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Diagnosis and Classification of Prion Diseases

Biomarkers are more likely to be positive in patients with typical disease presentations than in patients with a longer disease course or younger age at onset.

Prion diseases such as Creutzfeldt-Jakob disease (CJD) represent a unique form of neurologic illness, with a pathologic mechanism that results in sporadic, familial, and transmissible forms (including variant CJD). Three new studies focus on biomarkers in diagnosing these diseases and on different classification schemes. Currently, the pathologic form of the prion protein (PrP-sc) is classified according to two features (producing six variations): the amino acid polymorphism at the polymorphic codon 129 in the coding region of the PrP gene (MM, VV, or MV), and the size of the PrP fragment that is resistant to proteinase K digestion (designated types 1 and 2).

Sanchez-Juan and colleagues examined levels of various neuronally derived proteins, including 14-3-3, tau, S100b, and neuron specific enolase (NSE), in nearly 3000 CSF samples submitted to prion disease surveillance centers; 1859 of the patients had some form of CJD, and roughly half of these had neuropathologic confirmation. As reported previously, elevation of each protein, in particular 14-3-3 and tau, was a marker of prion disease — although the sensitivities and specificities were less than ideal for diagnostic use. For example, 14-3-3 testing was at best 85% sensitive and (by a different measurement) 85% specific for sporadic CJD (sCJD). Accuracy increased with the combination of two protein tests: 14-3-3 plus either S100b or tau. Overall, the sensitivity of these markers was lower in atypical presentations of prion disease (i.e., onset at age 40 or younger, or disease duration longer than 6 months); sensitivity was also lower in MV heterozygotes than in MM or VV homozygotes.

Collins and colleagues examined clinical factors that affect the findings of 14-3-3, EEG, and MRI testing in 2451 patients in whom sCJD was proven by neuropathologic examination. Longer disease duration — but not age at onset — was associated with a lower likelihood of a positive 14-3-3 result. Both disease duration and age at onset affected EEG results; younger patients were less likely than were older patients to have abnormal EEGs. Neither age at onset nor disease duration appeared to influence MRI results. The form of PrP-sc affected these measures as well: Abnormal MRI findings were most consistently associated with form VV2; abnormal EEG findings with MM1. The 14-3-3 test was the mostly likely to be positive (88.1% sensitivity), but was less commonly associated with MV2 and MM2 than with the other forms.

Originally, subjects with PrP-sc forms MM1 or MV1 were described as having typical, rapid sCJD courses. Now, some researchers have divided MM1 subjects into two classes — those with longer and those with shorter durations of illness, reportedly correlating with variation in PrP fragment length. In 22 patients with sCJDMM1 (10 with disease duration 5 months, 12 with duration 7 months), Cali and colleagues carefully demonstrated that the reaction conditions during tissue homogenization and proteinase K digestion affect PrP fragment length. The researchers identified pH as the most critical variable. With tighter control during sample preparation, there was no evidence of a biochemical difference among MM1 subjects, despite variations in clinical course.

Comment: These studies demonstrate that the utility of biomarkers for diagnosing prion disease remains highest when the disease follows a typical clinical course (later age of onset, shorter duration). When combined with neurologic examination and the exclusion of other entities, these tests can increase the accuracy of clinical diagnosis. However, there remains an important role for the autopsy or, occasionally, brain biopsy in diagnosis and classification of prion diseases and for disease surveillance.

— Matthew P. Frosch, MD, PhD

Dr. Frosch is Associate Professor of Pathology, Harvard Medical School, and Neuropathologist in the C.S. Kubik Laboratory for Neuropathology, Department of Pathology, Massachusetts General Hospital, Boston.

Published in Journal Watch Neurology November 7, 2006

Citation(s):

Sanchez-Juan P et al. CSF tests in the differential diagnosis of Creutzfeldt-Jakob disease. Neurology 2006 Aug 22; 67:637-43.

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Collins SJ et al. Determinants of diagnostic investigation sensitivities across the clinical spectrum of sporadic Creutzfeldt-Jakob disease. Brain 2006 Sep; 129:2278-87.

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Cali I et al. Classification of sporadic Creutzfeldt-Jakob disease revisited. Brain 2006 Sep; 129:2266-77.

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• Medline abstract (Free)