Determinants of diagnostic investigation sensitivities across the clinical spectrum of sporadic Creutzfeldt-Jakob disease

Abstract

To validate the provisional findings of a number of smaller studies and explore additional determinants of characteristic diagnostic investigation results across the entire clinical spectrum of sporadic Creutzfeldt-Jakob disease (CJD), an international collaborative study was undertaken comprising 2451 pathologically confirmed (definite) patients. We assessed the influence of age at disease onset, illness duration, prion protein gene (PRNP) codon 129 polymorphism (either methionine or valine) and molecular sub-type on the diagnostic sensitivity of EEG, cerebral MRI and the CSF 14-3-3 immunoassay. For EEG and CSF 14-3-3 protein detection, we also assessed the influence of the time point in a patient's illness at which the investigation was performed on the likelihood of a typical or positive result. Analysis included a large subset of patients (n = 743) in whom molecular sub-typing had been performed using a combination of the PRNP codon 129 polymorphism and the form of protease resistant prion protein [type 1 or 2 according to Parchi et al. (Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeffer W, Windl O, Zerr I, Budka H, Kopp N, Piccardo P, Poser S, Rojiani A, Streichemberger N, Julien J, Vital C, Ghetti B, Gambetti P, Kretzschmar H. Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 1999; 46: 224-233.)] present in the brain. Findings for the whole group paralleled the subset with molecular sub-typing data available, showing that age at disease onset and disease duration were independent determinants of typical changes on EEG, while illness duration significantly influenced positive CSF 14-3-3 protein detection; changes on brain MRI were not influenced by either of these clinical parameters, but overall, imaging data were less complete and consequently conclusions are more tentative. In addition to age at disease onset and illness duration, molecular sub-type was re-affirmed as an important independent determinant of investigation results. In multivariate analyses that included molecular sub-type, time point of the investigation during a patient's illness was found not to influence the occurrence of a typical or positive EEG or CSF 14-3-3 protein result. A typical EEG was most often seen in MM1 patients and was significantly less likely in the MV1, MV2 and VV2 sub-types, whereas VV2 patients had an increased likelihood of a typical brain MRI. Overall, the CSF 14-3-3 immunoassay was the most frequently positive investigation (88.1%) but performed significantly less well in the very uncommon MV2 and MM2 sub-types. Our findings confirm a number of determinants of principal investigation results in sporadic CJD and underscore the importance of recognizing these pre-test limitations before accepting the diagnosis excluded or confirmed. Combinations of investigations offer the best chance of detection, especially for the less common molecular sub-types such as MV2 and MM2.

Diagnostic value of CSF protein profile in a Portuguese population of sCJD patients

“…This is in agreement with recent data from an international collaborative study [9], and with the majority of the literature reporting the sensitivity of the 14-3-3 test [22,30,37,39]. However, the specificity of the 14-3-3 assay, in our population, was clearly sub optimal (78%), lower than the EEG (86%) and that reported in most previous studies [22,30,37,39].…”

“…Regarding the molecular characteristics of the sCJD group, the frequency of the various PRNP genotypes was broadly in accordance with the frequency distributions generally reported in the literature [9,24]. Also as expected [9,24], most patients had a type-1 PrP isoform, and MM1 molecular subtype was the most frequent.…”

“…Also as expected [9,24], most patients had a type-1 PrP isoform, and MM1 molecular subtype was the most frequent. There was however, a fairly strong representation of the less frequent MV1 subtype and one patient with the very rare VV1 subtype.…”

“…Contradictory results exist regarding this issue. Although disease duration clearly seems to affect 14-3-3 sensitivity, the influence of age is not so widely accepted [9,30,39]. As for t-tau and S-100b, earlier studies failed to find any influence of age and/or disease duration on these protein markers sensitivity [17,39], but a more recent study, conducted in a large population of CJD patients, succeeded in doing so [30].…”

“…One of the major limitations of this assay is that the 14-3-3 immunoblot is usually analysed in a qualitative manner, by visual inspection, leading to a subjective interpretation of borderline results. Moreover, its sensitivity is believed to be strongly influenced by disease duration [9,30,39], and a number of other conditions that lead to neuronal injury are known to give false positive results. These include central nervous system infections, cerebrovascular diseases, encephalopathies, brain tumours, inflammatory conditions and other types of dementia.…”