Impact of frequent cerebrospinal fluid sampling on Aβ levels: systematic approach to elucidate influencing factors.

Bianca Van Broeck,Steven Ramael,Jennifer Bogert,Luc Van Nueten,Maarten Timmers,Leslie M Shaw,Sebastiaan Engelborghs,John Slemmon,Marc Mercken,Johannes Rolf Streffer

doi:10.1186/s13195-016-0184-z

Abstract

BackgroundCerebrospinal fluid (CSF) amyloid-beta (Aβ) peptides are predictive biomarkers for Alzheimer’s disease and are proposed as pharmacodynamic markers for amyloid-lowering therapies. However, frequent sampling results in fluctuating CSF Aβ levels that have a tendency to increase compared with baseline. The impact of sampling frequency, volume, catheterization procedure, and ibuprofen pretreatment on CSF Aβ levels using continuous sampling over 36 h was assessed.MethodsIn this open-label biomarker study, healthy participants (n = 18; either sex, age 55 − 85 years) were randomized into one of three cohorts (n = 6/cohort; high-frequency sampling). In all cohorts except cohort 2 (sampling started 6 h post catheterization), sampling through lumbar catheterization started immediately post catheterization. Cohort 3 received ibuprofen (800 mg) before catheterization. Following interim data review, an additional cohort 4 (n = 6) with an optimized sampling scheme (low-frequency and lower volume) was included. CSF Aβ1–37, Aβ1–38, Aβ1–40, and Aβ1–42 levels were analyzed.ResultsIncreases and fluctuations in mean CSF Aβ levels occurred in cohorts 1–3 at times of high-frequency sampling. Some outliers were observed (cohorts 2 and 3) with an extreme pronunciation of this effect. Cohort 4 demonstrated minimal fluctuation of CSF Aβ both on a group and an individual level. Intersubject variability in CSF Aβ profiles over time was observed in all cohorts.ConclusionsCSF Aβ level fluctuation upon catheterization primarily depends on the sampling frequency and volume, but not on the catheterization procedure or inflammatory reaction. An optimized low-frequency sampling protocol minimizes or eliminates fluctuation of CSF Aβ levels, which will improve the capability of accurately measuring the pharmacodynamic read-out for amyloid-lowering therapies.Trial registrationClinicalTrials.gov NCT01436188. Registered 15 September 2011.Electronic supplementary materialThe online version of this article (doi:10.1186/s13195-016-0184-z) contains supplementary material, which is available to authorized users.

Highlights

Cerebrospinal fluid (CSF) amyloid-beta (Aβ) peptides are predictive biomarkers for Alzheimer’s disease and are proposed as pharmacodynamic markers for amyloid-lowering therapies
We investigated the impact of sampling frequency, volume, catheterization procedure, and pretreatment with an anti-inflammatory agent on changes in CSF amyloid beta (Aβ) levels over time
CSF Aβ levels were substantially affected by CSF sampling frequency and/or sampling volume

Summary

Introduction

Cerebrospinal fluid (CSF) amyloid-beta (Aβ) peptides are predictive biomarkers for Alzheimer’s disease and are proposed as pharmacodynamic markers for amyloid-lowering therapies. Frequent sampling results in fluctuating CSF Aβ levels that have a tendency to increase compared with baseline. Alzheimer’s disease (AD) neuropathology is characterized by deposition in the brain of amyloid plaques, consisting mainly of amyloid-beta (Aβ) peptides, and neurofibrillary tangles, composed of hyperphosphorylated tau protein. Levels of cerebrospinal fluid (CSF) biomarkers Aβ and tau closely reflect the central pathogenic processes in AD and have proven their utility in evaluating disease risk or prognosis, guiding clinical diagnosis and monitoring therapeutic interventions [1, 2]. Several studies report pronounced increases in CSF Aβ levels relative to baseline upon repeated CSF sampling with spinal catheters [3,4,5,6,7,8,9].

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