The impact of preanalytical variables on measuring cerebrospinal fluid biomarkers for Alzheimer's disease diagnosis: A review

Oskar Hansson; Alvydas Mikulskis; Anne M Fagan; Charlotte Teunissen; Henrik Zetterberg; Hugo Vanderstichele; Jose Luis Molinuevo; Leslie M Shaw; Manu Vandijck; Marcel M Verbeek; Mary Savage; Niklas Mattsson; Piotr Lewczuk; Richard Batrla; Sandra Rutz; Robert A Dean; Kaj Blennow

doi:10.1016/j.jalz.2018.05.008

The impact of preanalytical variables on measuring cerebrospinal fluid biomarkers for Alzheimer's disease diagnosis: A review

Alzheimers Dement. 2018 Oct;14(10):1313-1333. doi: 10.1016/j.jalz.2018.05.008. Epub 2018 Jun 23.

Authors

Oskar Hansson¹, Alvydas Mikulskis², Anne M Fagan³, Charlotte Teunissen⁴, Henrik Zetterberg⁵, Hugo Vanderstichele⁶, Jose Luis Molinuevo⁷, Leslie M Shaw⁸, Manu Vandijck⁹, Marcel M Verbeek¹⁰, Mary Savage¹¹, Niklas Mattsson¹², Piotr Lewczuk¹³, Richard Batrla¹⁴, Sandra Rutz¹⁵, Robert A Dean¹⁶, Kaj Blennow¹⁷

Affiliations

¹ Department of Neurology, Skåne University Hospital, Lund, Sweden; Memory Clinic, Skåne University Hospital, Malmö, Sweden. Electronic address: oskar.hansson@med.lu.se.
² Biogen, Boston, MA, USA.
³ Department of Neurology, Washington University School of Medicine, St Louis, MO, USA.
⁴ VU University Medical Center, Amsterdam, The Netherlands.
⁵ UK Dementia Research Institute, London, UK; Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
⁶ ADx NeuroSciences, Gent, Belgium.
⁷ BarcelonaBeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain.
⁸ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁹ Fujirebio-Europe NV, Gent, Belgium.
¹⁰ Radboud University Medical Center, Departments of Neurology and Laboratory Medicine, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
¹¹ Merck and Company, West Point, PA, USA.
¹² Department of Neurology, Skåne University Hospital, Lund, Sweden.
¹³ Department of Psychiatry and Psychotherapy, Universitätsklinikum Erlangen, and Friedrich-Alexander Universität Erlangen-Nürnberg, Germany; Department of Neurodegeneration Diagnostics, Medical University of Bialystok, Poland.
¹⁴ Roche Diagnostics GmbH, Rotkreuz, Switzerland.
¹⁵ Roche Diagnostics GmbH, Penzberg, Germany.
¹⁶ Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁷ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.

PMID: 29940161
DOI: 10.1016/j.jalz.2018.05.008

Abstract

Introduction: Cerebrospinal fluid (CSF) biomarkers have the potential to improve the diagnostic accuracy of Alzheimer's disease, yet there is a lack of harmonized preanalytical CSF handling protocols.

Methods: This systematic review summarizes the current literature on the influence of preanalytical variables on CSF biomarker concentration. We evaluated the evidence for three core CSF biomarkers: β-amyloid 42, total tau, and phosphorylated tau.

Results: The clinically important variables with the largest amount of conflicting data included the temperature at which samples are stored, the time nonfrozen samples can be stored, and possible effects of additives such as detergents, blood contamination, and centrifugation. Conversely, we discovered that there is consensus that tube material has a significant effect.

Discussion: A unified CSF handling protocol is recommended to reduce preanalytical variability and facilitate comparison of CSF biomarkers across studies and laboratories. In future, experiments should use a gold standard with fresh CSF collected in low binding tubes.

Keywords: Alzheimer's disease diagnosis; Biomarkers; Cerebrospinal fluid; Phosphorylated tau; Preanalytical variables; Total tau; β-Amyloid 42.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Systematic Review

MeSH terms

Alzheimer Disease / cerebrospinal fluid*
Biomarkers / cerebrospinal fluid
Humans
Specimen Handling* / instrumentation
Specimen Handling* / methods

Substances

Biomarkers

Grants and funding

U19 AG024904/AG/NIA NIH HHS/United States