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1.  Updated clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease 
Brain  2009;132(10):2659-2668.
Several molecular subtypes of sporadic Creutzfeldt–Jakob disease have been identified and electroencephalogram and cerebrospinal fluid biomarkers have been reported to support clinical diagnosis but with variable utility according to subtype. In recent years, a series of publications have demonstrated a potentially important role for magnetic resonance imaging in the pre-mortem diagnosis of sporadic Creutzfeldt–Jakob disease. Magnetic resonance imaging signal alterations correlate with distinct sporadic Creutzfeldt–Jakob disease molecular subtypes and thus might contribute to the earlier identification of the whole spectrum of sporadic Creutzfeldt–Jakob disease cases. This multi-centre international study aimed to provide a rationale for the amendment of the clinical diagnostic criteria for sporadic Creutzfeldt–Jakob disease. Patients with sporadic Creutzfeldt–Jakob disease and fluid attenuated inversion recovery or diffusion-weight imaging were recruited from 12 countries. Patients referred as ‘suspected sporadic Creutzfeldt–Jakob disease’ but with an alternative diagnosis after thorough follow up, were analysed as controls. All magnetic resonance imaging scans were assessed for signal changes according to a standard protocol encompassing seven cortical regions, basal ganglia, thalamus and cerebellum. Magnetic resonance imaging scans were evaluated in 436 sporadic Creutzfeldt–Jakob disease patients and 141 controls. The pattern of high signal intensity with the best sensitivity and specificity in the differential diagnosis of sporadic Creutzfeldt–Jakob disease was identified. The optimum diagnostic accuracy in the differential diagnosis of rapid progressive dementia was obtained when either at least two cortical regions (temporal, parietal or occipital) or both caudate nucleus and putamen displayed a high signal in fluid attenuated inversion recovery or diffusion-weight imaging magnetic resonance imaging. Based on our analyses, magnetic resonance imaging was positive in 83% of cases. In all definite cases, the amended criteria would cover the vast majority of suspected cases, being positive in 98%. Cerebral cortical signal increase and high signal in caudate nucleus and putamen on fluid attenuated inversion recovery or diffusion-weight imaging magnetic resonance imaging are useful in the diagnosis of sporadic Creutzfeldt–Jakob disease. We propose an amendment to the clinical diagnostic criteria for sporadic Creutzfeldt–Jakob disease to include findings from magnetic resonance imaging scans.
doi:10.1093/brain/awp191
PMCID: PMC2759336  PMID: 19773352
CJD; MRI; FLAIR; DWI; molecular subtypes; dementia
2.  Diagnosis of Creutzfeldt-Jakob disease by measurement of S100 protein in serum: prospective case-control study 
BMJ : British Medical Journal  1998;316(7131):577-582.
Objective: To analyse serum concentrations of brain specific S100 protein in patients with Creutzfeldt-Jakob disease and in controls.
Design: Prospective case-control study.
Setting: National Creutzfeldt-Jakob disease surveillance unit.
Subjects: 224 patients referred to the surveillance unit with suspected Creutzfeldt-Jakob disease and 35 control patients without dementia.
Main outcome measure: Serum concentration of S100 protein in patients with Creutzfeldt-Jakob disease, in patients with other diseases causing dementia, and in the control group.
Results: Of the 224 patients with suspected Creutzfeldt-Jakob disease, 65 were classed as definitely having the disease after neuropathological verification, an additional 6 were classed as definitely having the disease as a result of a genetic mutation, 43 as probably having the disease, 36 as possibly having the disease, and 74 patients were classed as having other disease. In the 108 patients classed as definitely or probably having Creutzfeldt-Jakob disease the median serum concentration of S100 was 395 pg/ml (SD 387 pg/ml). This was significantly higher than concentrations found in the 74 patients classed as having other diseases (median 109 pg/ml; SD 177 pg/ml; P=0.0001). At a cut off point of 213 pg/ml sensitivity for the diagnosis of the disease was 77.8% (95% confidence interval 68.8% to 85.2%) and specificity was 81.1% (70.3% to 89.3%). There was a significant difference in survival at different concentrations of S100 in Kaplan-Meier curves (P=0.023).
Conclusion: Measurement of serum concentrations of S100 is a valuable tool which can be used more easily than tests on cerebrospinal fluid in the differential diagnosis of Creutzfeldt-Jakob disease. More studies are needed to determine whether serial testing of serum S100 improves diagnostic accuracy.
Key messages Creutzfeldt-Jakob disease is a rare, fatal neurodegenerative disease. Diagnosis is made clinically and neuropathologically There is no serum test which allows the diagnosis to be made while the patient is alive In this study raised serum concentrations of S100 protein were found in patients with Creutzfeldt-Jakob disease Serum concentrations of S100 could be used with a sensitivity of 77.8% and a specificity of 81.1% to confirm Creutzfeldt-Jakob disease in the differential diagnosis of diseases that cause dementia Serial measurement of S100 concentrations will enhance diagnostic accuracy
PMCID: PMC28459  PMID: 9518907
3.  A Test for Creutzfeldt–Jakob Disease Using Nasal Brushings 
The New England journal of medicine  2014;371(6):519-529.
BACKGROUND
Definite diagnosis of sporadic Creutzfeldt–Jakob disease in living patients remains a challenge. A test that detects the specific marker for Creutzfeldt–Jakob disease, the prion protein (PrPCJD), by means of real-time quaking-induced conversion (RT-QuIC) testing of cerebrospinal fluid has a sensitivity of 80 to 90% for the diagnosis of sporadic Creutzfeldt–Jakob disease. We have assessed the accuracy of RT-QuIC analysis of nasal brushings from olfactory epithelium in diagnosing sporadic Creutzfeldt– Jakob disease in living patients.
METHODS
We collected olfactory epithelium brushings and cerebrospinal fluid samples from patients with and patients without sporadic Creutzfeldt–Jakob disease and tested them using RT-QuIC, an ultrasensitive, multiwell plate–based fluorescence assay involving PrPCJD-seeded polymerization of recombinant PrP into amyloid fibrils.
RESULTS
The RT-QuIC assays seeded with nasal brushings were positive in 30 of 31 patients with Creutzfeldt–Jakob disease (15 of 15 with definite sporadic Creutzfeldt–Jakob disease, 13 of 14 with probable sporadic Creutzfeldt–Jakob disease, and 2 of 2 with inherited Creutzfeldt–Jakob disease) but were negative in 43 of 43 patients without Creutzfeldt–Jakob disease, indicating a sensitivity of 97% (95% confidence interval [CI], 82 to 100) and specificity of 100% (95% CI, 90 to 100) for the detection of Creutzfeldt–Jakob disease. By comparison, testing of cerebrospinal fluid samples from the same group of patients had a sensitivity of 77% (95% CI, 57 to 89) and a specificity of 100% (95% CI, 90 to 100). Nasal brushings elicited stronger and faster RT-QuIC responses than cerebrospinal fluid (P<0.001 for the between-group comparison of strength of response). Individual brushings contained approximately 105 to 107 prion seeds, at concentrations several logs10 greater than in cerebrospinal fluid.
CONCLUSIONS
In this preliminary study, RT-QuIC testing of olfactory epithelium samples obtained from nasal brushings was accurate in diagnosing Creutzfeldt–Jakob disease and indicated substantial prion seeding activity lining the nasal vault. (Funded by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases and others.)
doi:10.1056/NEJMoa1315200
PMCID: PMC4186748  PMID: 25099576
4.  Symptomatic aggravation after corticosteroid pulse therapy in definite sporadic Creutzfeldt-Jakob disease with the feature of Hashimoto’s encephalopathy 
BMC Neurology  2014;14(1):179.
Background
Creutzfeldt-Jakob disease and Hashimoto’s encephalopathy often show similar clinical presentation. Among Creutzfeldt-Jakob disease mimics, Hashimoto’s encephalopathy is particularly important as it is treatable with corticosteroids. Thus, in cases of middle-aged woman diagnosed with probable Creutzfeldt-Jakob disease and who exhibit high titers of antithyroid antibodies, corticosteroid pulse therapy is typically performed with expectations of near complete recovery from Hashimoto’s encephalopathy. Herein, we provide the first case report that exhibited a negative effect of corticosteroid pulse therapy for a patient with Creutzfeldt-Jakob disease with features of Hashimoto’s encephalopathy.
Case presentation
We report a case of 59-year-old Asian woman with blurred vision, dysarthria, myoclonus, and rapidly progressive dementia. Cerebrospinal fluid showed 14-3-3 protein positive. Electroencephalogram showed periodic sharp waves (1.5 Hz) at the bilateral frontal or occipital areas. Magnetic resonance imaging showed high signal intensities at the bilateral cerebral cortex, caudate nucleus, and putamen. The patient was diagnosed with probable Creutzfeldt-Jakob disease. However, serum analysis showed a high titer of antithyroid antibodies. We started corticosteroid pulse therapy with subsequent aggravation of seizure activity including generalized myoclonus, epilepsia parialis continua, and ballistic dyskinesia, which was effectively treated with clonazepam.
Conclusion
We provide evidence of a case of Creutzfeldt-Jakob disease that exhibited clinical deterioration after corticosteroid therapy. Although histopathological confirmation with brain biopsy is not easily available in Creutzfeldt-Jakob disease patients, selective initiation of corticosteroid pulse therapy should be considered in cases of uncertain diagnosis for differentiation with Hashimoto’s encephalopathy.
doi:10.1186/s12883-014-0179-y
PMCID: PMC4172833  PMID: 25196053
Creutzfeldt-Jakob disease; Hashimoto’s encephalopathy; Corticosteroid; Seizure
5.  Creutzfeldt-Jakob disease mimicking autoimmune encephalitis with CASPR2 antibodies 
BMC Neurology  2014;14(1):227.
Background
Differential diagnosis of severe progressive dementia includes a wide spectrum of inflammatory and neurodegenerative diseases. Particularly challenging is the differentiation of potentially treatable autoimmune encephalitis and Creutzfeldt-Jakob disease. Such a coincidence may indeed complicate the correct diagnosis and influence subsequent treatment.
Case presentation
A 75-year-old woman was admitted due to rapid progressive cognitive impairment. Her husband observed a temporal disorientation and confusion. The initial neurological examination and an extensive neuropsychological evaluation showed significant impairments in almost all tested cognitive domains. All other neurological functions including motor, sensory and coordinative function were intact. Initial diagnostics included EEG, MRI and lumbar puncture with unspecific results. Complementary blood testing revealed a positive result for antineural antibodies to Contactin-associated protein 2 (CASPR2) and the patient received treatment for CASPR2 autoimmune encephalitis. Further symptoms and results, including 14-3-3 proteins, led to suspected Creutzfeldt-Jakob disease. The postmortem examination supported the diagnosis of a definitive Creutzfeldt-Jakob disease.
Conclusion
One could argue that global screening for antineural antibodies may lead to a false diagnosis triggering intense and potentially dangerous procedures. We believe, however, that potentially treatable causes of dementia should aggressively sought out and subsequently treated in an attempt to curtail the course of disease and ultimately reduce the rate of mortality.
doi:10.1186/s12883-014-0227-7
PMCID: PMC4255969  PMID: 25434587
CASPR2; VGKC; Creutzfeldt-Jakob disease; Encephalitis; Autoimmune; Autoantibody; Thyroperoxidase antibodies
6.  Cerebrospinal fluid markers in Creutzfeldt-Jakob disease 
Background
The objective was to assess the utility of total tau protein (tTau), the ratio of (tTau)/181 phosphorylated tau protein (P-Tau) and 14-3-3 protein, as diagnostic markers in cerebrospinal fluid (CSF) for Creutzfeldt-Jakob disease (CJD).
Methods
CSF samples received from Norwegian hospitals between August 2005 and August 2007 were retrospectively selected from consecutive patients with tTau values > 1200 ng/L (n = 38). The samples from patients clinically diagnosed with CJD (n = 12) were compared to those from patients with other degenerative neurological diseases: Alzheimer's/vascular dementia (AD/VaD, n = 21), other neurological diseases (OND, n = 5). Total Tau, P-Tau, and β-Amyloid (Aβ42) were measured with commercial kits. Additionally, 14-3-3 protein was measured semi-quantitatively by immunoblot.
Results
The minimum cut-off limits for diagnosis of CJD were chosen from the test results. For tTau the lower limit was fixed at 3000 ng/L, for the tTau/P-Tau ratio it was 60, and for 14-3-3 protein it was 0.75 arbitrary units. For tTau and tTau/P-Tau ratio, all but three CJD patients had levels above the minimum, whereas almost all of the other patients were below. For the 14-3-3 protein, two CJD patients were below the minimum and five were above. Only one of the other patients was higher than the limit. The sensitivities, specificities and diagnostic efficiencies were: tTau 75%, 92%, and 87%; tTau/P-Tau 75%, 96%, and 89%; and 14-3-3 protein 80%, 96%, and 91%.
Conclusion
The results suggest that 14-3-3 protein may be the better marker for CJD, tTau/P-Tau ratio and tTau are also efficient markers, but showed slightly inferior diagnostic properties in this study, with tTau/P-Tau marginally better than tTau.
doi:10.1186/1743-8454-5-14
PMCID: PMC2531166  PMID: 18727840
7.  Agraphia of Kanji (Chinese characters): an early symptom of sporadic Creutzfeldt-Jakob disease in a Japanese patient: a case report 
Introduction
Slowly progressive cognitive decline is the most frequent initial manifestation in MM2-cortical-type sporadic Creutzfeldt-Jakob disease. Agraphia has never been noted in patients with this type of sporadic Creutzfeldt-Jakob disease, however, we report the case of a Japanese patient with sporadic Creutzfeldt-Jakob disease in whom agraphia of Kanji was an initial cardinal symptom.
Case presentation
A 59-year-old right-handed Japanese woman complained of agraphia of Kanji (Chinese characters) as an initial symptom. A neurological examination revealed mild word-finding difficulty, constructive disturbance, hyperreflexia in her jaw and lower limbs, and bilateral extensor plantar reflexes. An examination of her cerebrospinal fluid revealed increased levels of 14-3-3 and total tau proteins, and abnormal conformation of the proteinase K-resistant prion protein. Diffusion-weighted magnetic resonance imaging showed diffuse hyperintensity in bilateral cerebral cortices. Single-photon emission computed tomography scans revealed hypoperfusion in the left temporal lobe, bilateral parietal and occipital lobes. An analysis of the prion protein gene demonstrated no mutation with homozygous for methionine at the codon 129. We diagnosed our patient with sporadic Creutzfeldt-Jakob disease. Although a histological examination was not performed, it was assumed that our patient could be the MM2-cortical type according to the clinical findings and the elevated levels of 14-3-3 protein in her cerebrospinal fluid. The left posterior inferior temporal area, which was affected in our patient as a hypoperfusion area, is associated with selecting and recalling Kanji characters.
Conclusions
Focal signs as an early symptom and hypoperfusion areas in sporadic Creutzfeldt-Jakob disease are critical to recognize initial brain lesions damaged by the proteinase K-resistant prion protein accumulation.
doi:10.1186/1752-1947-8-269
PMCID: PMC4132354  PMID: 25098795
Agraphia; Creutzfeldt-Jakob disease; Kana (Japanese syllabary); Kanji (Chinese characters); Magnetic resonance imaging
8.  The value of magnetic resonance imaging in the early diagnosis of Creutzfeldt-Jakob disease – own experience 
Polish Journal of Radiology  2012;77(1):63-67.
Summary
Background:
Creutzfeldt-Jakob disease (CJD) is a rare progressive neurodegenerative disorder, caused by the deposition of the pathological isoform of prion protein PrPsc in the central nervous system. The classic triad of symptoms consists of: rapidly progressive dementia, myoclonus and typical electroencephalographic findings (intermittent rhythmic delta activity and periodic sharp wave complexes). Detection of 14-3-3 protein in the cerebrospinal fluid plays an important diagnostic role as well. Magnetic resonance (MR) images of the brain have been recently incorporated into the diagnostic criteria of sporadic Creutzfeldt-Jakob disease.
Case Report:
MR examinations were performed in a 65-year-old man and a 54-year-old woman with delusional disorder and cognitive dysfunction, respectively. Diffusion restriction (hyperintense signal in DWI) was shown in the cortex of the left parietal and occipital lobe in the first patient and symmetrically in the cortex of both cerebral hemispheres except for precentral gyri in the second one. In both cases, the first examinations were misread, with the suspicion of ischemic infarcts as the first differential diagnosis. Consultations and subsequent MR examinations in which lesions in subcortical nuclei appeared allowed for a diagnosis of probable CJD. In the first case it was confirmed by clinical picture, EEG and finally – autopsy. In the second case, EEG was not typical for CJD but the clinical course of the disease confirmed that diagnosis.
Conclusions:
The authors present the cases of two patients with characteristic MR images that allowed early diagnosis of probable Creutzfeldt-Jakob disease before the characteristic clinical picture appeared. Early diagnosis is nowadays important for the prevention of disease transmission and in the future – hopefully – for early treatment.
PMCID: PMC3389956  PMID: 22802869
Creutzfeldt-Jakob disease (CJD); magnetic resonance imaging (MRI)
9.  A prospective study of CSF markers in 250 patients with possible Creutzfeldt–Jakob disease 
Objective: To investigate various cerebrospinal fluid (CSF) markers that could assist in the clinical diagnosis of Creutzfeldt–Jakob disease (CJD).
Methods: CSF samples were analysed for the presence of 14-3-3 protein, microtubule associated protein tau, and ß amyloid in 250 patients with possible CJD. Densitometric analysis was used to quantify the level of 14-3-3 in all patients.
Results: Analysis of the clinical data showed that cerebellar signs or myoclonus combined with progressive dementia were the main features leading to a clinical suspicion of CJD. While 14-3-3 detection had a sensitivity of 100% and a specificity of 92%, tau determination using a threshold of 1300 pg/ml had a sensitivity of 87% and a specificity of 97%. If the protocol for the analysis of 14-3-3 was modified (using densitometric analysis) a higher specificity (97%) could be obtained, but with a lower sensitivity (96%). Maximum sensitivity, specificity, and positive predictive value were obtained with a combination of 14-3-3 and ß amyloid determinations. The concentrations of 14-3-3 and tau in the CSF were reduced in CJD patients with a long duration of disease (more than one year; p < 0.05). The concentrations of 14-3-3 or tau were lowest at the onset or at the end stage of the disease, while the ß amyloid concentration remained low throughout the course of the disease.
Conclusions: Both 14-3-3 and tau protein are sensitive and specific biomarkers for CJD. The combination of 14-3-3 and ß amyloid analysis resulted in the maximum sensitivity, specificity, and positive predictive value. When these biomarkers are used in the diagnosis of CJD, the phase of the disease in which the CSF sample was obtained should be taken into account. Disease duration, dependent on the PrP genotype, also has a significant influence on the level of 14-3-3 and tau in the CSF.
doi:10.1136/jnnp.74.9.1210
PMCID: PMC1738637  PMID: 12933920
10.  Cerebrospinal Fluid Markers in Sporadic Creutzfeldt-Jakob Disease 
Sporadic Creutzfeldt-Jakob disease (sCJD) is the commonest form of human prion diseases, accounting for about 85% of all cases. Current criteria for intra vitam diagnosis include a distinct phenotype, periodic sharp and slow-wave complexes at electroencephalography (EEG), and a positive 14-3-3-protein assay in the cerebrospinal fluid (CSF). In sCJD, the disease phenotype may vary, depending upon the genotype at codon 129 of the prion protein gene (PRNP), a site of a common methionine/valine polymorphism, and two distinct conformers of the pathological prion protein. Based on the combination of these molecular determinants, six different sCJD subtypes are recognized, each with distinctive clinical and pathologic phenotypes. We analyzed CSF samples from 127 subjects with definite sCJD to assess the diagnostic value of 14-3-3 protein, total tau protein, phosphorylated181 tau, and amyloid beta (Aβ) peptide 1-42, either alone or in combination. While the 14-3-3 assay and tau protein levels were the most sensitive indicators of sCJD, the highest sensitivity, specificity and positive predictive value were obtained when all the above markers were combined. The latter approach also allowed a reliable differential diagnosis with other neurodegenerative dementias.
doi:10.3390/ijms12096281
PMCID: PMC3189782  PMID: 22016658
sporadic Creutzfeldt-Jakob disease; 14-3-3 protein; tau protein; amyloid beta peptide
11.  Voltage-Gated Potassium Channel Autoimmunity Mimicking Creutzfeldt-Jakob Disease 
Archives of neurology  2008;65(10):1341-1346.
Background
Rapidly progressive dementia has a variety of causes, including Creutzfeldt-Jakob disease (CJD) and neuronal voltage-gated potassium channel (VGKC) autoantibody–associated encephalopathy.
Objective
To describe patients thought initially to have CJD but found subsequently to have immunotherapy-responsive VGKC autoimmunity.
Design
Observational, prospective case series.
Setting
Department of Neurology, Mayo Clinic, and the Memory and Aging Center, University of California, San Francisco.
Patients
A clinical serologic cohort of 15 patients referred for paraneoplastic autoantibody evaluation. Seven patients were evaluated clinically by at least one of us. Clinical information for the remaining patients was obtained by physician interview or medical record review.
Main Outcome Measures
Clinical features, magnetic resonance imaging abnormalities, electroencephalographic patterns, cerebrospinal fluid analyses, and responses to immunomodulatory therapy.
Results
All the patients presented subacutely with neurologic manifestations, including rapidly progressive dementia, myoclonus, extrapyramidal dysfunction, visual hallucinations, psychiatric disturbance, and seizures; most (60%) satisfied World Health Organization diagnostic criteria for CJD. Magnetic resonance imaging abnormalities included cerebral cortical diffusion-weighted imaging hyperintensities. Electroencephalographic abnormalities included diffuse slowing, frontal intermittent rhythmic delta activity, and focal epileptogenic activity but not periodic sharp wave complexes. Cerebrospinal fluid 14-3-3 protein or neuron-specific enolase levels were elevated in 5 of 8 patients. Hyponatremia was common (60%). Neoplasia was confirmed histologically in 5 patients (33%) and was suspected in another 5. Most patients’ conditions (92%) improved after immunomodulatory therapy.
Conclusions
Clinical, radiologic, electrophysiologic, and laboratory findings in VGKC autoantibody–associated encephalopathy may be confused with those of CJD. Serologic evaluation for markers of neurologic autoimmunity, including VGKC autoantibodies, may be warranted in suspected CJD cases.
doi:10.1001/archneur.65.10.1341
PMCID: PMC2736144  PMID: 18852349
12.  Rapid and Sensitive RT-QuIC Detection of Human Creutzfeldt-Jakob Disease Using Cerebrospinal Fluid 
mBio  2015;6(1):e02451-14.
ABSTRACT 
Fast, definitive diagnosis of Creutzfeldt-Jakob disease (CJD) is important in assessing patient care options and transmission risks. Real-time quaking-induced conversion (RT-QuIC) assays of cerebrospinal fluid (CSF) and nasal-brushing specimens are valuable in distinguishing CJD from non-CJD conditions but have required 2.5 to 5 days. Here, an improved RT-QuIC assay is described which identified positive CSF samples within 4 to 14 h with better analytical sensitivity. Moreover, analysis of 11 CJD patients demonstrated that while 7 were RT-QuIC positive using the previous conditions, 10 were positive using the new assay. In these and further analyses, a total of 46 of 48 CSF samples from sporadic CJD patients were positive, while all 39 non-CJD patients were negative, giving 95.8% diagnostic sensitivity and 100% specificity. This second-generation RT-QuIC assay markedly improved the speed and sensitivity of detecting prion seeds in CSF specimens from CJD patients. This should enhance prospects for rapid and accurate ante mortem CJD diagnosis.
Importance  A long-standing problem in dealing with various neurodegenerative protein misfolding diseases is early and accurate diagnosis. This issue is particularly important with human prion diseases, such as CJD, because prions are deadly, transmissible, and unusually resistant to decontamination. The recently developed RT-QuIC test allows for highly sensitive and specific detection of CJD in human cerebrospinal fluid and is being broadly implemented as a key diagnostic tool. However, as currently applied, RT-QuIC takes 2.5 to 5 days and misses 11 to 23% of CJD cases. Now, we have markedly improved RT-QuIC analysis of human CSF such that CJD and non-CJD patients can be discriminated in a matter of hours rather than days with enhanced sensitivity. These improvements should allow for much faster, more accurate, and practical testing for CJD. In broader terms, our study provides a prototype for tests for misfolded protein aggregates that cause many important amyloid diseases, such as Alzheimer’s, Parkinson’s, and tauopathies.
Importance 
A long-standing problem in dealing with various neurodegenerative protein misfolding diseases is early and accurate diagnosis. This issue is particularly important with human prion diseases, such as CJD, because prions are deadly, transmissible, and unusually resistant to decontamination. The recently developed RT-QuIC test allows for highly sensitive and specific detection of CJD in human cerebrospinal fluid and is being broadly implemented as a key diagnostic tool. However, as currently applied, RT-QuIC takes 2.5 to 5 days and misses 11 to 23% of CJD cases. Now, we have markedly improved RT-QuIC analysis of human CSF such that CJD and non-CJD patients can be discriminated in a matter of hours rather than days with enhanced sensitivity. These improvements should allow for much faster, more accurate, and practical testing for CJD. In broader terms, our study provides a prototype for tests for misfolded protein aggregates that cause many important amyloid diseases, such as Alzheimer’s, Parkinson’s, and tauopathies.
doi:10.1128/mBio.02451-14
PMCID: PMC4313917  PMID: 25604790
13.  Progressive Stroke-Like Symptoms in a Patient with Sporadic Creutzfeldt-Jakob Disease 
Case Reports in Neurology  2010;2(1):12-18.
Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare neurodegenerative disorder in which accumulation of a pathogenic isoform of prion protein (PrPSc) induces neuronal damage with distinct pathologic features. The prognosis of sCJD is devastating: rapid clinical decline is followed by death generally within months after onset of symptoms. The classic clinical manifestations of sCJD are rapidly progressing dementia, myoclonus, and ataxia. However, the spectrum of clinical features can vary considerably. We describe a definite, neuropathologically verified sCJD in a 67-year-old woman who initially presented with progressive stroke-like symptoms: left-sided hemiparesis and ataxia within a few days. The initial brain magnetic resonance imaging (MRI) showed bilateral cortical hyperintensity on diffusion-weighted sequences (DWI) resembling multiple ischemic lesions. Despite anticoagulation with low-molecular-weight heparin, the patient deteriorated rapidly, became dysphagic and bedridden with myoclonic jerks on her left side extremities correlating with intermittent high-amplitude epileptiform discharges on electroencephalography (EEG). Basal ganglia hyperintense signal changes in addition to cortical ribboning were seen in DWI images of a follow-up MRI. Repeated EEG recordings showed an evolution to periodic sharp wave complexes. Protein 14-3-3 was positive in her cerebrospinal fluid specimen, in addition to an abnormally high total tau level. In the terminal stage the patient was in an akinetic, mutistic state with deteriorating consciousness. She died 19 days after admission to the hospital. Neuropathologic investigation corroborated the clinical diagnosis of sCJD with spongiform degeneration and immunohistochemical demonstration of the deposition of pathologic PrPSc.
doi:10.1159/000289177
PMCID: PMC2914366  PMID: 20689629
Atypical; Stroke-like onset; Creutzfeldt-Jakob disease; Prion diseases
14.  Creutzfeldt-Jakob Disease: A Case Report and Differential Diagnoses 
Sporadic Creutzfeldt-Jakob disease is a rare neurodegenerative disorder of unknown etiology that causes rapidly progressive dementia. This disease is uniformly fatal and most patients die within 12 months. Clinical findings include myoclonus, visual disturbances, and cerebellar and pyramidal/extrapyramidal signs in addition to rapidly progressive cognitive and functional impairment. These findings are all non-specific and it is often difficult and challenging to diagnose premortem because of low awareness and clinical suspicion.
We present a 66-year-old woman with a 5-month history of rapidly progressive dementia. After a series of extensive diagnostic examinations and continuous follow-up, she was diagnosed with probable sporadic Creutzfeldt-Jakob disease based on Centers for Disease Control and Prevention (CDC) criteria, with key findings of rapidly progressive dementia, blurry vision, extrapyramidal signs (cogwheel rigidity), and abnormal hyperintensity signals on diffusion-weighted MRI. Her symptoms progressively worsened and she died 7 months after the onset. The postmortem brain autopsy demonstrated the presence of abnormal protease-resistant prion protein by Western Blot analysis.
A literature review was performed on differential diagnoses that present with rapidly progressive dementia and thereby mimic sporadic Creutzfeldt-Jakob disease. These include Alzheimer's disease, dementia with Lewy Bodies, frontotemporal dementia, meningoencephalitis, corticobasal degeneration, progressive supranuclear palsy, CADASIL, and paraneoplastic encephalomyelitis.
PMCID: PMC3689509  PMID: 23795314
sporadic Creutzfeldt-Jakob disease; prion disease; rapidly progressing dementia
15.  Diagnostic accuracy of cerebrospinal fluid protein markers for sporadic Creutzfeldt-Jakob disease in Canada: a 6-year prospective study 
BMC Neurology  2011;11:133.
Background
To better characterize the value of cerebrospinal fluid (CSF) proteins as diagnostic markers in a clinical population of subacute encephalopathy patients with relatively low prevalence of sporadic Creutzfeldt-Jakob disease (sCJD), we studied the diagnostic accuracies of several such markers (14-3-3, tau and S100B) in 1000 prospectively and sequentially recruited Canadian patients with clinically suspected sCJD.
Methods
The study included 127 patients with autopsy-confirmed sCJD (prevalence = 12.7%) and 873 with probable non-CJD diagnoses. Standard statistical measures of diagnostic accuracy were employed, including sensitivity (Se), specificity (Sp), predictive values (PVs), likelihood ratios (LRs), and Receiver Operating Characteristic (ROC) analysis.
Results
At optimal cutoff thresholds (empirically selected for 14-3-3, assayed by immunoblot; 976 pg/mL for tau and 2.5 ng/mL for S100B, both assayed by ELISA), Se and Sp respectively were 0.88 (95% CI, 0.81-0.93) and 0.72 (0.69-0.75) for 14-3-3; 0.91 (0.84-0.95) and 0.88 (0.85-0.90) for tau; and 0.87 (0.80-0.92) and 0.87 (0.84-0.89) for S100B. The observed differences in Sp between 14-3-3 and either of the other 2 markers were statistically significant. Positive LRs were 3.1 (2.8-3.6) for 14-3-3; 7.4 (6.9-7.8) for tau; and 6.6 (6.1-7.1) for S100B. Negative LRs were 0.16 (0.10-0.26) for 14-3-3; 0.10 (0.06-0.20) for tau; and 0.15 (0.09-0.20) for S100B. Estimates of areas under ROC curves were 0.947 (0.931-0.961) for tau and 0.908 (0.888-0.926) for S100B. Use of interval LRs (iLRs) significantly enhanced accuracy for patient subsets [e.g., 41/120 (34.2%) of tested sCJD patients displayed tau levels > 10,000 pg/mL, with an iLR of 56.4 (22.8-140.0)], as did combining tau and S100B [e.g., for tau > 976 pg/mL and S100B > 2.5 ng/mL, positive LR = 18.0 (12.9-25.0) and negative LR = 0.02 (0.01-0.09)].
Conclusions
CSF 14-3-3, tau and S100B proteins are useful diagnostic markers of sCJD even in a low-prevalence clinical population. CSF tau showed better overall diagnostic accuracy than 14-3-3 or S100B. Reporting of quantitative assay results and combining tau with S100B could enhance case definitions used in diagnosis and surveillance of sCJD.
doi:10.1186/1471-2377-11-133
PMCID: PMC3216246  PMID: 22032272
16.  High sensitivity of an ELISA kit for detection of the gamma-isoform of 14-3-3 proteins: usefulness in laboratory diagnosis of human prion disease 
BMC Neurology  2011;11:120.
Background
The gamma-isoform of the 14-3-3 protein (14-3-3 gamma) is expressed in neurons, and could be a specific marker for neuronal damage. This protein has been reported as a detectable biomarker, especially in the cerebrospinal fluid (CSF) of Creutzfeldt-Jakob disease (CJD) patients by Western blotting (WB) or enzyme-linked immunosorbent assays (ELISAs). Western blotting for 14-3-3 gamma is not sensitive, and the reported data are conflicting among publications. An ELISA specific for 14-3-3 gamma is not available.
Methods
CJD patients (n = 114 sporadic CJD patients, 7 genetic CJD, and 3 iatrogenic CJD) and 99 patients with other neurodegenerative diseases were examined in this study. The CSF samples obtained were analyzed by Western blotting for 14-3-3 gamma, and by ELISA for total tau protein. We evaluated the sensitivity and specificity of the newly developed sandwich ELISA for 14-3-3 gamma.
Results
The cut-off value of the 14-3-3 gamma ELISA was > 1, 683 AU/ml; and sensitivity was 95.2%, with 72.7% specificity. This specificity was the same for the total tau protein ELISA. Seven CJD cases were negative by WB but positive using the 14-3-3 gamma ELISA, indicating that the ELISA is more sensitive. All 21 cases of early stage CJD could be diagnosed using a combination of the 14-3-3γ ELISA and diffusion weighted MR imaging (DWI-MRI).
Conclusion
The 14-3-3 gamma ELISA was more sensitive than conventional WB, and was useful for laboratory diagnosis of CJD, similar to the ELISA for the tau protein. Using DWI-MRI and these ELISA tests on CSF, diagnosis of CJD will be possible even at early stages of the disease.
doi:10.1186/1471-2377-11-120
PMCID: PMC3204235  PMID: 21970675
CJD; CSF; ELISA; prion disease; 14-3-3 protein; tau protein
17.  Brain-water diffusion coefficients reflect the severity of inherited prion disease 
Neurology  2010;74(8):658-665.
Objective:
Inherited prion diseases are progressive neurodegenerative conditions, characterized by cerebral spongiosis, gliosis, and neuronal loss, caused by mutations within the prion protein (PRNP) gene. We wished to assess the potential of diffusion-weighted MRI as a biomarker of disease severity in inherited prion diseases.
Methods:
Twenty-five subjects (mean age 45.2 years) with a known PRNP mutation including 19 symptomatic patients, 6 gene-positive asymptomatic subjects, and 7 controls (mean age 54.1 years) underwent conventional and diffusion-weighted MRI. An index of normalized brain volume (NBV) and region of interest (ROI) mean apparent diffusion coefficient (ADC) for the head of caudate, putamen, and pulvinar nuclei were recorded. ADC histograms were computed for whole brain (WB) and gray matter (GM) tissue fractions. Clinical assessment utilized standardized clinical scores. Mann-Whitney U test and regression analyses were performed.
Results:
Symptomatic patients exhibited an increased WB mean ADC (p = 0.006) and GM mean ADC (p = 0.024) compared to controls. Decreased NBV and increased mean ADC measures significantly correlated with clinical measures of disease severity. Using a stepwise multivariate regression procedure, GM mean ADC was an independent predictor of Clinician's Dementia Rating score (p = 0.001), Barthel Index of activities of daily living (p = 0.001), and Rankin disability score (p = 0.019).
Conclusions:
Brain volume loss in inherited prion diseases is accompanied by increased cerebral apparent diffusion coefficient (ADC), correlating with increased disease severity. The association between gray matter ADC and clinical neurologic status suggests this measure may prove a useful biomarker of disease activity in inherited prion diseases.
GLOSSARY
= Alzheimer's Disease Assessment Scale–Cognitive subscale;
= apparent diffusion coefficient;
= Barthel Activities of Daily Living scale;
= brain extraction tool;
= Brief Psychiatric Rating Scale;
= bovine spongiform encephalopathy;
= Clinician's Dementia Rating Scale;
= Clinician's Global Impression of Disease;
= confidence interval;
= diffusion-weighted imaging;
= fluid-attenuated inversion recovery;
= field of view;
= gray matter;
= left head of caudate;
= left putamen;
= left pulvinar;
= Mini-Mental State Examination;
= normalized brain volume;
= peak height;
= peak location;
= right head of caudate;
= right putamen;
= right pulvinar;
= region of interest;
= sporadic Creutzfeldt-Jakob disease;
= echo time;
= inversion time;
= repetition time;
= variant Creutzfeldt-Jakob disease;
= whole brain;
= white matter.
doi:10.1212/WNL.0b013e3181d0cc47
PMCID: PMC2830920  PMID: 20177119
18.  Case series of probable sporadic Creutzfeldt-Jakob disease from Eastern India 
Background:
Creutzfeldt-Jakob disease is a rapidly progressive, fatal, transmissible neurodegenerative disorder caused by prion protein. It is still considered rare in countries like India. This is probably due to nonavailability of autopsy studies in majority of the center. The recent European diagnostic criterion for sporadic CJD (sCJD) is useful for making an early diagnosis.
Objective:
To report a series of patients of probable sCJD from a neurology institute of eastern India.
Materials and Methods:
Patients of rapidly developing dementia fulfilling the diagnostic criteria for sCJD were included. All were investigated in detail to find out any possible treatable cause including electroencephalography (EEG), magnetic resonance imaging (MRI) of brain, and cerebrospinal fluid analysis.
Results:
A total 10 patients of probable sCJD diagnosed using the European diagnostic criterion between December 2011 and January 2013. The clinical features are consistent with other reported series. While 60% of patients had the classical EEG findings, 100% had typical MRI features. Eight patients died within a mean duration of 4.56 months from the disease onset.
Conclusions:
The clinical features are similar to other reported series. Our observation raises question about the prevalence of this disease in India which needs more elaborate studies.
doi:10.4103/0972-2327.120486
PMCID: PMC3841621  PMID: 24339600
Creutzfeldt-Jakob disease; electroencephalography; magnetic resonance imaging
19.  A Low-Molecular-Weight Ferroxidase Is Increased in the CSF of sCJD Cases: CSF Ferroxidase and Transferrin as Diagnostic Biomarkers for sCJD 
Antioxidants & Redox Signaling  2013;19(14):1662-1675.
Abstract
Aims: Most biomarkers used for the premortem diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) are surrogate in nature, and provide suboptimal sensitivity and specificity. Results: We report that CJD-associated brain iron dyshomeostasis is reflected in the cerebrospinal fluid (CSF), providing disease-specific diagnostic biomarkers. Analysis of 290 premortem CSF samples from confirmed cases of CJD, Alzheimer's disease, and other dementias (DMs), and 52 non-DM (ND) controls revealed a significant difference in ferroxidase (Frx) activity and transferrin (Tf) levels in sporadic Creutzfeldt-Jakob disease (sCJD) relative to other DM and ND controls. A combination of CSF Frx and Tf discriminated sCJD from other DMs with a sensitivity of 86.8%, specificity of 92.5%, accuracy of 88.9%, and area-under-the receiver-operating-characteristic (ROC) curve of 0.94. This combination provided a similar diagnostic accuracy in discriminating CJD from rapidly progressing cases who died within 6 months of sample collection. Surprisingly, ceruloplasmin and amyloid precursor protein, the major brain Frxs, displayed minimal activity in the CSF. Most of the Frx activity was concentrated in the <3-kDa fraction in normal and diseased CSF, and resisted heat and proteinase-K treatment. Innovation: (i) A combination of CSF Frx and Tf provides disease-specific premortem diagnostic biomarkers for sCJD. (ii) A novel, nonenzymatic, nonprotein Frx predominates in human CSF that is distinct from the currently known CSF Frxs. Conclusion: The underlying cause of iron imbalance is distinct in sCJD relative to other DMs associated with the brain iron imbalance. Thus, change in the CSF levels of iron-management proteins can provide disease-specific biomarkers and insight into the cause of iron imbalance in neurodegenerative conditions. Antioxid. Redox Signal. 19, 1662–1675.
doi:10.1089/ars.2012.5032
PMCID: PMC3809602  PMID: 23379482
20.  The Appropriate Use of Neuroimaging in the Diagnostic Work-Up of Dementia 
Background
Diagnosis of dementia is challenging and requires both ruling out potentially treatable underlying causes and ruling in a diagnosis of dementia subtype to manage patients and suitably plan for the future.
Objectives
This analysis sought to determine the appropriate use of neuroimaging during the diagnostic work-up of dementia, including indications for neuroimaging and comparative accuracy of alternative technologies.
Data Sources
A literature search was performed using Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid Embase, the Wiley Cochrane Library, and the Centre for Reviews and Dissemination database, for studies published between 2000 and 2013.
Review Methods
Data on diagnostic accuracy and impact on clinical decision making were abstracted from included studies. Quality of evidence was assessed using GRADE.
Results
The search yielded 5,374 citations and 15 studies were included. Approximately 10% of dementia cases are potentially treatable, though less than 1% reverse partially or fully. Neither prediction rules nor clinical indications reliably select the subset of patients who will likely benefit from neuroimaging. Clinical utility is highest in ambiguous cases or where dementia may be mixed, and lowest for clinically diagnosed Alzheimer disease or clinically excluded vascular dementia. There is a lack of evidence that MRI is superior to CT in detecting a vascular component to dementia. Accuracy of structural imaging is moderate to high for discriminating different types of dementia.
Limitations
There was significant heterogeneity in estimates of diagnostic accuracy, which often prohibited a statistical summary of findings. The quality of data reported by studies prohibited calculation of likelihood ratios in the present analysis. No studies from primary care were found; thus, generalizability beyond tertiary care settings may be limited.
Conclusions
A diagnosis of reversible dementia is rare. Imaging has the most clinical utility in cases where there is potentially mixed dementia or ambiguity as to the type of dementia despite prolonged follow-up (e.g., 2 years or more). Both CT and MRI are useful for detecting a vascular component of dementia.
Plain Language Summary
Dementia is a devastating condition of memory loss and behaviour change that affects many Canadians, especially older adults. Diagnosis is complex because symptoms can be caused by different brain diseases, such as Alzheimer disease, and in some cases by other causes such a tumour or cerebrovascular disease. Although dementia rarely improves much, an accurate diagnosis is important because it determines the treatment a patient should receive and helps patients and families understand what the future holds.
Brain imaging, using computed tomography (CT) or magnetic resonance imaging (MRI) scans, may help in the diagnosis by allowing doctors to see changes in brain structure or function that explain the dementia. Unfortunately, it is not well understood which patients will most likely benefit from a brain scan and which type of scan works best to diagnose dementia. This study reviewed the published evidence about these questions.
The study found that relying on specific symptoms to decide who should have a brain scan, rather than imaging all dementia patients, is unreliable and can miss some potentially treatable conditions. The study also found that scans have most value when doctors are uncertain as to the type of dementia despite monitoring the patient for a while (e.g., 2 years) or when the patient may have a combination of dementia types. Brain scans are often less helpful in the diagnosis of Alzheimer disease, and doctors can often use clinical assessment to rule out vascular dementia (another common type of dementia, related to cerebrovascular disease). The evidence also shows that MRI is not better than CT in detecting vascular dementia as a contributing cause. For Alzheimer disease, Creutzfeldt-Jakob disease, and clinically ambiguous dementias, both CT and MRI are highly accurate in correctly ruling out these diagnoses, but both types of scans have only low to moderate ability to correctly identify patients with any of these conditions. Importantly, the quality of the evidence available for this study was limited by considerable differences in research and analysis methods.
PMCID: PMC3937983  PMID: 24592296
21.  Comparative peptidome analyses of the profiles of the peptides ranging from 1–10 KD in CSF samples pooled from probable sporadic CJD and non-CJD patients 
Prion  2012;6(1):46-51.
The shotgun strategy applying tandem mass spectrometry has been widely used to identify the proteins that are differentially distributed among diseases for its high reliability and efficiency. To find out the potential difference of protein profiles in cerebrospinal fluids (CSF) between Creutzfeldt-Jakob disease (CJD) and non-CJD patients, especially in the fraction ranging from 1–10 KD, the CSF samples of 40 probable sporadic CJD (sCJD) patients, 32 non-CJD cases with dementia and 17 non-CJD cases without dementia were separately pooled and enriched by the magnetic beads based weak cation exchange chromatography (MB-WCX). After trypsin digestion, each enriched CSF was separated and identified by RP-HPLC-ESI-QTOF MS/MS. In total, 42, 53 and 47 signals of proteins were identified in the pooled CSF fraction less than 10 KD of probable sCJD, non-CJD with dementia and non-CJD without dementia, respectively. Compared with that of probable sCJD, the similarity of CSF protein profiles of non-CJD with dementia (76.2%) were higher than that of non-CJD without dementia (57.1%). Nine CSF proteins were found to be specially observed in probable sCJD group. Those data may help to select the potential biomarkers for diagnosis of CJD. Additionally, further studies of the small segments of cellular proteins in CSF of CJD patients may also provide scientific clues for understanding the neuropathogenesis of TSEs.
doi:10.4161/pri.6.1.18082
PMCID: PMC3338965  PMID: 22453178
Creutzfeldt-Jakob disease; CSF; MB-HPLC-ESI-QTOF; 1–10 KD; comparative peptidome
22.  CSF Concentrations of cAMP and cGMP Are Lower in Patients with Creutzfeldt-Jakob Disease but Not Parkinson's Disease and Amyotrophic Lateral Sclerosis 
PLoS ONE  2012;7(3):e32664.
Background
The cyclic nucleotides cyclic adenosine-3′,5′-monophosphate (cAMP) and cyclic guanosine-3′,5′-monophosphate (cGMP) are important second messengers and are potential biomarkers for Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Creutzfeldt-Jakob disease (CJD).
Methodology/Principal Findings
Here, we investigated by liquid chromatography/tandem mass spectrometry (LC-MS/MS) the cerebrospinal fluid (CSF) concentrations of cAMP and cGMP of 82 patients and evaluated their diagnostic potency as biomarkers. For comparison with a well-accepted biomarker, we measured tau concentrations in CSF of CJD and control patients. CJD patients (n = 15) had lower cAMP (−70%) and cGMP (−55%) concentrations in CSF compared with controls (n = 11). There was no difference in PD, PD dementia (PDD) and ALS cases. Receiver operating characteristic (ROC) curve analyses confirmed cAMP and cGMP as valuable diagnostic markers for CJD indicated by the area under the curve (AUC) of 0.86 (cAMP) and 0.85 (cGMP). We calculated a sensitivity of 100% and specificity of 64% for cAMP and a sensitivity of 67% and specificity of 100% for cGMP. The combination of both nucleotides increased the sensitivity to 80% and specificity to 91% for the term cAMPxcGMP (AUC 0.92) and to 93% and 100% for the ratio tau/cAMP (AUC 0.99).
Conclusions/Significance
We conclude that the CSF determination of cAMP and cGMP may easily be included in the diagnosis of CJD and could be helpful in monitoring disease progression as well as in therapy control.
doi:10.1371/journal.pone.0032664
PMCID: PMC3292568  PMID: 22396786
23.  Cerebrospinal fluid biomarkers in human genetic transmissible spongiform encephalopathies 
Journal of Neurology  2009;256(10):1620-1628.
The 14-3-3 protein test has been shown to support the clinical diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) when associated with an adequate clinical context, and a high differential potential for the diagnosis of sporadic CJD has been attributed to other cerebrospinal fluid (CSF) proteins such as tau protein, S100b and neuron specific enolase (NSE). So far there has been only limited information available about biochemical markers in genetic transmissible spongiform encephalopathies (gTSE), although they represent 10–15% of human TSEs. In this study, we analyzed CSF of 174 patients with gTSEs for 14-3-3 (n = 166), tau protein (n = 78), S100b (n = 46) and NSE (n = 50). Levels of brain-derived proteins in CSF varied in different forms of gTSE. Biomarkers were found positive in the majority of gCJD (81%) and insert gTSE (69%), while they were negative in most cases of fatal familial insomnia (13%) and Gerstmann-Sträussler-Scheinker syndrome (10%). Disease duration and codon 129 genotype influence the findings in a different way than in sporadic CJD.
doi:10.1007/s00415-009-5163-x
PMCID: PMC3085782  PMID: 19444528
Creutzfeldt-Jakob disease; CSF proteins; 14-3-3 protein; Tau
24.  Clinical range and MRI in Creutzfeldt-Jakob disease with heterozygosity at codon 129 and prion protein type 2 
A 68 year old woman with sporadic Creutzfeldt-Jakob disease is described, who neither showed characteristic EEG abnormalities nor a positive test of the neuronal protein 14-3-3 or neuron specific enolase (NSE) in CSF, despite a clinical presentation with ataxia of cerebellar type, rapidly progressive dementia, myoclonus, and marked hyperintense signal abnormalities in the deep cortical layers and the basal ganglia on T2 and diffusion weighted MRI. Moreover she showed atypical clinical features with a syndrome of inappropriate antidiuretic hormone (ADH) secretion (SIADH) and a peripheral sensorimotor polyneuropathy. Whether these disturbances are independent of Creutzfeldt-Jakob disease or a feature of it is discussed. It has recently been shown that in Creutzfeldt-Jakob disease different clinical and pathological phenotypes correlate with the polymorphism at codon 129 of the prion protein gene (PRNP) and the type of the protease resistant fragment that accumulates in the brain. According to the new classification at least six sporadic variants of Creutzfeldt-Jakob disease exist. The molecular genetic analysis showed heterozygosity of PRNP at codon 129 for methionine and valine and the presence of PrPCJD type 2 in the brain of this patient. As a new feature of changes on MRI, striking cortical changes of hyperintense signals are described in diffusion weighted as well as T2 weighted MRI that directly correlate with the histomorphological spongy degeneration of the brain in this region. In cases of rapidly progressive dementia, Creutzfeldt-Jakob disease always needs to be considered even if unusual features are present and current diagnostic criteria are not in favour of this disease.


PMCID: PMC1736619  PMID: 10519881
25.  Prions in the Urine of Patients with Variant Creutzfeldt–Jakob Disease 
The New England journal of medicine  2014;371(6):530-539.
BACKGROUND
Prions, the infectious agents responsible for transmissible spongiform encephalopathies, consist mainly of the misfolded prion protein (PrPSc). The unique mechanism of transmission and the appearance of a variant form of Creutzfeldt–Jakob disease, which has been linked to consumption of prion-contaminated cattle meat, have raised concerns about public health. Evidence suggests that variant Creutzfeldt–Jakob disease prions circulate in body fluids from people in whom the disease is silently incubating.
METHODS
To investigate whether PrPSc can be detected in the urine of patients with variant Creutzfeldt–Jakob disease, we used the protein misfolding cyclic amplification (PMCA) technique to amplify minute quantities of PrPSc, enabling highly sensitive detection of the protein. We analyzed urine samples from several patients with various transmissible spongiform encephalopathies (variant and sporadic Creutzfeldt–Jakob disease and genetic forms of prion disease), patients with other degenerative or nondegenerative neurologic disorders, and healthy persons.
RESULTS
PrPSc was detectable only in the urine of patients with variant Creutzfeldt–Jakob disease and had the typical electrophoretic profile associated with this disease. PrPSc was detected in 13 of 14 urine samples obtained from patients with variant Creutzfeldt–Jakob disease and in none of the 224 urine samples obtained from patients with other neurologic diseases and from healthy controls, resulting in an estimated sensitivity of 92.9% (95% confidence interval [CI], 66.1 to 99.8) and a specificity of 100.0% (95% CI, 98.4 to 100.0). The PrPSc concentration in urine calculated by means of quantitative PMCA was estimated at 1×10−16 g per milliliter, or 3×10−21 mol per milliliter, which extrapolates to approximately 40 to 100 oligomeric particles of PrPSc per milliliter of urine.
CONCLUSIONS
Urine samples obtained from patients with variant Creutzfeldt–Jakob disease contained minute quantities of PrPSc. (Funded by the National Institutes of Health and others.)
doi:10.1056/NEJMoa1404401
PMCID: PMC4162740  PMID: 25099577

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