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Brain Advance Access originally published online on July 1, 2006
Brain 2006 129(9):2278-2287; doi:10.1093/brain/awl159
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Determinants of diagnostic investigation sensitivities across the clinical spectrum of sporadic Creutzfeldt–Jakob disease

S. J. Collins1,*, P. Sanchez-Juan2,*, C. L. Masters1, G. M. Klug1, C. van Duijn2, A. Poleggi3, M. Pocchiari3, S. Almonti3, N. Cuadrado-Corrales4, J. de Pedro-Cuesta4, H. Budka5, E. Gelpi5, M. Glatzel6,13, M. Tolnay6, E. Hewer6, I. Zerr7, U. Heinemann7, H. A. Kretszchmar8, G. H. Jansen9, E. Olsen9, E. Mitrova10, A. Alpérovitch11, J.-P. Brandel11, J. Mackenzie12, K. Murray12 and R. G. Will12

1 Australian National Creutzfeldt–Jakob disease Registry, Department of Pathology, The University of Melbourne Parkville, Vic., Australia 2 Department of Epidemiology and Biostatistics, Erasmus MC Rotterdam, The Netherlands 3 National Registry of Creutzfeldt–Jakob disease, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanita’ Rome, Italy 4 National HTSE Laboratory Unit at Centre of Microbiology and National HTSE Registry at Centre of Epidemiology, Instituto de Salud Carlos III Calle Sinesio Delgado 6, Madrid, Spain 5 Austrian Reference Centre for Human Prion Diseases, Institute of Neurology, Medical University Vienna Wien, Austria 6 Institute of Neuropathology and National Reference Center for Prion Diseases, University Hospital Zurich Zurich, Switzerland 7 Department of Neurology, Georg-August University Göttingen, Germany 8 Department of Neuropathology, Ludwig-Maximilian University Munich, Germany 9 Centre for Infectious Disease Prevention and Control, Public Health Agency of Canada Ottawa, ON, Canada 10 Institute of Preventive and Clinical Medicine, Research Base of Slovak Medical University Bratislava, Slovak Republic 11 U.708 INSERM, Hôpital de la Salpêtrière Paris, France 12 National CJD Surveillance Unit, Western General Hospital Edinburgh, UK 13 Present address: University Medical Center Hamburg-Eppendorf, Institute of Neuropathology Hamburg, Germany

Correspondence to: S. J. Collins, Australian National CJD Registry, Department of Pathology, Level 3, Alan Gilbert Building, 161 Barry Street, Carlton South, Vic., 3053, Australia E-mail: stevenjc{at}unimelb.edu.au

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.

Key Words: sporadic CJD; diagnostic investigation results; molecular sub-typing

Abbreviations: CJD, Creutzfeldt–Jakob disease; PrPres, protease-resistant prion protein; PSWC, periodic sharp wave complexes

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Received October 6, 2005. Revised May 9, 2006. Accepted May 16, 2006.

*These authors contributed equally to this work.


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