gyrus, hippocampus and amygdala and the globus pallidus.

Figure 2. Average signal intensity in each region at baseline and follow up.

Figure 2

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Average signal intensity in each of the 31 brain regions at baseline (grey) and follow-up (black).

Volume loss

Frontal volume loss was most often seen with an average score of 0.89 ± 0.62, followed by parietal volume loss with an average score of 0.76 ± 0.89. The average global atrophy score of 0.54 ± 0.77 was next most common with mesio-temporal lobe atrophy rarely seen (average score 0.16 ± 0.55).

Follow up MRIs

Anatomical regions

There was a significant increase in number of anatomical regions demonstrating signal abnormality on the follow up studies: 28.0 ± 12.6 versus 21.8 ± 10.76 at baseline, p=0.001; right 14.2 ± 7.0, p<0.001; left 13.8 ± 6.8, p=0.004. Figure 3 A-D demonstrate the increase in extent of cortical signal abnormality in follow up studies.

Figure 3. Typical examples of change in extent and intensity of signal abnormality on DWI.

Figure 3

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Axial diffusion-weighted images in a 66 year old female, codon 129MV, with (A) left temporo-occipital cortical signal abnormality progressing to (B) bilateral temporo-occipital cortical signal abnormality on follow-up 30 months later (arrow), (C) SI 0 in right putamen at baseline progresses to (D) SI 2 in (arrow) and new right lateral occipital cortical signal abnormality on follow-up, (E) bifrontal and biparietal cortical signal abnormality progresses to (F) increased right superior parietal cortical signal abnormality on follow-up. Note that the cortical signal abnormality progresses in contiguous cortical areas. In the same patient, coronal T1-weighted images show progression of central and parietal atrophy from baseline (G) to follow-up (H). Axial diffusion-weighted images in 60 year old female with codon 129 VV showing increase in caudate and thalamic SI (arrows) from baseline (I) to follow up (J) 4 months later. Baseline (K and M) and follow-up (L and N) axial diffusion-weighted images in a 53 year old female codon 129MM showing decrease in cortical signal abnormality in the occipital lobes (arrows) on follow-up (L) compared to baseline (K) and decrease in cortical signal abnormality in the parietal lobes (arrows) on follow-up (N) compared to follow-up (M). T1-weighted coronal images, in the same patient, showing progression of central and perisylvian atrophy (arrows) from baseline (O) to follow-up (P).

Signal Intensity

On average 59 of the 62 regions showed an increase in SI on the follow up study. The regions that showed the greatest increase in signal intensity were the caudate (baseline right 0.84 ± 0.76 versus follow-up right 1.35 ± 0.77, p<0.001; baseline left 0.89 ± 0.77 versus follow-up left 1.38 ± 0.72, p<0.001) and putamen (baseline right 0.62 ± 0.64 versus follow up right 1.11 ± 0.74, p<0.001; baseline left 0.70 ± 0.71 versus left 1.19 ± 0.70, p<0.001; Figure 2 and eTable 2). Examples of this increase in basal ganglia signal intensity can be seen in Figure 3 D and J. The right inferior frontal gyrus showed the next largest increase in SI (Figure 2). The left middle temporal gyrus remained stable in signal intensity on follow up (Figure 2).

Volume loss

There was an increase in all the atrophy scores on the follow up studies (frontal 0.92 ± 0.76, global 0.76 ± 0.86, parietal 0.89 ± 0.97 and mesiotemporal 0.35 ± 0.72), with the most significant increase in global atrophy (p=0.009), Figure 3 H and P.

Total brain score

29 of the 37 patients showed an increase in total brain score on follow up MRI. On average, there was an increase in total brain score from 30.2 ± 17.3 to 40.5 ± 20.6, p=0.001 due to an increase in cortical Si (26.0 ± 19.1 to 35.3 ± 22.2, p=0.005 and subcortical SI (4.46 ±.3.95 to 6.5 ± 4.27, p=0.008). There was a positive correlation between baseline and follow up total brain score and disease duration (Figure 4) but no correlation between total brain score and age at baseline MRI, MRC rating scale or atrophy (data not shown).

Figure 4. Correlation of total brain score with disease duration at baseline and follow up.

Figure 4

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Scatter plots showing positive correlation between baseline total brain score and disease duration (A) Spearman rank correlation =0.422 and follow up total brain score and disease duration (B) Spearman rank correlation =0.409.

The remaining 8 patients showed a decrease in total brain score on the follow up study due to a decrease in signal intensity in cortical regions (35.1 to 25.0, 29% decrease) but not subcortical regions (2.8 to 5.9, 53% increase) (Figure 3 K-P). When we compared the patients that showed a decrease in total brain score to those that showed an increase in total brain score on follow up, we found a slight increase in global atrophy scores (0.79 ± 0.92 versus 0.71±0.77) and an increase in patients with the codon 129MV mutation (50% of patients in the group that showed decrease in total brain score had codon 129MV polymorphism compared to 25% of patients in the group that showed an increase in total brain score.) but this did not reach statistical significance. No significant difference was also found in terms of disease duration, time to death, age or MRC rating scale.

Mean Diffusivity

In the seven patients imaged at our institution, serial measurements of MD showed a significant decrease in MD values in the left caudate and left putamen on the follow up studies compared to the baseline studies (Figure 5). The average left caudate mean diffusivity was 646.1 ± 99.5 x 10-3 mm2/s at baseline compared to 591.1 ± 89.7 10-3 mm2/s on follow up; p=<0.001. The average left putamen mean diffusivity was 591.1 ± 123.6 10-3 mm2/s at baseline versus 531.2 ± 99.0 10-3 mm2/s on follow up; p=0.05. However no significant difference was seen for the frontal white matter.

Figure 5. Change in basal ganglia mean diffusivity with time.

Figure 5

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Line graphs showing the change in left caudate mean diffusivity (A) and left putamen mean diffusivity (B) with time. Symbols represent separate subjects.

Quantitative histopathological correlation

For clinical details of the 8 patients that underwent quantitative histopathological analysis, please see supplementary Table 1. There was a significant correlation between left frontal MRI signal intensity and number of vacuoles per cm2 in the left frontal cortex, r=0.64, eFigure 2A. There was also a significant correlation between disease duration at death and number of vacuoles per cm2 in the left frontal cortex, r=0.65, eFigure 2B.

Discussion

This is the largest study to describe the evolution of MRI signal abnormality on diffusion-weighted imaging in patients diagnosed with sporadic CJD with histopathological correlation. We have shown that disease progression is accompanied by an increase in both extent and intensity of signal abnormality. The basal ganglia show a consistent and the most significant increase in signal intensity as disease progresses. Measurements of the mean diffusivity performed in a subgroup show that the signal increase on the trace-weighted DWI images suggests restriction of water diffusion. In the vast majority of patients disease progression is also associated with an increase of cortical signal abnormalities which correlate with severity of spongiosis. However in some patients, we have seen a decrease in extent and intensity of cortical signal abnormality which is a potential pitfall that clinicians should be made aware of.

Although the distribution of cortical and subcortical signal abnormality in sCJD has been well characterised in large cohorts (2, 4–6, 15, 19), few studies have examined the evolution of signal abnormality in sCJD. In the largest series of 8 patients with serial imaging (9), striatal involvement was seen in 7 of the 8 patients on the final study. In another report of serial MRIs in 6 patients with sCJD, 3 of 5 patients with only cortical lesions seen on the initial study progressed to basal ganglia involvement and increased cortical involvement on the subsequent studies (20). In a further single case report, increased basal ganglia and thalamic signal abnormality was seen on the third MRI at 9 months (21). In our study, the caudate and putamen were the most commonly involved subcortical regions and showed the greatest signal intensity on the follow up study.

Involvement of the thalamus and striatum are well established in sCJD (22). The putamen and caudate nuclei receive input from diverse cortical areas, including prefrontal and limbic structures with non-motor output from the striatum projecting via the mediodorsal and ventrolateral thalamic nuclei to the dorsolateral prefrontal cortex, lateral orbitofrontal cortex and the anterior cingulate (19). These subcortical structures appear to be increasingly involved as disease progresses in sCJD, perhaps reflecting the increased cortical involvement with disease duration as demonstrated in this study.

DWI hyperintensity is thought to be due to a combination of diffusion restriction and T2 prolongation. Studies that have measured MD in sCJD, have shown decreased MD in the caudate, putamen and thalamus (12, 23, 24). Longitudinal MD measurements in sCJD have demonstrated conflicting reports with one study reporting decreased MD in the striatum over two weeks (9) and other reports of an increase in basal ganglia MD values with time, suggesting that MD may vary according to the stage of disease (12, 25). We found a significant decrease in MD the caudate and putamen on follow up in all the patients with sCJD that had serial imaging at our institution. Some of the changes in individual patients were modest, whilst other patients demonstrated more rapid change. Severe spongiform change causing cell swelling and restricting the extracellular space has been advocated as a potential cause of decreased mean diffusivity (26, 27) and it is likely that increased spongiform change as disease progresses reduces MD in the subcortical structures even further.

The distribution of cortical signal abnormality in our study is in line with previous reports where frontal, limbic and parietal lobes are predominantly involved with relative sparing of the precentral and central gyri (2, 3, 15). These cortical signal changes correspond anatomically to the prominent cognitive features of memory loss and frontal executive dysfunction seen in prion diseases (28), although subcortical circuits are likely to be involved. We found that not only were these cortical regions most commonly involved with the highest signal intensity at baseline, these regions all showed an increase in extent and signal intensity over time. The degree of signal intensity in the left frontal cortex correlated with degree of spongiosis.

Increase in extent of cortical signal abnormality with disease progression has previously been reported in sCJD (9–11). In 6 cases where DWI signal abnormality was seen in the cortex on the early scan, in 2 of the cases, the cortical signal progressed from asymmetrical to symmetrical abnormalities on the follow up study (11). In another single case report, cortical signal abnormality had progressed from cingulate, calcarine and left temporal cortex involvement to also include the left temporo-parietal cortex on the follow up study 3 months later (10). We have shown that not only is there on average an increase in extent of cortical signal abnormality as disease progresses in a large cohort of sCJD patients, we also describe an increase in the degree of signal intensity in specific cortical brain regions, the inferior frontal gyrus being the cortical region showing the largest increase in SI on follow up studies. The combination of increase in extent and degree of signal intensity, as captured in the total brain score, correlates with disease duration. If severe spongiform change is the basis of the DWI signal (25, 29, 30), it is likely that the increase in total brain score reflects increased spongiform degeneration in grey matter structures as the disease progresses, as shown by the increase in severity of spongiosis in the left frontal cortex that correlates with MRI signal intensity.

The majority of patients had an increase in total brain score on the follow up MRI, but we observed a decrease in total brain score in 8 of our patients. The decrease was due to decreased cortical SI but not subcortical SI and the areas that showed the greatest decrease were the left inferior temporal gyrus and right lingual gyrus. The disappearance or decreased conspicuity of DWI cortical signal has been previously reported in the literature and attributed anecdotally to increased atrophy at the end stage of disease (10, 11). Our observations in a larger cohort of patients confirm the dynamic nature of the cortical DWI signal abnormality in sCJD. We noted a slightly higher atrophy score on the follow up MRI study in patients where cortical signal abnormality decreased, but this did not reach statistical significance, possible due to the small number of patients in the cohort. It is likely that as the disease progresses, neuronal death and gloss causes augmentation of the extracellular space with increased diffusion and decreased DWI signal abnormality before there is frank atrophy.

In the 8 patients with decreased cortical signal abnormality on follow up, we also found a higher proportion of patients who were heterozygote at codon 129. Although the numbers are small and this needs to be confirmed in a larger cohort, it is known that patterns of MRI signal abnormality in sCJD are influenced by codon 129 status (7). It is therefore possible that evolution of the signal abnormality is also influenced by codon 129 status, reflecting the known longer disease duration (31).

Limitations of the study include the subjective nature of the semi-quantitative MRI analysis, MRI studies performed of different MRI scanners which differed in scan parameters and field strength and MRI readers having knowledge of the diagnosis. Viewing all the images on an off line workstation with appropriate windowing was performed to limit these variables. The small number of patients included in the quantitative histopathological analysis is also a potential limitation. The study needs to be repeated in a larger cohort with more extensive quantitative histopathological and MRI correlation.

Conclusion

Patients diagnosed with sCJD show an increase in extent and degree of signal abnormality in cortical and subcortical regions that correlates with disease duration and degree of spongiosis. Although cortical signal abnormality may fluctuate, increase in basal ganglia signal intensity was a consistent finding that was due to an increase in restriction of diffusion. Diffusion abnormalities in the basal ganglia in sCJD may provide a non-invasive biomarker of disease severity for future therapeutic trials, which needs to be confirmed in larger studies.

Supplementary Material

6

Acknowledgements

This work was supported by the department of health (England) through funding of the National Prion Monitoring Cohort. Some of this work was undertaken at University College London Hospitals/University College London, which received a proportion of funding from the National Institute for Health Research Comprehensive Biomedical Research Centres funding scheme.

Footnotes

Authors contributions:

Laura Eisenmenger: substantial contributions to acquisition, analysis, and interpretation of data for the work and drafting of the work.

Marie-Claire Porter: substantial contributions to the acquisition, analysis, and interpretation of data for the work.

Christopher Carswell: substantial contributions to acquisition and analysis of the work.

Andrew Thompson: substantial contributions to the acquisition and analysis of the work.

Simon Mead: substantial contributions to conception, interpretation of data for the work and drafting of the work.

Peter Rudge: substantial contributions to interpretation of data for the work and revising it critically for important intellectual content.

John Collinge: substantial contributions to interpretation of data for the work and revising it critically for important intellectual content.

Rolf Jäger: substantial contributions to conception or design of the work, drafting of the work and revising it critically for important intellectual content.

Harpreet Hyare: substantial contributions to conception, design of the work, acquisition, analysis, interpretation of data for the work and drafting of the work.

Conflict of Interest Disclosures:

Laura Eisenmenger: no disclosures.

Marie-Claire Porter: no disclosures.

Christopher Carswell: no disclosures.l

Andrew Thompson: no disclosures.

Simon Mead: no disclosures.

Peter Rudge: no disclosures.

John Collinge: Prof John Collinge serves on the editorial boards of Neurobiology of Disease, Journal of Neurobiology, Neurogenetics and Neurodegenerative Disease Management; is a director and shareholder of D-Gen Ltd., an academic spin-out company working in the field of prion disease diagnosis, decontamination, and therapeutics; and receives research support from the UK Medical Research Council, the National Institute for Health Research (England), and the Wolfson Foundation.

Rolf Jäger: no disclosures.

Harpreet Hyare: no disclosures.

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