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Development of an Ultra-Rapid Diagnostic Method Based on Heart-Type Fatty Acid Binding Protein Levels in the CSF of CJD Patients

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Abstract

Creutzfeldt-Jakob disease (CJD) is a transmissible, fatal, neurodegenerative disease in humans. Recently, various drugs have been reported to be useful in the treatment of CJD; however, for such treatments to be useful it is essential to rapidly and accurately diagnose CJD. 124 CJD patients and 87 with other diseases causing rapid progressive dementia were examined. Cerebral spinal fluid (CSF) from CJD patients was analyzed by 2D-PAGE and the protein expression pattern was compared with that from healthy subjects. One of three CJD-specific spots was found to be fatty acid binding protein (FABP), and heart-type FABP (H-FABP) was analyzed as a new biochemical marker for CJD. H-FABP ELISA results were compared between CJD patients and patients with other diseases (n = 211). Visual readout accuracy of the Rapicheck® H-FABP test panel for CSF was analyzed using an independent measure of CSF H-FABP concentration. The distribution of H-FABP in the brains of CJD patients was examined by immunohistochemistry. ELISA sensitivity and specificity were 90.3% and 92.9%, respectively, and Rapicheck® H-FABP sensitivity and specificity were 87.9% and 96.0%, respectively. ELISA and Rapicheck® H-FABP assays provided comparable results for 14-3-3 protein and total tau protein. Elevated H-FABP levels were associated with an accumulation of abnormal prion protein, astrocytic gliosis, and neuronal loss in the cerebral cortices of CJD patients. In conclusion, Rapicheck® H-FABP of CSF specimens enabled quick and frequent diagnosis of CJD. H-FABP represents a new biomarker for CJD distinct from 14-3-3 protein and total tau protein.

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Acknowledgments

We thank the members of the CJD Surveillance Committee in Japan. This work was supported by Grants-in-Aid of the Research Committee of Prion disease and Slow Virus Infection from the Ministry of Health, Labor and Welfare of Japan.

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Authors and Affiliations

  1. Faculty of Pharmaceutical Sciences, Department of Pharmaceutical Care and Health Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan

    Yuki Matsui, Takuya Watanabe & Yasufumi Kataoka

  2. First Department of Internal Medicine, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan

    Katsuya Satoh, Kazuo Mutsukura & Katsumi Eguchi

  3. Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Science, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan

    Katsuya Satoh & Noriyuki Nishida

  4. Laboratory of Immunobiology, Department of Molecular and Applied Bioscience, Graduate School of Biosphere Science, Hiroshima University, 1-4-4 Kagamiyama, Higashi-Hiroshima, Hiroshima, 739-8528, Japan

    Hideo Matsuda

  5. First Department of Internal Medicine, Division of Neurology, Osaka Medical College, 2-7 Daigaku-machi, Takatsukishi, Osaka, 569-8686, Japan

    Masaichi Sugino

  6. Center for Community and Campus Health, Nagasaki University, 1-14 Bunkyo, Nagasaki, 852-8521, Japan

    Susumu Shirabe

Authors
  1. Yuki Matsui
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  2. Katsuya Satoh
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  3. Kazuo Mutsukura
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  6. Hideo Matsuda
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  7. Masaichi Sugino
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  8. Susumu Shirabe
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  9. Katsumi Eguchi
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  10. Yasufumi Kataoka
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Corresponding author

Correspondence to Katsuya Satoh.

Electronic supplementary material

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Supplementary Fig. 1

Chronological changes in the ELISA for H-FABP results in CSF of CJD patients. 1-a. Chronological changes in H-FABP levels during the clinical course in the CSF of CJD patients, as detected by ELISA (cases 1–5); as reported by Satoh et al. [14]. 1-b. Comparative analysis of H-FABP levels in CSF as measured by ELISA before and after the onset of akinetic mutism (cases 6–10)

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Supplementary Fig. 2

Rapicheck® H-FABP 2-a. Structure of the Rapicheck® H-FABP system. 2-b. Rapid semi-quantitative test for human H-FABP. The appearance of an indicator test line (in addition to the quality control line) within 5 min was graded ±3 (strongly positive); appearance of a test line within 15 min was graded ±2 (moderately positive); and the appearance of a weak test line within 15 min was graded ±1 (weakly positive). The absence of a test line at 15 min was reported as 0 (negative)

(JPEG 347 kb)

Supplementary Fig. 3

Correlation analysis between H-FABP levels and either total tau protein or S-100 protein levels. 3-a. Correlation analysis between H-FABP and total tau protein levels. 3-b. Correlation analysis between H-FABP and S-100 protein levels

(JPEG 194 kb )

Supplementary Fig. 4

Neuropathology of H-FABP immunostaining in brain sections from CJD patients. 4-a. H-FABP immunostaining in brain sections from CJD patients. 4-b. Strong immunostaining of neurons surrounding the disease lesion. There is a lot of neuronal loss in the cerebral cortex of CJD patients and immunostaining of the surviving neurons in H-FABP, but H-FABP immunostaining is stronger in the lesion with an abundant accumulation of abnormal prion protein. 4-c. Reactive astrocytes surrounding spongiform changes were positive for H-FABP. 4-d. The distribution pattern of H-FABP matches that of abnormal prion protein

(JPEG 1081 kb)

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Matsui, Y., Satoh, K., Mutsukura, K. et al. Development of an Ultra-Rapid Diagnostic Method Based on Heart-Type Fatty Acid Binding Protein Levels in the CSF of CJD Patients. Cell Mol Neurobiol 30, 991–999 (2010). https://doi.org/10.1007/s10571-010-9529-5

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  • DOI: https://doi.org/10.1007/s10571-010-9529-5

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