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.

Magnetic resonance imaging (MRI), with diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR), is a useful diagnostic investigation for Creutzfeldt-Jakob disease (CJD). Amendment of the diagnostic criteria for sporadic CJD (sCJD) to include defined MRI alterations has just recently been proposed. We analyzed MRI scans with FLAIR and/or DWI available of 29 patients with the E200K or the V210I mutation, and a control group of 29 sCJD patients to compare the MRI lesion profile and evaluate the applicability of new MRI criteria to genetic CJD patients. FLAIR images of all 29 patients and controls and DWI images of 15 genetic CJD and 13 sCJD were rated by 2 neuroradiologists blinded to diagnosis and genetic testing. In genetic CJD (gCJD) patients, hyperintensities on FLAIR could be found in the putamen in 55% and the caudate nucleus in 66% and on DWI in 33% and 60%, respectively. Lesion profile and frequency of hyperintensities did not differ significantly from the findings in sCJD. New diagnostic MRI criteria yield similar sensitivity for gCJD and sCJD, being 79% and 72%, respectively. MRI provides useful information in E200K and V210I gCJD patients. The alterations strongly resembled those seen in sCJD, once again demonstrating the similarity of the clinical syndrome in patients with these particular mutations.

No abstract

No abstract

The genetic forms of human transmissible spongiform encephalopathies (TSEs) are linked to mutations in the gene encoding the prion protein (PRNP) and account for 10% to 15% of human TSE cases. Some are distinct with respect to clinical signs, disease onset/duration, and diagnostic findings, whereas others closely resemble sporadic Creutzfeldt-Jakob disease (sCJD). We report a comprehensive analysis of 4 patients carrying the rare E196K (GAG→AAG) mutation who presented with clinical features of CJD. To date, information on this PRNP mutation is limited to clinical and genetic data. Consequently, the E196K mutation could not be unequivocally assigned to human prion disease. We report histopathologic and biochemical findings in addition to clinical observations, thus providing a more comprehensive analysis of this presumably genetic prion disease. Our data indicate that (i) the E196K mutation is causally linked to human prion disease, (ii) there is a complex phenotypic spectrum of this mutation that includes nonspecific symptoms at onset and features typical of sCJD during disease progression, and (iii) the corresponding histologic picture comprises both cases with atypical neuropathology and cases that closely resemble subtypes of sCJD corresponding to the classification of Parchi et al, with subtle modifications in hippocampal regions CA1-4.