Review
Cerebrospinal fluid biomarkers in Creutzfeldt–Jakob disease

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Abstract

Creutzfeldt–Jakob disease (CJD) is a rare neurodegenerative disorder. Since the emergence of variant CJD (vCJD) vigilance concerning the disease's incidence has increased and the interest in accurate in vivo diagnosis has augmented. So far, a large number of biomarkers has been investigated as aid in the differential diagnosis of sporadic Creutzfeldt–Jakob disease (sCJD) and vCJD. These include, among others, neuron-specific enolase (NSE), microtubuli associated protein Tau, S-100β, amyloid-beta (Aβ1–42) and the 14-3-3 protein. Multiple studies have confirmed that CSF detection of 14-3-3 protein by Western blot was the best single biomarker for sCJD with an average sensitivity and specificity of 92%. Also, in genetic and iatrogenic CJD (iCJD) patients with an average disease duration of less than 1 year, 14-3-3 is the best differential biomarker. Unfortunately, the 14-3-3 protein has a lower sensitivity if the disease duration exceeds beyond 1 year in both sporadic CJD and other CJD types (vCJD, and specific genetic or iatrogenic CJD types).

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.

Section snippets

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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