ReviewCerebrospinal fluid biomarkers in Creutzfeldt–Jakob disease
Introduction
Creutzfeldt–Jakob disease (CJD) is a progressive neurodegenerative and ultimately fatal disorder which is thought to be caused by prions and belonging to the group of the transmissible spongiform encephalopathies [1]. In CJD, four distinct subtypes can be identified [2]. The most common form is sporadic CJD (sCJD) and accounts for 85% of all patients. Genetic CJD has also been known for a long time and consists of about 10–15% of all patients. Numerous pathogenic mutations have been identified in the prion protein gene (PRNP), which can be specifically linked to a wide range of clinical and pathological phenotypes [3]. After the discovery that sCJD could be transmitted [4], a number of accidental transmissions between humans have been documented (called iatrogenic CJD (iCJD)) [5]. These transmissions mostly involved central nervous tissue transplants of a contaminated source or cadaver extracted hormones [6]. The most recently identified form is variant CJD (vCJD) in the United Kingdom [7] and was causally linked to bovine spongiform encephalopathy (BSE) [8], [9].
Biochemical markers in the cerebrospinal fluid (CSF) for the diagnosis of CJD have been investigated since the eighties. In this review, we will give a detailed overview of the clinical and CSF diagnosis of all CJD types.
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Sporadic Creutzfeld–Jakob disease
Sporadic CJD is the most common form of CJD with an incidence of 1–2 per 106 inhabitants/year [3]. This neurodegenerative disorder is clinically rapidly progressive and ultimately fatal within 6–8 months after onset. The average age at onset of sCJD is 65 years (range 30–90 years) and the average disease duration is 6 months (range 1–49 months)[10].
The largest number (60%) of sCJD patients present with rapidly evolving dementia. If dementia is absent, a wide variety of signs or symptoms can be
14-3-3 Protein
After the identification of a possible biomarker for Alzheimer's disease (microtubuli associated protein (MAP) Tau), CSF of patients with other neurodegenerative disorders was analysed in search of new markers [14]. In the CSF of sCJD patients, two proteins, p130 and p131, were identified using two-dimensional poly-acrylamide gel electrophoresis and further analysis showed that they belonged to the 14-3-3 protein family. The 14-3-3 protein was already known to be expressed in most tissues but
Variant Creutzfeldt–Jakob disease
In the United Kingdom, 146 (April 2004) vCJD patients have been identified. Patients have further been identified in France (n = 8), Ireland (n = 1), Italy (n = 1), USA (n = 1), Hong Kong (n = 1) and Canada (n = 1). Recent reports indicate that the incidence is decreasing [47]. The average age of onset is 27 years (range 12–74 years) and the average disease duration is 18 months (range 6–39 months) [48], [49].
All patients showed early psychiatric and behavioural symptoms followed by cerebellar ataxia [49].
The use of 14-3-3 in the diagnosis of vCJD
After the identification of vCJD in young patients, a reliable differential biomarker was essential, not only for an early diagnosis but also to have a tool for following the incidence of the disease at it progresses. All previously described CSF biomarkers (NSE, S-100β, 14-3-3 and Tau) for sCJD were analysed in vCJD patients. Surprisingly, none of the markers had a sufficient sensitivity and specificity to be considered as a diagnostic test [27], [36]. If combinations of Tau determination were
Genetic and iatrogenic Creutzfeldt–Jakob disease
In genetic CJD, an autosomal dominant inherited mutation of the prion protein gene is causally linked to the disease origin. The familial occurrence of CJD was already known for a long time (1930s) and in about 10–15% of all patients, a mutation was found. Next to numerous point mutations, one stop-codon mutation (V145Stop) and several octapeptide repeat insertions/deletions in the coding sequence of PRNP have been reported [52]. The multiple mutations in PRNP are associated with specific
The use of 14-3-3 in the diagnosis of genetic and iatrogenic CJD
Presently, only limited studies have investigated the usefulness of 14-3-3 analysis in either genetic or iatrogenic CJD, due to the extreme rarity of both disorders [53], [56]. In multiple studies analysing 14-3-3 in CJD based upon a country surveillance network also small groups of one to six genetic and iatrogenic CJD patients were identified and separately discussed [24], [25], [26], [57].
In genetic CJD, it was found that in mutations that mimic the sporadic phenotype (e.g. E200K, V2001I),
Conclusions
In the differential diagnosis of CJD with other types of dementia so far, the only useful CSF biomarker identified is the 14-3-3 protein. The 14-3-3 protein is a stable, reliable biomarker with an average specificity and specificity of 92% and is used worldwide. However, this marker is not suitable as a screening tool for CJD in the dementia population. For the other types of CJD, a positive 14-3-3 test strongly strengthens the clinical diagnosis, while a negative test, on the other hand, does
Acknowledgements
The authors thank the Fund for Scientific Research (FWO) for supporting this research. B.V.E. is a postdoctoral researcher of the Fund for Scientific Research (FWO).
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Cited by (67)
Lumbar punctures and cerebrospinal fluid analysis
2016, Medicine (United Kingdom)Citation Excerpt :Repeated LPs are often required to identify malignant cells. Measurement of the brain-specific protein 14-3-3 in the CSF is used in the diagnosis of rapidly progressive dementia.5 In an appropriate clinical scenario, an elevated concentration is very suggestive of Creutzfeld–Jakob disease.
Sporadic Creutzfeldt-Jakob disease diagnostic accuracy is improved by a new CSF ELISA 14-3-3γ assay
2016, NeuroscienceCitation Excerpt :In a recent study, the long-term stability of 14-3-3 in CSF samples was evaluated and the authors concluded that there is an initial loss of about 20% in samples stored at −80 °C for up to 1 year but older samples (up to 9 years) can remain relatively stable further on (Schmitz et al., 2015). Published data have shown that extremely elevated levels of total Tau with low phosphorylated Tau to total Tau ratio are common features in almost all CJD types (Green et al., 2001; Otto et al., 2002; Blennow et al., 2005; Van Everbroeck et al., 2005a). Some authors found CSF Tau protein to have greater specificity and efficiency than 14-3-3 in distinguishing sCJD from other rapidly progressive neurodegenerative conditions (Riemenschneider et al., 2003; Hamlin et al., 2012; Skillbäck et al., 2014).
Creutzfeldt-Jakob disease: An Emergency Department presentation
2015, American Journal of Emergency MedicineLumbar punctures and cerebrospinal fluid analysis
2012, Medicine (United Kingdom)Citation Excerpt :Repeated lumbar punctures are often required to identify malignant cells. Measurement in CSF of the brain-specific protein 14-3-3 is used in the diagnosis of rapidly progressive dementia.5 In the appropriate clinical scenario, an elevated concentration is very suggestive of Creutzfeld–Jakob disease (CJD), but is not entirely specific as it can be elevated in other rapidly progressive dementias and following prolonged seizures.
Comparison of mRNA expression levels of selected genes in the brain stem of cattle naturally infected with classical and atypical BSE
2010, Brain ResearchCitation Excerpt :However its detectable level appears at the late stage of the incubation period, making the ante mortem diagnosis impossible. Detection of 14-3-3 protein in cerebro-spinal fluid (CSF) of patients suspected of sporadic Creutzfeldt-Jacob disease was described and approved by WHO as helpful method in early diagnosis, however the level of this protein increases also in other diseases such as brain stroke or meningoencephalitis (Van Everbroeck et al., 2005). 14-3-3 protein is a marker of brain damage and its presence in CSF is thought to be connected with its excretion after the cell lysis rather than with its function in the prion diseases pathogenesis.
Interpretation of cerebrospinal fluid protein tests in the diagnosis of sporadic Creutzfeldt-Jakob disease: An evidence-based approach
2014, CMAJ. Canadian Medical Association JournalCitation Excerpt :However, observer dependence and variability among disease subtypes can complicate the application of MRI.21,23 The most widely used supporting investigations are immunoassays for certain protein markers that are markedly elevated in lumbar cerebrospinal fluid in most affected patients (Box 2).24,25 The most commonly used cerebrospinal fluid markers are 14-3-3 proteins, the microtubule-associated protein tau and the S100B protein, for which many studies have reported estimates of diagnostic sensitivity and specificity in the range 0.80–0.90 (Appendix 1).26,27