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CSF biomarkers cutoffs: the importance of coincident neuropathological diseases

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Abstract

The effects of applying clinical versus neuropathological diagnosis and the inclusion of cases with coincident neuropathological diagnoses have not been assessed specifically when studying cerebrospinal fluid (CSF) biomarker classification cutoffs for patients with neurodegenerative diseases that cause dementia. Thus, 142 neuropathologically diagnosed neurodegenerative dementia patients [71 Alzheimer’s disease (AD), 29 frontotemporal lobar degeneration (FTLD), 3 amyotrophic lateral sclerosis, 7 dementia with Lewy bodies, 32 of which cases also had coincident diagnoses] were studied. 96 % had enzyme-linked immunosorbant assay (ELISA) CSF data and 77 % had Luminex CSF data, with 43 and 46 controls for comparison, respectively. Aβ42, total, and phosphorylated tau181 were measured. Clinical and neuropathological diagnoses showed an 81.4 % overall agreement. Both assays showed high sensitivity and specificity to classify AD subjects against FTLD subjects and controls, and moderate sensitivity and specificity for classifying FTLD subjects against controls. However, among the cases with neuropathological diagnoses of AD plus another pathology (26.8 % of the sample), 69.4 % (ELISA) and 96.4 % (Luminex) were classified as AD according to their biomarker profiles. Use of clinical diagnosis instead of neuropathological diagnosis led to a 14–17 % underestimation of the biomarker accuracy. These results show that while CSF Aβ and tau assays are useful for diagnosis of AD and neurodegenerative diseases even at MCI stages, CSF diagnostic analyte panels that establish a positive diagnosis of Lewy body disease and FTLD are also needed, and must be established based on neuropathological rather than clinical diagnoses.

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Acknowledgments

This work was supported by the NIH (AG033101, AG17586, AG10124, AG17586, NS053488, NS44266, and AG15116), the Wyncote Foundation, and the Koller Family Foundation. VMYL is the John H. Ware, 3rd, Professor of Alzheimer’s Disease Research. JQT is the William Maul Measey-Truman G. Schnabel, Jr., Professor of Geriatric Medicine and Gerontology. JBT is supported by a grant of the Fundación Alfonso Martín Escudero. JB is supported by a grant of the Deutsche Forschungsgemeinschaft DFG (AOBJ586910). We acknowledge Christopher Clark’s previous work at the ADCC and PMC. We thank Sue Leight for her work with the ELISA and Young Baek for his work with INDD.

Conflict of interest

J.Q.T., L.M.S. V.M.Y.L., S.X.X., W.T.H., J.B., M.G., S.E.A. and J.B.T. have no conflicts of interest.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, CNDR, University of Pennsylvania School of Medicine, 3rd Floor Maloney Building, 3600 Spruce Street, Philadelphia, PA, 19104, USA

    Jon B. Toledo, Johannes Brettschneider, Virginia M.-Y. Lee, Leslie M. Shaw & John Q. Trojanowski

  2. Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Murray Grossman

  3. Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Steven E. Arnold

  4. Department of Neurology, Center for Neurodegenerative Diseases, Emory University, Atlanta, GA, USA

    William T. Hu

  5. Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA

    Sharon X. Xie

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  1. Jon B. Toledo
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Toledo, J.B., Brettschneider, J., Grossman, M. et al. CSF biomarkers cutoffs: the importance of coincident neuropathological diseases. Acta Neuropathol 124, 23–35 (2012). https://doi.org/10.1007/s00401-012-0983-7

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