Cerebrospinal Fluid Biomarker Supported Diagnosis of Creutzfeldt–Jakob Disease and Rapid Dementias

A Longitudinal Multicentre Study Over 10 Years

Katharina Stoeck; Pascual Sanchez-Juan; Joanna Gawinecka; Alison Green; Anna Ladogana; Maurizio Pocchiari; Raquel Sanchez-Valle; Eva Mitrova; Theodor Sklaviadis; Jerzy Kulczycki; Dana Slivarichova; Albert Saiz; Miguel Calero; Richard Knight; Adriano Aguzzi; Jean-Louis Laplanche; Katell Peoc'h; Gabi Schelzke; Andre Karch; Cornelia M. van Duijn; Inga Zerr

Disclosures

Brain. 2012;135(10):3051-3061. 

In This Article

Abstract and Introduction

Abstract

To date, cerebrospinal fluid analysis, particularly protein 14-3-3 testing, presents an important approach in the identification of Creutzfeldt–Jakob disease cases. However, one special point of criticism of 14-3-3 testing is the specificity in the differential diagnosis of rapid dementia. The constant observation of increased cerebrospinal fluid referrals in the national surveillance centres over the last years raises the concern of declining specificity due to higher number of cerebrospinal fluid tests performed in various neurological conditions. Within the framework of a European Community supported longitudinal multicentre study ('cerebrospinal fluid markers') we analysed the spectrum of rapid progressive dementia diagnoses, their potential influence on 14-3-3 specificity as well as results of other dementia markers (tau, phosphorylated tau and amyloid-β1–42) and evaluated the specificity of 14-3-3 in Creutzfeldt–Jakob disease diagnosis for the years 1998–2008. A total of 29 022 cerebrospinal fluid samples were analysed for 14-3-3 protein and other cerebrospinal fluid dementia markers in patients with rapid dementia and suspected Creutzfeldt–Jakob disease in the participating centres. In 10 731 patients a definite diagnosis could be obtained. Protein 14-3-3 specificity was analysed for Creutzfeldt–Jakob disease with respect to increasing cerebrospinal fluid tests per year and spectrum of differential diagnosis. Ring trials were performed to ensure the comparability between centres during the reported time period. Protein 14-3-3 test specificity remained high and stable in the diagnosis of Creutzfeldt–Jakob disease during the observed time period across centres (total specificity 92%; when compared with patients with definite diagnoses only: specificity 90%). However, test specificity varied with respect to differential diagnosis. A high 14-3-3 specificity was obtained in differentiation to other neurodegenerative diseases (95–97%) and non-neurological conditions (91–97%). We observed lower specificity in the differential diagnoses of acute neurological diseases (82–87%). A marked and constant increase in cerebrospinal fluid test referrals per year in all centres did not influence 14-3-3 test specificity and no change in spectrum of differential diagnosis was observed. Cerebrospinal fluid protein 14-3-3 detection remains an important test in the diagnosis of Creutzfeldt–Jakob disease. Due to a loss in specificity in acute neurological events, the interpretation of positive 14-3-3 results needs to be performed in the clinical context. The spectrum of differential diagnosis of rapid progressive dementia varied from neurodegenerative dementias to dementia due to acute neurological conditions such as inflammatory diseases and non-neurological origin.

Introduction

The clinical diagnosis of Creutzfeldt–Jakob disease is based on clinical syndrome and results of established paraclinical tests (EEG, CSF analysis and cranial MRI) (Zerr et al., 2000a, 2009; Collins et al., 2006). The predominant clinical symptoms are characterized by rapid progressive dementia followed by development of neurological signs, e.g. ataxia and myoclonus (Gambetti et al., 2003). The disease is fatal and leads to death in a few months.

Detection of periodic sharp wave complexes on EEG substantiated the diagnosis of sporadic Creutzfeldt–Jakob disease for a long period of time (Masters et al., 1979; Zerr et al., 2000a, b). From 1995 onwards, detection of neuronal destruction markers in CSF have become more and more important. They have been established in diagnostic work-up, with protein 14-3-3 as the most promising surrogate marker finally included in the WHO criteria (Hsich et al., 1996; Zerr et al., 2000a). Because elevated levels of protein 14-3-3 are also reported in a range of non-prion-related diseases, mostly caused by an acute neurological event such as encephalitis, stroke, epileptic fit or tumour, positive results must be interpreted in the clinical context.

Another major step in the diagnosis of sporadic Creutzfeldt–Jakob disease was the introduction of MRI, where a specific pattern in patients with sporadic Creutzfeldt–Jakob disease, characterized by hyperintense signals in basal ganglia and cortical regions, was identified (Tschampa et al., 2007; Meissner et al., 2008). Especially sensitive MRI techniques such as FLAIR and diffusion-weighted MRI sequences allow a diagnosis of sporadic Creutzfeldt–Jakob disease with high sensitivity and specificity (Satoh et al., 2007; Meissner et al., 2009). As a result, a positive MRI scan was proposed to be included into the clinical criteria in 2009 (Zerr et al., 2009).

To date, CSF analysis, in particular protein 14-3-3 testing, presents an important approach in the identification of Creutzfeldt–Jakob disease cases and a request for CSF testing to specialized laboratories is frequently a major way to obtain referrals to surveillance centres. However, one special point of criticism of 14-3-3 testing was a potential loss of specificity and several reports on that have been published (Chohan et al., 2010; Coulthart et al., 2011; Perry and Geschwind, 2011). Within the framework of a European Community (EC) supported longitudinal multicentre study ('CJD markers') we evaluated the specificity of 14-3-3 in Creutzfeldt–Jakob disease diagnosis from the years 1998–2008. In addition we analysed the spectrum of rapid progressive dementia diagnoses, their potential influence on 14-3-3 specificity as well as results of related dementia markers (tau, phosphorylated tau, amyloid β1–42) in different forms of rapid dementias. We present results of regular ring trials conducted in participating surveillance laboratories to analyse inter-laboratory reliability (Supplementary material).

The term 'rapid progressive dementia' or shortened 'rapid dementia' we used in this study summarizes a condition of cognitive deterioration that can be attributed to either a neurological (most commonly neurodegenerative) or non-neurological disease (Geschwind et al., 2008). Potentially reversible conditions (e.g. acute delirium, pseudo-dementia in depression, CNS inflammation) can appear frequently and need to be considered in the diagnostic process.

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