Cerebrospinal fluid biomarker supported diagnosis of Creutzfeldt–Jakob disease and rapid dementias: a longitudinal multicentre study over 10 years

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.

Dysregulation of 14‐3‐3 proteins in neurodegenerative diseases with Lewy body or Alzheimer pathology

“…Measurement of 14‐3‐3s in CSF has been used clinically as a diagnostic biomarker for Creutzfeldt‐Jakob Disease (CJD), although recent studies have demonstrated that the specificity for CJD is lower than initially thought 48, 49, 50, 51. However, this body of research has demonstrated that 14‐3‐3 measurements in CSF are reliable and stable in patients, and can help with diagnosis in the right clinical context 48, 49. Further evaluation of 14‐3‐3 phosphorylation in CSF and plasma is indicated for these disorders.…”

New Frontiers in Alzheimer's Disease Diagnosis

“…It is believed that deregulated tau may be reflecting the neuronal and axonal damage present in brain tissue and, as a consequence, the presence of increased tau levels is not a specific event for AD. Accordingly, transient tau increments have been also reported in acute stroke [123], and the most increased tau levels are observed in prion diseases such as in CJD, where massive neuronal cell death is present [124,125]. Higher CSF tau is also associated with smaller brain volume in individuals with AD [126].…”

Enfermedad de Creutzfeldt-Jakob en el Perú: reporte de once casos

“…El análisis de algunas proteínas, como la proteína 14-3-3, es útil y su elevación en LCR representa daño neuronal aunque no es específico de ECJ (15) y tiene una mayor sensibilidad en la esECJ que en las otras formas. Según Chohan et al la proteína 14-3-3 tiene una sensibilidad de 86% y una especificidad de 74% en fases avanzadas de la enfermedad (16) .…”