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CSF α-synuclein improves diagnostic and prognostic performance of CSF tau and Aβ in Alzheimer’s disease

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Abstract

Alzheimer’s disease (AD) and Lewy body diseases (LBD), e.g., Parkinson’s disease (PD) dementia and dementia with Lewy bodies (DLB), are common causes of geriatric cognitive impairments. In addition, AD and LBD are often found in the same patients at autopsy; therefore, biomarkers that can detect the presence of both pathologies in living subjects are needed. In this investigation, we report the assessment of α-synuclein (α-syn) in cerebrospinal fluid (CSF) and its association with CSF total tau (t-tau), phosphorylated tau181 (p-tau181), and amyloid beta1-42 (Aβ1-42) in subjects of the Alzheimer’s Disease Neuroimaging Initiative (ADNI; n = 389), with longitudinal clinical assessments. A strong correlation was noted between α-syn and t-tau in controls, as well as in patients with AD and mild cognitive impairment (MCI). However, the correlation is not specific to subjects in the ADNI cohort, as it was also seen in PD patients and controls enrolled in the Parkinson’s Progression Markers Initiative (PPMI; n = 102). A bimodal distribution of CSF α-syn levels was observed in the ADNI cohort, with high levels of α-syn in the subjects with abnormally increased t-tau values. Although a correlation was also noted between α-syn and p-tau181, there was a mismatch (α-syn–p-tau181-Mis), i.e., higher p-tau181 levels accompanied by lower α-syn levels in a subset of ADNI patients. We hypothesize that this α-syn–p-tau181-Mis is a CSF signature of concomitant LBD pathology in AD patients. Hence, we suggest that inclusion of measures of CSF α-syn and calculation of α-syn–p-tau181-Mis improves the diagnostic sensitivity/specificity of classic CSF AD biomarkers and better predicts longitudinal cognitive changes.

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Acknowledgments

ADNI is funded by the NIA, NIBIB, and through generous contributions from the following: Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (http://www.fnih.org). The grantee organization for ADNI is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. We thank all of the ADNI subjects for their generous participation in ADNI. We thank the Michael J. Fox Foundation, all of our PPMI colleagues and the many individuals who have given their time and of themselves to be subjects in this study. This study is funded by The Michael J. Fox Foundation for Parkinson’s Research and industrial funding partners, including Abbott, Avid Radiopharmaceuticals, Biogen Idec, Covance, Elan, Eli Lilly & Co., F. Hoffman-La Roche Ltd., GE Healthcare, Genentech, GlaxoSmithKline, Merck and Company, Pfizer Inc and UCB Pharma SA. This research was also supported by NIA grants (AG10124, ES004696-5897, ES007033-6364, AG033398, ES016873, ES019277, NS057567, NS062684-6221 and NS082137). J.Q.T. is the William Maul Measey-Truman G. Schnabel, Jr., Professor of Geriatric Medicine and Gerontology and was supported by the Morris K. Udall Center for PD Research Core grant NS053488.

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Jon B. Toledo, Leslie M. Shaw & John Q. Trojanowski

  2. Department of Pathology, University of Washington School of Medicine, HMC Box 359635, 325 9th Avenue, Seattle, WA, 98104, USA

    Ane Korff & Jing Zhang

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  1. Jon B. Toledo
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Correspondence to Jing Zhang.

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For the Alzheimer’s Disease Neuroimaging Initiative and the Parkinson’s Progression Marker Initiative.

Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.ucla.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete list of ADNI investigators can be found at: http://adni.loni.ucla.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.

Data used in the preparation of this article were obtained from the Parkinson’s Progression Markers Initiative (PPMI) database (March 18, 2013; http://www.ppmi-info.org/data). As such, the investigator-authors within Version 2·02 March 4, 2011 PPMI contributed to the design and implementation of PPMI and/or provided data but did not participate in the analysis or writing of this report. PPMI study team members include (complete listing at PPMI site).

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Toledo, J.B., Korff, A., Shaw, L.M. et al. CSF α-synuclein improves diagnostic and prognostic performance of CSF tau and Aβ in Alzheimer’s disease. Acta Neuropathol 126, 683–697 (2013). https://doi.org/10.1007/s00401-013-1148-z

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  • DOI: https://doi.org/10.1007/s00401-013-1148-z

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