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.
Highlights
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 main analysis comprised 3616 samples from patients with various forms of transmissible spongiform encephalopathies (3254 samples being from patients with sporadic Creutzfeldt–Jakob disease) and 7115 from control subjects (Table 1)
If we exclude all patients with transmissible spongiform encephalopathies from the analysis, the distribution was as follows: 42.6% neurodegenerative dementia, 27.3% acute neurological disease and 13.2% non-neurological, potentially treatable cognitive deterioration (6.8% metabolic and 6.4% psychiatric disease)
Summary
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). 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 included in the WHO criteria (Hsich et al, 1996; Zerr et al, 2000a). Because elevated levels of protein 14-3-3 are 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
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