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Molecular subtype-specific clinical diagnosis of prion diseases
Uta Heinemann, Anna Krasnianski, Bettina Meissner B, Sara Friederike Gloeckner Glöckner, Hans A. Kretzschmar, Inga Zerr I
To cite this version:
Uta Heinemann, Anna Krasnianski, Bettina Meissner B, Sara Friederike Gloeckner Glöckner, Hans A. Kretzschmar, et al.. Molecular subtype-specific clinical diagnosis of prion diseases. Veterinary Microbiology, Elsevier, 2007, 123 (4), pp.328. �10.1016/j.vetmic.2007.04.002�. �hal-00532235�
Accepted Manuscript
Title: Molecular subtype-specific clinical diagnosis of prion diseases
Authors: Uta Heinemann, Anna Krasnianski, Bettina Meissner B, Sara Friederike Gloeckner Gl¨ockner, Hans A. Kretzschmar, Inga Zerr I
PII: S0378-1135(07)00169-1
DOI: doi:10.1016/j.vetmic.2007.04.002
Reference: VETMIC 3646
To appear in: VETMIC
Please cite this article as: Heinemann, U., Krasnianski, A., Meissner B, B., Gl¨ockner, S.F.G., Kretzschmar, H.A., Zerr I, I., Molecular subtype-specific clinical diagnosis of prion diseases,Veterinary Microbiology(2007), doi:10.1016/j.vetmic.2007.04.002 This is a PDF file of an unedited manuscript that has been accepted for publication.
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Accepted Manuscript
Molecular subtype-specific clinical diagnosis of prion diseases 1
2
Uta Heinemann1, Anna Krasnianski1, Bettina Meissner B1, Sara Friederike Gloeckner 3
Glöckner1, Hans A. Kretzschmar 2, Inga Zerr I1,*
4 5
1 National TSE Reference Centre, Department of Neurology, Georg-August University 6
Göttingen, Germany 7
2 Department of Neuropathology, Ludwig-Maximilian University Munich, Germany 8
9
Corresponding author at:
10
National TSE Reference Centre, Department of Neurology, Georg-August University 11
Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany 12
Tel.: +49 551 396636 ; fax: +49 551 397020 13
E-mail: IngaZerr@med.uni-goettingen.de (Inga Zerr) 14
15 16 17
Accepted Manuscript
Abstract 17
Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare transmissible disease caused by 18
accumulation of pathological prion protein (PrPsc) in the CNS. According to the codon 129 19
polymorphism (methionine or valine) and the prion protein type 1 or 2, a classification into 20
distinct subtypes was established. Further analysis of these subtypes detected atypical clinical 21
forms with longer disease duration or younger age at onset.
22
The CJD subtype influences sensitivity of the technical investigations such as 14-3-3 23
in CSF, periodic sharp wave complexes in the EEG or hyperintense basal ganglia in MRI. A 24
further characterization of these subtypes is important for reliable diagnosis and identification 25
of rare disease variants. The aim is to establish specific patterns of test results and clinical 26
findings. These improvements in diagnostics may be the reason for the apparent increase in 27
sCJD incidence in Germany from 0.9 in 1994 to 1.6 in a million in 2005. Despite careful 28
surveillance, no patient with variant CJD has been detected to date in Germany.
29
Here we present the data of the CJD surveillance of the last 13 years. Additionally, the 30
improvements in diagnostics and differential diagnosis are discussed.
31 32
Keywords: Dementia, CJD, subtype, 14-3-3, transthyretin, MRI 33
34 35 36 37 38 39 40 41
Accepted Manuscript
1. Introduction 41
Creutzfeldt-Jakob disease (CJD) is a rapid progressive disorder characterized by 42
dementia associated with cerebellar signs, visual disturbances, extrapyramidal/pyramidal 43
signs, myoclonus and akinetic mutism in the final disease stages (Zerr and Poser, 2002).
44
Clinical diagnosis is supported by periodic sharp wave complexes (PSWC) in EEG and 14-3- 45
3 detection (a neuronal protein, which is used as a surrogate marker of rapid neuronal 46
destruction) in CSF. Additionally, MRI findings such as hyperintensities of basal ganglia, 47
thalamus or cortex are often detected, but the pathogenetic correlate is still not known 48
(Kallenberg et al., 2006). A new potential CSF marker for dementia is transthyretin (TTR), a 49
carrier of the thyroid hormone thyroxine. TTR levels are known to be lower in CSF in 50
patients suffering from Alzheimer’s disease (AD) (Castano et al., 2006).
51
CJD is caused by accumulation of the β-sheet rich, pathological PrPsc after conversion 52
of the alpha-helical, physiological PrPc. Most patients (around 85%) suffer from the sporadic 53
form of CJD (sCJD). Also, mutations of the prion protein gene (PRNP) on chromosome 20 54
can destabilize the protein conformation and thus enhance conversion of PrPc to PrPsc. A lot 55
of mutations have been described so far with point mutations and inserts (Kovacs et al., 2005) 56
occurring. The clinical spectrum of genetic prion diseases is wide and such separate entities as 57
fatal familial insomnia (FFI) and Gerstmann-Straeussler-Scheinker syndrome (GSS) have 58
been defined. As prion diseases are also infectious, acquired forms are known. Iatrogenic 59
transmission can be caused by dura mater grafts, cadaveric human growth hormone, 60
neurosurgical procedures or the use of deep brain electrodes (Will, 2003). In 1996, a new 61
variant of CJD (vCJD) was described in the UK, and a causal link to uptake of BSE- (bovine 62
spongiform encephalopathy) contaminated food was shown (Will et al., 1996).
63
Polymorphism at codon 129 of the prion protein gene (PRNP) with either methionine 64
(M) or valine (V) is known to alter susceptibility (MM is a risk factor for sCJD), incubation 65
time and phenotype of the disease. In combination with PrPsc type 1 or 2, there were defined 66
Accepted Manuscript
six subtypes with different clinical and neuropathological characteristics (Parchi et al., 1996;
67
Parchi et al., 1999).
68
The different forms of CJD in humans, with variable clinical syndromes and origins, 69
makes surveillance and detection of the disease particularly difficult. Thus, a detailed 70
knowledge of the subtype-specific clinical spectrum and findings in CSF, EEG and MRI is 71
essential. Here, we characterize subtype-specific findings and describe the resulting data of 72
the German CJD Surveillance of the last 13 years.
73 74
2. Patients and Methods 75
2.1. Surveillance 76
The surveillance of Creutzfeldt-Jakob disease in Germany has been performed 77
prospectively since 1993. The patients were reported by the treating physicians to the 78
specialized Unit in Göttingen, and examined by a study physician in the notifying hospital.
79
CSF samples for 14-3-3 analysis as well as copies of EEG and MRI were obtained. Blood 80
samples for full sequencing of the prion protein gene (PRNP) and codon 129 analysis 81
completed the data set. Clinical diagnosis was performed according to the established criteria 82
as probable or possible CJD or other diagnoses (WHO, 1998; Zerr et al., 2000). Autopsy for 83
confirmation of the clinical diagnosis by immunohistochemistry and histological parameters 84
were sought. Prion protein type 1 or 2 was determined according to (Parchi et al., 1996).
85 86
2.2. CSF analysis 87
CSF samples of the patients were collected for each patient included in the 88
surveillance, also during the course of the surveillance period. The samples were stored at – 89
80°C. 14-3-3 were measured by Western blot with the K19 antibody (Santa Cruz) by standard 90
methods and evaluated qualitatively as positive or negative (Zerr et al., 1998). Total tau 91
(Innotest AG, Eschlikon, Switzerland) and β−amyloid (Genetics) were measured 92
Accepted Manuscript
quantitatively by ELISA as described in the literature (Sunderland et al., 2003). Transthyretin 93
was measured by nephelometry (N Antiserum to Human Albumin, Prealbumin and Retinol- 94
binding Protetin®; Dade Behring, Marburg, Germany).
95 96
2.2. MRI analysis 97
MR scans were collected during surveillance at the reporting hospitals. Scans of 98
FLAIR, T2 and DWI were evaluated for CJD typical findings, while in other weightings no 99
CJD typical findings are described. Evaluation was performed according to a standardized 100
protocol for hyperintensities in 6 different cortical regions, 4 parts of the basal ganglia and 101
three thalamic nuclei.
102 103
3. Results 104
3.1. Epidemiology 105
During the 13 years of surveillance (1993-2006), we identified 1332 patients with 106
sporadic CJD (696 confirmed, 636 probable). Autopsies were performed on 66% of all 107
patients who were suspected to have died from sporadic CJD. The annual incidence of sCJD 108
is continuously rising, up to 1.6 in a million in 2005. In parallel, we observed a change in the 109
distribution of the codon 129 genotypes. While the proportion of the most frequent MM type 110
is decreasing (73% to 55%), atypical genotypes MV (12% to 23%) and VV (15% to 23%) are 111
increasing. An analysis of codon 129 distribution stratified by age showed different results 112
between patients below the age of 40 (MM 44%, MV 17%, VV 39%) and over 80 at onset 113
(MM 72%, MV 10%, VV 18%) (Figure 1). In 245 patients, data on codon 129 polymorphism 114
and prion protein type were available. The distribution of the six subtypes found the most 115
frequent MM1 (62%) and the rare subtypes MV2 (12%), VV1 (3%) and MM2 (6%).
116
In 116 patients (8% of all TSE patients), a mutation of PRNP was detected: 68% had a 117
genetic CJD, 33 patients FFI (D178N-M) and only 12 patients GSS (P102L). Within the 118
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genetic CJD patients, a genotype distribution similar to normal population was found (MM 119
44%, MV 42%, VV 14%). As FFI has to be associated with methionine on codon 129, we 120
found 71% MM and 29% MV. Interestingly, none of the patients with P102L-GSS were 121
homozygous for valine (MM 50%, MV 50%).
122
Ten patients with iatrogenic transmission were identified, nine of them by lyophilized 123
dura and one by a cornea transplant. Seven of the patients were methionine homozygous, 124
while one patient was heterozygous. No patients with transmission by human growth 125
hormone were identified. Additionally, vCJD has not yet been detected in Germany 126
(31.01.2007).
127 128
3.2. CSF parameters 129
14-3-3 sensitivity varied considerably in different prion diseases. While a good 130
diagnostic value was found in sporadic CJD (96%) and iatrogenic CJD (100%), it is lower for 131
genetic CJD (84%). It is rarely detectable in fatal familial insomnia (12%) and Gerstmann- 132
Straeussler-Scheinker syndrome (20%).
133
Codon 129 polymorphism has an influence on test sensitivity of 14-3-3 with a 134
decreased detection rate in the clinically atypical MV patients (92% MV, 96% MM, 97% VV;
135
p<0.05 ANOVA). Additionally, sensitivity varies between PrPsc type 1 (98%) and type 2 136
(87%)(p=0.166). This explains the range of sensitivity within the CJD subtypes due to codon 137
129 polymorphism and prion protein type (Figure 2). Age at onset revealed a lower 14-3-3 138
sensitivity in patients below the age of 50 (88%), while a maximum was found for patients 139
between 70-79 at onset (98%) (p=0.01 ANOVA). Another positive association was found for 140
disease duration below 6 (98%) and 7 to 12 months (97%) in contrast to only 91% for a 141
duration of more than 12 months (p<0.001) (Table 1).
142
We tested patients with CJD and other dementing diseases for the presence of CSF 143
transthyretin (TTR). While most of the samples showed similar levels as the controls, TTR 144
Accepted Manuscript
was lower in patients with Alzheimer’s disease (AD) and normal pressure hydrocephalus 145
(NPH) (Table 2). In AD, the decrease was disease-stage dependent with lower levels in 146
advanced stages. Beta-amyloid1-42 was decreased in all samples investigated and therefore did 147
not distinguish between these disorders. Total tau was elevated in most samples with a 148
maximum increase in CJD (median).
149 150
3.3. MRI analysis 151
To date, the scans of 206 different patients with sCJD and known subtypes have been 152
analysed. Cortical hyperintensities in DWI seem to present with different localization patterns 153
and frequency within different subtypes (Figure 3, Figure 4c). While frontal and parietal 154
hyperintensities are the most frequent ones in MM1 (79% both localisations) and MM2 (67%
155
both localisations), a marked difference is present in the hippocampus: Whereas only 7% of 156
all investigated MM1 patients have abnormalities in this area, 57% of the MM2 patients 157
showed pathological hyperintensities. In both subtypes, cortical changes were more frequent 158
(93% and 83%) than the CJD typical finding of hyperintense basal ganglia (71% and 50%) 159
(Figure 3, Figure 4a). Interestingly, we found thalamic hyperintensities in one third of the 160
MM2 patients and 7 out of 10 MV2 patients, but in none of the MM1 patients (Figure 4b).
161 162
4. Discussion 163
The diagnosis of CJD has been much improved since prospective surveillance systems 164
were established in many countries worldwide (in Germany 1993). While diagnosis was 165
initially made according to the criteria suggested by Masters et al. 1979, such as typical 166
clinical features and PSWC in EEG, in 1998 these criteria were improved by adding 14-3-3 167
detection in CSF (WHO, 1998; Zerr et al., 2000). Several investigations showed high 168
sensitivity and specificity of this parameter for sCJD (Sanchez-Juan et al., 2006).
169
Nevertheless, false positive 14-3-3 in case reports and lower sensitivity in several studies 170
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were reported (Saiz et al., 1999; Berg et al., 2003). Thus, we performed a detailed analysis of 171
14-3-3 influenced by several conditions such as disease subtype or clinical parameters.
172
Parchi et al. described subtypes by association of codon 129 polymorphism and prion 173
protein type (Parchi et al., 1996). These subtypes present with broadly varying phenotypes, 174
and some of them with atypical clinical presentation. Thus, these subtypes might be clinically 175
underestimated and paraclinical markers are more important. Our data revealed lower 176
sensitivity of 14-3-3 for patients with MV genotype, prion protein type 2, age at onset below 177
50 and disease duration over 12 months. However 14-3-3 was found in more than two thirds 178
of patients in all patient groups evaluated. These differences between the subtypes might 179
explain the lower sensitivity in some studies (Geschwind et al., 2003; Blennow et al., 2005), 180
because no data on the subtype in these studies were available. Additionally, 14-3-3 is less 181
helpful in genetic TSE and full length sequencing of PRNP in atypical suspects can detect 182
these cases.
183
A new dementia marker, TTR, has been found to be valuable in Alzheimer’s disease, 184
one of the main differential diagnoses of CJD (Castano et al., 2006; Merched et al., 1998;
185
Riisoen, 1988). We were able to confirm these data and additionally found decreased TTR 186
levels in NPH patients. A combination of several neurodegenerative CSF markers seems to be 187
the most promising diagnostic tool for differential diagnosis of dementia with 14-3-3, total tau 188
and TTR.
189
MRI can support the clinical diagnosis with typical findings of hyperintense basal 190
ganglia in sCJD and thalamic hyperintensities in vCJD (Shiga et al., 2004). Additionally, 191
cortical signal increase is described with increasing frequency, probably due to improved 192
technical standards. For several atypical CJD subtypes, a high value of MRI has been shown 193
(Collins et al., 2006). Until now, no detailed analysis of subtype specific findings for all 194
subtypes has been reported. Our data on more than 200 MRI scans found differences between 195
the subtypes with characteristic findings for location of cortical signal increase and varying 196
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frequency of hyperintense basal ganglia (Meissner et al., 2005). An interesting finding was 197
thalamic hyperintensities in MM2 and MV2 patients (Krasnianski et al., 2006b; Krasnianski 198
et al., 2006a) Thalamic hyperintensities and in detail the pulvinar sign are known to be 199
characteristic of variant CJD in contrast to sCJD (Summers et al., 2004). Whether these 200
similarities on MRI between sporadic and variant CJD are due to similarities on pathogenesis 201
or the spread of PrPsc, has to be evaluated in further studies.
202
Therefore, we suggest a diagnostic approach for suspected CJD patients. For any 203
patient, believed to be suffering from CJD, lumbar puncture with the measuring of 14-3-3 204
should be performed (sensitivity up to 100% depending on molecular subtype, disease 205
progression and disease stage). Additionally, other brain-derived proteins in CSF such as total 206
tau can increase diagnostic accuracy. Other markers such as transthyretin might be helpful to 207
distinguish CJD from Alzheimer’s disease, but these findings have to be confirmed in larger 208
patient groups. Secondly, a cerebral MRI, including diffusion-weighted images, helps 209
diagnosis, especially in early forms or atypical presentation. Thirdly, EEG should be analysed 210
for presence of PSWC’s, but this test becomes more relevant in later disease stages.
211 212
5. Conclusion 213
Summarizing, the diagnosis of prion disease has improved in recent years. This has 214
serious implications for clinical diagnosis and epidemiology. Firstly, detailed analysis of 215
subtype characteristics increases the detection rate of these patients. Secondly, clinical CJD 216
diagnosis is supported by new CSF parameters or subtype-specific marker combinations.
217
Finally, the progress in MR imaging will markedly improve clinical diagnosis. All these 218
factors might explain the continuous increase in incidence of sporadic CJD in Germany.
219 220 221
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Acknowledgement 221
This study was funded by the Robert Koch Institute through funds provided by the 222
Federal Ministry of Health (grant no 1369-341), the Federal Ministry of Education and 223
Research (BMBF 01GI0301 and KZ: 0312720) and by the European Commission (EC) 224
(QLG3-CT-2002-81606 to IZ).
225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245
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Table 1 – 14-3-3 sensitivity sorted by disease duration; p<0.001 ANOVA 336
337 338
14-3-3 positive 14-3-3 negative Sensitivity
0-6 months 548 14 97.5
7-12 months 253 9 96.5
>12 months 236 23 91.1
339 340
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Table 2 – Median of CSF parameters in differential diagnosis of CJD: AD = Alzheimer’s 340
disease, NPH = normal pressure hydrocephalus, LBD = Lewy-body dementia, CJD = 341
Creutzfeldt-Jakob disease; TTR = transthyretin 342
343
AD NPH LBD CJD
TTR mg/l
14.7
▼
12.6
▼ 18.6 18.9
Total tau pg/ml
302
▲ 165 291
▲
8171
▲ ▲ ▲ Aß1-42
pg/ml 391
▼ 483
▼ 126
▼ 238
▼
14-3-3 ▲ ▲ ▲
344 345 346
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Table 3: Different values of the technical investigations EEG, CSF and MRI stratified by 346
CJD subtype 347
348
sporadic vCJD
MM1/
MV1
VV1 MM2 MV2 VV2 MM2b
EEG PSWCs +
CSF 14-3-3 + + (+) (+) + (+)
Cortex + + + + ? (+)
Basal ganglia + (+) + + (+)
hyperintensity (+) + + +
Thalamus
pulvinar sign (+) +
MRI
Hippocampus + + ? ?
349 350
Accepted Manuscript
Figure Legends:
350
Figure 1:
351
Proportion of the codon 129 genotype over the years of surveillance with a trend to increase 352
of the atypical genotypes MV and VV 353
354 355
Figure 2: Levels of 14-3-3 measured by ELISA in the six CJD subtypes 356
357
Figure 3: MRI findings of the MM1 and MM2 CJD subtype 358
359 360
Figure 4:
361
(a) Axial diffusion-weighted MRI of an sCJD patient (63-year-old woman) with hyperintense 362
caput ncl. caudate on both sides 363
(b) sCJD patient with less intense hyperintense basal ganglia and additionally signal increase 364
in both thalami (diffusion-weighted image) 365
(c) cortical hyperintensities in a 81-year-old female sCJD patient, predominantly in the right 366
hemisphere, diffusion-weighted image 367
Accepted Manuscript
1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005
%
0 10 20 30 40 50 60 70 80
MM MV VV MV+VV
Accepted Manuscript
1 = MM1 2 = MM2 3 = MV1 4 = MV2 5 = VV1 6 = VV2
sC JD subtype
1 2 3 4 5 6
pg/ml
0 2000 4000 6000 8000 10000 12000 14000
Accepted Manuscript
71
0 86
43
29 93
0 10 20 30 40 50 60 70 80 90 100
Cortex Basal ganglia Thalamus
% MM1
MM2
