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Human Prion Diseases
Human Prion Diseases H Hyare, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK T Yousry, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, London, UK ã 2015 Elsevier Inc. All rights reserved.
Abbreviations ADC DWI FA FDG FLAIR GSS hGH CJD IPD M MD
Apparent diffusion coefficient Diffusion-weighted imaging Fractional anisotropy Fluorodeoxyglucose Fluid attenuation inversion recovery Gerstmann–Stra¨ussler–Scheinker disease Human growth hormone Creutzfeldt–Jakob disease Inherited prion disease Methionine Mean diffusivity
Introduction With the routine clinical use of diffusion-weighted imaging (DWI), magnetic resonance imaging (MRI) has gained increasing importance in the diagnosis of human prion diseases (Kallenberg et al., 2006; Murata, Shiga, Higano, Takahashi, & Mugikura, 2002; Shiga et al., 2004; Tschampa et al., 2005; Young et al., 2005). For some time, MRI studies have been included in the WHO diagnostic criteria for variant Creutzfeldt–Jakob disease (vCJD) (Will et al., 2000), but with the emergence of DWI as the most sensitive sequence for the diagnosis of sporadic CJD (sCJD) (Kallenberg et al., 2006), it is now proposed that MRI studies also be included in the WHO diagnostic criteria for sCJD (Zerr et al., 2009). The presence of characteristic MRI signal abnormality in human prion diseases is unique across neurodegeneration. However, these characteristic MRI findings are not always identified on initial scan at the referring hospital (Carswell et al., 2012). This article highlights the typical MRI findings in all forms of human prion diseases with an emphasis on recent technical advances in the field.
Prion Pathophysiology Human prion diseases are a group of rare neurodegenerative conditions characterized by template misfolding of the normal cellular prion protein (PrPc) into abnormal disease-associated forms generally referred to as PrPSc (Prusiner, 1991). PrPc is a glycoprotein consisting of an N-terminal region and a C-terminal domain. The N-terminal unstructured region contains five repeats of eight amino acid sequence (the octapeptide region), and mutations in this region can lead to forms of inherited prion disease (IPD) (Collinge, 2005). In this region, there are two tight binding sites for Cu ions, suggesting a role for PrP in copper metabolism or transport (Riek et al., 1996).
Brain Mapping: An Encyclopedic Reference
MRI MTR PET PiB PRNP PrPc PrPSc sCJD V VBM vCJD
Magnetic resonance imaging Magnetization transfer ratio Positron-emission tomography Pittsburgh compound B Prion protein gene Normal prion protein Abnormal disease-associated form of prion protein Sporadic Creutzfeldt–Jakob disease Valine Voxel-based morphometry Variant Creutzfeldt–Jakob disease
Disturbance of this function could be involved in prion-related neurotoxicity. The remainder of the molecule has three helices joined by b-pleated areas. Human prion diseases have been traditionally classified on clinical grounds into Creutzfeldt–Jakob disease (CJD), Gerstmann–Stra¨ussler–Scheinker disease (GSS), and Kuru but can also be classified as occurring in inherited, sporadic, and acquired forms with subclassification according to molecular criteria. IPDs comprise 15% of recognized prion disease and are associated with 1 of the more than 30 recognized coding mutations in the PRNP gene (Mead, 2006). Kindreds with IPD have been described with the phenotypes of classical CJD and GSS and with other clinicopathologic syndromes including familial fatal insomnia (FFI) (Figure 1). sCJD makes up 85% of all recognized human prion diseases and occurs in all countries with an apparently random distribution and annual incidence of 1–2 per million. Possible causes are spontaneous production of PrPSc via rare stochastic events, somatic mutation of PRNP, or unidentified environmental exposure. There is a marked genetic susceptibility with most cases occurring in homozygotes of methionine (M) or valine (V) at codon 129 of the PRNP gene. MV heterozygotes appear to be relatively protected from developing sCJD (Palmer, Dryden, Hughes, & Collinge, 1991). Acquired prion diseases include iatrogenic CJD, Kuru, and vCJD. Iatrogenic exposure occurs through accidental exposure to human prions through medical or surgical procedures, most frequently through implantation of dural grafts or through administration of growth hormone derived from the pituitary glands of human cadavers (Brown, Preece, & Will, 1992). Kuru arose from exposure to prions during cannibalistic mortuary feasts. vCJD has been shown through strain-typing studies and transmission studies in transgenic mice to be caused by the same prion strain as that causing bovine spongiform encephalopathy (Hill et al., 1997).
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Magnetic Resonance Imaging Sporadic Creutzfeldt–Jakob Disease DWI has emerged as the most sensitive sequence of the diagnosis of sCJD (Kallenberg et al., 2006; Tschampa et al., 2007; Young et al., 2005) with many studies showing that it is the best sequence for detecting signal change in the cortex (Kropp, Finkenstaedt, Zerr, Schroter, & Poser, 2000; Matoba, Tonami, Miyaji, Yokota, & Yamamoto, 2001; Shiga et al., 2004). Visual inspection of the diffusion-weighted trace image demonstrates typically increased signal intensity in the cortex with up to 95% of cases showing hyperintensity affecting the insula, cingulate,
Glycans
Helix 1
Helix 2
Membrane anchor Figure 1 Model of the C-terminal domain of human prion protein indicating positions of the a-helices and carbohydrate and the membrane anchor, which attaches the protein to the outer surface of the cell membrane.
and superior frontal cortex independently of deep gray matter involvement (Tschampa et al., 2007). DWI is superior to fluid attenuation inversion recovery (FLAIR) for detecting cortical signal intensity, and this has been shown to correlate with lateralized clinical and electroencephalograph abnormalities (Cambier, Kantarci, Worrell, Westmoreland, & Aksamit, 2003). Increased signal in the striatum, in the cortex, and to a lesser extent in the thalamus is the classical finding in sCJD (Figure 2). The extent of involvement and the distribution of signal changes vary among patients, thought to be influenced by the PRNP genotype and PrPSc strain type (Fukushima et al., 2004; Hamaguchi et al., 2005). In 40 patients with sCJD, the combination of signal changes in the cortex and deep gray matter occurred in 68% of subjects, while involvement of the cortex alone was less common (24%) and high signal in the deep gray matter without cortical signal change was extremely rare (5%). The cortical signal changes involve all lobes, mainly the frontal (89%), limbic (79%), parietal (72%), and temporal (65%), while the precentral and central gyri are usually spared (Young et al., 2005). A recent study of 48 cases of sCJD reported a sensitivity of 98% and sensitivity of 93% using DWI and FLAIR MRI, respectively, after consensus review, higher than those of any other diagnostic test (Vitali et al., 2011). The authors identified four distinguishing MRI features: Cortical hyperintensity on DWI is greater than FLAIR; subcortical areas hyperintense on DWI are hypointense on apparent diffusion coefficient (ADC); isolated limbic involvement is not seen; and characteristic patterns of gray matter involvement are seen affecting the precuneus and cingulate, angular, parahippocampal, and superior and middle frontal gyri and caudate in 50% of sCJD cases. The temporal sequence of signal abnormality in sCJD has been studied by a few authors. A defined temporal sequence of events has been reported where high signal starts in the anteroinferior putamen and spreads to the posterior part, leading to complete involvement of the putamen (Murata et al., 2002). There is one report of expansion of the signal changes and general progression to cerebral atrophy (Tribl et al., 2002), and there are two reports of disappearance of diffusion signal
Figure 2 DWI trace-weighted images demonstrating the variable pattern of hyperintensity in sCJD ranging from (a) the classical appearance of diffuse cortical and basal ganglia signal change, to (b) cortical signal change only (which can be asymmetrical), to (c) additional hyperintensity in the thalamus (arrow).
INTRODUCTION TO CLINICAL BRAIN MAPPING | Human Prion Diseases
changes (Tschampa et al., 2003; Ukisu et al., 2005). In the end stages of disease, there are severe cerebral and cerebellar atrophy, ventricular enlargement, and midbrain atrophy (Schroter et al., 2000). DWI hyperintensity is thought to be due to a combination of diffusion restriction and T2 prolongation. Studies that have measured ADC in sCJD have shown decreased ADC in the caudate, putamen, and thalamus (Hyare, Thornton, et al., 2010; Hyare, Wroe, et al., 2010; Lin, Young, Chen, Dillon, & Wong, 2006; Tschampa et al., 2003). Decreased ADC measurements before signal change were detected in the thalamus in sCJD, suggesting that ADC measurements could be more sensitive than visual DWI inspection to pathology in this disease (Tschampa et al., 2003). Longitudinal ADC measurements in sCJD have demonstrated conflicting reports with one study reporting decreased ADC in the striatum over 2 weeks (Murata et al., 2002) and another report of an increase in basal ganglia ADC values with time, suggesting that ADC may vary according to the stage of disease (Tschampa et al., 2003). High-b-value DWI at b ¼ 3000 or 2000 s mm2 has been shown to improve detection of abnormal signal in sCJD compared with conventional DWI (Figure 3), particularly in the cortex and thalamus, improving confidence in the radiological diagnosis (Hyare, Thornton, et al., 2010; Hyare, Wroe, et al., 2010). High-b-value DWI is now included in the diagnostic MRI protocol for human prion disease at our institution. It is suggested that at higher b-values, the DWI signal intensity is weighted toward the slow diffusion component. DWI weighted toward the slow diffusion component at higher b-values appears to be more sensitive to pathology in sCJD (Hyare, Thornton, et al., 2010; Hyare, Wroe, et al., 2010).
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Inherited Prion Diseases Unlike in other forms of prion disease, MRI is less important in the diagnosis of IPD since a definitive diagnosis can be made with PRNP genotyping performed on a blood sample. MRI is still useful to exclude treatable diseases such as subdural collections or vasculitis and can point toward the diagnosis in the early stages, perhaps before an IPD has been considered. In a European study of 445 patients with IPD, MRI scan data were available in 43% of cases but only demonstrated findings in 50% of patients with the E200K mutation, 33% of cases with the GSS clinical phenotype, and 18% of cases with the FFI clinical phenotype (Kovacs et al., 2005). However, the study did not specify which MRI sequences were available. There are few reports of MRI findings in specific genotypes. A recent report of a family with the E200K mutation has described increased signal in the caudate, putamen, and thalamus bilaterally (Fulbright et al., 2006). On DWI, abnormalities in the cingulate, frontal, and occipital cortices were also identified in a pattern similar to that seen in sCJD (Fulbright et al., 2008), enhanced at high-b-value DWI (Lee et al., 2009). IPDs being slowly progressive offer a unique opportunity to assess microstructural changes in the brain with MRI, particularly in presymptomatic mutation carriers that could benefit from future therapeutic interventions. Decreased ADC in the basal ganglia has been reported in a cohort of patients with the E200K mutation before symptom onset suggesting that ADC measurements could be used for the timing of such therapeutic interventions (Lee et al., 2009). Further work in this mutation has shown significant reductions in fractional anisotropy (FA) in symptomatic patients in distinct and functionally relevant
Figure 3 MRI findings in different sequences in sCJD. (a) T2-weighted images show hyperintensity in the basal ganglia, which can also be seen on DWI (b) but is more conspicuous at high-b-value DWI (c) where thalamic hyperintensity is also seen. The corresponding b ¼ 1000 s m2 ADC map (d) shows decreased signal in the basal ganglia. Cortical hyperintensity in the cingulate gyrus bilaterally cannot be seen on T2-weighted images (d) and may be artifactual on DWI (e) but is clearly seen at high-b-value DWI (f) and demonstrates corresponding hypointensity in the b ¼ 1000 s m2 ADC map (g).
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white matter tracts including the corticospinal tract, internal capsule, external capsule, fornix, and posterior thalamic radiation. The FA deficits were mainly determined by an increase in radial diffusivity, suggesting elevated permeability of axonal membranes (Lee et al., 2012). In patients with the 6-OPRI mutation, correlation of neuropsychology with MRI revealed cortical thinning in the precuneus, inferior parietal lobule, supramarginal gyrus, and lingula (Figure 4) (Alner et al., 2012). This distribution of cortical damage relates well to the clinical symptoms in patients with this mutation where apraxia is an early feature
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and visuoperceptual and visuospatial impairments are quite common in this patient group (Alner et al., 2012). A further multiparameter MRI investigation using voxelbased morphometry (VBM) and voxel-based analysis of magnetization transfer ratio (MTR) and mean diffusivity (MD) in patients with this mutation has confirmed these findings with significant gray matter volume loss predominantly involving the perisylvian cortex, precuneus, and lingual gyrus without significant mesial temporal lobe involvement (Figure 5; De Vita et al., 2013). Significant MTR reductions and significant increases in MD were observed in the posteromedial thalamus (not detected
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Figure 4 Cortical thickness maps showing patterns of reduced cortical thickness in the 6-OPRI mutation compared to healthy controls. The left hemisphere is shown on the left of the figure and the right hemisphere on the right of the figure. In the center, the brain is viewed from above. Maps are thresholded at p < 0.01 after false discovery rate (FDR) correction for multiple comparisons over the whole brain volume. The color bar represents FDR-corrected p-values. The maps demonstrate symmetrical cortical thinning predominantly in the parietal and posterior frontal lobes in patients with the 6-OPRI mutation.
Figure 5 SPM-t maps for patients with the 6-OPRI mutation compared with healthy control participants for family-wise error p < 0.05. The color bar represents the t-value range. The maps demonstrate significant gray matter volume loss predominantly involving the perisylvian cortex, precuneus, and lingual gyrus (a and b). Significant MTR reductions (c) and significant increases in MD (d) were observed in the posteromedial thalamus (not detected on VBM) and cortical gray matter areas corresponding to those displaying VBM changes and also in adjacent subcortical white matter where no significant volume changes were detected.
INTRODUCTION TO CLINICAL BRAIN MAPPING | Human Prion Diseases
on VBM) and cortical gray matter areas corresponding to those displaying VBM changes and also in adjacent subcortical white matter where no significant volume changes were detected. This finding suggests that MTR and MD data are a useful complement to T1-weighted structural data and are potentially more sensitive to subcortical white matter and thalamic changes in prion diseases than volume measurements. Further investigation of MTR and MD in patients with IPD with a variety of different mutations not only has shown significant whole brain and regional MTR and MD differences between symptomatic patients and controls but also has shown a correlation between these MTR parameters and mini mental state examination (MMSE) (Hyare, Thornton, et al., 2010; Hyare, Wroe, et al., 2010; Siddique et al., 2010), suggesting that these measures can reflect disease severity. Ongoing investigation of these MRI measures will prove whether they can be used as secondary endpoints in future clinical trials in this disease.
Acquired Creutzfeldt–Jakob Disease Variant Creutzfeldt–Jakob disease Symmetrical hyperintensity in the pulvinar thalami (relative to the cortex and especially the anterior putamen) is characteristic of vCJD and is known as the pulvinar sign (Figure 6). The pulvinar sign was initially reported to have a sensitivity of 78–90% and a specificity of 100% for vCJD and was originally described on T2W, PD, and FLAIR images (Collie et al., 2003;
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Will et al., 2000). The mediodorsal thalamic nucleus is additionally affected in 56% of cases, and the combination of this with pulvinar signal change on axial MRI produces an appearance named the ‘hockey stick’ sign. In 86 neuropathologically confirmed cases, the caudate nucleus was involved in 40% of cases, the putamen in 23.3%, and the periaqueductal gray matter in 83.3% (Collie et al., 2003). Variant CJD has the most consistent changes on MRI of any human prion disease type, perhaps because only one molecular strain is present. Due to this reported high sensitivity on conventional MRI, very few studies have investigated the sensitivity of DWI for the diagnosis of vCJD. Although the abnormal pulvinar signal appears hyperintense on trace-weighted images in vCJD (Waldman, Jarman, & Merry, 2003), a study of eight vCJD patients found increased ADC in the thalamus compared to healthy volunteers and concluded that the abnormal signal was due to T2 prolongation rather than restricted diffusion (Hyare, Thornton, et al., 2010; Hyare, Wroe, et al., 2010). As yet, there is no evidence to support the use of the pulvinar sign in presymptomatic testing for vCJD as all reports refer to symptomatic patients. In one report of a blood transfusionacquired case of vCJD, imaging at the time of initial clinical presentation was negative for the pulvinar sign and was only positive when the patient was severely affected, suggesting that the pulvinar sign could be a late feature of vCJD (Wroe et al., 2006).
Human growth hormone CJD There are no large series reporting the MRI findings in human growth hormone (hGH) CJD. A few case reports describe caudate and putamen hyperintensity on FLAIR, DWI, and T2weighted imaging with additional thalamic hyperintensity on DWI in two cases (Caboclo et al., 2002; Oppenheim et al., 2004). Serial scanning showed progressive atrophy with reduction and eventual disappearance of the FLAIR and DWI changes (Oppenheim et al., 2004). In our experience, cortical signal abnormality is also a feature of hGH CJD and can have similar appearances to that seen in sCJD (Figure 7).
Correlation of MRI with Neuropathology
Figure 6 Axial FLAIR image shows classical MRI appearance in vCJD. The pulvinar sign (arrow) is defined as T2-weighted or FLAIR hyperintensity in the pulvinar and dorsomedial nuclei of the thalamus that is greater than the signal intensity in the posterior putamen and is reported to have a sensitivity for vCJD of over 90%. Note the hyperintensity in the caudate and anterior putamen nuclei, reported in 40–55% of cases.
The precise histopathologic correlates for the DWI changes in human prion diseases are not yet known. The histopathologic hallmarks of prion diseases are spongiosis, neuronal loss, and gliosis (Figure 8). It is likely that the proportion of these histological changes that are present in the target tissue determine the ADC. Severe spongiform change with areas of confluent vacuolation, restricting the extracellular space, has been advocated as a potential cause of the decreased ADC (Lim, Tan, Verma, Yin, & Venketasubramanian, 2004; Mittal, Farmer, Kalina, Kingsley, & Halperin, 2002; Murata et al., 2002). However, in a single case report, a reduction of ADC values in all regions with spongiform alterations was seen but no correlation between the histological degree of spongiform alteration and the decrease in ADC values (Russmann et al., 2005). In a study of six patients who died from vCJD, MRI at 9.4 T of postmortem specimens showed a correlation between decreasing MTR and increasing degree of spongiosis in the frontal cortex, suggesting that MTR could be a surrogate of spongiosis (Siddique et al., 2010).
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Figure 7 Typical MRI findings in hGH CJD. Basal ganglia and thalamic hyperintensity are seen in the basal ganglia and thalamus on T2-weighted images (a), DWI at b ¼ 1000 s mm2 (b), and (c) DWI at b ¼ 3000 s mm2. Cortical hyperintensity in the paracentral lobule bilaterally is not visualized on T2-weighted images (a) but is seen on DWI b ¼ 1000 s mm2 (e) and (f) DWI at b ¼ 3000 s mm2.
Positron-Emission Tomography 18F-Fluorodeoxyglucose 18F-Fluorodeoxyglucose (FDG) positron-emission tomography (PET) shows widespread hypometabolism in predominantly bilateral parietal and temporal cortical areas, which differentiates it from other dementias such as Alzheimer’s disease (Goldman et al., 1993; Henkel et al., 2002). In a series of 14 cases of definite or probable sCJD, 18F-FDG PET detected hypometabolism in the basal ganglia in two patients where DWI signal change was not seen, arguing that 18F-FDG PET is more sensitive than DWI in the diagnosis of sCJD (Xing et al., 2012).
11C-Pittsburgh Compound B Pittsburgh compound B (PiB), also known as benzothiazole-1 (BTA-1), has been shown to bind PrP amyloid in tissue slices when mice are infected with prion strains (Ishikawa et al., 2004). Methoxy-X04, a Congo red derivative, will also label PrP amyloid in human brain samples of prion subjects verified at autopsy (Sadowski et al., 2004). Despite this, the first reports of 11C-PiB PET findings in human prion diseases showed no significant differences from controls in a patient with the 6OPRI mutation (Boxer et al., 2007) and two patients with sCJD (Villemagne et al., 2009). In the largest series of five patients,
including a vCJD patient who died 7 months later and postmortem revealed extensive PrP plaque formation in the frontal and occipital cortices and cerebellum, there was no abnormal cerebral cortical or subcortical 11C-PiB retention in any of the subjects (Figure 9; Hyare et al., 2011). It may be that the level of 11C-PiB binding achieved during PiB PET studies may be insufficient for adequate detection by PET in vivo. Other amyloid agents developed for Alzheimer’s disease have been reported to detect PrP amyloid in patients in vivo (Kepe et al., 2009) and include the naphthol 18F-FDDNP but need further evaluation in larger cohorts in order to establish their true utility.
Recommended Imaging Protocol For the diagnostic workup of a suspected human prion disease patient, we recommend a routine MRI brain with DWI at a standard b-value of 1000 s mm2 and a high b-value of 3000 s mm2 as the imaging protocol. The most important sequence is the DWI, which can be performed quickly in an agitated patient. Performing an additional DWI sequence at high b-value can increase confidence when DWI signal abnormality is suspected. We also recommend that the ADC map is viewed in conjunction with the DWI trace image where
INTRODUCTION TO CLINICAL BRAIN MAPPING | Human Prion Diseases
ICSM35 (PrP)
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Figure 8 Abundant presence of prion protein plaques in the occipital cortex of a patient with vCJD. (a) A section of the cortex, immunostained for abnormal prion protein with ICSM35, an antibody that reacts with PrP. The blue box indicates the approximate area that is shown at higher magnification in (b). (b) A higher-magnification image of the area delineated by the blue box in (a), stained with hematoxylin and eosin. Note the two florid plaques with a dense core and radiating spicules, surrounded by small vacuoles. Scale bar corresponds to 480 mm (a) and 120 mm (b).
Figure 9 Trace PET images at 75 min postinjection of 11C-PiB showing background uptake in the white matter in which it is similar to that seen in controls in (a) a patient with vCJD, (b) symptomatic patient with P102L mutation, (c) asymptomatic patient with P102L mutation, and (d) normal control. 11C-PiB retention is shown in the frontal and temporal cortex in a typical case of Alzheimer’s disease (e) for comparison.
corresponding decreased signal is seen. Structural imaging should be performed with T1-weighted, T2-weighted, and FLAIR sequences. For the exclusion of differential diagnoses such as inflammation, infection, and tumor, a contrast study should be considered on the initial examination.
Conclusion MRI has emerged as an important diagnostic test in the workup for patients suspected of human prion disease and has a high reported sensitivity for the diagnosis of sCJD and vCJD. The additional use of high-b-value DWI can improve confidence in the detection of MRI signal changes. As we enter a new era of therapeutic clinical trials in human prion disease (Nicoll et al.,
2010), we will see the emergence of MRI measures as secondary endpoints in such clinical trials.
See also: INTRODUCTION TO ACQUISITION METHODS: Diffusion MRI; Positron Emission Tomography and Neuroreceptor Mapping In Vivo; INTRODUCTION TO CLINICAL BRAIN MAPPING: Amyloid Tracers.
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Lee, H., Cohen, O. S., Rosenmann, H., Hoffmann, C., Kingsley, P. B., Korczyn, A. D., et al. (2012). Cerebral white matter disruption in Creutzfeldt–Jakob disease. American Journal of Neuroradiology, 33(10), 1945–1950. Lee, H., Hoffman, C., Kingsley, P. B., Degnan, A., Cohen, O., & Prohovnik, I. (2009). Enhanced detection of diffusion reductions in Creutzfeldt–Jakob disease at a higher B factor. American Journal of Neuroradiology, 31(1), 49–54. Lee, H., Rosenmann, H., Chapman, J., Kingsley, P. B., Hoffmann, C., Cohen, O. S., et al. (2009). Thalamo-striatal diffusion reductions precede disease onset in prion mutation carriers. Brain, 132, 2680–2687. Lim, C. C., Tan, K., Verma, K. K., Yin, H., & Venketasubramanian, N. (2004). Combined diffusion-weighted and spectroscopic MR imaging in Creutzfeldt–Jakob disease. Magnetic Resonance Imaging, 22(5), 625–629. Lin, Y. R., Young, G. S., Chen, N. K., Dillon, W. P., & Wong, S. (2006). Creutzfeldt–Jakob disease involvement of rolandic cortex: A quantitative apparent diffusion coefficient evaluation. American Journal of Neuroradiology, 27(8), 1755–1759. Matoba, M., Tonami, H., Miyaji, H., Yokota, H., & Yamamoto, I. (2001). Creutzfeldt–Jakob disease: Serial changes on diffusion-weighted MRI. Journal of Computer Assisted Tomography, 25(2), 274–277. Mead, S. (2006). Prion disease genetics. European Journal of Human Genetics, 14(3), 273–281. Mittal, S., Farmer, P., Kalina, P., Kingsley, P. B., & Halperin, J. (2002). Correlation of diffusion-weighted magnetic resonance imaging with neuropathology in Creutzfeldt–Jakob disease. Archives of Neurology, 59(1), 128–134. Murata, T., Shiga, Y., Higano, S., Takahashi, S., & Mugikura, S. (2002). Conspicuity and evolution of lesions in Creutzfeldt–Jakob disease at diffusion-weighted imaging. American Journal of Neuroradiology, 23(7), 1164–1172. Nicoll, A. J., Trevitt, C. R., Tattum, M. H., Risse, E., Quarterman, E., Ibarra, A. A., et al. (2010). Pharmacological chaperone for the structured domain of human prion protein. Proceedings of the National Academy of Sciences of the United States of America, 107, 17610–17615. Oppenheim, C., Zuber, M., Galanaud, D., Detilleux, M., Bolgert, F., Mas, J. L., et al. (2004). Spectroscopy and serial diffusion MR findings in hGH-Creutzfeldt–Jakob disease. Journal of Neurology, Neurosurgery, and Psychiatry, 75(7), 1066–1069. Palmer, M. S., Dryden, A. J., Hughes, J. T., & Collinge, J. (1991). Homozygous prion protein genotype predisposes to sporadic Creutzfeldt–Jakob disease. Nature, 352, 340–342. Prusiner, S. B. (1991). Molecular biology and transgenetics of prion diseases. Critical Reviews in Biochemistry and Molecular Biology, 26, 397–438. Riek, R., Hornemann, S., Wider, G., Billeter, M., Glockshuber, R., & Wuthrich, K. (1996). NMR structure of the mouse prion protein domain PrP (121–231). Nature, 382, 180–182. Russmann, H., Vingerhoets, F., Miklossy, J., Maeder, P., Glatzel, M., Aguzzi, A., et al. (2005). Sporadic Creutzfeldt–Jakob disease: A comparison of pathological findings and diffusion weighted imaging. Journal of Neurology, 252(3), 338–342. Sadowski, M., Pankiewicz, J., Scholtzova, H., Tsai, J., Li, Y., Carp, R. I., et al. (2004). Targeting prion amyloid deposits in vivo. Journal of Neuropathology and Experimental Neurology, 63(7), 775–784. Schroter, A., Zerr, I., Henkel, K., Tschampa, H. J., Finkenstaedt, M., & Poser, S. (2000). Magnetic resonance imaging in the clinical diagnosis of Creutzfeldt–Jakob disease. Archives of Neurology, 57(12), 1751–1757. Shiga, Y., Miyazawa, K., Sato, S., Fukushima, R., Shibuya, S., Sato, Y., et al. (2004). Diffusion-weighted MRI abnormalities as an early diagnostic marker for Creutzfeldt–Jakob disease. Neurology, 63(3), 443–449. Siddique, D., Hyare, H., Wroe, S., Webb, T., Macfarlane, R., Rudge, P., et al. (2010). Magnetization transfer ratio may be a surrogate of spongiform change in human prion diseases. Brain, 133(Pt 10), 3058–3068. Tribl, G. G., Strasser, G., Zeitlhofer, J., Asenbaum, S., Jarius, C., Wessely, P., et al. (2002). Sequential MRI in a case of Creutzfeldt–Jakob disease. Neuroradiology, 44(3), 223–226. Tschampa, H. J., Kallenberg, K., Kretzschmar, H. A., Meissner, B., Knauth, M., Urbach, H., et al. (2007). Pattern of cortical changes in sporadic Creutzfeldt–Jakob disease. American Journal of Neuroradiology, 28(6), 1114–1118. Tschampa, H. J., Kallenberg, K., Urbach, H., Meissner, B., Nicolay, C., Kretzschmar, H. A., et al. (2005). MRI in the diagnosis of sporadic Creutzfeldt–Jakob disease: A study on inter-observer agreement. Brain, 128(Pt 9), 2026–2033. Tschampa, H. J., Murtz, P., Flacke, S., Paus, S., Schild, H. H., & Urbach, H. (2003). Thalamic involvement in sporadic Creutzfeldt–Jakob disease: A diffusion-weighted MR imaging study. American Journal of Neuroradiology, 24(5), 908–915. Ukisu, R., Kushihashi, T., Kitanosono, T., Fujisawa, H., Takenaka, H., Ohgiya, Y., et al. (2005). Serial diffusion-weighted MRI of Creutzfeldt–Jakob disease. American Journal of Roentgenology, 184(2), 560–566.
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Villemagne, V. L., Mclean, C. A., Reardon, K., Boyd, A., Lewis, V., Klug, G., et al. (2009). 11C-PiB PET studies in typical sporadic Creutzfeldt–Jakob disease. Journal of Neurology, Neurosurgery, and Psychiatry, 80(9), 998–1001. Vitali, P., Maccagnano, E., Caverzasi, E., Henry, R. G., Haman, A., Torres-Chae, C., et al. (2011). Diffusion-weighted MRI hyperintensity patterns differentiate CJD from other rapid dementias. Neurology, 76(20), 1711–1719. Waldman, A. D., Jarman, P., & Merry, R. T. (2003). Rapid echoplanar diffusion imaging in a case of variant Creutzfeldt–Jakob disease; where speed is of the essence. Neuroradiology, 45(8), 528–531. Will, R. G., Zeidler, M., Stewart, G. E., Macleod, M. A., Ironside, J. W., Cousens, S. N., et al. (2000). Diagnosis of new variant Creutzfeldt–Jakob disease. Annals of Neurology, 47(5), 575–582. Wroe, S. J., Pal, S., Siddique, D., Hyare, H., Macfarlane, R., Joiner, S., et al. (2006). Clinical presentation and pre-mortem diagnosis of variant Creutzfeldt–Jakob
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disease associated with blood transfusion: A case report. Lancet, 368(9552), 2061–2067. Xing, X. W., Zhang, J. T., Zhu, F., Ma, L., Yin, D. Y., Jia, W. Q., et al. (2012). Comparison of diffusion-weighted MRI with 18F-fluorodeoxyglucose-positron emission tomography/CT and electroencephalography in sporadic Creutzfeldt–Jakob disease. Journal of Clinical Neuroscience, 19(10), 1354–1357. Young, G. S., Geschwind, M. D., Fischbein, N. J., Martindale, J. L., Henry, R. G., Liu, S., et al. (2005). Diffusion-weighted and fluid-attenuated inversion recovery imaging in Creutzfeldt–Jakob disease: High sensitivity and specificity for diagnosis. American Journal of Neuroradiology, 26(6), 1551–1562. Zerr, I., Kallenberg, K., Summers, D. M., Romero, C., Taratuto, A., Heinemann, U., et al. (2009). Updated clinical diagnostic criteria for sporadic Creutzfeldt–Jakob disease. Brain, 132, 2659–2668.
Abbreviations ADC DWI FA FDG FLAIR GSS hGH CJD IPD M MD
Apparent diffusion coefficient Diffusion-weighted imaging Fractional anisotropy Fluorodeoxyglucose Fluid attenuation inversion recovery Gerstmann–Stra¨ussler–Scheinker disease Human growth hormone Creutzfeldt–Jakob disease Inherited prion disease Methionine Mean diffusivity
Introduction With the routine clinical use of diffusion-weighted imaging (DWI), magnetic resonance imaging (MRI) has gained increasing importance in the diagnosis of human prion diseases (Kallenberg et al., 2006; Murata, Shiga, Higano, Takahashi, & Mugikura, 2002; Shiga et al., 2004; Tschampa et al., 2005; Young et al., 2005). For some time, MRI studies have been included in the WHO diagnostic criteria for variant Creutzfeldt–Jakob disease (vCJD) (Will et al., 2000), but with the emergence of DWI as the most sensitive sequence for the diagnosis of sporadic CJD (sCJD) (Kallenberg et al., 2006), it is now proposed that MRI studies also be included in the WHO diagnostic criteria for sCJD (Zerr et al., 2009). The presence of characteristic MRI signal abnormality in human prion diseases is unique across neurodegeneration. However, these characteristic MRI findings are not always identified on initial scan at the referring hospital (Carswell et al., 2012). This article highlights the typical MRI findings in all forms of human prion diseases with an emphasis on recent technical advances in the field.
Prion Pathophysiology Human prion diseases are a group of rare neurodegenerative conditions characterized by template misfolding of the normal cellular prion protein (PrPc) into abnormal disease-associated forms generally referred to as PrPSc (Prusiner, 1991). PrPc is a glycoprotein consisting of an N-terminal region and a C-terminal domain. The N-terminal unstructured region contains five repeats of eight amino acid sequence (the octapeptide region), and mutations in this region can lead to forms of inherited prion disease (IPD) (Collinge, 2005). In this region, there are two tight binding sites for Cu ions, suggesting a role for PrP in copper metabolism or transport (Riek et al., 1996).
Brain Mapping: An Encyclopedic Reference
MRI MTR PET PiB PRNP PrPc PrPSc sCJD V VBM vCJD
Magnetic resonance imaging Magnetization transfer ratio Positron-emission tomography Pittsburgh compound B Prion protein gene Normal prion protein Abnormal disease-associated form of prion protein Sporadic Creutzfeldt–Jakob disease Valine Voxel-based morphometry Variant Creutzfeldt–Jakob disease
Disturbance of this function could be involved in prion-related neurotoxicity. The remainder of the molecule has three helices joined by b-pleated areas. Human prion diseases have been traditionally classified on clinical grounds into Creutzfeldt–Jakob disease (CJD), Gerstmann–Stra¨ussler–Scheinker disease (GSS), and Kuru but can also be classified as occurring in inherited, sporadic, and acquired forms with subclassification according to molecular criteria. IPDs comprise 15% of recognized prion disease and are associated with 1 of the more than 30 recognized coding mutations in the PRNP gene (Mead, 2006). Kindreds with IPD have been described with the phenotypes of classical CJD and GSS and with other clinicopathologic syndromes including familial fatal insomnia (FFI) (Figure 1). sCJD makes up 85% of all recognized human prion diseases and occurs in all countries with an apparently random distribution and annual incidence of 1–2 per million. Possible causes are spontaneous production of PrPSc via rare stochastic events, somatic mutation of PRNP, or unidentified environmental exposure. There is a marked genetic susceptibility with most cases occurring in homozygotes of methionine (M) or valine (V) at codon 129 of the PRNP gene. MV heterozygotes appear to be relatively protected from developing sCJD (Palmer, Dryden, Hughes, & Collinge, 1991). Acquired prion diseases include iatrogenic CJD, Kuru, and vCJD. Iatrogenic exposure occurs through accidental exposure to human prions through medical or surgical procedures, most frequently through implantation of dural grafts or through administration of growth hormone derived from the pituitary glands of human cadavers (Brown, Preece, & Will, 1992). Kuru arose from exposure to prions during cannibalistic mortuary feasts. vCJD has been shown through strain-typing studies and transmission studies in transgenic mice to be caused by the same prion strain as that causing bovine spongiform encephalopathy (Hill et al., 1997).
http://dx.doi.org/10.1016/B978-0-12-397025-1.00077-4
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Magnetic Resonance Imaging Sporadic Creutzfeldt–Jakob Disease DWI has emerged as the most sensitive sequence of the diagnosis of sCJD (Kallenberg et al., 2006; Tschampa et al., 2007; Young et al., 2005) with many studies showing that it is the best sequence for detecting signal change in the cortex (Kropp, Finkenstaedt, Zerr, Schroter, & Poser, 2000; Matoba, Tonami, Miyaji, Yokota, & Yamamoto, 2001; Shiga et al., 2004). Visual inspection of the diffusion-weighted trace image demonstrates typically increased signal intensity in the cortex with up to 95% of cases showing hyperintensity affecting the insula, cingulate,
Glycans
Helix 1
Helix 2
Membrane anchor Figure 1 Model of the C-terminal domain of human prion protein indicating positions of the a-helices and carbohydrate and the membrane anchor, which attaches the protein to the outer surface of the cell membrane.
and superior frontal cortex independently of deep gray matter involvement (Tschampa et al., 2007). DWI is superior to fluid attenuation inversion recovery (FLAIR) for detecting cortical signal intensity, and this has been shown to correlate with lateralized clinical and electroencephalograph abnormalities (Cambier, Kantarci, Worrell, Westmoreland, & Aksamit, 2003). Increased signal in the striatum, in the cortex, and to a lesser extent in the thalamus is the classical finding in sCJD (Figure 2). The extent of involvement and the distribution of signal changes vary among patients, thought to be influenced by the PRNP genotype and PrPSc strain type (Fukushima et al., 2004; Hamaguchi et al., 2005). In 40 patients with sCJD, the combination of signal changes in the cortex and deep gray matter occurred in 68% of subjects, while involvement of the cortex alone was less common (24%) and high signal in the deep gray matter without cortical signal change was extremely rare (5%). The cortical signal changes involve all lobes, mainly the frontal (89%), limbic (79%), parietal (72%), and temporal (65%), while the precentral and central gyri are usually spared (Young et al., 2005). A recent study of 48 cases of sCJD reported a sensitivity of 98% and sensitivity of 93% using DWI and FLAIR MRI, respectively, after consensus review, higher than those of any other diagnostic test (Vitali et al., 2011). The authors identified four distinguishing MRI features: Cortical hyperintensity on DWI is greater than FLAIR; subcortical areas hyperintense on DWI are hypointense on apparent diffusion coefficient (ADC); isolated limbic involvement is not seen; and characteristic patterns of gray matter involvement are seen affecting the precuneus and cingulate, angular, parahippocampal, and superior and middle frontal gyri and caudate in 50% of sCJD cases. The temporal sequence of signal abnormality in sCJD has been studied by a few authors. A defined temporal sequence of events has been reported where high signal starts in the anteroinferior putamen and spreads to the posterior part, leading to complete involvement of the putamen (Murata et al., 2002). There is one report of expansion of the signal changes and general progression to cerebral atrophy (Tribl et al., 2002), and there are two reports of disappearance of diffusion signal
Figure 2 DWI trace-weighted images demonstrating the variable pattern of hyperintensity in sCJD ranging from (a) the classical appearance of diffuse cortical and basal ganglia signal change, to (b) cortical signal change only (which can be asymmetrical), to (c) additional hyperintensity in the thalamus (arrow).
INTRODUCTION TO CLINICAL BRAIN MAPPING | Human Prion Diseases
changes (Tschampa et al., 2003; Ukisu et al., 2005). In the end stages of disease, there are severe cerebral and cerebellar atrophy, ventricular enlargement, and midbrain atrophy (Schroter et al., 2000). DWI hyperintensity is thought to be due to a combination of diffusion restriction and T2 prolongation. Studies that have measured ADC in sCJD have shown decreased ADC in the caudate, putamen, and thalamus (Hyare, Thornton, et al., 2010; Hyare, Wroe, et al., 2010; Lin, Young, Chen, Dillon, & Wong, 2006; Tschampa et al., 2003). Decreased ADC measurements before signal change were detected in the thalamus in sCJD, suggesting that ADC measurements could be more sensitive than visual DWI inspection to pathology in this disease (Tschampa et al., 2003). Longitudinal ADC measurements in sCJD have demonstrated conflicting reports with one study reporting decreased ADC in the striatum over 2 weeks (Murata et al., 2002) and another report of an increase in basal ganglia ADC values with time, suggesting that ADC may vary according to the stage of disease (Tschampa et al., 2003). High-b-value DWI at b ¼ 3000 or 2000 s mm2 has been shown to improve detection of abnormal signal in sCJD compared with conventional DWI (Figure 3), particularly in the cortex and thalamus, improving confidence in the radiological diagnosis (Hyare, Thornton, et al., 2010; Hyare, Wroe, et al., 2010). High-b-value DWI is now included in the diagnostic MRI protocol for human prion disease at our institution. It is suggested that at higher b-values, the DWI signal intensity is weighted toward the slow diffusion component. DWI weighted toward the slow diffusion component at higher b-values appears to be more sensitive to pathology in sCJD (Hyare, Thornton, et al., 2010; Hyare, Wroe, et al., 2010).
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Inherited Prion Diseases Unlike in other forms of prion disease, MRI is less important in the diagnosis of IPD since a definitive diagnosis can be made with PRNP genotyping performed on a blood sample. MRI is still useful to exclude treatable diseases such as subdural collections or vasculitis and can point toward the diagnosis in the early stages, perhaps before an IPD has been considered. In a European study of 445 patients with IPD, MRI scan data were available in 43% of cases but only demonstrated findings in 50% of patients with the E200K mutation, 33% of cases with the GSS clinical phenotype, and 18% of cases with the FFI clinical phenotype (Kovacs et al., 2005). However, the study did not specify which MRI sequences were available. There are few reports of MRI findings in specific genotypes. A recent report of a family with the E200K mutation has described increased signal in the caudate, putamen, and thalamus bilaterally (Fulbright et al., 2006). On DWI, abnormalities in the cingulate, frontal, and occipital cortices were also identified in a pattern similar to that seen in sCJD (Fulbright et al., 2008), enhanced at high-b-value DWI (Lee et al., 2009). IPDs being slowly progressive offer a unique opportunity to assess microstructural changes in the brain with MRI, particularly in presymptomatic mutation carriers that could benefit from future therapeutic interventions. Decreased ADC in the basal ganglia has been reported in a cohort of patients with the E200K mutation before symptom onset suggesting that ADC measurements could be used for the timing of such therapeutic interventions (Lee et al., 2009). Further work in this mutation has shown significant reductions in fractional anisotropy (FA) in symptomatic patients in distinct and functionally relevant
Figure 3 MRI findings in different sequences in sCJD. (a) T2-weighted images show hyperintensity in the basal ganglia, which can also be seen on DWI (b) but is more conspicuous at high-b-value DWI (c) where thalamic hyperintensity is also seen. The corresponding b ¼ 1000 s m2 ADC map (d) shows decreased signal in the basal ganglia. Cortical hyperintensity in the cingulate gyrus bilaterally cannot be seen on T2-weighted images (d) and may be artifactual on DWI (e) but is clearly seen at high-b-value DWI (f) and demonstrates corresponding hypointensity in the b ¼ 1000 s m2 ADC map (g).
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white matter tracts including the corticospinal tract, internal capsule, external capsule, fornix, and posterior thalamic radiation. The FA deficits were mainly determined by an increase in radial diffusivity, suggesting elevated permeability of axonal membranes (Lee et al., 2012). In patients with the 6-OPRI mutation, correlation of neuropsychology with MRI revealed cortical thinning in the precuneus, inferior parietal lobule, supramarginal gyrus, and lingula (Figure 4) (Alner et al., 2012). This distribution of cortical damage relates well to the clinical symptoms in patients with this mutation where apraxia is an early feature
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and visuoperceptual and visuospatial impairments are quite common in this patient group (Alner et al., 2012). A further multiparameter MRI investigation using voxelbased morphometry (VBM) and voxel-based analysis of magnetization transfer ratio (MTR) and mean diffusivity (MD) in patients with this mutation has confirmed these findings with significant gray matter volume loss predominantly involving the perisylvian cortex, precuneus, and lingual gyrus without significant mesial temporal lobe involvement (Figure 5; De Vita et al., 2013). Significant MTR reductions and significant increases in MD were observed in the posteromedial thalamus (not detected
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Figure 4 Cortical thickness maps showing patterns of reduced cortical thickness in the 6-OPRI mutation compared to healthy controls. The left hemisphere is shown on the left of the figure and the right hemisphere on the right of the figure. In the center, the brain is viewed from above. Maps are thresholded at p < 0.01 after false discovery rate (FDR) correction for multiple comparisons over the whole brain volume. The color bar represents FDR-corrected p-values. The maps demonstrate symmetrical cortical thinning predominantly in the parietal and posterior frontal lobes in patients with the 6-OPRI mutation.
Figure 5 SPM-t maps for patients with the 6-OPRI mutation compared with healthy control participants for family-wise error p < 0.05. The color bar represents the t-value range. The maps demonstrate significant gray matter volume loss predominantly involving the perisylvian cortex, precuneus, and lingual gyrus (a and b). Significant MTR reductions (c) and significant increases in MD (d) were observed in the posteromedial thalamus (not detected on VBM) and cortical gray matter areas corresponding to those displaying VBM changes and also in adjacent subcortical white matter where no significant volume changes were detected.
INTRODUCTION TO CLINICAL BRAIN MAPPING | Human Prion Diseases
on VBM) and cortical gray matter areas corresponding to those displaying VBM changes and also in adjacent subcortical white matter where no significant volume changes were detected. This finding suggests that MTR and MD data are a useful complement to T1-weighted structural data and are potentially more sensitive to subcortical white matter and thalamic changes in prion diseases than volume measurements. Further investigation of MTR and MD in patients with IPD with a variety of different mutations not only has shown significant whole brain and regional MTR and MD differences between symptomatic patients and controls but also has shown a correlation between these MTR parameters and mini mental state examination (MMSE) (Hyare, Thornton, et al., 2010; Hyare, Wroe, et al., 2010; Siddique et al., 2010), suggesting that these measures can reflect disease severity. Ongoing investigation of these MRI measures will prove whether they can be used as secondary endpoints in future clinical trials in this disease.
Acquired Creutzfeldt–Jakob Disease Variant Creutzfeldt–Jakob disease Symmetrical hyperintensity in the pulvinar thalami (relative to the cortex and especially the anterior putamen) is characteristic of vCJD and is known as the pulvinar sign (Figure 6). The pulvinar sign was initially reported to have a sensitivity of 78–90% and a specificity of 100% for vCJD and was originally described on T2W, PD, and FLAIR images (Collie et al., 2003;
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Will et al., 2000). The mediodorsal thalamic nucleus is additionally affected in 56% of cases, and the combination of this with pulvinar signal change on axial MRI produces an appearance named the ‘hockey stick’ sign. In 86 neuropathologically confirmed cases, the caudate nucleus was involved in 40% of cases, the putamen in 23.3%, and the periaqueductal gray matter in 83.3% (Collie et al., 2003). Variant CJD has the most consistent changes on MRI of any human prion disease type, perhaps because only one molecular strain is present. Due to this reported high sensitivity on conventional MRI, very few studies have investigated the sensitivity of DWI for the diagnosis of vCJD. Although the abnormal pulvinar signal appears hyperintense on trace-weighted images in vCJD (Waldman, Jarman, & Merry, 2003), a study of eight vCJD patients found increased ADC in the thalamus compared to healthy volunteers and concluded that the abnormal signal was due to T2 prolongation rather than restricted diffusion (Hyare, Thornton, et al., 2010; Hyare, Wroe, et al., 2010). As yet, there is no evidence to support the use of the pulvinar sign in presymptomatic testing for vCJD as all reports refer to symptomatic patients. In one report of a blood transfusionacquired case of vCJD, imaging at the time of initial clinical presentation was negative for the pulvinar sign and was only positive when the patient was severely affected, suggesting that the pulvinar sign could be a late feature of vCJD (Wroe et al., 2006).
Human growth hormone CJD There are no large series reporting the MRI findings in human growth hormone (hGH) CJD. A few case reports describe caudate and putamen hyperintensity on FLAIR, DWI, and T2weighted imaging with additional thalamic hyperintensity on DWI in two cases (Caboclo et al., 2002; Oppenheim et al., 2004). Serial scanning showed progressive atrophy with reduction and eventual disappearance of the FLAIR and DWI changes (Oppenheim et al., 2004). In our experience, cortical signal abnormality is also a feature of hGH CJD and can have similar appearances to that seen in sCJD (Figure 7).
Correlation of MRI with Neuropathology
Figure 6 Axial FLAIR image shows classical MRI appearance in vCJD. The pulvinar sign (arrow) is defined as T2-weighted or FLAIR hyperintensity in the pulvinar and dorsomedial nuclei of the thalamus that is greater than the signal intensity in the posterior putamen and is reported to have a sensitivity for vCJD of over 90%. Note the hyperintensity in the caudate and anterior putamen nuclei, reported in 40–55% of cases.
The precise histopathologic correlates for the DWI changes in human prion diseases are not yet known. The histopathologic hallmarks of prion diseases are spongiosis, neuronal loss, and gliosis (Figure 8). It is likely that the proportion of these histological changes that are present in the target tissue determine the ADC. Severe spongiform change with areas of confluent vacuolation, restricting the extracellular space, has been advocated as a potential cause of the decreased ADC (Lim, Tan, Verma, Yin, & Venketasubramanian, 2004; Mittal, Farmer, Kalina, Kingsley, & Halperin, 2002; Murata et al., 2002). However, in a single case report, a reduction of ADC values in all regions with spongiform alterations was seen but no correlation between the histological degree of spongiform alteration and the decrease in ADC values (Russmann et al., 2005). In a study of six patients who died from vCJD, MRI at 9.4 T of postmortem specimens showed a correlation between decreasing MTR and increasing degree of spongiosis in the frontal cortex, suggesting that MTR could be a surrogate of spongiosis (Siddique et al., 2010).
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Figure 7 Typical MRI findings in hGH CJD. Basal ganglia and thalamic hyperintensity are seen in the basal ganglia and thalamus on T2-weighted images (a), DWI at b ¼ 1000 s mm2 (b), and (c) DWI at b ¼ 3000 s mm2. Cortical hyperintensity in the paracentral lobule bilaterally is not visualized on T2-weighted images (a) but is seen on DWI b ¼ 1000 s mm2 (e) and (f) DWI at b ¼ 3000 s mm2.
Positron-Emission Tomography 18F-Fluorodeoxyglucose 18F-Fluorodeoxyglucose (FDG) positron-emission tomography (PET) shows widespread hypometabolism in predominantly bilateral parietal and temporal cortical areas, which differentiates it from other dementias such as Alzheimer’s disease (Goldman et al., 1993; Henkel et al., 2002). In a series of 14 cases of definite or probable sCJD, 18F-FDG PET detected hypometabolism in the basal ganglia in two patients where DWI signal change was not seen, arguing that 18F-FDG PET is more sensitive than DWI in the diagnosis of sCJD (Xing et al., 2012).
11C-Pittsburgh Compound B Pittsburgh compound B (PiB), also known as benzothiazole-1 (BTA-1), has been shown to bind PrP amyloid in tissue slices when mice are infected with prion strains (Ishikawa et al., 2004). Methoxy-X04, a Congo red derivative, will also label PrP amyloid in human brain samples of prion subjects verified at autopsy (Sadowski et al., 2004). Despite this, the first reports of 11C-PiB PET findings in human prion diseases showed no significant differences from controls in a patient with the 6OPRI mutation (Boxer et al., 2007) and two patients with sCJD (Villemagne et al., 2009). In the largest series of five patients,
including a vCJD patient who died 7 months later and postmortem revealed extensive PrP plaque formation in the frontal and occipital cortices and cerebellum, there was no abnormal cerebral cortical or subcortical 11C-PiB retention in any of the subjects (Figure 9; Hyare et al., 2011). It may be that the level of 11C-PiB binding achieved during PiB PET studies may be insufficient for adequate detection by PET in vivo. Other amyloid agents developed for Alzheimer’s disease have been reported to detect PrP amyloid in patients in vivo (Kepe et al., 2009) and include the naphthol 18F-FDDNP but need further evaluation in larger cohorts in order to establish their true utility.
Recommended Imaging Protocol For the diagnostic workup of a suspected human prion disease patient, we recommend a routine MRI brain with DWI at a standard b-value of 1000 s mm2 and a high b-value of 3000 s mm2 as the imaging protocol. The most important sequence is the DWI, which can be performed quickly in an agitated patient. Performing an additional DWI sequence at high b-value can increase confidence when DWI signal abnormality is suspected. We also recommend that the ADC map is viewed in conjunction with the DWI trace image where
INTRODUCTION TO CLINICAL BRAIN MAPPING | Human Prion Diseases
ICSM35 (PrP)
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Figure 8 Abundant presence of prion protein plaques in the occipital cortex of a patient with vCJD. (a) A section of the cortex, immunostained for abnormal prion protein with ICSM35, an antibody that reacts with PrP. The blue box indicates the approximate area that is shown at higher magnification in (b). (b) A higher-magnification image of the area delineated by the blue box in (a), stained with hematoxylin and eosin. Note the two florid plaques with a dense core and radiating spicules, surrounded by small vacuoles. Scale bar corresponds to 480 mm (a) and 120 mm (b).
Figure 9 Trace PET images at 75 min postinjection of 11C-PiB showing background uptake in the white matter in which it is similar to that seen in controls in (a) a patient with vCJD, (b) symptomatic patient with P102L mutation, (c) asymptomatic patient with P102L mutation, and (d) normal control. 11C-PiB retention is shown in the frontal and temporal cortex in a typical case of Alzheimer’s disease (e) for comparison.
corresponding decreased signal is seen. Structural imaging should be performed with T1-weighted, T2-weighted, and FLAIR sequences. For the exclusion of differential diagnoses such as inflammation, infection, and tumor, a contrast study should be considered on the initial examination.
Conclusion MRI has emerged as an important diagnostic test in the workup for patients suspected of human prion disease and has a high reported sensitivity for the diagnosis of sCJD and vCJD. The additional use of high-b-value DWI can improve confidence in the detection of MRI signal changes. As we enter a new era of therapeutic clinical trials in human prion disease (Nicoll et al.,
2010), we will see the emergence of MRI measures as secondary endpoints in such clinical trials.
See also: INTRODUCTION TO ACQUISITION METHODS: Diffusion MRI; Positron Emission Tomography and Neuroreceptor Mapping In Vivo; INTRODUCTION TO CLINICAL BRAIN MAPPING: Amyloid Tracers.
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