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  • Review Article
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Cerebrospinal fluid biomarkers in trials for Alzheimer and Parkinson diseases

Nature Reviews Neurology volume 11, pages 41–55 (2015)Cite this article

Subjects

Key Points

  • Cerebrospinal fluid (CSF) biomarkers can track relevant pathophysiological changes that occur in the brains of patients with Alzheimer disease (AD)

  • In AD clinical trials, amyloid-β1–42 (Aβ1–42), total tau (t-tau) and phosphorylated tau (p-tau) are used to measure target engagement, for enrichment or stratification of patients at specific disease stages, or as secondary outcome measures

  • In Parkinson disease (PD), α-synuclein, Aβ1–42, t- tau and p-tau are the most investigated CSF biomarkers, but their value for differentiating parkinsonisms or measuring progression requires further investigation

  • Few clinical trials for PD have used CSF analyses as measures of target engagement, but this use is increasing

  • Areas for further development are harmonization and standardization of the sampling, storage and analysis of CSF samples, together with improved quality of biomarker assays, including the development of fully automated tests

  • Currently, there is no evidence to support the use of CSF biomarkers as surrogate markers of treatment efficacy in clinical trials of patients with AD or PD

Abstract

Alzheimer disease (AD) and Parkinson disease (PD) are the most common neurodegenerative disorders. For both diseases, early intervention is thought to be essential to the success of disease-modifying treatments. Cerebrospinal fluid (CSF) can reflect some of the pathophysiological changes that occur in the brain, and the number of CSF biomarkers under investigation in neurodegenerative conditions has grown rapidly in the past 20 years. In AD, CSF biomarkers are increasingly being used in clinical practice, and have been incorporated into the majority of clinical trials to demonstrate target engagement, to enrich or stratify patient groups, and to find evidence of disease modification. In PD, CSF biomarkers have not yet reached the clinic, but are being studied in patients with parkinsonism, and are being used in clinical trials either to monitor progression or to demonstrate target engagement and downstream effects of drugs. CSF biomarkers might also serve as surrogate markers of clinical benefit after a specific therapeutic intervention, although additional data are required. It is anticipated that CSF biomarkers will have an important role in trials aimed at disease modification in the near future. In this Review, we provide an overview of CSF biomarkers in AD and PD, and discuss their role in clinical trials.

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Figure 1: Main CSF biomarkers used in trials of anti-amyloid drugs in AD.
Figure 2: Monoclonal antibodies that target Aβ pathology.
Figure 3: Position of CSF biomarkers in AD clinical trials.

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Acknowledgements

This Review is based on an EU Joint Programme—Neurodegenerative Disease Research (JPND) project (www.jpnd.eu). The project is supported through the following funding organizations under the aegis of JPND: the Italian Ministry of Health; the Health Research Council of Academy of Finland (decision no. 263193); the Bundesministerium für Bildung und Forschung (BMBF), Germany; the General Secretary of Research and Technology, Ministry of Education, Greece; the Netherlands Organisation for Health Research and Development (ZonMw); the Leading National Research Centre, Poland; the Fundação para a Ciência e a Tecnologia, Portugal; the Instituto de Salud Carlos III, Spain; and the Swedish Research Council. R.G. is supported by the Ricerca Corrente, Italian Ministry of Health. P.L. is supported by the BMBF (grant 01ED1203D). B. Mollenhauer has received funding support from the BMBF, the Michael J. Fox Foundation for Parkinson's Research, the American Parkinson's Disease Association and the Stifterverband für die Deutsche Wissenschaft (Dr. Werner Jackstädt Stipend).

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Authors and Affiliations

  1. Department of Neurology, Institut d'Investigacions Biomèdiques, Hospital de Sant Pau, Sant Antoni Maria, Claret 167, Barcelona, 08025, Spain

    Alberto Lleó

  2. IRCCS Istituto Centro San Giovanni di Dio-Fatebenefratelli, Italy

    Enrica Cavedo & Roberta Ghidoni

  3. Ospedale Santa Maria della Misericordia, Università di Perugia, Italy

    Lucilla Parnetti

  4. ADxNeurosciences, Belgium

    Hugo Vanderstichele

  5. University of Eastern Finland and Kuopio University Hospital, Finland

    Sanna Kaisa Herukka

  6. Karolinska Institute, Sweden

    Niels Andreasen & Per Svenningsson

  7. Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany

    Piotr Lewczuk

  8. Quanterix, USA

    Andreas Jeromin

  9. Karolinska Institute, Sweden

    Bengt Winblad

  10. Aristotle University of Thessaloniki, Greece

    Magda Tsolaki

  11. Medical University of Białystok, Poland

    Barbara Mroczko

  12. Maastricht University, Netherlands

    Pieter Jelle Visser

  13. University of Coimbra, Portugal

    Isabel Santana

  14. The Sahlgrenska Academy at University of Gothenburg, Sweden

    Kaj Blennow & Henrik Zetterberg

  15. Stavanger University Hospital, Norway

    Dag Aarsland

  16. ICN Hospital Clinic i Universitari, IDIBAPS, Spain

    José Luis Molinuevo

  17. Paracelsus-Elena-Klinik, Germany

    Brit Mollenhauer

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  1. Alberto Lleó
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Contributions

All authors contributed to the researching of data for the article, and to the review/editing of the manuscript before submission. A.L., E.C., L.P., I.S., K.B., H.Z. and B. Mollenhauer wrote the article. A.L., H.V., S.K.H., N.A., B.W., K.B., D.A., J.L.M., H.Z. and B. Mollenhauer made substantial contributions to the discussion of content.

Corresponding author

Correspondence to Alberto Lleó.

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Competing interests

L.P. has served on advisory boards for Innogenetics. H.V. is a co-founder of ADx Neurosciences and a founder of Biomarkable. P.L. is a consultant for IBL and Innogenetics. A.J. is the founder and CSO of Atlantic Biomarkers and an advisor to Quanterix. P.J.V. has served on advisory boards for Bristol–Myers Squibb and Roche. K.B. has served on advisory boards for Eli Lilly, Kyowa Hakko Kirin Pharma, Pfizer and Roche. D.A. has received honoraria and/or research support from AbbVie Denmark, GE Health, GlaxoSmithKline, H. Lundbeck and Novartis. B. Mollenhauer has received honoraria from GlaxoSmithKline and Orion, and holds or has pending patents regarding methods of differential diagnosis of dementias, ELISA-based quantification of α-synuclein proteins in cerebrospinal fluid and peripheral blood products using 384-well plates, and microRNA expression profiling of cerebrospinal fluid. She serves as a consultant for Bayer Schering Pharma, and receives research support from Boehringer Ingelheim, Desitin Pharmaceuticals, GE Healthcare and Teva. The other authors declare no competing interests.

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Lleó, A., Cavedo, E., Parnetti, L. et al. Cerebrospinal fluid biomarkers in trials for Alzheimer and Parkinson diseases. Nat Rev Neurol 11, 41–55 (2015). https://doi.org/10.1038/nrneurol.2014.232

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  • DOI: https://doi.org/10.1038/nrneurol.2014.232

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